www.nature.com/nature Vol 443 | Issue no. 7107 | 7 September 2006 Energy shame

The history of energy research highlights the importance and inadequacies of markets, and a yawning gap in the priorities of governments. It’s time for a radical change.

rances Cairncross, chair of Britain’s Economic and Social the research may not get done is a reason for government to step in Research Council, has been thinking about the economics of and ensure that it does, while trying not to crowd out private capital in Fclimate change longer than most natural scientists and econo- the process. The current solar boom is dependent on old and trusted mists. In her presidential address to the annual meeting of the British technologies — the companies now piling in are mostly finding new Association for the Advancement of Science this week, she rightly ways to manufacture and process familiar products. If the current emphasized one of the most important things that governments rate of heady growth is to keep going for the quarter-century needed can do: invigorate and focus research into the basic and translational to start making a real change in the world’s energy outlook, we will science needed for new energy-conversion technologies. need new materials to capture the Sun’s power ever more cheaply and Solar power is a case in point. Its great economic attraction is that, easily, and new solutions to the problem of storing it. unlike nuclear power or carbon capture and storage, it does not need Many scientists are eager to set out in search of those technologies. vast capital investment in order to spread. Its products just need to It is essential that curiosity-led research should flourish in these areas, be priced in such a way that consumers and companies want to buy and that funding bodies should encourage it so to do. them. Once that point is reached, a solar-cell factory can produce the There are also areas where directed research might come into its capacity to generate electricity as easily as a power station does, thus own — where the best approach may “It is to the abiding offering the possibility of exponential growth. be to try out lots of possibilities, rather As we report on page 19, a boom in the solar-energy business, led by than go with what a few bright people shame of the world’s Japan and Germany, has now attracted serious interest from, among think is best. One of the strengths of the governments that others, the technologists and venture capitalists of California’s Silicon Manhattan project was that it tried out over the past two Valley. The people who brought the world Moore’s law are eager to as many roads to nuclear weaponry as decades, funding for help it sustain itself through clean technology while accumulating yet seemed plausible. Governments need energy research has more wealth on the way. Its most vigorous proponents suggest that to be willing to take advice on directed attracting the attention of high-tech entrepreneurs could in itself be research and then make it happen, actually fallen.” an end to our energy woes — a “distributed Manhattan project that rather than just hoping that curiosity will triumph unaided. attracts the smartest, most ideal people for the task’’, as Bill Gross, Talk of a Manhattan project to tackle the generation and storage serial entrepreneur and trustee of the California Institute of Technol- of ‘clean’ energy may seem overblown. It shouldn’t. The challenge of ogy, put it to The New York Times earlier this year. increasing energy use in the developing world while at least stabiliz- But a healthy respect for the power of entrepreneurs and free mar- ing and ideally decreasing carbon dioxide emissions is immense. It is kets cannot hide the fact that they do best when choosing between to the abiding shame of the world’s governments that, as the threat to possibilities that are close to market, rather than inventing entirely the climate has become ever more apparent over the past two decades, new options. There is research into new materials and technologies funding for energy research and development has actually fallen. To that small start-up companies can’t do, and that larger, more staid suggest that spending on energy research should be limited only by ones, if history is a guide, won’t. the capacity of scientists and technologists to make practical use of it History may not be a guide, of course. But even the possibility that is not to be profligate, but rational. ■

journey taken to prepare the compound is as important as arriving Beauties of synthesis at the destination. Indeed, chemists are frequently drawn to the field because there is not just one way to solve the problem, and the search How to excite an organic chemist. can reveal a bit more about how the world works. When a complex synthesis is first reported at a conference, the any organic chemists spend their days searching for creative excitement can be palpable. The audience can be inspired by the solutions to real-world problems, yet the media pays them speaker’s innovative approach, but there may be another reason for Mjust a fraction of the attention devoted to physicists or biol- their exhilaration: they might be able to apply the lessons learned ogists. Even fellow scientists think organic chemistry is esoteric. from that synthesis to their own research. Ask a group of organic chemists why they love their work, how- An impressive synthesis may be described as ‘beautiful’ or ‘elegant’ ever, and most will tell you that it enables them to make things that because of an aesthetic appreciation of the molecule itself or the way no one else has made before. Many spend their days trying to make it was created. But it often implies that the approach was creative and large, architecturally complex molecules, and some believe that the that the molecule was made efficiently. Because chemists design their

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syntheses by looking at the target molecule and working backwards complete ‘toolbox’ of reactions that can be applied to any synthesis. towards simpler starting materials, chemists can impress their peers But the toolbox is certainly not full; many desirable reactions remain by pursuing strategies no one else noticed, by using original sequences elusive. This is especially true in the area known as ‘asymmetric cat- of previously disparate reactions, or by developing new reactions that alysis’, which involves the creation of a chiral material from a non- enable them to construct bonds in an unexpected way. chiral substrate — molecules can exist in left-hand and right-hand The work isn’t over when the first synthesis of a complex molecule forms, and the development of catalysts that can selectively make is reported — there is always plenty of room for improvement, and one of the two forms is a major challenge in the field. To outsiders, chemists are fired up by the desire to make things better. Second- this is a particularly obscure field of work, but the inherent chal- generation syntheses are often very different from the original, and lenges involved attract vast numbers of researchers. Furthermore, the may have fewer steps or contain new and unexpected chemical reac- products of these reactions have enormous potential utility, as small- tions. This iterative process is not just an academic exercise: process molecule tools that can tease apart a complex biological system, or chemists in pharmaceutical companies are often the unsung heroes as lead compounds that can be developed into the next ‘blockbuster’ of the synthetic world, as they devise incredibly effective syntheses to drug. Without asymmetric synthesis, some hugely successful drugs produce kilogram quantities of potential drugs. By doing so, they save — such as AZT for HIV/AIDS, or lovastatin, which reduces choles- millions of dollars for their companies, and can reduce the environ- terol — would be extremely difficult to make. mental impact of the synthesis by minimizing the amounts of waste Today, a novice organic chemist is like a child in a sweetshop. There produced or the quantities of solvents required. are many ‘hot’ areas to work on: ‘green’ chemistry, which seeks ways In a similar vein, chemists enjoy finding improved catalysts. to eliminate environmentally harmful chemicals from common Catalysts exist for many reactions but are often expensive, toxic or processes; the burgeoning area of nanotechnology, constructing min- impractical for anything other than simple molecules. By explor- uscule components for a future age of molecular devices; or maybe ing the chemical mechanism of the catalyst, or perhaps by just plain just pushing the boundaries of chemical space, by concentrating on luck, chemists can develop second- and third-generation catalysts a single element such as boron and seeing what chemistry can be that dramatically outperform the first-generation system. This can be developed. The modern world requires medicines, agrochemicals invaluable both in the lab and for improving industrial processes. and advanced materials, and it is chemists who must provide these. A common misconception is that organic chemists now have a Far from being esoteric, organic chemistry serves global needs. ■

and concerted campaign by a coalition of scientific, university and Five years on industry organizations that warned policy-makers that such restric- tions would not be in the nation’s best interest. Immigration restrictions imposed after 11 September Researchers entering the United States today still find it a hassle, 2001 have eased, but improvements must continue. but most feel that it is worth the trouble to come to US labora tories. New statistics are showing a resurgence of foreign students, and he attack of 11 September 2001 changed many things, includ- researchers are probably following, although numbers reflecting their ing the way science is done in America. Before the attack, the movement are more difficult to obtain. TUnited States was a focal point for scientists from around the This could lead some to believe that the problem is largely solved. world who went there to study, conduct research and teach. But in But more should be done to ensure free scientific exchange between its aftermath, a series of restrictive new immigration measures led to the United States and other countries. Scientific groups in America lengthy delays for foreign researchers, and many were turned away. should continue to press for better training of embassy staff, and for In 2004, we warned that these policies were strangling scientific the hiring of more scientifically aware case-workers. They should exchange and could have dire consequences for the nation’s scientific work with the State Department and the Department of Homeland leadership (see Nature 427, 181; 2004). Security to try to bring some much-needed transparency to the visa As reported on page 6 of this issue, things have improved, although process. It is unlikely that the security checks at the heart of many perhaps not as much as many researchers would have liked. The researchers’ delays will become more open, but more could be done to Department of State has boosted staffing levels at its embassies and communicate with those entering the United States about the status consulates, and new computer systems are helping to prevent appli- of their applications. Finally, scientific organizations should support cations from becoming lost during interagency security reviews in immigration legislation that would make it easier for foreign scien- Washington. Waiting times for those reviews are down from months tists trained in US universities to remain after finishing their work. to weeks: in Beijing, a student visa that might have taken six months All this should be done with an eye to keeping an open dialogue can now be granted in just ten days. between scientists and the federal officials overseeing immigration. The government has taken other positive steps, abandoning a plan In the event of another attack on the United States, such lines of com- to force foreign scientists to obtain licences to operate lab equip- munication could help to ameliorate the immigration restrictions ment (see Nature 441, 679; 2006), and revising a rule that would that would almost certainly follow. The United States is a linchpin of have required foreign-born researchers on defence-funded projects the global scientific enterprise, and it is in everybody’s interest that it to work in ‘segregated areas’. These moves were in response to a vocal remain open for business. ■

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© Copyright 2007 by the American Chemical Society

Pattern Recognition in Retrosynthetic Analysis: Snapshots in Total Synthesis

Rebecca M. Wilson† and Samuel J. Danishefsky*,†,‡ Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York AVenue, New York, New York 10021, and Department of Chemistry, Columbia UniVersity, HaVemeyer Hall, 3000 Broadway, New York, New York 10027

[email protected]

ReceiVed April 25, 2007

In this Perspective, the value of small molecule natural products (SMNPs) in the discovery of active biological agents is discussed. The usefulness of the natural products-based method of potential pharma discovery is much augmented by the capacities of chemical synthesis. The great advances in synthetic methodology allow for major editing of the natural product in the hopes of optimizing potency and therapeutic index. As a consequence of the enormous increase in the power of multistep chemical synthesis, one can now approach structures of previously impractical complexity. In constructing a plan for a multistep synthesis, two complementary thought styles are often encountered. One is the traditional and extremely powerful concept of prioritized strategic bond disconnections. The other, which we term “pattern recognition,” involves the identification of moieties within the target, which are associated with reliable chemistry, and can serve to facilitate progress to the target. Recognition of such targets may require substantial recasting of the target structure to connect it to well-established types of transformations. Some of our older ventures, where ideas about pattern recognition were first being fashioned and used productively, are revisited. In addition, we provide snapshots of recently achieved total syntheses of SMNPs of novel biological potential. These vignettes serve to harmonize insights occasioned by pattern recognition, in concert with transformations enabled by the enormous growth in the power of synthesis.

I. Introduction tion of natural products. Still others, which may be termed “natural product inspired” (such as Lipitor), arise from a more In a recent Perspective,1 we attempted to demonstrate that casual, though still unmistakable, SMNP connection.2 The the small molecule natural product (SMNP) estate has been an modification of SMNPs by chemical means, or by the total important source of discovery of valuable pharmaceutical agents, synthesis of structures inspired by SMNPs, accomplishes what including blockbuster drugs. Interestingly, although big pharma may be termed “molecular editing.” Underlying the rationale has (unwisely!) de-emphasized SMNPs as potential resources in drug discovery, many of the most interesting compounds in of molecular editing of SMNPs is the supposition that many the pipelinessparticularly in oncology pipelinessare themselves natural products constitute high-pedigree, relatively privileged SMNPs. Others drugs have been derived by chemical modifica- structures. The thought is that recourse to SMNPs results in entering the drug discovery progression at a more advanced † Sloan-Kettering Institute for Cancer Research. stage than is the case through traditional medicinal chemistry. ‡ Columbia University. Obviously, the identification, isolation, and structural determi-

10.1021/jo070871s CCC: $37.00 © 2007 American Chemical Society Published on Web 06/01/2007 J. Org. Chem. 2007, 72, 4293-4305 4293 nation of SMNPs and the maintenance of natural product multistep ventures. We suspect that, from the beginning of the collections involve significant commitment and expense. The subject of complex molecule total synthesis, some form of real question is whether the advantages of working with retrosynthetic analysis was inherently involved in the planning privileged, high-pedigree structures can compete with the much phase. It would be improbable, to say the least, to plan the larger numbers of samples accessible through traditional med- synthesis of a complex target structure through a cognitive icinal chemistry, not to speak of the more recent techniques of process which is fully progressive in nature. Given the stupefy- combinatorial chemistry. ing number of ways in which one might begin and proceed, it A serious concern about SMNP-based discovery has been would seem unlikely that the human mind would go anywhere that of compound availability. Even for the laboratory which but in the retrosynthetic direction wherein, at least generally, first discovers the active SMNP, the source of the natural product complexity is reduced as the planning exercise goes on. must be secure and the isolation yield must be manageable. While there certainly is an artistic dimension in the building Given that these conditions are met, an efficient program in of complex molecules (vide infra), there are important boundary partial synthesis is then required, for the purposes of optimizing conditions. In artistic experiences, the goal itself may be initially the therapeutic index of the eventual clinical agent. Fine-tuning, perceived at a fairly imprecise level. The goal of a creative which might entail the addition or reduction of molecular artistic enterprise often unfolds as the exercise moves forward. complexity, may be circumscribed by existing noncompatible At some point, a coherent target begins to emerge. Different functionality of the SMNP. artists, depending on their creative styles, perceive different Laboratories which might attempt to build upon a published visions. At least in the early stages of the undertaking, the artist or potential account of a new SMNP, following reports of the enjoys the prerogative of a “work in progress,” which can be initial discovery elsewhere, face additional problems. For idealized, fashioned, and ultimately sculpted through artistic understandable reasons, the discoverers may be reluctant to mastery. distribute workable amounts of the SMNP to other laboratories. Not so in the case of the chemical synthesis of a SMNP. Moreover, in a pharma business context, there may be ap- Here, the goal structure is very clear and stubbornly inflexible. prehensions regarding the sustainability of claims to ensure To be of any great interest to those who are serious about “intellectual property” control. synthesis, the goal is quite likely to be complex. The planning Fortunately, concurrently with the identification of the process tends to be one of continuing reduction of complexity, concerns described above, came the means for rejuvenating to the point where one arrives at correspondence between the SMNPs as starting points for biological exploration. Thus, retrosynthetic starting material and that which is either known chemical synthesis is now an increasingly critical enabler in or likely to be quite available. When the retrosynthetic analysis leveraging the value of SMNPs. As we have shown in recent conVerges with a feasible starting material, a synthesis plan is reviews, chemical synthesis allows for the potential underlying at hand. Of course, there will be many such plans to consider. messages from SMNPs to be vastly extended and woven into However, coalescence of retrosynthetic analysis with available the discovery fabric. starting materials does constitute, in principle, a solution to the There has been, in our judgment, a quiet revolution in the planning problem. capacities of chemical synthesis (so quiet that it has not been Critical to the actual plan is the feasibility of conducting the properly appreciated). Before our eyes, tremendous advances presumed retrosynthetic steps in the forward direction. The in the methodology of preparative chemistry (and, to some analysis is heavily dependent on the massive database of extent, in its underlying logic) now render synthesis a practical chemical synthesis. Fortunately, the collection of available resource in exploring and exploiting the lead value of SMNPs. transformations is not a static one. In fact, huge advances in The complexity level of structures which are now accessible the methodology of chemical synthesis, and thus in the ability through synthesis for drug discovery programs has increased of retrosynthetic steps to chart in the forward direction, are being dramatically, and the timelines for accomplishing total syntheses made all the time. Moreover, it is not uncommon for powerful of targets of significant complexity have correspondingly been new methodologies to be uncovered in the context of planning decreased. and executing a difficult total synthesis. A major challenge in There is, of course, an underlying assumption “out there” to planning a synthesis lies in the management of the reams of the effect that the best chances for discovery lie in the screening information, and in identifying the pertinence of some element of large numbers of structures, via the medium of high- of the information morass to the precise problem at hand. throughput screening. No one should contest the potential The last two decades have been particularly fruitful in benefits to be had from evaluating ever-increasing numbers of enhancing the realm of the feasible. The most dramatic advances chemical agents. Chemistry and medicinal chemistry are empiri- have surely been registered by astute recognition of the critical cal sciences. The notion of high-throughput screening of large role of transition metals, in exploitable oxidation states and numbers of structures is in keeping with the relatively immature appropriately connected to ligands, in the catalysis of a range level of contemporary de novo theory. SMNPs will indeed of carbon-carbon bond formations, as well as functional group provide far fewer and more difficultly accessible entries than interchanges. Another huge advance is to be found in the will the general pharma sample collections. However, while capacity to generate enantiopure or highly enantiocontrolled SMNPs cannot compete at the “head count” level with substances through reagent control. An extension of this medicinal/combinatorial chemistry, natural product-derived col- application is the ability to exploit the same sort of reagent- lections may well yield a much higher candidate “hit rate” than lodged dominant stereoselectivity patterns, even in the presence the traditional pharma or combichem-derived sample collection. of existing elements of chirality. Accordingly, the value of Since chemical synthesis is so central to the fuller develop- powerful reagents with major stereo biases may go beyond the ment of SMNPs, we thought it well to focus in this Perspective introduction of de novo chirality and venture into the control on some of the underpinnings of systematic planning for of relative stereochemistry. Thus, retrosynthetic analysis through 4294 J. Org. Chem., Vol. 72, No. 12, 2007 SCHEME 1. Total Synthesis of Baccatin III

appropriate bond disconnections, strongly augmented by the Retrosynthetic analysis produces not a precisely defined blue- Corey concepts of strategic prioritization, is surely a key print, but rather a strategic framework. The most successful plans platform for synthetic planning.3 lend themselves to modification based on actual laboratory It is perhaps well to use the occasion of this Adams findings. Undoubtedly, someday down the road, there will be a Perspective to point out another modality of retrosynthetic higher correspondence between the strategic plan and the analysis, which we describe as “pattern recognition.” In this unfolding synthesis. However, for the more immediate future, form of conjecture, a structure is viewed with an eye to the interfacing of a plan of synthesis with the unfolding synthesis discerning substructural units, which we call patterns. Pattern is one of feedback loops, as the plan is being iterated in the recognition differs in a subtle but real way from bond discon- context of experimental findings. It is to be hoped (but is not nection analysis, wherein one begins by evaluating the implica- always the case) that papers addressed to the realization of a tions of disconnecting the various existing linkages. Impressive total synthesis would accurately reflect the many frustrations as are the sorting capacities of the human mind, the response which had to be overcome en route to the target. With these cannot be stochastic. By some difficultly articulatable mental preliminaries well understood, we now go on to recall some of process, the synthetic chemist is drawn to assess the implications our older efforts. These will hopefully bring home, by example, of various plausible retrosynthetic disconnections and to rank, the nature of pattern recognition in the total synthesis planning however non-explicitly, their likely productivities. What prompts process. various synthetic chemists to develop vastly different bond We start with the taxol problem. In studying the baccatin III disconnection schemes toward a fixed target is in itself a moiety of taxol,4 we came to discern a conceivably exploitable fascinating question. Surely, the increasing molecular complexity relationship to the mono-reduced form of the Wieland-Miescher with which we deal these days leads to a proliferation of (WM) ketone (see 1, Scheme 1).5 The WM ketone has a strong potentially relevant bond disconnections, whose prioritization history as a valuable intermediate, whose established synthetic can be continuously debated. potential could be mined and then expanded. The homology In pattern recognition, the entire structure is the focus of the between the WM ketone and baccatin III obviously encompasses search. The exercise may well be less “activist” than strategic carbons 3, 7, and 8. The homology deepens as we recognize bond disconnection. The total structure is mentally scanned and how functionality inherent in 1 might also be expanded to rescanned as one seeks to discover an exploitable substructural encompass C2,C9 (by late stage oxidation), as well as C4 and motif around which to organize first the thought process and C5 (by deconjugation of the R,â-enone double bond to the â,γ- then the synthesis. The cognitive challenge lies in the recognition slot). The reader is advised to revisit the original paper to of productive patterns, even in the presence of endless apparent assimilate the chemistry which, in fact, enabled progression from decoys. A still higher level challenge is that of creating, de novo, 1f3. Coupling of 3 with 4 set the stage, after considerable a body of chemistry which makes the pattern synthetically travail, to reach baccatin III. accessible or productive in a forward sense. There is often a Our total synthesis of eleutherobin also illustrates the ap- great challenge in fashioning a plan to close the gap between plication of pattern analysis to a starting material which provided the patterns and the target. the required chirality (Scheme 2).6 In studying the structure of We emphasize that pattern recognition goes well beyond the our target, we were struck by a possible connection to the known scanning of a structure, seeking familiar substructures. The most monoterpene R-phellandrene (5). Even with that realization, fascinating cases arise when the target itself must actually be there was a need to append a differentiated two-carbon unit to modified, mentally, before a staple pattern is revealed. There C10 (eleutherobin numbering) and a one-carbon unit to C1 of are many levels of opportunity for creativity in deeply disguised the phellandrene (5). This progression was initiated in practice patterns. We will first attempt to illustrate the idea of pattern bya[2+ 2] cycloaddition of dichloroketene to the phellandrene. recognition by revisiting some of our battlegrounds from years The regiochemistry of this reaction is undoubtedly related to ago. the propensity of the electrophilic component of the dichlo- Before browsing through our album, it is well (though it roketene to attack the diene system at its terminus with the should not be necessary) to underscore a key point in the proviso that the dichloro-bearing carbon be joined to an relationship between the charting of a synthetic plan and the unalkylated carbon. This reaction modality led to structure 6. achievement of a total synthesis on a target of some complexity. The methylene group of the cyclobutanone was susceptible to The theory of organic chemistry, and thus the predictability of one-carbon extension. Fragmentation of the resultant structure reactions, particularly as one attempts to advance beyond the eventually gave rise to a viable coupling partner, 7. Substrate 7 well trodden norms, is surprisingly shaky. Accordingly, it is serves as a subunit for merger with 8, leading eventually to the well to look upon a plan as a broad organizational prospectus. eleutherobin target. More often than not, the so-called “reduction to practice” phase, A more sophisticated pattern recognition can perhaps be in reality, involves recasting and restructuring of the plan. A discerned in our total synthesis of widdrol (Scheme 3).7 As one fine plan is one which has the elasticity and staying power to scans the seven-membered ring of widdrol, the mind quickly survive the inevitable setbacks and frustrations along the way. recognizes a homoallylic alcohol. This recognition might

J. Org. Chem, Vol. 72, No. 12, 2007 4295 SCHEME 2. Total Synthesis of Eleutherobin

SCHEME 3. Total Synthesis of Widdrol

SCHEME 4. Total Synthesis of Vernolepin

suggest, in the first instance, formation of a tertiary alcohol by potentially direct solutions to this problem. However, in the end, nucleophilic methylation of the corresponding â,γ-unsaturated they were rejected on the grounds of being overly speculative. ketone. Obviously such a proposal brings with it concerns as Instead, we sought to retreat to at least a more familiar port, to the degree of diastereocontrol in the nucleophilic alkylation that is, that of a cis-fused hexalin system. The hexalin (15) would step. We sought a solution which would be insulated from this carry an angular carbomethoxy group. This group, destined to type of uncertainty. This line of conjecture led to suggestion of become a vinyl function, would influence the functionalization a possibly exploitable pattern (see 10, derivable from cyclo- of the nonconjugated double bond, thereby eventually producing hexenal 9). However, to connect this type of pattern to the actual the vicinal trans, trans-hydroxy γ-lactone, en route to the structure of the target, it was necessary, in the mind’s eye,to introduction of the two conjugated R-methylene functions. Those imagine that the hydroxyl group of widdrol would have arisen were to be implemented at a very late stage of the synthesis. A from degradation of a carboxylic acid (cf. 12). It would be problem engendered by this analysis was that at the time there necessary that sound stereochemical principles govern the were no established and concise ways for reaching such a cis- relationship of the carboxyl group of 12 with the emerging fused hexalin system. The thought was that we would try to do hydroxyl of widdrol. The solution we proposed was that the so by a new extension of the Diels-Alder reaction, invoking hydroxyl group would have been generated from a “carboxy- cycloaddition of the then unknown diene 13 with dienophile inversion” sequence which started with the corresponding 14, itself the product of the Diels-Alder reaction of butadiene â-oriented carboxylic acid (see 12). At that point, one could with methyl propynoate. Since 14 is not a very powerful discern a γ,δ relationship of the carboxylic acid with its double dienophile, we needed a diene which would be sufficiently bond. In the mind of the pattern analyst, this arrangement would reactive to allow for the cycloaddition. We also needed the diene conjure up the possibility of a Claisen-type rearrangement. What to possess the functionality which would lead to the ready was also fascinating about this idea at the time is that the [3,3]- introduction of the enone of compound 15. It was this context sigmatropic rearrangement would occur not on the usual allyl which obliged us to think about the then unknown diene 13. ester but on a then novel vinyl lactone moiety (see 11). Given Indeed, this synergistically substituted diene proved to be very the R-orientation of the vinyl group of 11, the rearrangement reactive, and cycloadditions with many hitherto sluggish di- would necessarily create a â-disposed carboxylic acid in 12.In enophiles became an active possibility. the degradative sense, the carboxy inversion (which actually In the case at hand, at a later stage of the synthesis, the R,â- occurs with retention of configuration) would then install the unsaturated ketone in 15 was used as a conduit to the δ-lactone tertiary alcohol in the appropriate â-face stereochemistry (see (cf. 16 to 17). This involved excision of a one-carbon fragment, 12fwiddrol). as well as reductive cyclization of an aldehyde. Intermediate The challenges associated with the total synthesis of verno- 17 contained the required functionality to carry us to vernolepin. lepin carried with them opportunities for extended pattern As a final example in this introductory section on pattern analysis (Scheme 4).8 A provocative substructure in vernolepin analysis, we discuss the case of calicheamicin (Scheme 5).9 The is the cis-fused δ-lactone. At the time, there was no orderly non-glycoside core region of this molecule (i.e., calicheamici- method for synthesizing such a moiety, further complicated by none) was, at the time, considered rather complicated, and its the presence of the angular vinyl group. We struggled with complexity prompted us to seek a relatively safe substructural 4296 J. Org. Chem., Vol. 72, No. 12, 2007 I SCHEME 5. Total Synthesis of Calicheamicin γ1

SCHEME 6. Total Synthesis of Migrastatin

pattern, such as an aromatic system. We could discern within catalyzed diene aldehyde cyclocondensation (LACDAC) reac- the aglycon sector a potentially exciting possibility. The aromatic tion. We further anticipated that the macrolactone ring might structure which we selected (i.e., 18) would be converted to be fashioned through a ring-closing metathesis (RCM), which 19. We note that the R-spiroepoxyketone of 19 corresponds to would make use of the terminating olefin arising from the an otherwise difficultly manageable R-dicarbonyl system. The LACDAC sequence. Having thus identified a central structural aldehyde function, as well as the keto function, would serve as pattern of the migrastatin system, we next sought to adopt a electrophilic termini in a highly convergent but technically synthetic plan based upon the proposed LACDAC transforma- demanding 2-fold addition with the enediyne 20. There was tion.12 particular need to orchestrate the sequence in this coupling event As outlined in Scheme 6, the key chelation-controlled (see original paper). The Becker-Adler reaction10 was invoked LACDAC reaction, between the optically active dienophile, A1, as a route from 18 to the spiroepoxide 19. We came to view and synergistically activated diene, A2, proceeded with excellent the Becker-Adler reaction in the broader context of oxidative stereocontrol to provide intermediate A3. The latter was dearomatization. The thinking implied in Scheme 5 was advanced to aldehyde A4 and eventually to the coupling partner, implementable, though not without considerable challenges A5. Esterification with the carboxylic acid, A6, provided the along the way. key intermediate, A7. At this stage, we were able to implement We close this introduction on earlier examples of pattern a ring-closing metathesis strategy, using the Grubbs’ catalyst, recognition and move on to some rather recent synthetic A8, to provide, following deprotection, the natural product successes, which benefited from this retrosynthetic mode. migrastatin. Through the medium of these snapshots, the usefulness of B. Fludelone. Epothilone B (EpoB) is a naturally occurring pattern analysis is shown as a complement to strategic bond cytotoxic macrolide, which was first isolated from the myxo- disconnection. bacterium, Sorangium cellulosum.13 In 1997, we reported the inaugural total synthesis of EpoB.14 Although our early studies II. Discussion: Snapshots In Recent Total Synthesis revealed the natural product, EpoB, to be highly toxic in in vivo settings, we subsequently prepared a number of synthetic EpoB A. Migrastatin. Migrastatin is a tumor cell migration inhibitor derivatives, several of which have exhibited great promise in isolated from two different strains of Streptomyces.11 Upon preclinical settings. In the context of this ongoing effort directed studying this molecule, we took particular note of the crypto- toward the diverted total synthesis and biological evaluation of polypropionate sector of the macrolactone, incorporating three EpoB analogues, we sought access to a particular congener of contiguous stereocenters at C8,C9, and C10, as well as a C11- interest, which we term fludelone. As shown in Scheme 7, C12 Z-olefin (Scheme 6). To our eye, this pattern might well be fludelone differs from the parent natural product (EpoB) in a accessible through recourse to a chelation-controlled Lewis acid number of its structural features. Upon studying the structure

J. Org. Chem, Vol. 72, No. 12, 2007 4297 SCHEME 7. Total Synthesis of Fludelone

of fludelone, it was seen that the strategy so well employed for vivo settings. We postulated that the epoxide moiety of the the total synthesis of EpoB would not be directly translatable natural product was perhaps serving to undermine its stability to our newly conceived congener. In this evaluation, we noted and efficacy in vivo. Accordingly, we designed a synthetic the pattern of contiguous C6,C7, and C8 stereocenters lodged analogue, termed cycloproparadicicol, in which the possibly in the polypropionate domain. This pattern might conceivably offending epoxide functionality would be edited and replaced arise from a diastereoselective aldol reaction with the optically with a more stable cyclopropyl group (Scheme 8). Although active Roche aldehyde (B2). Furthermore, the macrolide might our first-generation synthesis of cycloproparadicicol was achieved be fashioned through ring-closing metathesis. by analogy to the original radicicol route, this synthesis was Indeed, the synthesis of fludelone was accomplished, as somewhat cumbersome and inefficient.18 On the basis of some outlined in Scheme 7.15 As hoped, B1 and B2 readily partici- promising findings in in vivo models, we sought to redesign pated in an aldol coupling to provide the â-hydroxyketone, B3, the synthetic route to cycloproparadicicol in order to secure properly presenting the three contiguous stereocenters required access to larger quantities of material for more extensive for fludelone. This intermediate was ultimately advanced, evaluations. through a second aldol reaction, to the carboxylic acid coupling As is our custom, we approached the design of our second- partner, B4. Esterification with alcohol B5 provided the me- generation route by first attempting to identify useful patterns tathesis precursor, B6. In the event, the desired ring-closing in the target structure around which we might design a viable metathesis proceeded smoothly to furnish a macrolide ketone, synthesis. In our first-generation route, we had encountered which, following installation of the heteroaromatic sector, difficulties in attempting to perform synthetic manipulations with afforded the target epothilone congener, fludelone. Although a the resorcinylic functionality intact. We thus wondered whether full accounting of the highly exciting biological activity of this particular unit could be installed at a late stage of the fludelone is beyond the purview of this disclosure, we note that synthesis through an ynolide-Diels-Alder cycloaddition. Ac- this compound, arising from diverted total synthesis, has indeed cording to this formulation, the tractable resorcinylic moiety revealed itself to be an exceptionally promising candidate for would be “masked” as an ynolide until the concluding phases further development. of the synthesis. The macrolide formation would be ac- C. Cycloproparadicicol. Radicicol, a resorcinylic macrolide complished at an earlier stage through ring-closing metathesis.19 isolated from M. bonorden, initially came to our attention as a The much improved, second-generation cycloproparadicicol consequence of its reported high affinity binding to, and synthesis is presented in brief form in Scheme 8. Thus, key inhibition of, the heat shock protein 90 (Hsp90) molecular intermediate C3 was reached from fragments C1 and C2,as chaperone.16 The Hsp90 protein is considered these days to be shown. Interestingly, we had observed that C3 was itself unable a promising target for cancer chemotherapy, and on the basis to function properly in the requisite RCM, presumably as a of these in vitro findings, we first launched a program directed consequence of geometric constraints imposed by the rigid to the synthesis of radicicol.17 Upon completion of our first total ynoate moiety. To circumvent this reactivity problem, we synthesis of radicicol, we went on to confirm its excellent in temporarily masked the alkyne functionality as a cobalt complex, vitro activity. However, the results of preliminary studies in as shown (cf. C4). Gratifyingly, this intermediate readily mouse models were quite disappointing, suggesting that radicicol underwent metathesis, under the influence of the Grubbs’ is not effectively able to manifest its pharma potential in in catalyst (A8), to provide, following I2-mediated removal of the 4298 J. Org. Chem., Vol. 72, No. 12, 2007 SCHEME 8. Total Synthesis of Cycloproparadicicol

SCHEME 9. Total Synthesis of Paecilomycine A

cobalt, the key ynoate macrolide, C5. At this stage, the crucial to proceed with such high levels of endo selectivity was, to us, Diels-Alder reaction with diene C6 proceeded smoothly to a most welcome surprise. Indeed, intermediate D3 was rapidly afford, following retro-Diels-Alder excision of isobutylene, the advanced to the key substrate D4. The latter readily underwent resorcinylic macrolactone, C7. The latter was readily advanced the anticipated Pauson-Khand reaction, as shown, to provide to cycloproparadicicol. the tricyclic adduct, D5. Even at this late stage, some not fully D. Paecilomycine A. Paecilomycine A is a terpenoid-derived anticipated difficulties ensued in attempting to install the angular 20 natural product, isolated from Isoria japonica. Our interest in C5 methyl group in a stereoselective fashion. After some this compound arose from reports of its potent neurite outgrowth investigation, we settled upon a route, outlined below, wherein activity in rat pheochromocytoma (PC12) cells. In the context the enone was diastereoselectively reduced to the â-allylic of our ongoing program devoted to the synthesis and evaluation alcohol, according to the logic originally set forth by Corey of neurotrophic factors,21 we targeted paecilomycine A for and Virgil some years ago.23 Directed cyclopropanation afforded synthetic investigations. Our examination of the natural product D7, which could indeed be advanced to D8 and, ultimately, to revealed two substructural patterns that we anticipated could the natural product itself. arise from well-established cyclization reactions (Scheme 9). E. Spirotenuipesine A. Isolated from the entomopathogenic Thus, the “cyclopenta” sector of the molecule suggested to us fungus, Paecilomyces tenuipes, spirotenuipesine A has been a Pauson-Khand pattern, while the A-ring might be perceived found to promote the expression of neurotrophic factors and to 24 through a Diels-Alder type lens. For maximal convergency, effect neuronal differentiation in rat PC12 cells. We undertook the Diels-Alder adduct would ideally incorporate the terminal the synthesis of spirotenuipesine A in the hopes of gaining alkyne necessary for the subsequent Pauson-Khand transforma- access to sufficient quantities of material for extensive in vitro tion.22 and in vivo investigations (Scheme 10). Close survey of the Indeed, this plan could be reduced to practice in a pleasingly structural topography of spirotenuipesine A helped to identify concise manner. Thus, we found that diene D1 readily undergoes a pattern that served to provoke a spiro-Diels-Alder cyclo- cycloaddition with the R-disubstituted aldehyde dienophile, D2, addition between a core R-methylene lactonic dienophile and a to provide adduct D3 in high yield, as a single observed synergistic diene. It was our conjecture that this transformation diastereomer (Scheme 9). The ability of the Diels-Alder would proceed in the desired sense, such that the diene would reaction to accommodate the resident alkynyl functionality and approach the dienophile from the less hindered exo face of the

J. Org. Chem, Vol. 72, No. 12, 2007 4299 SCHEME 10. Total Synthesis of Spirotenuipesine A

SCHEME 11. Total Synthesis of Peribysin E

bicyclic system. Under this formulation, the synthesis problem peribysin E. At an appropriate time, this moiety would be would then be reduced to the stereoselective preparation of the converted to a secondary alcohol, under the guidance of a 25 dienophilic component (cf. E5). sequence through which the stereochemical integrity at C2 would Our initial attempts to establish the relative stereochemistry remain intact.27 of E5 through a diastereoselective Claisen rearrangement had, In the event, the synthesis of peribysin E commenced with a surprisingly, failed. The [3,3] bond reorganization was virtually Diels-Alder cycloaddition reaction between (R)-carvone (F1) stereorandom. Accordingly, we devised an alternative strategy and diene F2 (Scheme 11). As expected, the resident isopropenyl which would take advantage of the benefits of intramolecularity group of F1 did indeed direct addition of the diene to the â-face in establishing the relative configurations at carbons 3, 5, and of the molecule, thus establishing the future C5 and C10 12. In the key transformation, diazoacetyl intermediate E1 configurations in the desired sense. Saegusa oxidation of underwent intramolecular cyclopropanation to ultimately afford intermediate F3 yielded enone F4, and the C4 ketone of F4 was the activated cyclopropane, E2 (Scheme 10). Under this stereoselectively converted to a methyl group (cf. F5). At this protocol, the demands of intramolecularity had effectively stage, we sought to convert the C2 isopropenyl moiety to a dictated the establishment of the relative C3,C5, and C12 hydroxyl functionality. This was accomplished through recourse stereocenters in the desired sense. Free-radical-mediated Bar- to a Johnson-Lemieux oxidation with OsO4, followed by ton-McCombie cleavage provided intermediate E3 which was Baeyer-Villiger oxidation, of course, with retention of stereo- readily advanced to iodolactone E4. The latter was converted chemistry. Following emplacement of a vinyl iodide, intermedi- to the requisite dienophile (E5) in straightforward fashion. At ate F6 was in hand. The latter was readily advanced to F7, and this stage, we were pleased to find that the key spiro-Diels- at this stage, we were able to effect a critical ring-contracting Alder reaction between E5 and diene E6 indeed progressed in reaction. Thus, following treatment with TiCl4, intermediate F7 the desired stereochemical fashion to provide, following workup, underwent rearrangement to provide, as the principal adduct, the spiroenone E7. This compound was advanced to spiro- F8, possessing the required configuration at the C7 quaternary tenuipesine A in due course. center. Treatment with HCl in methanol afforded the natural F. Peribysin E. Isolated from Periconia byssoides OUPS- product peribysin E, as shown. We note, in passing, that as a N133, peribysin E has recently been reported to inhibit cell consequence of this total synthesis, it was discovered that the adhesion.26 Guided by the admittedly unproven thesis that a original absolute configuration assignment of peribysin E had, small molecule adhesion inhibitor might potentially serve as in fact, been incorrect. The absolute configuration depicted in an effective anticancer agent, we sought to design an efficient Scheme 11 represents the naturally occurring enantiomer of total synthesis of optically active peribysin E (Scheme 11). In peribysin E. examining the nature of the stereogenic centers which punctuate G. Scabronine G. Scabronine G, a metabolite of the bitter the tricyclic framework, we noted a potential homology between mushroom Sarcodon scabrosis, is another member of the the A-ring of the natural product and the readily available, growing family of naturally occurring, small molecule neu- optically active, (R)-carvone (F1). Most importantly, we felt rotrophically active agents.28 Thus, scabronine G and, to an even confident that the isopropenyl group on F1 could serve as a greater extent, its methyl ester derivative have been demon- convenient handle in the early stages of the synthesis, dictating strated to induce the production and release of nerve growth the stereochemistry of critical transformations en route to factor in 1321N1 human astroglial cells.29 On the basis of these 4300 J. Org. Chem., Vol. 72, No. 12, 2007 SCHEME 12. Total Synthesis of Scabronine G

SCHEME 13. Total Synthesis of Garsubellin A

findings, we undertook the synthesis of this tricyclic diterpenoid H. Garsubellin A. Garsubellin A first came to our attention (Scheme 12). Upon studying the structural framework of on the basis of reports of its CNS activity. Isolated from the scabronine, we took note of a substructural pattern which to us wood of Garcinia subelliptica, garsubellin A has been shown suggested homology to the venerable Wieland-Miescher ketone to enhance choline acetyltransferase (ChAT) activity by up to (G1). Thus, our synthetic strategy was designed around the 154% in P10 rat septal neurons.31 Taking note of reports that recognition that the B,C-ring system of scabronine G might be the progression of Alzheimer’s disease is typically associated seen as a one-carbon ring-expanded version of the Wieland- with an attenuated level of hippocampal ChAT activity, we Miescher ketone (G1). Importantly, G1 can be readily obtained sought to synthesize and evaluate garsubellin A in the context in optically active form and could presumably provide the means of our broad-based program directed at the development of for an asymmetric synthesis of scabronine G. The A-ring of potential lead candidates in the treatment of a range of scabronine G would be established through a Nazarov cycliza- neurotrophic disorders (Scheme 13). In our structural analysis tion.30 of the natural product, we speculated that the central ring could Thus, the Wieland-Miescher ketone (G1) was advanced to be reached through an appropriately conceived dearomatization the Nazarov substrate, G2 (Scheme 12). As hoped, upon sequence. Increasingly, we have been drawn to dearomatized exposure to FeCl3, G2 underwent cyclization to provide the versions of highly functionalized arenes as valuable patterns in tricyclic adduct G3. Diastereoselective conjugate addition with total synthesis. Aromatic chemistry is used to incorporate Nagata’s reagent (Et2AlCN), with subsequent TMSCl trapping, extensive and varied functionality. A dearomatization step provided an intermediate silyl enol ether, which was readily removes the safety net of aromaticity, exposing a reactive transformed to the vinyl triflate, G4, as shown. The requisite multifunctionalized reactant for exploration. isopropyl group was installed through a Negishi coupling and, In the event, phloroglucinol derivative H1 was advanced to following conversion of the nitrile to a methyl ester and H2.32 The key dearomatization event, depicted in Scheme 13, appropriate functionalization of the C-ring, intermediate G5 was involved allylation of H2 at the para position (cf. H2 to H3). in hand. We were now prepared to attempt the critical expansion Fortunately, the diastereotopic olefins resulting from the dearo- of the C-ring. Thus, addition of lithiated methoxymethyl phenyl matization even lent themselves to differentiation in a pleasing sulfide to the G5 ketone provided G6 as a diastereomeric fashion. Thus, upon treatment of H3 with perchloric acid in mixture. We were pleased to find that, upon exposure to HgCl2, water and dioxane, the acetonide was removed. The resultant G6 indeed underwent the hoped-for one-carbon ring expansion secondary free hydroxyl group participated in Michael cycliza- to provide the cross-conjugated cycloheptenone G7. Thermo- tion to afford, following elimination of methanol, the cyclized dynamic isomerization of the olefin afforded scabronine G intermediate, H4, as a single diastereomer. Under prolonged methyl ester, and upon ester hydrolysis, the naturally occurring reaction times, H4 underwent removal of the vinylogous methyl scabronine G was in hand. ester to provide the desired adduct, H5. We note that, although

J. Org. Chem, Vol. 72, No. 12, 2007 4301 SCHEME 14. Total Synthesis of 11-O-Debenzoyltashironin

SCHEME 15. Total Synthesis of Cribrostatin IV

the product (H5) was isolated as a single diastereomer, there would be fashioned through a complexity-building oxidative had been observed an equilibrating mixture of Michael-like dearomatization (I2fI3)-transannular Diels-Alder cascade cyclization products during the reaction. Presumably, only the sequence (I3fI4).34 desired diastereomer, wherein the allyl and 2-propanol moieties Thus in the tashironin synthesis, the relative stability of are positioned on opposite faces of the tetrahydrofuran ring, is aromatic rings and the predictability of their reactions were well disposed for the subsequent methanol â-elimination. This exploited to build complex structure I2. It was now necessary elimination event would thus drive the diastereoselective to achieve high reactivity. To that purpose, I2 was treated with cyclization process. In any case, this sequence had enabled both an appropriate hypervalent oxidizing agent (phenyliodine(II) dearomatization and differentiation of the central ring of the acetate (PIDA)), leading to the dearomatized structure I3. This natural product. Intermediate H5 was subsequently advanced structure indeed undergoes a spontaneous Diels-Alder reaction, to the late stage compound, H6. At this point, the goal was the producing I4 containing all of the handles necessary to reach installation of the isobutyryl functionality at C6. In fact, this tashironin. While this progression was not a simple matter task presented a significant challenge, due to the difficulties (particularly the conversion of I6 to I7), in the end, it was associated with generating a bridgehead anion such as would possible, and this very complex sesquiterpene was reached by presumably be required. In the end, a workable solution was total synthesis. identified. First, H6 was treated with LDA and TMSCl, followed J. Cribrostatin. In planning our synthesis of the densely by iodine to generate H7. A magnesium-iodide exchange functionalized cribrostatin IV, we recognized C11 as possibly generated the requisite bridgehead nucleophile which, upon emanating from a precursory aldehyde (Scheme 15). If the C3- treatment with isobutyraldehyde, smoothly underwent aldol C4 double bond were to arise from a C4 ketone, a potential reaction to afford H8 in 72% yield. From this intermediate, Mannich pattern suggested itself. The key step to exploit the garsubellin A was reached in two straightforward transforma- potential Mannich connection would be J4fJ5.C4 of J4 would tions. be presented as a ketone. The aldehyde carbon of J4 would be I. 11-O-Debenzoyltashironin. Isolated from the pericarps of interpolated between the N-methyl group and C3, which is R to Illicium merrillianum, 11-O-debenzoyltashironin has been claimed the keto group at C4. The aldehyde carbon C11 is seen as a to induce neurite outgrowth in rat cortical neurons at concentra- lynchpin, joining the N-methyl group to C3 as a one-carbon 33 tions as low as 0.1 µM. This highly oxygenated, densely bridge. Introduction of the oxygen at C14 would be postponed functionalized natural product was targeted for total synthesis until after the formation of J5. The issue of relative stereo- in our laboratory as part of our neurotrophin-based research chemistry simply involves the joining of the proper enantiomers program (Scheme 14). Upon examining the structure of 11-O- (see J1 and J2), corresponding to C1 and C13. Needless to say, debenzoyltashironin, we formulated an overarching strategy, the configuration which emerges at C11 is dictated by the wherein virtually the entire tetracyclic framework of the target configuration of C13. It was necessary to merge J1 as an 4302 J. Org. Chem., Vol. 72, No. 12, 2007 SCHEME 16. Total Synthesis of Phalarine

SCHEME 17. Total Synthesis of Gelsemine

epimeric mixture of C4 alcohols with J2 since the attempted tion that this structure, in the context at hand, might well arise coupling failed with the corresponding keto version of J1. from a rearrangement of an uncharacterizable spiroindolenium Happily, the signature step (see J4fJ5), which we term a ring framework, generating in its wake a cation at the â-carbon lynchpin Mannich reaction, worked reasonably well. The of the â-carboline (see K5). Happily, this plan worked, though progression of J5 to cribrostatin IV was nontrivial but, in the a precise mechanistic description cannot yet be provided with end, proved to be manageable.35 appropriate rigor. Advancement of K6 to phalarine was K. Phalarine. In studying and prioritizing various conceptions significantly enabled by application of the Gassman Indole with respect to a projected total synthesis of phalarine, we came synthesis, exploiting a [2,3]-sigmatropic rearrangement. In this to favor one in which a tetrahydro â-carboline (AB indole) is way, K7 progressed to K9 and, in due course, to phalarine joined through two critical bonds to a 4,5-disubstituted indole itself.36 (EF indole) (Scheme 16). With the benefit of hindsight, L. Gelsemine. From the start of the planning exercise of the fashioned by pitched trial-and-error empirical research, it would total synthesis of gelsemine, we envisioned that the tetrahydro- be necessary to present the EF indole in a segmental fashion pyran ring would be established from a precedented ring closure (E then F). We moved on to a line of thinking adumbrated in of a bis-homoallylic alcohol (see L8fgelsemine, Scheme 17). Scheme 16. Coupling of K1 with K2 produced an intermediate, We further speculated that perhaps the hindered hydroxymethyl K3 (in the actual case, a fully characterized N-tosylamino- group might arise from an internal alkylative opening of an ketone), which would go on to the fugitive K4 (or a structural oxetane electrophile, by a nitrogen-based nucleophile (see equivalent thereof). During this progression, the MOM protect- L4fL5). We took note that, in the projected L8, the disubsti- ing group was cleaved. We now come to the defining step. It tuted double bond is â,γ to the carbonyl group of the lactam was prompted at the conceptual level by focusing on the function. Given the context, one was prompted to conjecture tetrahydro â-carboline moiety. We were struck by the recogni- about the possibility of interpolating in the mind’s eye an

J. Org. Chem, Vol. 72, No. 12, 2007 4303 SCHEME 18. Total Synthesis of Salinosporamide A

additional methylene group in L8, such that the disubstituted Claisen-like condensation. The progression of M4 to M5 set double bond would be γ,δ with respect to the lactam carbonyl the stage for a signature step. This important transformation group. By the same token, one could think about interpolating, involved intramolecular oxyselenation of the terminal methylene through another gedanken experiment, a carbonyl function group of M5 through the hydroxyl group of a fugitive within the nitrogen nucleophile segment. The “reward” for doing hemiacetal. This step set the stage for presenting the all-critical so was that the vinyl group would then have a γ,δ relationship methyl group at the base of the â-lactone. It is well to notice with respect to the carbonyl group of this formal lactam. that the ester functions in M6 are in effect differentiated by Recollection that the disubstituted double bond would also have their protecting groups. The functional group distinction of the a γ,δ relationship to the carbonyl carbon of the cyclic anilide esters in M6 could be exploited, allowing us to reach M7 by prompted the possibility of producing, in a properly sequenced the corresponding addition of cyclohexenyl zinc to the aldehyde fashion, each wing of the emerging system through a Johnson- function, derived from the benzyl ester of M6. This stereocontrol Claisen rearrangement. At each end, there would be required, was borrowed from the E. J. Corey inaugural total synthesis of ultimately, excision of a single carbon atom. In each case, the salinosporamide.39 raison d’eˆtre of the extraneous carbon was to enable compat- ibility with a Claisen-directed pattern. At the vinyl end, the III. Conclusions excision would be through a Curtius rearrangement. At the anilide end, the excision would have been through oxidative Above we have attempted to make several points. The first fragmentation. We illustrate these notions in the context of a is that SMNPs have proven to be valuable sources for the hypothetical entity L1. This structure is not intended to discovery of new and interesting biological agents, which, on correspond, per se, to an actual synthetic subgoal. Rather it is some occasions, have matured into blockbuster drugs.2 Pros- a patterning device to bring out the notion of two Claisen-type pecting in the SMNP area will produce fewer lead structures transformations.37 for potential pharmaceutical advancement than the unlimited These thoughts matured into the total synthesis shown in terrain of medchem/combichem. However, judging by any fair Scheme 17. The allylic alcohol L2 was exploited for purposes reading of pharma history, particularly in oncology, anti- of an ortho-acetate Claisen rearrangement, leading to the γ,δ- infectives, anti-inflammatories, and anti-hypercholestemic ap- unsaturated ester L3. Indeed, the Curtius degradation scheme plications, SMNPs and SMNP-inspired structures have a most led to L4, which, happily, functioned as planned. Under Lewis impressive track record. acid catalysis, the nitrogen displaced the secondary carbon- We further argue that the revolutionary advances in the oxygen bond of the oxetane to produce L5. After some capacity of synthetic methodology over the last three decades manipulation, allylic hydroxylation was accomplished (see L6). allow for leveraging the already powerful SMNP estate, enabling Another Claisen-type rearrangement followed by cyclization led much more profound molecular editing than was previously the to pyradinone, L7. Following a one-carbon degradation, L7 was case (cf. inter alia migrastatin, fludelones, and cycloproparadici- converted to L8, and shortly thereafter, the total synthesis of col). To a large extent, these advances in methodology are the gelsemine was accomplished. pay-off of years of insufficiently appreciated scholarship and M. Salinosporamide. In studying the structure of salino- experimentation in transition-metal-mediated transformations. sporamide, we took note of a potentially productive pyro- The advances in the methodology of synthesis have had no glutamate pattern (cf. M1, Scheme 18). This moiety would serve small impact in the fashioning of the strategy of reaching to provide a suitable enantiodefined starting material.38 The relatively complex targets, including SMNPs themselves, or pyroglutamate was to be converted by known steps to M2 SMNP-inspired structural space. We have identified two styles (Scheme 18). At this stage, it would be necessary to first in retrosynthetic analysis. The first is the established3 and accomplish an R,â-bisdialkylation of the conjugated double bond powerful concept of prioritized strategic bond disconnection. and then to protect the lactam center. In practice, this was done In principle, every complex target would fall within the scope through imino ether formation. The vinyl group which was of strategic bond disconnection. A complementary and, we think, appended to the â-carbon of the unsaturated lactam would, in worthwhile planning modality seeks out patterns in the form of time, be converted to a mixed carbonate ester (see M2fM3). substructural motifs. This line of analysis may perhaps follow The carbonyl carbon of the mixed carbonate of M3 corresponds a more holistic approach than strategic bond disconnection. to the all-critical carbon dioxide equivalent, which is then joined Often the pattern is recognized only after substantial intellectual to the imino ether containing ring, through a base-induced modification of the actual structure to connect the target with a 4304 J. Org. Chem., Vol. 72, No. 12, 2007 dominant exploitable motif. We emphasize that there is much H.; Nakae, K.; Imoto, M.; Shiro, M.; Matsumura, K.; Watanabe, H.; Kitahara, T. J. Antibiot. 2002, 55, 442. (e) Woo, E. J.; Starks, C. M.; opportunity for innovation in the recognition of the guiding Carney, J. R.; Arslanian, R.; Cadapan, L.; Zavala, S.; Licari, P. J. Antibiot. pattern and in planning the progression from the governing motif 2002, 55, 141. to the complex target. Particularly fascinating and rewarding (12) (a) Gaul, C.; Njardarson, J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 6042. (b) Njardarson, J. T.; Gaul, C.; Shan, D.; Huang, X.-Y.; are the opportunities for creating new methodology level Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 1038. (c) Gaul, C.; chemistry to enable access to the governing pattern and to Njardarson, J. T.; Shan, D.; Dorn, D. C.; Wu, K.-D.; Tong, W. P.; Huang, smooth the pathway onto the target. X.-Y.; Moore, M. A. S.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 11326. (d) Shan, D.; Chen, L.; Njardarson, J. T.; Gaul, C.; Ma, X.; Again, we emphasize that these and other thought processes Danishefsky, S. J.; Huang, X.-Y. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, are really complementary, as the creative powers of the human 3772. mind are challenged by provocative structural targets. It is (13) (a) Ho¨fle, G.; Bedorf, N.; Gerth, K.; Reichenbach, H. (GBF), DE-B 4138042, 1993; Chem. Abstr. 1993, 120, 52841. Structure elucidation: interesting to note that, in the area of synthetic analysis, the (b) Ho¨fle, G. H.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.; raw power of the human intellect has held its own with Reichenbach, H. Angew. Chem., Int. Ed. 1996, 35, 1567. electronically driven capacities. Perhaps this is telling us that (14) Su, D.-S.; Meng, D.; Bertinato, P.; Balog, A.; Sorensen, E. J.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 757. organic synthesis, particularly in the context of SMNPs, remains (15) (a) Rivkin, A.; Yoshimura, F.; Gabarda, A. E.; Cho, Y. S.; Chou, T.-C.; a fascinating blend of highly sophisticated science, mediated Dong, H.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 10913. (b) to a major extent by difficultly quantifiable but clearly discern- Rivkin, A.; Chou, T.-C.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2005, 44, 2838. (c) Cho, Y. S.; Wu, K.-D.; Moore, M. A. S.; Chou, T.-C.; ible levels of sheer artistry. While the mind cannot compete Danishefsky, S. J. Drugs Future 2005, 30, 737. with the computer in speed and efficiency, it still has huge (16) (a) Delmontte, P.; Delmontee-Plaque´e, J. Nature 1953, 171, 344. (b) Ayer, contributions to offer in the domain of “close call” judgment W. A.; Lee, S. P.; Tsunda, A.; Hiratsuka, Y. Can. J. Microbiol. 1980, 26, 766. (c) Roe, S. M.; Prodromou, C.; O’Brien, R.; Ladbury, J. E.; Piper, and pristine elegance if we allow and even encourage it to roam P. W.; Pearl, L. H. J. Med. Chem. 1999, 42, 260. about. Given the multifactorial nature of contemporary medical (17) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J. J. and material sciences, it seems safe to predict that the future Am. Chem. Soc. 2001, 123, 10903. (18) Yamamoto, K.; Garbaccio, R. M.; Stachel, S. J.; Solit, D. B.; Chiosis, will provide wrenching challenges as well as exciting opportuni- G.; Rosen, N.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 1280. ties for the “artscience” of organic total synthesis. (19) Yang, Z.-Q.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 9602. (20) Kikuchi, H.; Miyagawa, Y.; Shashi, Y.; Inatomi, S.; Haganuma, A.; Nakahata, N.; Oshima, Y. Tetrahedron Lett. 2004, 45, 6225. Acknowledgment. The quilt “Painted Sun” was designed (21) Wilson, R. M.; Danishefsky, S. J. Acc. Chem. Res. 2006, 39, 539. and made by Lorrie Faith Cranor, Associate Research Professor (22) Min, S.-J.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 2199. of Computer Science at Carnegie Mellon University. (23) Corey, E. J.; Virgil, S. C. J. Am. Chem. Soc. 1990, 112, 6429. (24) Kikuchi, H.; Miyagawa, Y.; Sahashi, Y.; Inatomi, S.; Haganuma, A.; Nakahata, N.; Oshima, Y. J. Org. Chem. 2004, 69, 352. References (25) Dai, M.; Danishefsky, S. J. J. Am. Chem. Soc. 2007, 129, 3498. (26) Yamada, T.; Doi, M.; Miura, A.; Harada, W.; Hiramura, M.; Minoura, (1) Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2006, 71, 8329. K.; Tanaka, R.; Numata, A. J. Antibiot. 2005, 58, 185. (2) For lead references on the role of natural products in drug development, (27) Angeles, A. R.; Dorn, D. C.; Kou, C. A.; Moore, M. A. S.; Danishefsky, see: (a) Newman, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod. 2003, S. J. Angew. Chem., Int. Ed. 2007, 46, 1451. 66, 1022. (b) Butler, M. S. J. Nat. Prod. 2004, 67, 2141. (c) Shu, Y.-Z. (28) Kita, T.; Takaya, Y.; Oshima, Y.; Ohta, T.; Aizawa, K.; Hirano, T.; J. Nat. Prod. 1998, 61, 1053. (d) Newman, D. J.; Cragg, G. M.; Snader, K. M. Nat. Prod. Rep. 2000, 17, 215. Inakuma, T. Tetrahedron 1998, 54, 11877. (3) Corey, E. J.; Cheung, X.-M. The Logic of Chemical Synthesis; Wiley- (29) Obara, Y.; Kobayashi, H.; Ohta, T.; Ohizumi, Y.; Nakahata, N. Mol. Interscience: New York, 1995. Pharmacol. 2001, 59, 1287. (4) Danishefsky, S. J.; Masters, J. J.; Link, J. T.; Young, W. B.; Snyder, L. (30) Waters, S. P.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J. Am. Chem. Soc. B.; Magee, T. V.; Jung, D. K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, 2005, 127, 13514. C. A.; Coburn, C. A.; DiGrandi, M. J. J. Am. Chem. Soc. 1996, 118, (31) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull. 1997, 2843. 45, 947. (5) Wieland, P.; Miescher, K. HelV. Chim. Acta 1950, 33, 2215-2228. (32) Siegel, D. R.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 1048. (6) (a) Chen, X.-T.; Zhou, B.; Bhattacharya, S. K.; Gutteridge, C. E.; Pettus, (33) Huang, J. M.; Yokoyama, R.; Yang, C. S.; Fukuyama, Y. J. Nat. Prod. T. R. R.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 789. (b) 2001, 64, 428. Chen, X.-T.; Battacharya, S. K.; Zhou, B.; Gutteridge, C. E.; Pettus, T. (34) (a) Cook, S. P.; Gaul, C.; Danishefsky, S. J. Tetrahedron Lett. 2005, 46, R. R.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 6563. 843. (b) Cook, S. P.; Polara, A.; Danishefsky, S. J. J. Am. Chem. Soc. (7) Danishefsky, S. J.; Tsuzuki, K. J. Am. Chem. Soc. 1980, 102, 6891. 2006, 128, 16440. (8) Danishefsky, S. J.; Kitahara, T.; Schuda, P. F.; Etheredge, S. J. J. Am. (35) Chan, C.; Heid, R.; Zheng, S.; Guo, J.; Zhou, B.; Furuuchi, T.; Chem. Soc. 1976, 98, 3028. Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 4596. (9) (a) Cabal, M. P.; Coleman, R. S.; Danishefsky, S. J. J. Am. Chem. Soc. (36) (a) Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew. Chem., 1990, 112, 3253. (b) Haseltine, J. N.; Cabal, M. P.; Mantlo, N. B.; Int. Ed. 2007, 46, 1444. (b) Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, Iwasawa, N.; Yamashita, D. S.; Coleman, R. S.; Danishefsky, S. J.; S. J. Angew. Chem., Int. Ed. 2007, 46, 1448. Schulte, G. K. J. Am. Chem. Soc. 1991, 113, 3850. (c) For an account of (37) (a) Lin, H.; Ng, F. W.; Danishefsky, S. J. Tetrahedron Lett. 2002, 43, the enediyne program, see: Danishefsky, S. J.; Shair, M. D. J. Am. Chem. 549. (b) Ng, F.; Lin, H.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, Soc. 1996, 61, 16. 9812. (c) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, (10) Becker, H.-D.; Bremholt, T.; Adler, E. Tetrahedron Lett. 1972, 13, 4205. 36. (11) (a) Nakae, K.; Yoshimoto, Y.; Sawa, T.; Homma, Y.; Hamada, M.; (38) Endo, A.; Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 8298. Takeuchi, T.; Imoto, M. J. Antibiot. 2000, 53, 1130. (b) Nakae, K.; (39) (a) Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004, Yoshimoto, Y.; Ueda, M.; Sawa, T.; Takahashi, Y.; Naganawa, H.; 126, 6230. (b) Hogan, P. C.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, Takeuchi, T.; Imoto, M. J. Antibiot. 2000, 53, 1228. (c) Takemoto, Y.; 15386. Nakae, K.; Kawatani, M.; Takahashi, Y.; Naganawa, H.; Imoto, M. J. Antibiot. 2001, 54, 1104. (d) Nakamura, H.; Takahashi, Y.; Naganawa, JO070871S

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MICROREVIEW

DOI: 10.1002/ejoc.201200665

Oxidative Coupling of Enolates, Enol Silanes, and Enamines: Methods and Natural Product Synthesis

Fenghai Guo,[a] Michael D. Clift,[b] and Regan J. Thomson*[a]

Keywords: Oxidative coupling / Enols / Natural products / Synthesis design / C–C coupling

Oxidative coupling of enolates, enol silanes, and enamines there have been a number of reports from several research provides a direct method for the construction of useful 1,4- groups demonstrating advances in several neglected areas of dicarbonyl synthons. Despite its first being reported in 1935, oxidative coupling. This microreview summarizes these new with subsequent important advances beginning in the 1970s, advances in methodology and provides an overview of recent the development of this powerful reaction into a reliable natural product syntheses that showcase the power of these methodology was somewhat limited. In recent years, though, transformations.

Introduction exposed to dioxygen or molecular iodine. The reported re- actions were plagued by low yields and the formation of The oxidative coupling of two enolates provides a direct multiple unwanted side products, and it was not until the and convergent method for the construction of 1,4-dicarb- 1970s that synthetically useful methods for preparative oxi- onyl motifs (Figure 1). At the strategic level, application of dative enolate coupling were pioneered. In 1971, Rathke such transformations during retrosynthetic planning can al- and co-workers reported oxidative dimerizations of ester low for the concise synthesis of complex molecules by the enolates in the presence of CuII bromide or CuII valerate to efficient, and often stereocontrolled, formation of a σ-bond afford substituted succinate esters.[2] In 1975, Saegusa and between two functional groups arranged in an otherwise co-workers reported the use of CuII chloride as an effective dissonant relationship. One advantage of such a strategy is stoichiometric oxidant for the dimerization of ketone enol- that it can provide a more streamlined synthesis by avoiding ates, and further demonstrated that intramolecular variants the need for functional group Umpolung or the use of oper- were quite efficient.[3] They also reported cross-couplings of ational equivalents that in many cases can require ad- two different enolates to generate unsymmetrical 1,4-diket- ditional synthetic manipulations. ones, but these required the use of one ketone enolate in a threefold excess over the other. After these reports, various other oxidants were established for the oxidative coupling of enolates; they included CuII triflate,[4] FeIII chloride,[5] iodine,[6] TiIV chloride,[7] and AgI chloride.[8] Contempora- neously, the use of non-enolate carbonyl derivatives for oxi- dative coupling was also pioneered. This research led to ef- fective methods for oxidative couplings of enol silanes,[9] Figure 1. Oxidative enolate coupling: An overview. enamines,[10] and enol acetates.[11] In several instances cross- coupling could also be achieved, but as in the case of lith- On a tactical level, oxidative coupling represents a ium enolates this typically came at the expense of one reac- powerful methodology for the construction of 1,4-diket- tion partner. ones, highly useful precursors to a wide range of useful The synthetic utility of these powerful methods for bond structures such as pyrroles and furans. The earliest report construction has been demonstrated through application in [1] of such an oxidative enolate coupling dates back to 1935, the total syntheses of several structurally diverse natural when Ivanoff and Spasoff demonstrated that the enolate of products (Figure 2), including lamellarin G trimethyl ether phenylacetic acid undergoes oxidative dimerization when (1),[12] rac-chimonanthine (2),[13] rac-folicanthine (3),[14] cis- jasmone (4),[3] and rac-hirsutene (5).[15] Notably, the groups [a] Department of Chemistry, Northwestern University, 2145 Sheridan Rd, Evanston, Illinois 60208, USA of both Kise and Helmchen developed useful strategies for E-mail: [email protected] the stereocontrolled enantioselective synthesis of several lig- Homepage: http://chemgroups.northwestern.edu/thomson/ nans, such as ent-hinokinin (6), through the oxidative di- home.htm [16] [b] Department of Chemistry, Princeton University, merization of Evans oxazolidinones. In addition to natu- Princeton, New Jersey 08544, USA ral product synthesis, Paquette and co-workers made use of

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MICROREVIEW F. Guo, M. D. Clift, R. J. Thomson an intramolecular oxidative enolate coupling in their ele- Despite the body of literature pertaining to oxidative gant synthesis of the structurally unusual hemispheric hy- enolate coupling that appeared in the last century, it re- drocarbon C16 hexaquinacene (7).[17] mained a relatively underinvestigated research area. In terms of methodology development, cross-coupling with equal stoichiometry of reacting partners remained a signifi- cant challenge, and systems that enabled uniformly high levels of diastereocontrol were underexplored. Moreover, no straightforward catalytic and enantioselective methods for oxidative enolate coupling were available. Beginning with the turn of the new millennium, however, significant advances have been made in all of these areas and have led to several powerful new methods for oxidative enolate coupling. The purpose of this microreview is to summarize these contributions and to provide recent examples of stra- tegic applications of oxidative enolate coupling in the realm of natural product total synthesis. This microreview does not cover related oxidative bond-forming reactions that in- volve enolates (or derivatives thereof) with aromatic sys- tems, such as electron-rich aryl groups, pyrroles, indoles, and furans.[18]

Methodology Development Recent methodological developments in oxidative enol- ate coupling (the term is used here to broadly describe reac- tions based on alkali metal enolates, enol silanes, and en- Figure 2. Natural products and other compounds prepared by oxi- amines) have focused on solving the cross-coupling prob- dative enolate coupling. lem, while simultaneously addressing the question of

Dr. Fenghai Guo studied chemistry at Shanghai Jiaotong University in Shanghai, China. He then moved to Clemson University, South Carolina, where he completed his Ph.D. with Prof. Karl Dieter in 2009 studying organometallic reagent- mediated synthesis of heterocycles. Since 2010 he has been a postdoctoral research associate with Prof. Regan J. Thomson at Northwestern University, working on the enantioselective synthesis of biaryls through traceless stereochemical exchange and the total synthesis of axially chiral alkaloids such as bismurrayaquinone A.

Dr. Michael D. Clift was born in Bellevue, Michigan. He received his B.S. in Biochemistry from Western Michigan University in 2005 working with Dr. James J. Kiddle. He graduated with a Ph.D. in Chemistry from Northwestern University in 2010, where he worked in the laboratory of Prof. Regan J. Thomson. His graduate studies focused on the development of silyl bis-enol ethers as useful species for the controlled oxidative cross-coupling of ketones, and on the total synthesis of alkaloids. He is currently a postdoctoral research fellow in the labs of Prof. David W. C. MacMillan at Princeton University.

Prof. Regan J. Thomson was born in Balclutha, New Zealand. After completing three years of his undergraduate studies at The University of Auckland, New Zealand, he moved to Australia where he completed his B.Sc. (First Class Honours) at The Australian National University (ANU), Canberra, in 1998. He received his Ph.D. in 2003 at The Research School of Chemistry at ANU working with Professor Lewis N. Mander. Following postdoctoral studies with Professor David A. Evans at Harvard University, he began his independent career at Northwestern University in 2006. His research interests are broadly focused on reaction methodology and natural product total synthesis.

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Oxidative Coupling of Enolates, Enol Silanes and Enamines stereocontrol, both relative and absolute. In recent years, tive for advanced ketone intermediates en route to complex several complementary methods for oxidative enolate cou- natural products. It would be 30 years until synthetic chem- pling have been reported and this work is summarized in ists returned to this problem. the following subsections. In 2006, Baran and DeMartino reported the develop- ment of a system that enabled selective intermolecular oxi- dative coupling of lithium enolates with use of equal stoi- Lithium Metal Enolates chiometries of the reacting partners for the first time [19] In 1971, Rathke and Lindert disclosed a significant ad- (Table 3). vance in the area of oxidative enolate coupling. They Table 3. Baran and DeMartino’s intermolecular cross-coupling.[a] showed that when treated with either CuII bromide or CuII valerate, the lithium enolates of several esters underwent efficient oxidative coupling to generate succinate derivatives (Table 1).[2]

Table 1. Rathke and Lindert’s oxidative dimerization.[a]

[a] Yields refer to isolated yields after vacuum distillation. cHex = cyclohexyl. Although only six substrates were reported in total, and diastereoselectivities were poor (for 9b and 9c, for example), this work provided much precedent for subsequent work in the field. In 1975, Saegusa and co-workers reported the use of CuII chloride to bring about the oxidative coupling of ketone- [3] derived lithium enolates. In this early report, they demon- [a] Yields refer to isolated yields after chromatography. strated that cross-coupled products could be obtained in synthetically useful yields when one enolate was used in ex- A subsequent paper detailing the full scope of the reac- cess (Table 2). tion was later published in 2008.[20] Using LDA to generate the appropriate enolates, they found that subsequent ad- [a] Table 2. Saegusa and co-workers’ intermolecular cross-coupling. dition of FeIII or CuII oxidants enabled the formation of cross-coupled 1,4-dicarbonyl compounds derived from ox- azolidinones or oxindoles with ketones or esters (Table 3). Good yields were obtained across a range of diverse sub- strates, and in some cases preparatively useful levels of dia- stereocontrol were observed. The cross-coupling reactions of Evans oxazolidinones offer an especially concise route to enantioenriched products that are useful precursors to natural products (see later for example), whereas the use of α-substituted oxindoles afforded products containing newly forged quaternary stereocenters. As well as further estab- [a] Yields refer to isolated yields after chromatography. lishing the range of useful compounds that could be pre- Although the power of this approach for the synthesis of pared by this powerful reaction, the 2008 publication also simple unsymmetrical 1,4-diketones is clear, the necessary provided some insight into the reaction. The stereochemical use of a large excess of one ketone limited its use in more outcome for the FeII-mediated oxidative coupling of phen- complex settings. The enolate used in excess is lost due to ylacetyl oxazolidinones (i.e., Table 3, 15a–d) was the oppo- competitive dimerization; this situation is of little conse- site of that obtained for related dihydrocinnamyl derivatives quence for the case of acetone, but would become prohibi- under CuII-promoted conditions (i.e., Table 3, 15g–i), a

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MICROREVIEW F. Guo, M. D. Clift, R. J. Thomson somewhat surprising result. For enolate alkylations of Ev- good yield (although typically this would undergo epimeri- ans oxazolidinones, the expected relationship between the zation to the “anti” isomer). In contrast, for the Cu-based auxiliary and the α-stereocenter is syn, as is observed for oxidations, mechanistic studies revealed little preference for the CuII-promoted reactions. In an effort to reconcile the oxidation of the ketone enolate over the oxazolidinone anti stereochemistry observed for the FeIII-mediated reac- enolate. Selective coupling was therefore proposed as a con- tions with the expected outcome for Evans auxiliaries, Ba- sequence of favorable formation of a Cu-bound bis-enolate ran and co-workers showed that exposure of the “syn” iso- mer 16 to LDA followed by acidic enolate quenching led to complete inversion of the Ph-bearing stereocenter to pro- duce anti isomer 16 (Scheme 1).

Scheme 1. Anomalous stereochemical outcome explained.

It thus appeared that for phenylacetyl adducts the α- stereocenter is sufficiently acidic that the presumed initial syn adduct of oxidative coupling undergoes base-promoted epimerization to give the observed anti configuration. In addition to these interesting substrate-based stereo- chemical quandaries, different reaction outcomes were found depending upon the oxidant employed, which was interpreted as being due to differing mechanisms for CuII versus FeIII oxidations. For the Fe-based oxidations, it ap- peared that the ketone enolate was more readily oxidized, leading to preferential coupling with the oxazolidinone enolate via an open transition state akin to intermediate 20 (Figure 3). Carbon bond formation, followed by oxidation of the intermediate radical 21, provides the product 22 in Figure 3. Baran’s mechanistic and stereochemical model.

Table 4. Casey and Flowers’ studies on Li-enolate aggregation effects of oxidative cross-coupling.[a]

[a] Ratios and yields determined by NMR spectroscopy. CTAN = ceric tetra-n butylammonium nitrate.

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Oxidative Coupling of Enolates, Enol Silanes and Enamines intermediate such as 23 (Figure 3). Once again, the cross- co-workers[25] for the asymmetric conjugate addition of coupled product was isolated in good yield, with the major arylzinc reagents. We thus prepared a selection of aryl-sub- diastereomer consistent with the intermediacy of a species stituted monomers and demonstrated that the oxidative di- such as bisenolate 23. Together, these models also serve to merization/stereochemical transfer process proceeded as explain the higher than statistical yields for the cross-cou- well as for the alkyl derivatives.[22] pled products over dimers. Table 5. Elaboration of traceless stereochemical transfer.[a] Whereas the studies of Baran and co-workers provided important insights into the cross-coupling of lithium enol- ates, subsequent work reported by Flowers and Casey in 2011 presented spectroscopic and mechanistic results show- ing that the selective generation of cross-coupled products for the ketones they investigated was the result of heteroag- gregation of the lithium enolates (Table 4).[21] Using 7Li NMR spectroscopy, they showed that 1:1 mix- Entry Ar % Yield 31 (er) 32 (er) tures of different Li enolates (i.e., A and B) tended preferen- tially to form heteroaggregates (A B ) and that the ratio of 1Ph(30a) 56 (99:1) 77 (99:1) 2 2 2 2-naphthyl (30b) 51 (99:1) 82 (99:1) the heteroaggregate to the monomeric aggregates (A4 +B4) 3 4-OMeC6H4 (30c) 50 (99:1) 86 (99:1) correlated well with the ratio of cross-coupled to homocou- 4 4-MeC6H4 (30d) 63 (99:1) 89 (99:1) pled products obtained upon oxidative coupling (Table 4). 5 4-FC6H4 (30e) 66 (99:1) 88 (99:1) These fascinating and important studies revealed a level of 6 3,5-Me2C6H4 (30f) 73 (99:1) 85 (99:1) complexity to the situation that had not previously been 7 3,5-(OMe)2C6H4 (30g) 48 (99:1) 75 (99:1) 8 3,4-methylenedioxy-C H (30h) 52 (99:1) 78 (99:1) recognized, and provided key insights for future develop- 6 4 ment of cross-coupling reactions (and the interpretation of [a] Yields refer to isolated yields after chromatography. Enantio- meric ratios determined by HPLC. results). In 2011 we reported the use of stereoselective oxidative This new method for the concise preparation of enanti- enolate dimerization of enantioenriched monoketal dihy- oenriched axially chiral biphenols has potential applications droquinones for the assembly of nonracemic biphenols for the synthesis of new ligands for asymmetric catalysis, (Scheme 2).[22] Treatment of the readily prepared enone pre- and has already found use in natural products synthesis (see cursors 27a or 27b[23] with LDA followed by CuII chloride later). forged the hindered central σ-bond linking the two rings We conclude this section by describing attempts by within the dione products 28a or 28b. We had reasoned that Nguyen and Schäfer to develop enantioselective oxidative conformational rigidity about this bond would enable coupling.[26] In their 2001 report, Nguyen and Schäfer transfer of the point chirality present in the dimers to the axial chirality present in the aromatized biphenol products Table 6. Nguyen and Schäfer’s enantioselective dimerization.[a] (i.e., 29). We thus found that Lewis-acid-induced loss of methanol with simultaneous keto-to-enol tautomerization afforded the desired biphenols in good yields and with com- plete transfer of stereochemical information from starting material to product. The dimerization process itself is inter- esting in that an amplification of enantiopurity from the monomer is observed, due to loss of the minor enantiomer through formation of a meso isomer.[24]

Scheme 2. Traceless stereochemical transfer from 1,4-diketones. Entry Additive L* % Yield 34 dl/meso % ee Reagents and conditions: (a) LDA (1.1 equiv.), CuCl2 (1.15 equiv.), THF/DMF, –78 °C to room temp., 1.5 h. (b) BF3·OEt2 1 A 67 54:46 39 [22] (15.0 equiv.), toluene, 110 °C, 12 h. Reprinted from ref. Copy- 2 B 63 31:69 5 right 2011 American Chemical Society. 3 C 52 24:76 16 4 D 59 35:65 6 In an effort to expand the scope of this method for the 5 E 81 45:55 24 synthesis of nonracemic biphenols, we devised an enantio- 6 F 58 48:52 46 selective synthesis of aryl-substituted enones (i.e., 30, 7 G 91 25:75 76 Table 5) by modifying chemistry reported by Hayashi and [a] Ratios determined by NMR spectroscopy.

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MICROREVIEW F. Guo, M. D. Clift, R. J. Thomson showed that generation of the titanium enolate of acyl ox- the synthesis of the unsymmetrical silyl bis-enol ethers azolidinone 33 (Table 6) with Fe(Cp)2BF4 as the stoichio- could be conducted with use of only 1.1 equiv. of 40, negat- metric oxidant allows for effective oxidative dimerization to ing the need for a large excess of one reacting partner. produce 34. The use of chiral additives in stoichiometric [a] quantities provided the product in good yields, but with Table 7. Silyl bis-enol ether cross couplings of 2-methyltetralone. varying levels of diastereo- and enantioselectivity. Unfortu- nately, whereas the best additive for enantioselectivity (i.e., G, Table 6, Entry 7) provided the product in 76% ee, the ratio of dl/meso isomers was only 1:3. Additional sub- strates were not reported, but although this reaction is somewhat limited it does provide a possible template for future efforts in the design of methods for the enantioselec- tive oxidative coupling of enolates.

Silyl Bis-Enol Ethers

In 1998, Schmittel and co-workers reported that silyl bis- enol ether 35 (Scheme 3) undergoes intramolecular oxidat- ive coupling when treated with CeIV ammonium nitrate (CAN) to generate diketone 36 in good yield with high [a] Yields refer to isolated yields after chromatography. LDA = lith- levels of diastereocontrol.[27] ium diisopropylamide; CAN = ceric ammonium nitrate. After these initial studies, we investigated the diastereo- selective synthesis of linked bicyclic diketones from silyl bis- enol ethers. Initial studies focused on the dimerization of cyclohexanone via bis-enol ether 43 (Table 8).[29]

Table 8. The influence of silicon substituents on diastereoselectiv- ity.[a]

Scheme 3. Schmittel’s silyl bis-enol ether coupling.

Entry R2Si dr (44/45) % Yield 44 In addition, they showed that cross-coupling could also 1Me(43a) 2.4:1 29 be achieved when unsymmetrical silyl bis-enol ethers were 2Et(43b) 5:1 47 utilized: bis-enol ethers 37a and 37b thus gave rise to diket- 3Ph(43c) 5:1 29 ones 38a and 38b, respectively. Although only four sub- 4 iPr (43d) 10:1 57 strates were examined in total, the formation of diketone 5–C4H8–(43e) 3:1 31 8–CH –(43f) 6:1 56 38b from bis-enol ether 37b represented the first time that 5 10 highly stereoselective cross-coupling had been achieved. As [a] Yields refer to isolated yields after chromatography. Dia- 1 such, the concept of silicon-tethering represents a powerful stereomeric ratios determined by H NMR spectroscopy. CAN = ceric ammonium nitrate. strategy for developing a general method for controlled oxi- dative coupling that should have broad utility in natural As an important benchmark, it was known from the lit- products synthesis. Our own research group sought to ex- erature that dimerization of the lithium enolate of cyclo- pand upon these preliminary findings of Schmittel with this hexanone gave low yields and poor diastereocontrol slightly long-term goal in mind. favoring the meso isomer 45.[30] We prepared several silyl In 2007 we reported the development of a general bis-enol ethers with varying silicon substituents, and noted method for oxidative cross-couplings of 2-methyltetralone enhanced bias towards the chiral diastereomer 44 with (39, Table 7) to afford unsymmetrical 1,4-diketones (i.e., larger substituents. Ultimately, we found that diisoprop- compounds 42) with simultaneous generation of quaternary ylsilyl bis-enol ether 43d gave the best combination of high stereocenters.[28] Although the room for modification of the diastereoselectivity and chemical yield (Entry 4, Table 8). tetralone component was somewhat limited, the reactions We explained the inherent preference for the chiral iso- displayed good substrate scope for the methyl ketone com- mer over the meso isomer by invoking two possible reactive ponent (representative examples shown), yielding 1,4-diket- conformations during carbon–carbon bond formation in ones in good yields. As had been a criterion from the outset, the intermediate radical-cation species (Figure 4). Confor-

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Oxidative Coupling of Enolates, Enol Silanes and Enamines mation I minimizes eclipsing interactions between the two an added element of facial control was observed. As ex- rings relative to conformer II, thus providing a selection pected, the newly forged σ-bond formed opposite to the β- bias for generation of the chiral diastereomer. This destabi- disposed substituent (47g–i, Table 9). The uniformly high lizing effect within II is further enhanced with larger sub- diastereoselectivities observed for both dimerization and stituents on silicon; a Thorpe–Ingold effect would reduce cross-coupling are the highest yet reported and should pave the size of angle γ whenR=iPr versus R = Me, thereby the way for future applications in complex molecule synthe- creating a larger energy difference between I and II reflected sis. in the product distribution. For all the cases discussed thus far, the silyl bis-enol ethers had been formed from the corresponding enolates generated by deprotonation of the immediate ketone pre- cursors. We speculated that it should be possible to form silyl bis-enol ethers (i.e., 50, Table 10) by trapping of enol- ates generated through conjugate addition to appropriate enone starting materials (i.e., 48). In this way, 1,4-addition would allow for a merged three-component sequence when coupled with a subsequent oxidative carbon–carbon bond- forming event.[31]

Table 10. Merged conjugate additions/oxidative cross-couplings.[a] Figure 4. Model for stereoselectivity. Reprinted with permission from ref.[29] Copyright 2008 American Chemical Society.

The developed reaction conditions proved remarkably general for the stereoselective dimerization of cyclic ketones (47a–c, Table 9).

Table 9. Diastereoselective dimerizations and cross-couplings.[a]

[a] Yields refer to isolated yields after chromatography. CAN = ceric ammonium nitrate; DTBP = di-tert-butylpyridine.

The reactions displayed generality for a variety of dif- ferent substrates, allowing a concise route to structurally diverse 1,4-diketones in reasonably good yields over the two-step merged sequence (i.e., 48 Ǟ 51). A subsequent Paal–Knorr pyrrole synthesis demonstrated the usefulness of this methodology for the synthesis of substituted pyrroles and led to application of this approach to the total synthesis of prodigiosin alkaloids (see later).

Enamine Catalysis In 1992, Narasaka and co-workers reported efficient oxi- dative cross-couplings of preformed enamines with enol [a] Yields refer to isolated yields after chromatography. Dia- IV 1 silanes upon treatment with Ce ammonium nitrate stereomeric ratios determined by H NMR spectroscopy. CAN = [9] ceric ammonium nitrate. (Table 11). Although the majority of the examples in this publication reported cross-coupling with enamine 52 to Highly diastereoselective cross-coupling could also be generate stable enamine products (i.e., 54), there was one achieved (47d–i, Table 9), and in the cases in which one re- isolated example of a cross-coupling with a morpholine-de- action partner possessed a β-substituent (such as carvone) rived enamine that afforded the corresponding 1,4-diketone.

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MICROREVIEW F. Guo, M. D. Clift, R. J. Thomson

Table 11. Narasaka and co-workers’ oxidative cross couplings.[a] In 2010, Jia’s group developed a new method for the di- rect construction of symmetrical pyrroles through oxidative dimerizations of aldehydes in the presence of amines (Table 13).[33] In these reactions, the amines 59 serve not only to facilitate pyrrole formation through the Paal–Knorr pyrrole synthesis, but also promote oxidative coupling through initial enamine formation. Optimum yields were obtained with silver acetate as the stoichiometric oxidant. Although currently limited to the construction of symmetri- cal pyrroles, the Jia group has successfully employed this methodology in the rapid total syntheses of numerous pyr- role-containing natural products (see later section).

[a] Yields refer to isolated yields after chromatography. CAN = Table 13. Jia and co-workers’ oxidative dimerization.[a] ceric ammonium nitrate.

The scope of this chemistry went largely unexplored until the MacMillan group creatively leveraged their expertise in enamine organocatalysis to develop the first, and to date the only, method for catalytic enantioselective oxidative coupling (Table 12).[32] Under the reported reaction condi- tions, two equivalents of an enol silane 56 will undergo oxi- dative bond formation (promoted by CeIV ammonium ni- trate) with an aldehyde 55 in the presence of 20 mol-% of an organocatalyst (A). For the wide variety of substrates reported, the yields of the 1,4-dicarbonyl adducts 57 were high and the enantioselectivities obtained were uniformly excellent. [a] Yields refer to isolated yields after chromatography. OAc = acet- ate, PMP = 4-methoxyphenyl. Table 12. MacMillan and co-workers’ enantioselective couplings.[a]

Natural Product Synthesis Paralleling the development of new methods for oxidat- ive coupling there have been a number of significant appli- cations of oxidative coupling to the successful syntheses of a variety of different natural products. The range of struc- tures targeted and methods employed serve to demonstrate the great power of oxidative coupling reactions when they are deployed strategically in total synthesis. The following section summarizes this recent work and is divided into sec- tions dealing with dimerizations, cross-coupling reactions, and intramolecular versions.

Oxidative Dimerization

The Lomaiviticin Aglycone Lomaivaticins A (61, Figure 5) and B (62) are two in- credibly complex glycosylated natural products isolated from a fermentation broth of a species of actinomycete.[34] [a] Yields refer to isolated yields after chromatography. Enantio- Their potent DNA-strand-cleaving abilities arise due to the meric excesses determined by GC or SFC analysis. CAN = ceric ammonium nitrate; DTBP = di-tert-butylpyridine. presence of the rather unusual diazo functionality, a feature they share with the biogenetically related kinamycin mole- This report is especially promising for new directions in cules.[35] Structurally, the aglycon core of the lomaiviticins oxidative enolate coupling because it demonstrates that cata- is dimeric, and it is therefore most likely that the biosynthe- lyst-controlled enantioselective variants are possible and sis of these compounds occurs through the oxidative dimer- paves the way for further exciting developments in the future. ization of a suitable monomeric precursor, such as 63.

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Oxidative Coupling of Enolates, Enol Silanes and Enamines

Scheme 4. The Shair group’s approach to the lomaiviticin core. Reagents and conditions: (a) LiHMDS (1.7 equiv.), HMPA (5 equiv.), THF, –78 °C, 1.5 h; then [Cp2Fe]PF6 (3 equiv.), –20 °C, 20 h, 45–51%. (b) Aq. HF (48%, 20 equiv.), MeCN, 23 °C, 3 d. (c) DMP (3 equiv.), CH2Cl2, 23 °C, 3 h, 26% over two steps. (d) K2CO3 (6 equiv.), MeOH, 0 to 23 °C, 3 h, 14%. [Cp2Fe]PF6 = Figure 5. Lomaiviticins A (61)andB(62). ferrocenium hexafluorophosphate, HMDS = hexamethyldisilazane, HMPA = hexamethylphosphoramide, TBS = tert-butyldimethylsil- yl, DMP = Dess–Martin periodinane. From a strategic standpoint, when contemplating a total synthesis of the lomaiviticins, this symmetry leads to the Shair lab suggest that a robust route to the natural product logical conclusion that such a dimerization strategy should is in place and highlight the power of oxidative coupling to enable the most efficient synthesis. The question is then one forge sterically congested bonds. of tactics to deal with the complexity of this approach. Major issues facing this oxidative dimerization strategy via an enolate are the possibility of elimination of the β-hy- droxy group and the question of diastereofacial control. In their published work directed towards the lomaiviticins, Shair and co-workers utilized tricyclic ketone 64 to deal with each of these issues (Scheme 4).[36] The oxo-bridged [2.2.1] bicyclic ketone 64 ensures excellent diastereocontrol Scheme 5. The Shair group’s second approach to the lomaiviticin for the exo-face, whereas geometric constraints limit the fa- core. Reagents and conditions: (a) LiHMDS (1.7 equiv.), HMPA cility of E1CB decomposition of the intermediate enolate (5 equiv.), THF, –78 °C, 2 h; then [Cp2Fe]PF6 (3 equiv.), –60 °C, under the reaction conditions. The complex polycyclic 1,4- 72 h, 80%. (b) [PdCl2(PPh3)2], Bu3SnH, AcOH, CH2Cl2, 0 °C, diketone 65 was thus formed in 45–51% yield as a single 90%. [Cp2Fe]PF6 = ferrocenium hexafluorophosphate, HMDS = hexamethyldisilazane, HMPA = hexamethylphosphoramide. stereoisomer. Further elaboration of dione 65 gave rise to the hydrate 66, which underwent a controlled fragmentation Herzon’s group opted to take a more direct approach of the oxo-bridge under basic conditions to install the req- and to tackle the problem of dimerization of a more fully uisite tertiary alcohol with simultaneous displacement of elaborated monomeric precursor already containing the di- the sulfone with methoxide. The central core of the lomaivi- azo functionality (akin to 63 in Figure 5). This maximally ticin aglycon (i.e., 67) was thus constructed with complete convergent approach led to the first synthesis of the lomaiv- stereocontrol in only four steps from the monomeric ketone iticin aglycon in 2011 (Scheme 6).[38] 64. Preparation of the requisite monomeric ketone 70 was In a subsequent publication in 2010, Shair and co- carried out by methods related to those used in the Herzon workers reported the successful oxidative coupling of a lab’s preparation of the kinamycins.[39] After extensive stud- more fully elaborated precursor that contained all the re- ies into conditions for oxidative dimerization (Ͼ1500 ex- quired rings associated with the lomiaviticin aglycon periments), it was found that treatment of the TMS enol (Scheme 5).[37] Synthesis of the precursor for oxidative cou- ether 71 with MnIII hexafluoroacetoacetate produced a pling (i.e., 68) proceeded by an approach related to that 26% yield of the desired 1,4-diketone 72, along with a 12 % used for the less complex monomer 64 (Scheme 4). Under yield of the undesired isomer possessing the bis-epimeric conditions similar to those used for the successful dimeriza- stereochemistry across the linking σ-bond. Use of the exo- tion of 64, ketone 68 underwent a highly stereoselective and mesityl acetal proved crucial in obtaining a facial preference high-yielding oxidative dimerization to generate the com- for 72. Deprotection of the diol function produced the agly- plex dimer 69 in 72 % yield after allyl group removal. The con of lomaitviticin B (i.e., 74) in 39 % yield. Isolation of stereochemistry of adduct 69 was confirmed by X-ray crys- the keto form corresponding to lomaiviticin A (i.e., 73)was tal analysis. The combination of these two reports from the also possible, although this was shown to convert rapidly

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MICROREVIEW F. Guo, M. D. Clift, R. J. Thomson

Scheme 7. The Mårtensson group’s synthesis of scytonemin. Rea- gents and conditions: (a) LDA, FeCl3, THF, –78 °C to room temp., 70%. (b) BBr3,CH2Cl2, –78 to 0 °C. (c) DDQ, THF, 0 °C, 28% over two steps. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquin- one.

treatment. Included among these alkaloids is the ACL in- hibitor purpurone (81, Scheme 8).[44] Recognizing the im- Scheme 6. The Herzon group’s synthesis of the Lomaiviticin agly- portance of this family of alkaloids, Jia’s group developed con. Reagents and conditions: (a) TMSOTf, Et3N, CH2Cl2, 0 °C. a general method for the direct construction of dimeric pyr- (b) Manganese tris(hexafluoroacetylacetonate), PhH, 21 °C, 26%. roles from simple amine and aldehyde precursors (see pre- (c) TFA, TBHP, CH2Cl2, –35 °C, 12 h, 39%. TMS = trimethylsilyl, vious section) and initially targeted purpurone for total syn- Tf = trifluoromethylsulfonyl, TFA = trifluoroacetic acid, TBHP = tert-butylhydroperoxide. thesis by this method. into 74 on standing in chloroform. Although the reported yields for the transformations remain modest, the rapid es- calation of complexity achieved over this two-step sequence of oxidative coupling and deprotection is truly impressive and serves once more to demonstrate the power of oxidative coupling. Scytonemin Scytonemin (77, Scheme 7) is a unique cyanobacteria- produced alkaloid based on a dimeric 1,1Ј-linked cy- clopent[b]indol-2(1H)-one nucleus.[40] Inspired by biosyn- thetic studies by Balskus and Walsh,[41] Mårtensson and co- Scheme 8. The Jia group’s synthesis of purpurone. Reagents and conditions: (a) AgOAc (2.0 equiv.), NaOAc (2.0 equiv.), THF, room workers prepared ketone 75 in seven steps from indol-3- temp. to 60 °C, 59%. (b) 2,2,2-Trichloroethyl 2-bromo-2-(3,4-di- ylacetic acid and showed that dimer 76 is readily generated methoxyphenyl)acetate, Al2O3, DCM, reflux, 63%. (c) Zinc [42] when the lithium enolate of 75 is treated with FeCl3. The (50 equiv.), NH4OAc (4.0 equiv.), THF, room temp. (d) Ac2O (sol- diastereoselectivity of this coupling was inconsequential; af- vent), KOAc (2.6 equiv.), reflux, 58% (two steps). (e) NaOH (ex- cess), MeOH, air, 55 °C, 66%. (f) BBr3 (20 equiv.), cyclohexene ter cleavage of the methyl ethers with BBr3, DDQ-mediated (40 equiv.), DCM, –78 to –10 °C, 90%. OAc = acetate, THF = oxidation afforded the natural product 77 (28% over two tetrahydrofuran, DCM = dichloromethane. steps from 76). The Jia synthesis began with this key transformation. Sil- Purpurone and Related Alkaloids ver(I)-mediated oxidative dimerization of the enamine de- Alkaloids of the lamellarin family have been keenly pur- rived from condensation of amine 79 with aldehyde 78 pro- sued by synthetic chemists owing to their diverse array of vided direct access to the key pyrrole intermediate 80.[33] biological activities, including antitumor activity, HIV-1 in- The remainder of the synthesis followed methods developed tegrase inhibition activity, and reversal of multidrug resis- by Steglich,[45] allowing the authors to complete a concise tance.[43] Of particular interest are those members that are six-step synthesis of purpurone that proceeded in 13% over- potent inhibitors of ATP-citrate lyase (ACL), because these all yield, making it the most rapid and efficient synthesis of compounds have incredible therapeutic potential in cancer this alkaloid reported to date.

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Oxidative Coupling of Enolates, Enol Silanes and Enamines

After completion of this work, Jia and co-workers were Oxidative dimerization of enantioenriched monomer 27a also able to demonstrate the versatility of their method by proceeded to afford the 1,4-diketone 28a, which was con- employing it in the total syntheses of four related natural verted into the biphenol 29a with no loss of optical purity [46] products (Figure 6). In each case the central pyrrole upon treatment with BF3·OEt2. Conversion of 29a into the could be accessed in rapid fashion through the use of this bis-aniline derivative 86 by a Buchwald–Hartwig amination powerful method, allowing each natural product to be con- set the stage for the crucial Pd-catalyzed carbazole-forming structed in seven or fewer synthetic manipulations and with reaction, which after oxidative demethylation led to bismur- high overall efficiency. rayaquinone A (87). An earlier approach had formed the carbazolequinone ring system from a biquinone, but afforded racemic 87. These observations led to a comprehensive study into the configurations of axially chiral biquinones and established the barrier to racemization of 87 as 54 kcal mol–1 (the natu- ral product is configurationally stable at room temperature). Unfortunately, at this point no data exist as to whether the naturally derived material exists in enantiomerically en- riched form or is a racemate. Regardless, the synthesis Figure 6. Related natural products prepared by the Jia group. served to provide a demonstration of the usefulness of oxi- dative coupling for the synthesis of axially chiral natural products. Bismurrayaquinone A The curry leaf plant has been the source of numerous biologically active carbazole natural products. Amongst Oxidative Cross-Coupling these compounds are a number of dimeric carbazoles, such Bursehernin as the unusual biquinone bismurrayaquinone A (87, Scheme 9).[47] Biosynthetically, it is hypothesized that such The dimeric lignan natural products have been attractive compounds originate from oxidative coupling of mono- targets for total synthesis through oxidative dimerization. meric phenols, and this approach was successfully employed The concise enantioselective synthesis of hinokinin (see Fig- by Bringmann and co-workers in their inaugural synthesis ure 2), for example, was achieved through the oxidative di- of racemic 87.[48] Although this strategy is optimally con- merization of the appropriate Evans oxazolidinone.[16] Ap- vergent, control of absolute stereochemistry is challenging. plication of such approaches to the synthesis of unsymmet- Our previous methodological study on the dimerization of rical lignans remained elusive, however, until the contri- ketones as precursors to enantioenriched biphenols (see butions of Baran and co-workers. Using their oxidative previous section) served as the primary driving force behind cross-coupling methodology they were able to conduct an our bidirectional approach to bismurrayaquinone A (87).[49] efficient synthesis of enantioenriched bursehernin (91, Scheme 10).[19,20] The key cross-coupling event was con-

Scheme 9. The Thomson group’s synthesis of bismurrayaquin- one A. Reagents and conditions: (a) LDA (1.1 equiv.), CuCl2 (1.1 equiv.), 63%. (b) BF3·OEt2 (10 equiv.), toluene, reflux, 87%. Scheme 10. The Baran group’s synthesis of bursehernin. Reagents (c) Br2 (2.0 equiv.), 90%. (d) MeI (10 equiv.), KOH (3.0 equiv.), and conditions: (a) 88, LDA (THF, 1.15 equiv.), LiCl (5.0 equiv.), 84%. (e) 2-Chloroaniline (3.0 equiv.), Pd(OAc)2 (8 mol-%), PhMe, –78 to 0 to –78 °C (10 min each), 89 (1.75 equiv.), PhMe, II [HPtBu3][BF4] (11 mol-%), NaOtBu (11 equiv.), toluene, reflux, LDA (THF, 1.85 equiv.), –78 °C, 30 min, then Cu 2-ethylhex- 90%. (f) Pd(OAc)2 (20 mol-%), [HPtBu3][BF4] (28 mol-%), Na- anoate, –78 to 23 °C, 20 min. (b) LiBH4 (10 equiv.), MeOH OtBu (7.0 equiv.), 160 °C, microwave, 73%. (g) CAN (10 equiv.), (5.0 equiv.), THF, –78 to –10 °C, 1.5 h. (c) DBU (10 equiv.), PhMe, MeCN/H2O, 95%. LDA = lithium diisopropylamide, CAN = ceric 110 °C, 24 h, 41% (three steps). DBU = 1,8-diazabicyclo[5.4.0]un- ammonium nitrate. dec-7-ene.

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MICROREVIEW F. Guo, M. D. Clift, R. J. Thomson ducted with an excess of the less “expensive” ester 89 to than 50%, but we were happy to press forward because of afford the unsymmetrical 1,4-dicarboxylate 90 as a 1.6:1 the efficient nature of the sequence, which readily allowed mixture of stereoisomers. This modest diastereocontrol ad- access to the otherwise challenging unsymmetrical diketone. jacent to the tert-butyl ester was inconsequential; reduction Ring-closing metathesis to form the 12-membered ring, fol- of the unpurified mixture and treatment of the resulting lowed by condensation with ammonium acetate, gave rise to alcohol with DBU induced lactonization and equilibration the pyrrole nucleus 96 in good yield. From here, a selective of the diastereomeric mixture to afford the target 91 in 41% oxidation of the methyl group in 96 set the stage for a vin- yield as a single diastereomer. This synthesis served to dem- ylogous aldol condensation to afford 97, which underwent onstrate the strategic utility of this powerful method for Suzuki cross-coupling with 1-(tert-butoxycarbonyl)pyrrole- intermolecular cross-coupling. 2-boronic acid to give the natural product 98. This short sequence thus enabled the first enantioselective synthesis of Metacycloprodigiosin and Prodigiosin R1 metacycloprodigiosin (98) and established its absolute con- The prodigiosins are a family of polypyrrole natural figuration for the first time.[51] The usefulness of this silicon- products that have attracted much interest from the chemi- tethered method for oxidative cross-coupling was further cal community due to their interesting structures, pro- demonstrated by the synthesis of prodigiosin R1 (99)bythe nounced biological activities, and fascinating biosynthe- same strategy. sis.[50] As part of our development of the merged 1,4-ad- dition/oxidative coupling sequence of silyl bis-enol ethers Maoecrystal V (see Table 10), we targeted metacycloprodigiosin (98, The complex polycyclic norditerpene maoecrystal V Scheme 11), a 12-membered cyclophane prodigiosin.[29] Our (106, Scheme 12)[52] poses several challenges to any syn- synthesis commenced with an enantioselective conjugate thetic attempt and has led to a number of creative ap- addition of EtMgBr to enone 92, followed by trapping with proaches,[53] and one completed total synthesis to date.[54] chloroenol silane 93. Perhaps foremost amongst the challenges is how to devise a convergent fragment coupling about the centrally located carbon–carbon bond possessing vicinal quaternary substi- tution. In their model study directed towards maoecrystal V (106), Baran and co-workers utilized an intermolecular oxi- dative cross-coupling of enol 100 and cross-conjugated sil- oxydiene 101 to produce 1,4-diketone 102 in 46 % yield (Scheme 12).[53b] Redox state adjustments led to the synthe- sis of linked bicyclic dione 104 in five steps from 102 and set the stage for an intramolecular Diels–Alder reaction to deliver a cycloadduct incorporating the core features of the nature product (i.e., 105). The cycloadduct 105 was shown, however, to possess the incorrect relative stereochemistry required for the natural product, which led to the develop-

Scheme 11. The Thomson group’s synthesis of metacycloprodi- giosin. Reagents and conditions: (a) EtMgBr, CuBr·DMS (5 mol- %), (R,S)-JosiPhos (6 mol-%), then 93. (b) CAN, 2,6-di-tBu-Py, MeCN/EtCN, 35% from 92. (c) Second-generation Grubbs catalyst (10 mol-%), dichloromethane, 69% (82% brsm). (d) Pd(OAc)2,H2, EtOH, then NH4OAc, 87%. (e) DDQ, H2O, MeCN, 69%. (f) 1. 4- Methoxy-1,5-dihydro-2H-pyrrol-2-one, TMSOTf, iPr2NEt, di- chloromethane; 2. HCl, THF, 98% (two steps). (g) Tf2O, dichloro- methane, –50 °C to 0 °C, 1 h. (h) 1. Pd(PPh3)4 (3 mol-%), 1-(tert- butoxycarbonyl)pyrrole-2-boronic acid, Na2CO3, DME, 80 °C; 2. NaOMe, MeOH, room temp., 76% over three steps. CAN = ceric ammonium nitrate. Tf = trifluoromethanesulfonyl. Scheme 12. Baran’s model study directed towards maoecrystal V. Exposure of unpurified bis-enol ether 94 to CAN in- Reagents and conditions: (a) CAN, NaHCO3, MeOH, 0 °C, 46%. duced the desired oxidative coupling to generate 1,4-diket- (b) Li(tBuO)3AlH, THF, –78 °C, 53%. (c) Acryloyl chloride, Et3N, DMAP, DCM, 0 °C, 36 %. (d) TBSOTf, Et N, DCM, 63%. (e) Pd/ one 95 in 35 % yield over the two-step sequence. The yield 3 C, O2, PhMe, 110 °C, 99%. (f) Pb(OAc)4, AcOH, 59%. (g) 165 °C, for this sequence was a little disappointing because related o-DCB, 60%; CAN = ceric ammonium nitrate, DMAP = 4-dimeth- substrates lacking the terminal alkenes gave yields greater ylaminopyridine, o-DCB = ortho-dichlorobenzene.

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Oxidative Coupling of Enolates, Enol Silanes and Enamines ment of a second model system that corrected this issue (but did not use oxidative enolate coupling). Although com- pound 105 was not taken forward to a completed total syn- thesis, this study demonstrated the feasibility of the cyclo- addition approach to maoecrystal V and provides an excel- lent example of formation of a quaternary stereocenter through oxidative enolate coupling.

Intramolecular Oxidative Coupling

Stephacidins A and B and Avrainvillamide Stephacidin B (107, Figure 7), a unique fungi-derived metabolite, is one of the most structurally complex natural products known.[55] Formally, 107 is a dimer of the simpler compound avrainvillamide (109), which arises from oxi- dation of stephacidin A (108). Common to these alkaloids is the presence of the bicyclo[2.2.2]diazaoctane core, which is believed to be derived biosynthetically from an intramo- lecular Diels–Alder reaction. Although such approaches Scheme 13. The Baran group’s synthesis of stephacidins A and B [56] have enabled the total syntheses of related compounds, and avrainvillamide. Reagents and conditions: (a) LDA (2.2 equiv.), Baran and co-workers sought to apply a different strategy. THF, –78 °C, 5 min; then Fe(acac)3 (2.2 equiv.), –78 °C, 5 min; then –78 to 20 °C, 20 min, 61%. (b) B-Bromocatecholborane (1.5 equiv.), CH2Cl2, 0 °C, 10 min, 63%. (c) MeMgBr (6.0 equiv.), toluene, 20 °C, 10 min. (d) Burgess reagent (2.0 equiv.), benzene, 50 °C, 30 min, 88% yield over two steps. (e) 200 °C, sulfolane, 1 h, Ͼ 28–45%. (f) NaBH3CN (40 equiv.), AcOH, 20 °C, 24 h, 95%. (g) SeO2 (0.25 equiv.), aqueous H2O2 (35%, 50 equiv.), 1,4-dioxane, 20 °C, 40 h, 27%.

selenium dioxide, then provided ent-avranvillamide (ent- 109), which was shown to undergo a spontaneous and re- versible dimerization to afford ent-stephacidin B (ent- 107).[58] Figure 7. Stephacidins A and B and avrainvillamide. Access to these compounds in optically enriched form Rather than form the common bicyclo[2.2.2]diazaoctane enabled the Baran lab to establish that the absolute configu- core through the more precedented Diels–Alder reaction, ration of the natural material was the opposite of that of Baran and co-workers viewed these compounds as ideal tar- their synthetic compounds (i.e., as shown in Figure 7 gets for exploration of the strategic application of oxidative above). From a purely synthetic viewpoint, the successful enolate coupling (Scheme 13).[57] Diketopiperazine 110 implementation of an intramolecular oxidative enolate cou- could be readily prepared in a minimal number of opera- pling between two different functionalities embedded within tions, setting the stage for the key oxidative coupling event. a complex precursor amply serves as an example of the util- At that time there were no examples of effectively couplings ity of such reactions in total synthesis. between ester enolates and enolates derived from amides. Actinophyllic Acid After screening of a number of oxidizing reagents, FeIII acetoacetate was found to be the most effective, and expo- In 2005, Quinn and co-workers reported the structure of [59] sure of diketopiperazine 110 to LDA and Fe(acac)3 under actinophyllic acid (119, Scheme 14). This indole alkaloid, the optimized conditions afforded the desired product 111 isolated from the leaves of Alstonia actinophylla, was shown as a single diastereomer in 61% yield. to be an inhibitor of carboxypeptidase U and was thus of The power of the reaction is evident in that it could be interest for its potential in treating cardiovascular disorders. conducted on a gram scale without diminished yields. From a structural viewpoint, the unprecedented combina- MOM removal and subsequent conversion of the methyl tion of both a 1-azabicyclo[4.4.2]dodecane and 1-azabicy- ester to afford the corresponding disubstituted alkene 112 clo[4.2.1]nonane ring system is unique amongst the indole was carried out as a prelude to the final ring-closing step. alkaloids. This mixture of promising biological profile and Thermal Boc removal and cyclization at 240 °C furnished impressive molecular complexity spurred Overman and co- ent-stephacidin A (ent-108) in 45 % yield. Partial reduction workers to develop a concise route to 119 amenable to of the indole ring in ent-108, followed by oxidation with multigram scale-up for future biological testing.

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MICROREVIEW F. Guo, M. D. Clift, R. J. Thomson

synthesis of actinophylic acid (119) from enantioenriched indole 113.[60b] The tactical combination of intramolecular oxidative enolate coupling and the aza-Cope/Mannich reac- tion seen in this concise synthesis is a particularly effective example of seamless synthetic planning involving very few function group manipulations between key bond-forming events. Axinellamine A The intricate structures of the pyrrole alkaloids derived from marine organisms, such as axinellamine A (124, Scheme 15), have caught the imaginations of synthetic chemists across the globe.[61] In 2012, Harran and co- workers reported an approach to the core structure of axi- nellamine A that takes advantage of hidden symmetry within the compound to simply the approach signifi- cantly.[62]

Scheme 14. Overman and co-workers’s synthesis of actinophyllic acid. Reagents and conditions: (a) LDA (3.2 equiv.), [Fe(DMF)3- Cl2][FeCl4] (3.5 equiv.), THF, –78 °C to room temp., 60–63%. (b) CeCl3,CH2=CHMgBr, THF, –78 °C, 99%. (c) 1. TFA, di- chloromethane, 0 °C; 2. (CH2O)n, CSA, PhH, 70 °C. (d) TFA, room temp., 76% (3 steps). (g) LDA, CH2O, THF, –78 °C, TFA. (h) 4 m HCl, 70 °C, 50% (2 steps).

The crux of the synthesis began with the key intramolec- ular oxidative enolate coupling between the malonate and ketone functionalities in the readily prepared indole 113 (Scheme 14).[60] Exposure of 113 to LDA, followed by the addition of

[Fe(DMF)3Cl2][FeCl4], forged the key keto-bridged hexahy- droazocino[4,3-b]indole ring system in 60–63% yield. Note- worthy aspects of the construction of this particular bond are that it did not require protection of the indole subunit and could be performed effectively on a 10 gram scale. 1,2- Addition of a vinyl Grignard reagent into the bridging carbonyl group in 114 took place with complete dia- Scheme 15. Harran and co-workers’ approach to axinellamine A. stereocontrol, due to the shielding afforded by the exo tert- Reagents and conditions: (a) (iPrCp)2TiCl2 (1.05 equiv.), THF, butyl ester substituent, to deliver alcohol 115. Cleavage of –78 °C, 10 min, then KHMDS (1.2 equiv.), –78 °C, 30 min, Cu- the N-Boc group, followed by exposure to paraformalde- (OTf)2 (1.5 equiv., slurry in THF), –78 °C, 3 h, 55%, dr = 1.2:1. (b) [ClRh(PPh3)3] (0.6 equiv.), H2 (600 psi), THF, 40 °C, 3 d, 67%. hyde in the presence of camphorsulfonic acid, initiated the (c) NBS (4.0 equiv.), THF, 0 °C, 45 min, 57%. (d) [18]Crown-6 planned aza-Cope/Mannich cascade, to provide 117 cleanly (3.5 equiv.), KHMDS (4.0 equiv.), THF, –78 °C, dilute with EtOAc, via intermediate 116. Exposure of 117 to neat TFA, fol- quench with phosphate buffer (pH = 7.8), 54% (mixture of dia- lowed by treatment of the resulting acid with methanolic stereomers). (e) TBD (1.2 equiv.), THF, room temp., 1 h. (f) Aq. NH OH, 1,2-dimethoxyethane/H O (4:1), 120 °C, 90 min, then HCl, enabled the generation of methyl ester 118, which was 4 2 TFA, CH2Cl2, room temp., 1 h, followed by Et3N, MeOH; 43% isolated as its TFA salt. Ultimately, this sequence was re- (two steps). (g) Li(NH2BH3) (excess), THF, 60 °C, 10 h, TFA/H2O duced to a single one-pot transformation of allylic alcohol (1:9), 60 °C, 4 h, 39% (mixture of epimers). (h) 3-(3-Nitrophenyl)- 115 into ester 118 in 62 % yield. Completion of the synthesis 2-(phenylsulfonyl)oxaziridine (1.4 equiv.), TFA/H2O (1:9), 55 °C, 5 entailed a stereoselective aldol reaction of the lithium enol- h, 26% (dr = 4:1). (i) SmI2 (excess), THF/H2O, –40 °C to room temp., 45%. ate of 118 with monomeric formaldehyde to install the furan ring, followed by acidic hydrolysis of the ester. Actin- The readily prepared tetracyclic compound 120 was ophylic acid was thus prepared in just five steps from the treated with KHMDS and diisopropyltitanocene dichloride readily accessed indole 113 (or eight steps if the aza-Cope/ to generate a putative extended titanocene dienolate, which Mannich sequence of 115 Ǟ 118 was carried out in stepwise underwent γ-selective oxidative coupling when treated with fashion). Subsequent work elaborated the enantioselective CuII triflate. The dimer 121 was thus produced in 55 % yield

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Oxidative Coupling of Enolates, Enol Silanes and Enamines

[7] I. Ojima, S. M. Brandstadter, R. J. Donavan, Chem. Lett. 1992, as a 1.2:1 mixture of C2-symmetric and meso diastereomers that were readily separable. Alkene reduction and halogen- 1591–1594. [8] J. H. Babler, R. A. Haack, Synth. Commun. 1983, 13, 905–911. ation of the acyl pyrrole groups set the stage for an intri- [9] a) Y. Ito, T. Konoike, T. Saegusa, J. Am. Chem. Soc. 1975, 97, guing base-promoted ring contraction to afford the spirocy- 649–651; b) E. Baciocchi, A. Casu, R. Ruzziconi, Tetrahedron clic species 122 as a mixture of isomers. This mixture could Lett. 1989, 30, 3707–3710; c) T. Fujii, T. Hirao, Y. Ohshiro, be transformed successfully into bisguanidinium salt 123 by Tetrahedron Lett. 1992, 33, 5823–5826; d) A. B. Paolobelli, D. a five-step sequence involving oxidation state adjustment Latini, R. Ruzziconi, Tetrahedron Lett. 1993, 34, 721–724; e) K. Ryter, T. Livinghouse, J. Am. Chem. Soc. 1998, 120, 2658– and intramolecular cyclization. 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Aoyama, J. Org. Chem. 1995, 60, 1100–1101; b) T. Langer, M. Illich, G. Helmchen, Synlett 1996, with high levels of stereocontrol. Highly diastereoselective 1137–1139. processes are now possible through the use of silicon te- [17] L. A. Paquette, C. R. Degenhardt, H. C. Berk, J. Am. Chem. thers, and in the cases of aldehydes as substrates high Soc. 1978, 100, 1600–1602. enantioselectivities can now be achieved through the use [18] For an earlier review of stereoselective enolate coupling, see: a) A. G. Csákÿ, J. Plumet, Chem. Soc. Rev. 2001, 30, 313–320. of organocatalysis. Mechanistic insights into the nature of For a recent review of oxidative dehydrogenative coupling that lithium enolate aggregation in solution have begun to an- includes sections on oxidative arylation and related transfor- swer questions as to why certain conditions allow for selec- mations, see: C. S. Yeung, V. M. Dong, Chem. 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Oxidative Coupling of Enolates, Enol Silanes and Enamines

Oxidative Enolate Coupling

Recent years have seen the development of F. Guo, M. D. Clift, several new methods for the oxidative R. J. Thomson* ...... 1–17 coupling of enolates and related deriva- tives. This microreview summarizes some Oxidative Coupling of Enolates, Enol Sil- key methodology addressing issues of anes, and Enamines: Methods and Natural cross-coupling and stereocontrol. The util- Product Synthesis ity of oxidative enolate coupling is high- lighted by descriptions of recent strategic Keywords: Oxidative coupling / Enols / applications of the reaction in natural Natural products / Synthesis design / C–C product total synthesis. coupling

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pubs.acs.org/CR

Cyclizations of Alkynes: Revisiting Baldwin’s Rules for Ring Closure Kerry Gilmore and Igor V. Alabugin* Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, 32306-4390

CONTENTS 3.2.4. Effect of Metal/External Electrophiles on 1. Introduction 6513 4-exo/5-endo Regioselectivity 6531 2. Baldwin Rules 6514 3.2.5. Summary of 4/5 6531 2.1. Terminology and Classification of Cyclization 3.3. 5-exo/6-endo Cyclizations 6532 Modes 6514 3.3.1. Radical Cyclizations 6532 2.1.1. Classification for an Isolated Reactive 3.3.2. Anionic Cyclizations 6539 Center 6514 3.3.3. Electrophilic Cyclizations 6545 ff 2.1.2. Classification for Cyclizations Including 3.3.4. The E ect of Metal/External Electrophiles Two Orbital Arrays 6514 on 5-exo/6-endo Regioselectivity 6548 2.2. Summary of the Rules: Favorable and 3.3.5. Summary of 5/6 6549 Unfavorable Reactions 6515 4. Conclusions: Revised Rules for Alkyne Cyclizations 6549 2.2.1. Radical Cyclizations: Beckwith’s Author Information 6550 Biographies 6550 Guidelines 6515 Acknowledgment 6551 2.3. Rationale for the Baldwin Rules: Originally References 6551 Proposed Angles of Attack and Favorable Note Added after ASAP Publication 6556 Trajectories 6516 2.3.1. General Considerations. Tet and Trig Processes 6516 1. INTRODUCTION 2.3.2. Attack Trajectories for Alkynes 6516 1 ff According to the CRC dictionary of natural products, 90% of 2.4. Di erences Between Nucleophilic, Radical, and chemically individual molecules discovered in nature contain either Electrophilic Trajectories 6517 a carbocyclic or a heterocyclic subunit.2 Not surprisingly, the ability 2.4.1. Nucleophile-Promoted Electrophilic to perform the key bond-forming step which transforms an acyclic Cyclizations 6518 precursor into the desired cyclic structure in a regio- and stereo- 2.4.2. Electrophile-Promoted Nucleophilic controlled manner remains critical to the construction of complex molecules. A concise set of guidelines for the rational design of Cyclizations: Effect of External Electrophile such cyclization steps, known as “the Baldwin rules”, historically on Trajectory 6518 has served as one of the most useful tools in the arsenal of synthetic 2.5. Secondary Electronic, Structural, and Geometric organic chemists. The seminal 1976 paper entitled “Rules for Ring Effects on Cyclization Trajectories 6519 Closure” by Sir Jack E. Baldwin is the most cited article in the 40+ 3 2.5.1. Orbital Polarization 6519 year history of RSC Chemical Communications (Figure 1). Not fi 2.5.2. Distortions 6519 only did this paper de ne the nomenclature necessary for de- scribing and classifying ring closure steps, but it also utilized 2.6. Thermodynamic Contribution to the Reaction empirical knowledge, with basic geometric and orbital overlap Barriers 6520 considerations, to predict favorable cyclization modes.4 2.7. Rules for Alkynes: Time to Reevaluate? 6521 Despite the broad utility of the Baldwin rules, the most recent 3. Specific Patterns of Digonal Cyclizations 6521 comprehensive review (1993) concentrated only on a subset of ff fi 3.1. 3-exo versus 4-endo 6522 examples: the stereoelectronic e ects in ve- and six-membered ring formation.5 The present review will illustrate the important 3.1.1. Radical Cyclizations 6522 role of the Baldwin rules in the development of organic chem- 3.1.2. Anionic Cyclizations 6522 istry, but, at the same time, it will point to the pressing need for 3.1.3. Electrophilic Cyclizations 6524 the critical reexamination and partial refinement of these rules in 3.1.4. Summary of 3/4 6524 relation to the cyclizations of alkynes. 3.2. 4-exo versus 5-endo Cyclizations 6525 Not only has a larger body of experimental data been ’ 3.2.1. Radical Cyclizations 6525 accumulated since the time of Baldwin s original publication, 3.2.2. Anionic Cyclizations 6529 Received: May 11, 2011 3.2.3. Electrophilic Cyclizations 6531 Published: August 23, 2011

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describes the position of the bond that has to be broken in the cyclization, relative to the forming ring (or the smallest of the rings when several rings are formed simultaneously). Exo indicates that the breaking bond is outside of (exocyclic to) the formed ring, while endo indicates that the breaking bond is inside of (endocyclic to) the new ring. The last prefix, -tet, -trig, and -dig, refers to the hybridization at the ring closure point (dot in Figure 2), -tet (tetrahedral) for sp3, -trig (trigonal) for sp2, and -dig (digonal) for an sp-hybridized atom. 2.1.2. Classification for Cyclizations Including Two Orbital Arrays. Subsequently, Baldwin expanded this terminol- Figure 1. Number of citations for the “Rules for Ring Closure” through ogy to include those cases where two orbital arrays need to be May 3, 2011. aligned in the cycle-closing bond formation, such as the cyclizations of enolates.6,7 If the enolate CdC bond is exocyclic to the ring being formed, the cyclization was referred to as an “enolexo” cyclization, while if the enolate is endocyclic to the ring being formed, the process was designated “enolendo”.Itis important to note that enolate closure can occur at either the carbon or oxygen, and the stesreoelectronic requirements are different for each due to the in-plane lone pair of the oxygen (Figure 3).6

Figure 2. Patterns of ring closure for 3- to 6-membered rings (endo-tet processes do not formally form cyclic products but are included here because, if concerted, they should proceed through the cyclic transition states as well). Reactions predicted to be favorable by Baldwin are boxed. a denotes no prediction was made. but the development of more accurate theoretical models and computational methods has led to a better understanding of underlying stereoelectronic principles for the formation and cleavage of chemical bonds, providing both an impetus and an opportunity for a critical reevaluation of structural and electronic effects involved in nucleophilic, radical, and electrophilic ring Figure 3. (top) Distinction between (C-enolexo) and (C-enolendo). closure processes. This review will present such reevaluation for ff alkyne cyclizations. Compared to the cyclizations that proceed at (bottom) Di erent stereoelectronic requirements for the C- and O-centered the expence of single or double bond (tet and trig cyclizations), cyclizations of enolates. cyclizations of alkynes (digonal cyclizations) remain relatively under- represented. This, at least partially, may be the result of it being easier As similar stereoelectronic considerations should be applicable to manipulate the reactivity of alkenes via substitution: alkynes to enamines and other allylic and heteroallylic systems, both simply can not bear the same number of substituents as alkenes. allylic and heteroallylic cyclizations will fall under this classifica- Conversely, cyclizations of alkynes often reflect the fundamental tion (e.g., C/O/N-allyl etc., where the C, O, or N designates the stereoelectronic factors more accurately without the camouflage of nucleophilic site). One can also extend this classification to electro- steric or electronic effects introduced by multiple substituents. philic cyclizations where a cationic center is stabilized by the overlap with an adjacent lone pair, for example, oxycarbenium and iminium 2. BALDWIN RULES ions (Y = O, N (π-vinylexo) and (π-vinylendo), Scheme 1). Crich and Fortt have also distinguished between π-exo and 2.1. Terminology and Classification of Cyclization Modes π-endo closures in their discussion of 5- and 6-membered ring 2.1.1. Classification for an Isolated Reactive Center. In formation in the digonal cyclizations of vinyl radicals.8 Note, his seminal publication,4 Baldwin developed a unified classification however, that here the π-system is not part of the reacting orbital of cyclization processes based on three factors. A cyclization is array but constrained to be perpendicular to the attacking radical characterized by three prefixes (e.g., 5-endo-dig, Figure 2), the first center. As such, we propose to differentiate these two π-exo/endo of which provides the number of atoms in the forming ring and systems by describing the orientation of the reactive center, where can adopt any value g3. The second prefix, endo- versus exo-, π-vinylexo/endo (D/E) refers to reactive centers incorporated

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a Scheme 1. Extended Classification of Possible Ring Closure Table 1. Baldwin’s Rules for Ring Closure a Patterns Separated into Structural Motifs

a Green indicates favorable cyclizations, and red indicates unfavorable cyclizations. a indicates that no prediction was made. Columns represent the size of the ring being formed. A revised version of these rules will be provided in final section.

systems as (X-allylendo2) and (X-allylendo3), where the number designates the number of atoms from the allylic π-system which are included in the ring. 2.2. Summary of the Rules: Favorable and Unfavorable Reactions The original “Baldwin rules” are reproduced in Table 1.9 All three factors involved in the classification (ring size, exo versus endo attack and hybridization at the site of attack) are critical in determining whether a particular cyclization mode is favorable. Due to a larger atomic radii and bond distances for heavier atoms, one stipulation is that atom X in Scheme 1 must be a first row a Top: Isolated reactive center (“X*” can either be a cation, anion, or element. For a similar reason, reactions which involve the radical). Center: The reactive center is orthogonal to the second cleavage and formation of the much shorter bonds to hydrogen π-system. Bottom: The reactive center is included in a larger π-system often do not follow the rules as well. For example, radical 1,5- which can be positioned either outside or inside the formed ring. hydrogen transfers, which formally proceed via the unfavorable 6-endo-tet transition state, are quite common.10 2.2.1. Radical Cyclizations: Beckwith’s Guidelines. A Scheme 2. Decreasing Stereoelectronic Flexibility with well-known set of guidelines for radical reactions was developed Increasing Number of Endocyclic sp2 Centers for the Three by Beckwith11 who combined steric and steroelectronic factors (X-Allyl) Systems and complemented general predictions of favorable cyclizations modes with stereochemical analysis. These guidelines do not explicitly separate trigonal and digonal cyclizations and are briefly summarized below. (i) Intramolecular addition under kinetic control in lower alkenyl and alkynyl12 radicals and related species occurs preferentially in the exo-mode. In systems, where the chain between the radical and unsaturated system contains five linking carbons or less, the kinetic favorability for exocyclic closure has been observed experimentally. (ii) Substituents on an olefinic bond disfavor homolytic addition at the substituted position. The preference for exo closure can be overwritten by an appropriate substituent at the internal position of the alkene. Note that this rule has only into the π-system (i.e., oxycarbenium and iminium ions) and limited relevance to alkynes where only a single substituent σ-vinylexo/endo (B/C) refers to reactive centers perpendicular can be present at each of the acetylenic carbons. to the π-system (i.e., vinyl anions/radicals). Cyclizations of aryl (iii) Homolytic cleavage is favored when the bond concerned lies nucleophiles/radicals fall under the category of σ-vinylendo (C) close to the plane of an adjacent semioccupied orbital or of closures whereas benzylic species fall under π-vinylendo (H) an adjacent filled nonbonding or π-orbital. This stereo- cyclizations. The utility of motifs D and E is limited to radical and electronic guideline is related to cyclizations because electrophilic closures. exo-radicals can readily acquire the required orbital Scheme 2 illustrates the differences in stereoelectronic flex- overlap, whereas endo-radicals often cannot due to the ibility for the three possible cyclizations of allylic/heteroallylic ring constraints. reagents. The greatest flexibility exists when only one atom of the (iv) 1,5-Ring closures of substituted hex-5-enyl and related allylic π-system lies inside the formed ring (X-allylexo, where X radicals are stereoselective: 1- or 3-substituted systems indicates the type of atom X at the closure point). The endocyclic afford mainly cis-disubstituted products, whereas 2- or π-system can exist in two different ways with either two or three 4-substituted systems give mainly trans-products. The atoms within the forming ring. We propose to differentiate these stereoselectivity observed in 2-, 3-, or 4-substitued

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5-hexenyl radicals reflects conformational preferences Scheme 3. Original Favored Trajectories for Cyclic Closure of the chairlike transition states,11 where the substitu- in Tetrahedral, Trigonal, and Digonal Systems Suggested by a ents preferentially occupy pseudoequatorial positions.13 Baldwin. In both Baldwin’s and Beckwith’s rules, reactions predicted to be unfavorable are not completely forbidden. Rather, such processes are expected to be relatively slow and incapable of competing with faster reactions (if the latter are available). In principle, a product, defined as unfavorable by the Baldwin rules, may be formed in good yield either when the reaction proceeds under thermodynamic control or when other kinetically favor- able pathways are blocked.14,15 A significant point of divergence between the Baldwin and Beckwith rules includes cyclizations of alkynes. Endo-dig cyclizations are favored by the Baldwin rules, whereas the Beckwith rules predict exo-dig cyclizations to be preferred. a Bottom: Comparison of two “least motion” trajectories showing the 2.3. Rationale for the Baldwin Rules: Originally Proposed “conserved subtended angle R” between the three interacting atoms. Angles of Attack and Favorable Trajectories Note that R is different from the attack angle β for the acute trajectory in 2.3.1. General Considerations. Tet and Trig Processes. alkynes. Baldwin postulated that ring closures were favored to occur “when the length and nature of linking chain enables the terminal atoms to achieve the required trajectories” for bond formation. In contrast, disfavored reactions require severe distortion of bond angles and distances to reach the optimal trajectories and, thus, will not be able to compete with faster alternative pathways, if available. Baldwin suggested three favorable trajectories for closures, one for each of the three common hybridization states of carbon (sp, sp2, and sp3, dark circle in Scheme 1). In what could be taken as an essentially least motion argument, he stated: “In each case (tetragonal, trigonal, digonal) the subtended angle R between the three interacting atoms is maintained during the reaction pathway, becoming the angle between these atoms in the product.” However, the proposed trajectories also had a stereoelectronic component because the suggested angles maximized Figure 4. Three examples used to define the original Baldwin rules for the bond-forming, stabilizing two-electron orbital interactions. alkynes. (a) With a divergent angle of 60°, only the reduced product is Indeed, a footnote stated “This angular relationship is to be expected obtained. (b) A “neutral” parallel array with the angle of 0° results in in interactions of p-type orbitals to maximize orbital overlap.” 5-endo-dig closure of the carbanion. (c) A convergent angle of 60° The rules for the cyclizations of enolates included an addi- exclusively yields the 5-exo-dig product. The expected acute attack angle tional constraint requiring the alignment of the enolate π-orbitals is shown with a red arrow. with those of the breaking bond. Particularly, for the intramole- cular alkylation of enolates, “the requirements of backside “refined”). This choice was based upon “the X-ray work of displacement of the leaving group and approach of the electro- Wegner18 and Baughman”,19 as well as a “general predominance philic halide carbon on a trajectory perpendicular to the enolate for endoring closures in digonal systems”.4 6,7 place at the R-carbon atom” was suggested to be important. The latter statement was primarily derived from the work of The optimal trajectory for tetrahedral cyclizations was defined Kandil and Dessey20 who compared the reactivities of three based upon the classic backside attack of SN2 reaction, yielding carbanions generated in close proximity to acetylenic groups at an attack angle of 180°. Trigonal cyclizations were defined based different geometrical arrays - a divergent angle of 60°, parallel upon the now well-established B€urgi-Dunitz16 angle of attack (angle of 0°) and a converging angle of 60°. No cyclic products on sp2 carbon atoms of ∼105109°. These trajectories optimize were obtained when the angle was divergent (2.009). For parallel σ the overlap of incoming nucleophiles with the *CY (tet) and orbital arrangement 2.011, however, the anionic species cyclized π *CdY (trig) orbitals respectively (Scheme 3). There is no thermo- in a 5-endo-dig fashion (2.012). When the geometry of the two dynamic incentive for these trajectories to be closely followed at long functional groups was fixed at a convergent angle of 60° (2.014), incipient distances where these orbital interaction effects are weak.17 the aryl anion cyclized exclusively in a 5-exo-dig fashion However, the closer the attacking reactive species is to the target, the (Figure 4). more potentially stabilizing and favorable the above-mentioned At that time, the absence of the 4-exo product in the “parallel delocalizing bond-forming interactions become. arrangement” case constituted the only available experimental 2.3.2. Attack Trajectories for Alkynes. Out of the two evidence which could be interpreted in favor of an acute attack trajectories that would maintain the subtended angle between the upon the alkyne moiety. However, this example significantly three interacting atoms in digonal systems, Baldwin chose the distorts the intrinsic selectivity due to the additional strain one that corresponds to an acute angle of attack β (60°, Scheme 3 imposed by the polyclic core on the 4-exo product, whereas “original”) rather than an obtuse angle (120°, Scheme 3 the observed lack of 6-endo cyclization products in the less

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Table 2. Reaction Energies, Attack Angles, and LUMO Plots Visualizing the Arrangement of Alkyne π*-Orbital and Nucleophile Lone Pair for the Parent Anionic Additions to Acetylene at the B3LYP/6-31+G(d,p) and M05-2X/6-31 a +G(d,p) Levels of Theory

Figure 5. Stereoelectronic differences between alkenes and alkynes arising from the presence of the in-plane π-system in alkynes.

the π*-orbital. Instead, the incoming reactive center (radical, cation, anion, radical-cation, radical-anion) can attack the in-plane π-bond, thus, avoiding the additional distortion penalty inherent to, for example, the 5-endo-trig process (Figure 5). Alabugin, Gilmore, and Manoharan have recently examined the stereoelectronics of ring closures onto terminal and sub- stituted alkynes for carbon and heteroatom anions and radicals.24 It was observed that as the linker length increases, the obtuse ° ° a angle of the exo attack decreases from 140 (3-exo) to 116 (5-exo) M05-2X data are given in parentheses. for carbanions, approaching the angle of intermolecular attack (Table 2). strained “convergent” pattern is inconsistent with the suggested For the endo attack in small cycles, the cyclic constraints im- ° ° preference for the acute trajectory (Figure 4). pose an acute angle of nucleophilic attack (76 for 4-endo and 82 The proposed digonal trajectory also does not satisfy the for 5-endo closures). As the cycle size increases, the angle of attack stereoelectronic requirements for nucleophilic attack at a π-bond. changes to a more favorable obtuse approach in 6-endo-dig closure ° Basic MO considerations suggest that a better trajectory for (99 ). As expected, 4-endo and 5-endo cyclizations have much attack at the alkyne π*-orbital is provided by the obtuse approach, earlier transition states than the less exothermic competing analogous to the B€urgiDunitz trajectory for trig cyclizations exoclosures. (Figure 6). Indeed, a substantial body of experimental and com- At the same time, the incipient C 333C distance increases in putational evidence supports this notion, indicating that the the exo-series, indicating earlier transition states for the more Baldwin rules for alkynes need to be redefined (vide infra). exothermic cyclizations (3-exo < 4-exo < 5-exo). As will be discussed individually below, comparison of the intrinsic In an early computational challenge to the acute attack 25 trajectory, Strozier, Carmella, and Houk calculated transition states energies shows that, in every case, independent of the nature for the attack of a hydride anion at acetylene and ethylene.21 Not of nucleophile and alkyne substitution, exo cyclizations have lower intrinsic barriers than their endo competitors. Interest- only were the transition state energies found to be very similar for acetylene and ethylene (16.7 and 16.6 kcal/mol) but the angle of ingly, the intrinsic exo barriers change relatively little (12 16 kcal/mol), indicating that such variations in the attack trajectory attack was also found to be quite similar for the two substrates, with 24 a CC-Nuc angle of 127° and 124°, respectively,22 very different are well tolerated. from the 60° acute attack suggested by Baldwin.4 2.4. Differences Between Nucleophilic, Radical, and Electro- Recent higher level calculations23 have not changed this alter- philic Trajectories native stereoelectronic preference, providing further support to Another potentially controversial aspect of the Baldwin rules is the notion that the obtuse geometry provides the best trajectory whether their utility extends beyond nucleophilic closures. for nucleophilic attack at the triple bond and that TS geometries Although Baldwin mentioned in his seminal paper that this for nucleophilic addition to alkynes and alkenes are generally treatment “also applies to homolytic and cationic processes”,4 similar. this statement is valid only in the most general sense as a The representative intermolecular attack angles by three suggestion that basic stereoelectronic premises based on favor- nucleophiles (CH3 ,NH2 ,OH) on the triple bond of able trajectories would exist for other reactive intermediates. 24 ethyne are shown in Table 2. Athough the angle changes from However, one cannot simply “transfer” the guidelines, because o ∼115 to 130° with the transition from an early TS to a late TS, all the very nature of bond-forming interactions that define the data agree with the intrinsic stereoelectronic preference for obtuse favorable trajectories depends strongly on the attacking species. attack. For example, the ubiquitous cationic 1,2-shifts involved in the The obtuse nucleophilic attack trajectory is also supported by textbook WagnerMeerwein rearrangements are topogically ana- basic stereoelectronic considerations, as this approach avoids the logous to the anionic 3-endo-tet process. Although the anionic interaction of incoming nucleophiles with the nodal plane of processes are clearly unfavorable as illustrated by the nonconcerted π*-orbital. If this analysis is applied to the intramolecular nucleophilic nature of the [1,2]-Wittig and related anionic rearrangements,26 attack at the alkyne moiety (aka nucleophilic dig-cyclization), the the ubiquity of cationic processes shows that frontside approach is obtuse trajectory should be translated into stereoelectronic preference allowed for electrophilic attack at a σ-bond. for the exo attack, in close analogy to that of trig-cyclizations. Why do the stereoelectronic requirements differ for nucleo- It is also important to note that alkynes have two orthogonal philic and electrophilic attacks? As discussed above, the most π-bonds, thus alleviating the need for the nucleophile to deviate important stabilizing two-electron interaction for a nucleophilic out of plane in order to reach the ideal B€urgiDunitz attack at attack is the interaction of nucleophile’s HOMO with the

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Figure 7. Distinction between electrophilic cyclizations, nucleophile- promoted electrophilic closures (NPEC) and electrophile-promoted (EPNC) nucleophilic closures.

Figure 6. Comparison of orbital interactions and the expected regios- electivities for nucleophilic (left) and electrophilic (right) cyclizations of alkynes. Dominant stabilizing interactions are shown with straight arrows, secondary (stabilizing or destabilizing) interactions are shown with dashed lines. substrate’s LUMO. Such interaction is maximized by an obtuse angle of attack at a π*-system (alkene or alkyne) or by a backside attack at a σ*CY. Both of the above approaches also minimize the destabilizing HOMO/HOMO interactions (Figure 6). In contrast, attack of an electrophile at a π-bond (alkene or alkyne) Figure 8. Summary of key stereoelectronic factors involved in bond is controlled by a favorable 2e-interaction between the electro- forming interactions during different modes of ring formation from + phile LUMO and the π-bond HOMO. The latter interaction alkynes. (a, b) The FMOs of C2H2. (c) The LUMO of the I -acetylene favors an acute trajectory, which brings electrophiles at the center complex. Note the analogous symmetry of the top part of the LUMO of of the π-bond on route to the formation of 3-center, 2-electron the complex and the acetylene HOMO. (d) MO mixing diagram which nonclassical cations, common species in carbocation chemistry. shows how the alkyne LUMO symmetry changes upon coordination. This trajectory should enable both endo- and exo-ring closures. In the case of a radical attack at a π-bond, a nearly perpendicular particularly well represented by the 3-exo-/4-endo-dig competition, trajectory is observed, as a compromise between the interactions of where both products are formed from a common nonclassical theSOMOwithboththeπ and π* alkene/alkyne orbitals.27 Note cation intermediate via two alternative directions of nucleo- ff philic attack (see section 3.1.3). The regioselectivity of the that the intrinsic di erences in the underlying stereoelectronic ’ stabilizations should make endo cyclizations more favorable for nucleophile s attack is dictated by the partial positive charge cationic species and, to some extent, to electrophilic radicals. As will on the alkynyl carbons, which is determined by the adjacent be discussed in the individual sections below, the differences substituents. between the activation barriers of exo- and endocyclic closure Interception of an incipient vinyl cation by an external nucleo- are smaller for radicals than for the respective anions, to the philic attack has been described by Overman and Sharp as a “ ” 32,33 point where the more electrophilic oxygen radicals favor 6-endo Nucleophile-Promoted Electrophilic Cyclization (NPEC). closure over 5-exo-dig.24 This mechanism provides the only thermodynamically feasible path for 2.4.1. Nucleophile-Promoted Electrophilic Cyclizations. endo-dig cationic cyclizations leading to the formation of small cycles. Unlike nucleophilic and radical closure, electrophilic28 digonal 2.4.2. Electrophile-Promoted Nucleophilic Cyclizations: cyclizations are relatively scarce. One reason for this scarcity is Effect of External Electrophile on Trajectory. The umpo- that endocyclic closures should lead to the formation of cyclic lung of NPEC, where an external electrophile coordinates to a vinyl cations. These species are sp-hybridized and significantly π-system, activating it for intramolecular nucleophilic attack, has destabilized by the deviation from linearity imposed by inclusion been described as electrophile-promoted nucleophilic closure 24 in a small ring.29 For example, cyclohex-1-enyl and cyclopent-1- (EPNC). enyl cations, with 156° and 141° valence angles at the cationic Although these relatively common cyclizations are sometimes carbon, are 17 and 27 kcal/mol less stable than the linear (179°) misleadingly referred to as “electrophilic” cyclizations, these two prop-1-enyl cation.30 Cyclobut-1-enyl cation exists as a non- processes are mechanistically different, as illustrated in Figures 7 classical bridged ion31 and ab initio calculations fail to find a and 8. Whereas a truly electrophilic closure involves an intra- stationary-state structure for the smallest cycloprop-1-enyl cation molecular attack of an electrophile (e.g., carbenium, oxonium, which opens instead to form prop-2-ynyl cation.29b iminium ions) at a π-bond in a cycle-closing bond formation, Despite this scarcity, the relatively scattered data presented electrophile-induced nucleophilic closures involve intramolecular for the individual cyclizations patterns discussed in the follow- nucleophilic attack at the triple bond. The role of an external ing sections will illustrate that, in the absence of strongly direct- electrophile (a metal, halogen, selenium, etc) is to coordinate to ing group, electrophilic cyclizations of alkynes exhibit a notable the π-bond that is subsequently attacked intramolecularly by an preference for endocyclic closure, suggesting that the cycliza- internal nucleophile. Because it is the nucleophilic attack at a π-bond tions of cations have different stereoelectronic preferences in that closes the cycle, referring to such closures as electrophilic comparison to analogous nucleophilic and radical ring closures is misleading, even when these reactions do not proceed in the (see section 2.4). The delicately poised balance in such closures is absence of the electrophilic agent.

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Scheme 4. Effect of π*-Orbital Polarization on the Scheme 5. (Left) Differences in the Intrinsic Orientation of Magnitude of Stabilizing Orbital Interaction in a the Attacking Orbital at the Reactive Intermediate Center 5-exo-trig Nucleophilic Attack at a π-Bond Caused by Progressive Increase in Pyramidalization in Radicals and Anions and (Right) the Total Energies for Deformation of Methyl Reactive Intermediates a (β = Deviation from the Molecular Plane)

Another reason why EPN cyclizations should be considered separately is that reactions which involve the coordination of an external species do not fall under the umbrella of the original Baldwin rules because such coordination modifies the nature of alkyne frontier molecular orbitals (FMOs. Figure 6, Figure 8). For example, even though in both the nucleophilic and EPN closures, the nucleophilic attack on an alkyne follows a trajectory which maximizes the overlap between the LUMO of the acet- ylene and HOMO of the nucleophile, the acetylene LUMO symmetry is very different for the two cases. As the LUMO of free alkynes is a π*-orbital, purely nucleo- philic closures should exhibit exo preference because endo Reproduced with permission from ref 38. Copyright 1976 American π a approach brings nucleophile at the *-orbital node. Chemical Society. LCAO-SCF-MO/4-31G level. However, when a suitable Lewis acid (LA) complexes with a triple bond, the antibonding combination of alkyne HOMO and empty orbital of the LA creates the new LUMO. Although this destabilizing effects associated with the deformation of acyclic orbital is antibonding between the LA and alkyne, it has the same reagents from their ideal geometries needed in order to reach symmetry as the original alkyne HOMO (a π-orbital) from the the TS.36 The energy cost for pyramidalization of alkenes37 point of an incoming nucleophile. Thus, orbital symmetry offers no and bending in alkynes, as well as strain in the bridge should be additional penalty for an acute attack along the trajectory, analogous considered. to that of an electrophilic species. Because there is no stereoelectronic Distortion at the Reactive Intermediate Center (Anion penalty for the formation of endo products, in contrast to the usual versus Radical versus Cation; Carbon versus Heteroatom). nucleophlic attack at the π*ofa”naked” alkyne (Figure 8), the Although the original Baldwin rules concentrated on the orienta- regioselectivity of nucleophilic closures is often reversed upon tion and nature of the breaking bond (both exo/endo and tet/ 34 addition of an external electrophile such as I2. The change in the trig/dig notations refer to this bond), the requirement of orbital symmetry of the acetylenic LUMO as a result of such coordination alignment applies to both partners. In particular, the stereolec- enables endocyclic closures in the same way as endo cyclizations of tronic properties of the attacking orbital and its orientation in electrophilic species are enabled because of favorable overlap of space can impose significant effect on the efficiency and regios- cationic center with the HOMO of acetylene. electivity of cyclizations. Subsequent work on enolexo and Since a recent review by Godoi, Schumacher, and Zeni enolendo cyclizations illustrates this point very well.6,7 Scheme 5 34 provided comprehensive coverage of EPN cyclizations, de- illustrates how structural deviations along the reaction coordi- tailed coverage of this topic is out of the scope of this review. For nate also include energy cost for changing the geometry at the each section, we will only provide a selection of examples to reactive center (e.g., pyramidalizing a cation, or planarizing an illustrate the reversal of regioselectivity that is observed in a anion). These data suggest that the anion is the most flexible variety of cases when a metal or external electrophile is coordi- reactive intermediate, whereas pyramidalization of cations leads nated to the alkyne. to a significant energy penalty.38 The effect of the nature of the attacking atoms on the preferred 2.5. Secondary Electronic, Structural, and Geometric Effects attack trajectories is not well understood but deserves a more careful on Cyclization Trajectories study in the future. For example, one would expect that the presence 2.5.1. Orbital Polarization. Orbital factors in the TS can also of the two lone pairs at a neutral oxygen atom may increase be modulated by polarization of the π-bond by an appropriately stereoelectronic flexibility relative to an analogous nitrogen nucleo- positioned donor or acceptor substituent. For the substitution phile with a single lone pair where stereoelectronic adjustments are pattern illustrated in Scheme 4, the exo cyclization mode would mostly limited to rehybridization.39 be facilitated by a terminal acceptor and disfavored by a terminal Interestingly, after suggesting the initial preferred angle of attack donor group. of 105 ( 5 degrees at a carbonyl moiety by nitrogen nucleophiles, 2.5.2. Distortions. Setting aside the more complex non- B€urgi et al. performed the same analysis for an oxygen nucleophile statistical dynamics analysis of reaction trajectories of attacking a carbonyl (O 333CdO) and found that the approach Carpenter,35 additional factors have to be considered in angle varied in the broad region of 90130° with the strongest analyzing the overall energy landscape on the way from an interactions occurring at an approach of about 110°.16 acyclic reactant to a cyclic product. Equally important to the Distortion of the Target π-System. In a thorough comparison stabilizing two-electron bond-forming interactions are the of pyramidalization of nonbridgehead alkenes and the bending of

6519 dx.doi.org/10.1021/cr200164y |Chem. Rev. 2011, 111, 6513–6556 Chemical Reviews REVIEW alkynes, Borden noted that while the “trans-bending of acetylene is reactions, proposed that a 10° misalignment of reactant groups considerable easier than anti-pyrimidalization of ethylene...cis- relative to an ideal orientation would result in a large decrease bending of acetylene has a force constant about 25% greater than in rate,52 something that has been disputed in a subsequent that for the syn-pyrimidalization of ethylene.”37,40 He also identified literature.53,54 orbital interactions responsible for making anti-pyrimidalization Probing such effects in model systems, Menger and co- less energetically costly than the syn-pyramidalization in ethylene. workers investigated lactonization reactions in a rigid norbornyl Pyramidalization of alkenes also leads to significant orbital changes: system. By exchanging positions of the hydroxyl and carboxylic the LUMO energy is strongly lowered whereas the HOMO energy is acid moieties, the trajectory angles were changed by 10°,yet increased, albeit to a lesser extent.41,42 nearly identical rates of lactonization were obtained, demon- In a thorough computational analysis of “strain-promoted” strating that angular displacement of a few degrees is not click reactions with phenyl azide, Houk et al.43 have shown that kinetically significant.51 Lipscomb et al. also found that poten- the distortion of the alkyne moiety in cyclooctyne can provide up tial energy surfaces for carbonyl additions “point strongly to a to 60% of the barrier decrease (4.6 out of 8 kcal/mol).44,45 highly deformable TS.” For example, the addition of methanol Alabugin and Manoharan estimated the energy cost for alkyne to formic acid occurs via a reaction “funnel” that occupies bending along the Bergman cyclization pathway, comparing hex- approximately 18% of the hemispherical surface centered 3-ene-1,5-diyne with cyclic enediynes.46 While a significant at the carbonyl carbon.55 Our recent calculations also found reactant destabilization (∼13 kcal/mol) is observed upon con- littlechange(12.416.2 kcal/mol) in the intrinsic barriers of stricting the parent enediyne with the 9-membered cycle, the carbon radical 3-exo-, 4-exo-, and 5-exo-dig closure onto methyl acetylene bond breaking was found to be of only minor im- substituted alkynes, even though the angle of attack in the portance as indicated by the negligible changes in the C1C2 TS ranges from 140° (3-exo) to 116° (5-exo),24 further NBO π-bond orders (both in-plane and out-of plane) at C1C6 suggesting that deviation from the ideal intermolecular tra- distances above 3 Å. For Z-hex-3-ene-1,5-diyne, this negligible jectory is tolerated. change in bond order is notable as the C1C6 distance in the starting geometry is 4.1 Å. The CCC bond angle at this distance 2.6. Thermodynamic Contribution to the Reaction Barriers (3 Å) is 152°, showing the high flexibility of this functional group. It is important to bear in mind that kinetic preferences Even at the TS, the π-bonds are only 30% broken.47 described by the Baldwin rules are not applicable to transforma- The effect of acetylene bending on FMO orbital energies and tions that proceed under thermodynamic control. For such shapes has been analyzed extensively. A significant difference situations, relative reaction exothermicities can play a role in between alkynes and alkenes is that upon trans-bending the determining the cyclization outcome. The entropically disfa- LUMO of acetylene drops in energy two to three times faster vored dig and trig cyclizations are usually driven enthalpically by than that of ethylene. While the LUMO drops in a bent transition the formation of stronger bonds (e.g., trading a π-bond for a state, there is an increase in the charge-transfer and electrostatic σ-bond). The nature of bonds involved in the ring formation interactions, which is the cause of the increased reactivity of should be considered carefully, in particular for the formation of acetylenes over ethylenes toward nucleophilic attack. However, heterocycles.56 If a thermodynamic driving force for the process the authors state, “Bending has very little effect on HOMO is small or if the cyclizations is endothermic, kinetic preferences energies, so that no “driving force” for bending is present upon embodied in the Baldwin rules will not be applicable. interactions with electrophiles.”21 Houk et al. used these argu- However, thermodynamic contributions are important even ments to correlate the enhanced electrophilicity of benzyne with when reactions proceed under kinetic control because thermo- the LUMO energy lowering in this highly bent alkyne.21,48 dynamic factors can relax stereoelectronic requirements (optimal However, recent HF calculations with a larger 6-311++G(2d,p) trajectories) for exothermic cyclizations and modify kinetic pre- basis set suggest that the cis-LUMO drop may be smaller than ferences embodied in the Baldwin rules in two indirect ways. suggested earlier.49 First, in accord with the Hammond-Leffler postulate,57 exother- The correlation of angle strain and electronic structure of cyclic mic reactions have earlier, reactant-like transition states and conse- alkynes is consistent with electron transmission spectroscopy data quently require less distortion from the reactant geometry. by Ng et al.50 Comparison of vertical electron affinities (EAs), Decreased distortions alleviate geometric requirements needed which according to the Koopmans’ theorem correlate with the to reach the optimal bond-forming trajectories. unfilled orbitals energies, show a strong dependence of the Second, favorable thermodynamic contribution directly LUMO energy on the degree of bending. For example, the EA lowers activation barriers of exothermic cyclizations relative of cyclooctyne, where the triple bond is bent by 21.5° increases to the intrinsic barrier of an analogous thermoneutral reaction by ∼1 eV in comparison with that in di-tert-butylacetylene. In (as illustrated by stereoelectronically unfavorable but highly accord with the calculations discussed above, the π and π* exothermic reactions with low activation barriers, such as orbital energies, taken as the negatives of the vertical ionization 5-endo-trig cyclizations in the formation of acetonides from potential (IP) from Photoelectron Spectroscopy (PES) and the 1,2-diols).58 As a result, it is inappropriate to compare intrinsic vertical EA, respectively, suggest that bending has very little stereoelectronic favorabilities of two reactions with different effect on the HOMO.50 exothermicities. Such comparisons have to be done for reac- Deviation from Ideal Trajectories. The favorability of cycli- tions with equal thermodynamic driving force (Figure 9). zation modes depend strongly on how far reactions can deviate The effect of thermodynamics on the activation barrier can be from the previously discussed trajectories without an insurmoun- estimated via subtraction of thermodynamic contributions esti- table increase in activation energy, and whether one should mated using Marcus theory.59 61 In this approach, the energy of q consider an ensemble of trajectories instead of a single preferred activation (ΔE ) of a reaction is the sum of the intrinsic barrier path.51 Historically, there were conflicting views on this problem. and the thermodynamic contribution. The intrinsic barrier “ ” Δ q For example, the orbital steering theory, related to enzymatic ( Eo) represents the barrier of a thermoneutral process

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Figure 9. Thermodynamic effects on the activation energy and use of Marcus theory for approximating potential energy curves and separating intrinsic barriers from thermodynamic contributions. In the absence of a thermodynamic bias, the intinsically unfavorable cyclization #2 has a higher barrier. The parabolic model illustrates how the activation barrier for the unfavorable cyclization becomes identical (blue curve) to Figure 10. Effect of aromatic stabilization of the 6-endo product on the the overall barrier for the favorable reaction #1. When the thermo- kinetic competition between 5-exo-/6-endo-dig closures of fully con- dynamic driving force for reaction #2 increases further (red curve), this jugated substrates. cyclization becomes more kinetically favorable than the initially favored process #1. stabilization of the product can mask the intrinsic kinetic preferences Δ ( Erxn = 0). The thermodynamic contribution can be either based on transition state stereoelectronics. positive or negative depending upon whether the reaction is endothermic or exothermic. The activation energy increases 2.7. Rules for Alkynes: Time to Reevaluate? Δ when Erxn > 0 (an endothermic reaction) and decreases when In summary, the guidelines regarding the cyclizations of Δ Erxn < 0 (an exothermic reaction). When potential energy alkynes need to be reassessed and expanded. In particular, surfaces for the reactants and the products are approximated as the proposed dramatic difference in favorable trajectories for parabolas, the Marcus barriers can be calculated from eq 1. alkynes and alkenes and the subsequent predictions that endo-dig cyclizations are “favorable”, even though the analogous endo-trig q q 1 2 q cyclizations of alkenes are unfavorable, has to be reevaluated. ΔE ¼ ΔE þ ΔErxn þðΔErxnÞ =16ðΔE Þð1Þ o 2 o The following sections will provide a detailed analysis of the q available experimental and theoretical data regarding specific Alternatively, when the energy of activation (ΔE ) and Δ patterns of digonal cyclizations. We will organize this analysis by reaction energy ( Erxn) are known, one can estimate the intrinsic Δ q comparing pairs of reactions that correspond to competing barrier ( Eo) from the eq 2. Equation 2 allows a comparison of ff regioselectivities of attack at the same breaking bond (3-exo/4-endo, intrinsic stereoelectronic properties for cyclizations of di erent 4-exo/5-endo, 5-exo/6-endo). Since each of these pairs originates exothermicities. from a common starting material, this choice eliminates many pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 1 variables of comparison. The caveat, however, is that the observed ΔEq ΔE þ ΔEq2 ΔEqΔE q R R lack of one of the two possible cyclizations only means that the ΔE ¼ 2 ð2Þ missing reaction is “relatively” unfavorable in comparison to the o 2 observed alternative closure. Different types of reactive intermediates This analysis affords the understanding as to how even (cations, radicals, anions) for each of the pair will also be examined ff intrinsically unfavorable reactions become competitive once individually as these intermediates have di erent stereoelectronic made sufficiently exothermic (Figure 9). This is an important preferences. Following this detailed examination of the literature, the 24 caveat in using the stereoelectronic arguments incorporated in the refined rules for digonal cyclizations will be discussed. Baldwin rules for a priori predictions of regioselectivity in a ring ff closure. To illustrate the potentially misguiding e ect of thermo- 3. SPECIFIC PATTERNS OF DIGONAL CYCLIZATIONS dynamics, let us consider the 5-exo/6-endo competition shown in Figure 10. The two reactions have almost identical activation This section of the review will constitute a comprehensive barriers (difference of 0.2 kcal/mol). Does it mean that the two review of the literature from 1993-middle of 2010. Pre-1993 cyclizations are equally favorable stereoelectronically? How does work will be incorporated for the scarcely studied topics where the much greater exothermicity of the aromatic 6-endo-dig only a few examples are available. Closures involving external ΔΔ ≈ ff product formation ( Erxn 36 kcal/mol) a ect the activation electrophiles such as metals or halonium ions, for reasons described barrier? Can this effect be large enough to mask the intrinsic above (see section 2.4.2), are described only brieflybecauseoftheir trends arising from the orbital alignment requirements? These in depth discussion in an excellent recent review.34 The comprehen- questions can be readily answered by the energy dissection sive coverage will be limited to cyclic systems that include only described above, which can be used to estimate barriers for the the first row elements. Heavier elements will be included only in situation where 5-exo- and 6-endo-dig cyclizations would have selected cases. identical exothermicities. For this hypothetical scenario, the While the activation and intrinsic barriers, as well as the 6-endo cyclizations barrier would be much higher (∼15 kcal/ exothermicities, for carbon-, oxygen-, and nitrogen-centered mol) than that for the 5-exo closure (∼5 kcal/mol) and the radical cyclizations are similar (vide infra), there is a gap in the 6-endo-dig cyclization would not be kinetically competitive literature regarding the closures of the heteroatomic radicals onto (Figure 10). This example illustrates how selective thermodynamic carboncarbon triple bonds.62,63 The cyclizations of these species

6521 dx.doi.org/10.1021/cr200164y |Chem. Rev. 2011, 111, 6513–6556 Chemical Reviews REVIEW in trigonal systems, however, has been well documented,15 parti- Table 3. Activation, Reaction, and Intrinsic Energies cularly for oxygen radicals.64 (kcal/mol) for the Parent 3-exo- and 4-endo-dig Radical We have organized each section in several “motifs” (Scheme 1), Digonal Cyclizations at the B3LYP/6-31+G(d,p) and a each of which represents a certain combination of attacking species, M05-2X/6-31+G(d,p) Levels of Theory substitution at the target alkyne and nature of the tether that lead to a characteristic selectivity pattern.

3.1. 3-exo versus 4-endo

Figure 11

Even though the formation of a σ-bond at the expense of a π-bond is usually favorable, there are very few examples of the synthesis of highly strained three- and four-membered rings through attack at an alkyne. While 4-endo-dig cyclizations are favored by the original Baldwin rules, to the best of our knowl- a edge, there are no examples of simple nucleophilic closures which The M05-2X data are given in parentheses. Ring-closing bonds are follow this path and fit into the criteria of this work. However, shown in red. there are a few examples of the originally “disfavored” 3-exo-dig closure proceeding through both anionic and cationic paths. Table 4. Activation, Reaction, and Intrinsic Energies Interestingly, 4-endo-dig closures are reported only for NPE cycli- (kcal/mol) for the Parent 3-exo- and 4-endo-dig Radical Digonal Cyclizations at the B3LYP/6-31+G(d,p) and zations, lending strong support to the notion that the stereo- a electronic guidelines are different for nucleophiles and electro- M05-2X/6-31+G(d,p) Levels of Theory philes (vide supra). 3.1.1. Radical Cyclizations These processes have only been studied computationally. Computational data suggest that the greatest obstacle for the formation of small cycles via these processes is not kinetic but thermodynamic. The radical 3-exo- and 4-endo-dig cyclizations of carbon radicals are endothermic and, thus, are unlikely to be practically viable in their simplest versions as presented in Table 3. These data are consistent with the absence of 3-exo- and 4-endo-dig radical cyclizations in the literature. In agreement with the microscopic reversibility prin- ciple, the same stereoelectronic factors which facilitate 3-exo cyclizations render the opening of the strained cyclopropyl rings favorable as well. Indeed, the cyclic products of such exo cyclizations are expected to undergo a fast ring-opening, similar to the ring- opening of cyclopropylmethyl radicals.65 However, the significant decrease in endothermicity for the cyclization of the Ph-substituted a alkyne suggests that, with a proper effort, it may be possible to shift The M05-2X data are given in parentheses. Ring-closing bonds are the equilibrium in favor of the cyclic form and to design efficient shown in red. 3-exo-dig radical cyclizations, as has been accomplished for the respective trigonal closures (Table 4).15 Table 5. Literature Examples of 3-exo/4-endo-dig Anionic 3.1.2. Anionic Cyclizations (Table 5). These processes Closure with Respect to the Environment of the Anionic have been unknown experimentally until Johnson and co-workers a Center found that, upon exposure to a source of fluoride ions, silyl enol ethers undergo 3-(C-allylexo)-exo-dig cyclizations (motif F, Scheme 1).66 The cyclic closure is rendered irreversible via elimina- tion of a propargylic halide, yielding substituted vinylidene cyclo- propanes (VCP) in up to 95%. A similar strategy can be used for transforming acyclic diesters into 3-exo-dig products in 6290% yields(Scheme 6). This work illustrates that even the thermo- a An x denotes a gap in the literature. Motif structures are given in dynamically unfavorable formation of a small cycle can be Scheme 1. Motifs AC and GH are unknown, and D and E do not kinetically accessible when coupled with a subsequent highly apply to anionic closures. exothermic step. To the best of our knowledge, there are no examples of addition of metals or external electrophiles. Recent computational nucleophilic 4-endo-digonal closures that do not include the analysis24 suggests that this gap reflects the inaccuracy of the original

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Scheme 6. 3-exo-dig Cyclizations of Enolates and Pro- Table 7. Transition State Geometries, NICS (0) Values, pargylic Alcohols and LUMO Plots for 3-exo/4-endo Carbanionic Cyclizations for the Me-Substituted Alkyne Calculated at the a M05-2X/6-31+G** Level

Table 6. Activation, Reaction, and Intrinsic Energies (kcal/mol) for the Parent 3-exo- and 4-endo-dig Anionic Digonal Cyclizations at the B3LYP/6-31+G(d,p) and b M05-2X/6-31+G(d,p) Levels of Theory

a Bond lengths given in Å. Activation, reaction and intrinsic energies a b The ring-opening reaction is barrierless. The M05-2X data are given (kcal/mol) for the parent 3-exo- and 4-endo-dig anionic cyclizations at in parentheses. Ring-closing bond shown in red. the B3LYP/6-31+G(d,p) and M05-2X/6-31+G(d,p) levels of theory. M05-2X data are given in parentheses. Ring-closing bonds are shown in red. Baldwin rules rather than difficulties in trapping the cyclobutenyl reactiveintermediatebeforeitundergoes ring-opening or another unproductive reaction. On the basis of the >20 kcal/mol difference in activation barriers between 3-exo and 4-endo closures, the absence of nucleophilic 4-endo-dig cyclizations is not surprising, even though the parent 4-endo-dig cyclization is about ∼7 kcal/ mol more exothermic than its 3-exo-dig counterpart (Table 6, Figure 13). Anion-stabilizing substituents at the terminal alkyne carbon slighty increase the calculated kinetic preference for the 3-exo-dig closure (Table 7). Although only computational data are available for this class of Figure 12. Homoantiaromaticity in an anionic 4-endo-dig transition state. cyclizations, they provide sufficient background for illustrating the keytrends.Theremarkablyhighactivationenergy(∼30 kcal/mol) Even for the formation of strained cycles, all carbanionic cycliza- for the >10 kcal/mol exothermic 4-endo-dig cyclization of parent tions are exothermic and effectively irreversible due to the conver- but-3-ynyl carbanion67 was attributed to homoantiaromaticity24,68 sion of a weaker bond into a stronger bond (π-bond f σ-bond) f π and cancellation of the stabilizing nNu * interaction for the acute and the concomitant transformation of an alkyl anion into a more trajectory which brings the nucleophile at the node of the stable vinyl anion. This is true even for the formation of strained alkyne in-plane π*-orbital. The antiaromatic character of the 3-exo and 4-endo products. 4-endo TS is illustrated by the positive NICS69 value (Table 7) In contrast, the analogous cyclizations of the parent N- and and is consistent with its 4n-electron count (Figure 12). O-centered anions transform a heteroatom-centered anion into a

6523 dx.doi.org/10.1021/cr200164y |Chem. Rev. 2011, 111, 6513–6556 Chemical Reviews REVIEW carbanion. The energy cost due to this unfavorable change is Scheme 7. Substituent Effect on the 3-exo- versus 4-endo-dig substantial. For the N-anions, this effect renders 3-exo cyclizations Competing in an Electrophilic Ring Closure ∼10 kcal/mol endothermic, whereas 4-endo closure is essentially thermoneutral. For these cyclizations, B3LYP underestimates reaction exothermicity in comparison to M05-2X but the activa- tion energies provided by the two methods and the higher level CCSD(T) calculations are similar. For the O-anion, all reactions leading to the formation of 3- and 4-membered rings are strongly endothermic. Such unfavorable cyclizations should be quickly reversible, for example, ring-opening of the 3-exo product has only ∼3 kcal/mol activation barrier for the N-case, whereas the analogous opening to the more stable O-centered anion is barrierless in silico.

Scheme 8. 4-Endo-dig Cyclizations of Secondary Carboca- tions and Lack of Cyclization in the Case of Stable Tertiary Carbocations

Figure 13. Electronegativity effects on the M052X/6-31+G** poten- tial energy surfaces for the 3-exo-/4-endo-dig anionic cyclizations of C- (black solid, bold), N- (blue dashed, italics), and O- (red dashed, underlined) centered anions with terminal alkynes.

Table 8. Literature examples of 3-exo/4-endo-dig electro- philic closure with respect to the environment of the cationic a center formation of the 3-exo-dig product for the alkynyl ethyl ether, which is capable of stabilizing the exocyclic vinyl cation through formation of an oxycarbenium intermediate.72,73 These reac- tions are excellent examples of NPE closure, as the regioselec- tivity of closure is dictated by the position of greatest partial positive charge and, with the possible exception of the alkynyl a x marks denote gaps in the literature. Motif structures are given in ethyl ether, the ring closure does not occur until effected by Scheme 1. Motifs BH are unknown. nucleophilic attack. Secondary carbocations behave similarly, giving 4-endo-dig 70 3.1.3. Electrophilic Cyclizations (Table 8). Hanack and product 3.016 when the alkyne was substituted with a methyl 71 others have investigated the regioselectivity of the parent carbo- group (Scheme 8).72 Tertiary carbocation 3.018, however, fails cationic cyclizations and found that, depending on the substitution to undergo either 3-exo- or 4-endo-dig cyclizations,74 presumably pattern, products deriving from either a 3-exo- or 4-endo-dig closure because of the higher stability of the acyclic 3° cation with respect can be obtained after trapping of the 3-center, 2-electron nonclassi- to a vinyl cation and the absence of a strong-enough nucleophile cal carbocation by solvent. Through carbon-14 isotope effects, to induce the NPEC. This is in full agreement with the work of Hanack et al. determined that the bond-breaking and bond- Poutsma and Ibarbia,75 as well as Pasto et al.,76 who found that forming events, which occur upon solvolysis of 1-pent-3-ynyl upon generation of cyclopropylidenecarbinyl cations from alke- triflate, 3.007 are unsymmetrical and the process has a reactant- nylidenecyclopropane 3.021, only the ring-opened products like transition state.70h When terminal or alkyl-substituted triple 3.023 and 3.024 were obtained. bonds are employed, four-membered rings are mainly observed.70g 3.1.4. Summary of 3/4. No examples exist of radical 3-exo- This observation agrees well with a computational study (MP2/ or 4-endo-dig closure. Based on the endothermicity and high 6-311G(d,p) level) by Hopkinson and co-workers71c who activation barriers (particularly for 4-endo), these reactions may found that, for terminal alkynes, the primary vinyl cation not be feasible unless a highly stabilizing group is adjacent to the (3-exo-dig product) exists only as a transition state between cyclic vinyl radical or the product is trapped via an elimination the two cyclobut-1-enyl cations (4-endo-dig product). reaction. Computational studies suggest that simple carbanionic The same potential energy surface can be reached via solvo- closures are typically exothermic (Tables 6 and 7) because of the lysis of cyclobutene or methylene cyclopropane derivatives. conversion of a primary alkyl anion into the more stable vinyl Only when cationic center 3.012 is stabilized by an aromatic anion. However, only 3-exo closure of enolates has been achieved or cyclopropyl group does 3-exo formation become favored so far experimentally via coupling of the initial cyclizations (Scheme 7).70j Hanack and co-workers also observed exclusive product with an exothermic elimination reaction (Scheme 6), a

6524 dx.doi.org/10.1021/cr200164y |Chem. Rev. 2011, 111, 6513–6556 Chemical Reviews REVIEW process that can only occur for exocyclic closure. The regio- Table 9. Literature Examples of 4-exo/5-endo-dig Radical Closure b selectivity of the electrophilic closures of primary and secondary with Respect to the Environment of the Radical Center carbenium ions depends upon the substitution of the alkyne, directing nucleophilic attack via the buildup of partial positive charge. Cyclization is not observed for tertiary carbocations in the presence of weak nucleophiles (Scheme 8).

3.2. 4-exo versus 5-endo Cyclizations

Figure 14

Competition in this pair of cyclizations is fundamentally different from other pairs discussed in this work where the thermodynamic driving forces for the two competing cyclizations are similar (both products are either strained (3-exo/4-endo) or free of strain (5-exo/6-endo)) and where, in the case of nucleophilic and radical closures, there is usually a clear kinetic preference for the exo path. However, for the 4-exo/5-endo pair, one of the products (exo) is much more strained than the other (endo). As the result, the endo cyclization is much more a Outside scope of Baldwin Rules. b x marks denote gaps in the literature. exothermic, and the competition between 4-exo and 5-endo Motif structures are given in Scheme 1, and motifs DG are unknown. closure, onto both olefins77 and alkynes, becomes delicately balanced due to the thermodynamic contributions selectively facilitating the endo closure (see section 2.6). Table 10. Activation, Reaction, and Intrinsic Energies (kcal/mol) This competition also represents an interesting unresolved for the Parent (A), (σ-vinylexo, B), (σ-vinylendo, C), and (C- c question regarding stereoelectronic factors in organic reactions. allylendo3, H) 4-exo- and 5-endo-dig Radical Digonal Cyclizations While the product of the stereoelectronically favorable 4-exo-dig closure suffers from considerable strain, the formation of a five-membered ring, via a nucleophilic closure, has to overcome stereolectronic factors which disfavor anionic endo-dig cycli- zations (Figure 6). 3.2.1. Radical Cyclizations (Table 9). Whereas both 3-exo- and 4-endo-dig radical closures were found to be endothermic processes with no examples in the literature (vide supra), 4-exo radical cyclization of the parent radical is essentially thermo- Δ ≈ neutral ( Er 0), and 5-endo closure is significantly exothermic (Table 10). Remarkably, the calculated activation barriers suggest that the 4-exo-dig closure should still be capable of competing kinetically with the much more exothermic 5-endo-dig closure. For the parent carbon-centered radical, the 4-exo and 5-endo barriers are very close.78 While 4-exo-trig cyclizations are relatively well-documented,79 the literature examples of regioselective 4-exo-dig radical closures are scarce.15 A single example of 4-exo-dig closure of an alkyl radical (motif A, Table 9) has been observed experimentally (3.026, Scheme 9). This transformation has been reported by Malacria et al. as part of radical cascade leading to the formation of bicyclo[3.1.1]heptanes.80,81 The overall yield for the product is 85% yield after reaction with MeLi, serving as a lower boundary estimate for the 4-exo-dig step. The surprising efficiency of this unprecedented transformation has been attributed to the fast intramolecular trapping of the exocyclic vinyl radical via 1,6-H transfer from a SiCH3 moiety. The only reported literature attempt of a 5-endo-dig cyclization of a simple alkyl radical led to quantitative formation of acyclic reduced product 3.030 (Scheme 10).82 Alabugin and co-workers investigated the apparent discre- a B3LYP/6-31+G(d,p) and M052X/6-31+G(d,p) levels, ref 24. pancy between the Baldwin rules and the lack of an efficient b B3LYP/6-31G** level, ref 83. c Ring-closing bonds are shown in red.

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Scheme 9. 4-exo-dig Cyclization of an sp3-Carbon with a Table 11. Activation, Reaction, and Intrinsic Energies a Fully Saturated Linker As Part of a Cascade (kcal/mol) for the Parent 4-exo- and 5-endo-dig Radical Digonal Cyclizations at the B3LYP/6-31+G(d,p) and a M05-2X/6-31+G(d,p) Levels of Theory

a Bonds formed in the initial 5-exo-dig/1,6-H transfer/6-endo-trig cascade steps occurring before the 4-exo-dig closure are shown in red. a The M05-2X data are given in parentheses. Ring-closing bonds are shown in red. Scheme 10. Exclusive Formation of an Acyclic Product in the a Reaciton of Primary Bromide 3.029 with Bu SnH/AIBN 3 Scheme 11. (Top) Regioselective 4-exo-dig Cyclization of N-Acyl Radicals onto Terminal and Phenyl-Substituted Alkynes and (Bottom) Relative Energies of the Radical Intermediates Calculated at B3LYP/6-311G(d,p) and UB3PW91/cc-pVTZ (in Parentheses) Levels

a No evidence of the 4-exo- or 5-endo-dig product was found. radical 5-endo-dig cyclizations in an initial computational and subsequent experimental study.78 Analysis of the general factors controlling the efficiency of this process, using coupled cluster and DFT methods, revealed that the barriers for the parent 5-endo-dig and 4-exo-dig cyclizations are essentially identical, despite the much higher exothermicity for the 5-endo-dig closure.83 According to these data, both cyclizations are ex- ffi pected to be su ciently slow (Ea = 19.1, 18.4 kcal/mol for 4-exo Reproduced with permission from ref 84. Copyright 2009 Elsevier, Ltd. and 5-endo, respectively, at M052X/6-31+G(d,p) level), poten- tially allowing atom transfer to become kinetically competitive. Further information regarding substituent effects on the According to the DFT computations, the analogous cycliza- 4-exo-/5-endo-dig cyclizations has been provided by recent DFT tions of vinyl radicals are significantly faster (E = ∼1315 kcal/ a calculations.24 Regardless of the substituent, the 5-endo product mol, Table 10). Notably, the position of the double bond in the is >6 kcal/mol more stable than the 4-exo product, where the reactant is predicted to have a noticeable effect on the cyclization fi reactions are essentially thermoneutral for R = Me, TMS. The energy and selectivity. An interesting prediction (not con rmed phenyl group sufficiently stabilizes the exocyclic vinyl radical, yet experimentally) is that when the vinyl moiety is inside the making 4-exo closure exothermic and giving it a clear kinetic σ new 5-membered ring (the -vinylendo closure), 5-endo-dig preference. Removing thermodynamic contribution using cyclization should be kinetically favored over the 4-exo closure. Marcus theory reveals the inherent preference for exocyclic In contrast, when the vinyl group is outside of the new ring (the closure (Table 11). σ-vinylexo closure), 4-exo-dig cyclization has a 0.8 kcal/mol lower A remarkable deviation from Baldwin’s original predictions for barrier, despite being less exothermic than the 5-endo-dig process the relative favorabilities of the competition between 4-exo-/5- (Table 10). Cyclizations of stabilized allyl radical are unfavorable endo-dig cyclizations, though in line with the computed activa- because of the significant penalty caused by the 90° rotation of tion barriers (Table 10), has been reported by Fujiwara et al.84 the radical orbital out-of-conjugation before it can reach the in- Carbamoyl radicals (motif B), generated via photolysis of plane π-bond of the target alkyne. carbamotelluroates, proceed with high 4-exo selectivity for

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Scheme 12. Lack of Efficient 5-endo-dig Closures in PhSH Interestingly, the cyclizations were also stereoselective, since and Bu3SnH-Radical Reactions of 1,5-Hexadiynes the sulfonyl moiety is capable of selectively lowering the activa- tion barrier for 5-endo-dig closure through a favorable hydrogen- bonding interaction with the relatively acidic acetylenic CH bond (Table 12). A favorable stereoelectronic alignment of the vicinal diols (the gauche effect87) preorganized the two π-systems for cyclization without the introduction of concomitant strain.

Scheme 14. First Efficient 5-endo-dig Cyclization of a Carbon-Centered Radical

Scheme 13. 5-endo-dig Radical Cyclization of Si-Centered Radical

Table 12. Activation and Reaction Energies (kcal/mol) for 4-exo-dig and 5-endo-dig Cyclizations Calculated at the UBLYP/6-311+G**//UBLYP/6-31G** Level

terminal and phenyl-sustituted alkynes in up to 83% yield. Only when R1 was an ethyl group did 5-endo-dig closure become competitive (4-exo/5-endo ratio = 2.5:1). In accordance with the experimental findings, DFT calculations found that the 4-exo pathway is strongly preferred kinetically over the 5-endo process for R = Ph but by a much smaller margin (0.8 kcal/mol) when R = ffi ff Both the increased e ciency of the 5-endo-dig cyclization and the Me (Scheme 11). This important work suggests that e orts into observed stereoselectivity were fully supported by calculated activa- these unusual radical cyclizations (4-exo-dig) should be continued. tion barriers for the cyclizations. The sulfonyl group introduction The above report is consistent with earlier observations that next to the radical center leads to a >2 kcal/mol decrease in the most vinyl radicals generated by addition of radical species to the 5-endo-dig activation barrier, which is sufficient for switching the terminal carbon of 1,5-hexadiynes do not undergo 5-endo-dig 78 selectivity toward the five-membered ring formation (Table 12). closure or do it very inefficiently (Scheme 12). The bulk of the An earlier report of the 5-endo-dig closure of O- and S-centered reaction mixtures corresponds to polymeric materials which were radicals, formed from 2-methoxyphenyl and 2-methylthiophenyl proposed to originate from the 4-exo products, unstable under substituted phosphorus ylides, proceeded only under drastic con- the reaction conditions. For PhS-substituted radicals, attack at ditions (flash vacuum pyrolysis (FVP) at 850 °C, Scheme 15).88 the phenyl ring is preferred to 5-endo-dig cyclization. The activation barriers for these closures were calculated by The first efficient 5-endo-dig cyclization under kinetic control Alabugin and Manoharan (Table 13).83 As evidenced by the ex- was reported by Studer and co-workers for a Si-centered radical 85 perimental conditions, the cyclizations are only expected to pro- (Scheme 13). The increased efficiency of this 5-endo cycliza- ceed under high temperatures. The trends in calculated reaction tion is in excellent agreement with the calculated low cyclization 83 energies are controlled by the interplay of gain of aromatic stabi- barrier of ∼6 kcal/mol. In addition to the stereoelectronic lization and loss of conjugative radical stabilization as the starting consequences caused by the presence of long C Si bonds, this ff process is assisted by the captodative SOMOLUMO and materials are transformed into the products. The di erences in HOMOSOMO interactions and the β-Si-effect.86 reaction exothermicities are partially translated into the activa- The first efficient 5-endo-dig radical closure of a carbon- tion barriers. Interestingly, the cyclizations of CN and NMe2 centered radical, reported by Alabugin et al.,78 was discovered substituted radicals (Entries 4, 5) have almost identical reaction when radical cyclizations of 1,5-diynes were triggered with tosyl energies but the barrier is more than 10 kcal/mol lower in the case of the donor substituent. The data strongly suggest that both radicals (Scheme 14). The 5-endo-dig product was formed in q 5172% yield upon photolytical generation of Ts radicals from the activation energy (ΔE ) and the intrinsic reaction barrier Δ TsBr at the room temperature. Yields were noticeably lower ( Eo) decrease dramatically when electron density increases at fl 89 (2 23%) upon thermal activation (re uxing C6H6, AIBN). the radical center.

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Scheme 15. 5-endo-dig Radical Cyclizations Involved in FVP Scheme 16. Proposed Synchronous Double-Radical 5-endo- of Substituted Phosphorus Ylides dig Cyclization of Substituted Bis(arylcabonyl)diphenyl- a acetylenes upon Reduction with LiNaph

Table 13. Calculated Activation Barriers, Reaction Energies, and Intrinsic Barriers (kcal/mol) for the 5-endo-dig Cycliza- o tion of -X-Substituted (X = N, O, and CR2) Ethynyl Benzenes Along with the Incipient C 333X Distances (Å) at the B3LYP/ 6-31G** Level

a A dimerization product resulting from initial intermolecular attack is observed for the mono(arylcarbonyl)diphenylacetylene.

Scheme 17. Proposed 6-endo-dig/5-endo-dig Radical Cycli- zation Cascade in Brominated Biphenyl Diacetylenes (Top) Despite the above-mentioned penalty associated with the loss and an Alternative 5-exo-dig Mechanism (Bottom) of benzylic conjugation (Table 10), Yamaguchi et al. provide an example of motif H, corresponding to 5-endo-dig closure.90 Upon treatment with four equivalents of lithium naphthalenide (LiNaph), substituted bis(arylcarbonyl)- diphenylacetylenes are transformed into two tetracyclic compounds, 3.062, 3.063,in∼60% combined yield. According to B3LYP/6-31+G(d) computations with solva- tion and the counterion Li+ included, the two radical-anions are mostly localized on the carbonyl groups. The authors propose a highly unusual synchronous double-radical 5-endo-dig cyclization. In agreement with this scenario and the computational results in Table 13, single 5-endo-dig closure does not occur. Instead, reduction of the mono(arylcarbonyl)diphenylacetylene gives dimeric product 3.066 derived from intermolecular attack of the carbonyl radical anion at the triple bond (Scheme 16). products is still the dominant process, this important result Several other possible examples of 5-endo-dig cyclizations can showed that 5-endo-dig cyclizations are capable of competing be found in the literature. Anthony and co-workers91 considered (though not very efficiently) with H-abstraction even in the the involvement of a 5-endo-dig cyclization as a part of an presence of a good H-atom donor (1,4-cyclohexadiene). unprecedented 6-endo-dig/5-endo-dig cascade leading to a ffi relatively e cient (73% yield, Scheme 17) transformation of a Scheme 18. 5-(σ-Vinylendo)-endo-dig Cyclization of the constrained enediyne system into phenanthrene derivatives. Diradical Intermediate Formed upon Bergman Cyclization Subsequent computational analysis, however, suggested that this transformation is likely to proceed via an alternative mechanism which includes intermolecular attack of Sn-radical at the triple bond, 5-exo-dig closure, attack at the aromatic ring and proto- destannylation (3.071, 3.072, Scheme 17).83 The final examples are not formally covered by the Baldwin rules as it involves long CS bonds in the formed cycle. How- ever, 5-endo-dig radical cyclizations are so scarce that we will briefly discuss these results below. The experimental observations agree very well with the com- Matzger and co-workers92 reported that a radical cascade puted activation barrier for this reaction by Alabugin and initiated by Bergman cycloaromatization can be terminated via Manoharan.83 The barrier is decreased (by 4.9 kcal/mol) to the a5-(σ-vinylendo)-endo-dig closure (motif C), albeit in low yields extent where the cyclization should be able to compete with H-atom (<2.3%, Scheme 18). Although formation of acyclic reduced abstraction from CH donors. Most of the decrease comes from

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Table 14. Activation, Reaction and Intrinsic Energies (kcal/mol) for the Parent 4-exo- and 5-endo-dig Radical Digonal Cyclizations at the B3LYP/6-31+G(d,p) and a M05-2X/6-31+G(d,p) Levels of Theory

Figure 15. Conflict between unfavorable secondary orbital interactions (crossed red arrow) and in-plane aromaticity in anionic 5-endo-dig cyclizations.

the thermodynamic component as aromaticity of the benzothio- phene moiety provides an additional 1216 kcal/mol stabilization to the product. Thus, this example provides the first demonstration of aromatic stabilization being a driving force for 5-endo-dig radical cyclizations. Longer CS bonds also help in alleviating the geometric requirements in achieving the required attack angle. a The M05-2X data are given in parentheses and the ring-closing bond is Table 16. Literature Examples of 4-exo/5-endo-dig Anionic a shown in red. Closure with Respect to the Environment of the Anionic Center

Table 15. Transition state geometries, NICS (0) values and LUMO plots for 4-exo/5-endo carbanionic cyclizations for the Me-substituted alkyne calculated at the M05-2X/6-31+G** Level. Bond lengths given in Å. Activation, reaction and intrinsic energies (kcal/mol) for the parent 4-exo- and 5-endo- dig anionic cyclizations at the B3LYP/6-31+G(d,p) and M05- a 2X/6-31+G(d,p) levels of theory

a x marks denote gaps in the literature. Motif structures are given in Scheme 1. Motifs B and G are unknown, and D and E do not apply to anionic closures.

3.2.2. Anionic Cyclizations (Table 16). Recent computational analysis24 revealed that, unlike the smaller (3-exo/4-endo) and larger (5-exo/6-endo) analogs, the activation barriers of 4-exo- and 5-endo- dig anionic closure of the parent systems are quite similar (Table 14). This seemingly irregular trend has been suggested to stem not purely from stereoelectronic factors, but rather originate from their interplay with thermodynamic contribu- tions to the activation barrier.24 When thermodynamic driving forces for the two cyclizations are similar (both products are either strained (3-exo/4-endo) or not (5-exo/6-endo), there is a clear kinetic preference for the exo path. Only for the special case where the exo-product is much more strained than the endo product (the 4-exo/5-endo pair) and the endo cyclization is much more exothermic, the exo/endo kinetic competition be- a M05-2X data are given in parentheses. Ring-closing bonds are shown in red. comes relatively close.93

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Another factor aiding in the low 5-endo-dig activation barrier is As with the radical cyclizations discussed above, the regios- revealed in the negative NICS value94 observed for the 5-endo electivity can be reversed by changing the polarity of the alkyne. TS, unexpectedly suggesting σ-aromaticity and an increase in When the carbonyl group is relocated to the interior propargylic σ-delocalization in the TS, clearly reflected in the LUMO structure position, the enolate carbanion of compound 3.089 (motif F) given in Table 15.24 This observation was attributed to a σ-bridge cyclizes efficiently and selectively in a 5-endo-dig fashion in mediated coupling of the nucleophile lone pair and alkyne π*-orbital 82% yield (Scheme 21).100 Donor groups can also modify the 95 (Figure 15). This symmetry-allowed stabilizing interaction provides regioselectivity (see Section 2.5.1), as shown by the efficient an appealing explanation as to why the intrinsic barrier is lower for endocyclic closure of ethyoxyalkyne 3.092 (motif A).101 The 5-endo-dig closure than it is for the 6-endo-dig cyclization, where effects of alkyne polarity can be overturned if the alternate σ -aromaticity is disrupted by an additional methylene group. pathway can produce an aromatic product. After the initial The above-mentioned computational data agree well with the Michael addition of a primary amine to skipped diyne 3.095 fi “ ndings of Bailey and Ovaska who reported that The formation the nitrogen closes the ring in an anti-Michael fashion onto an of four-membered rings by 4-exo-dig cyclization of a 6-phenyl-5- adjacent alkynoate. This intermediate is trapped by a [3,3]- ” pentyn-1-yllithium is an unexpectedly rapid and clean process sigmatropic rearrangement to give the substituted pyrrole 3.098 and observed 93% yields of benzylidenecyclobutane 3.079A with in up to 74% yield (Scheme 21).102 no trace of the 5-endo-dig product.96 While TMS substituted alkynes also undergo regioselective 4-exo-dig closure, Bailey and co-workers were unable to facilitate closure with alkyl-substituted Scheme 21. Regioselectivity of Anionic Closure Can Be alkynes. It is noted that 4-exo-dig closure of these systems are Tuned Towards 5-endo-dig through Polarization of the Triple “significantly slower” than that of the analogous 5-exo-dig Bond or Stabilization of the Product by Aromatization cyclizations (Scheme 19).96b Scheme 19. 4-exo-dig Cyclizations of the Parent System Are Very Efficient for Phenyl- and Silyl-Substituted Alkynes

Other substituents on the alkyne are tolerated in 4-exo-dig anionic closures if they can either trap or sufficiently stabilize the vinyl anion. Alkyl-substituted alkynes can be utilized in 4-exo-dig closures terminated via β-elimination if they are functionalized with an appropriate leaving group, similar to the strategy utilized for the anionic 3-exo-dig closure in Scheme 6. For example, Bailey and Aspris have shown that a propargylic methoxy group is eliminated by the exocyclic vinyl lithium to trap the 4-exo-dig product in 7288% yield (Scheme 20).97 Cooke has demon- strated that dimesitylboryl substitution can stabilize the cyclic anion through resonance with the empty orbital of boron.98 tert-Butyl esters 3.086 gave a complex mixture of products containing only 11% of the desired product. However, if TMSCl was used as the electrophile, the 4-exo-dig product 3.088 can be trapped in 48% yield (Scheme 20).99 Scheme 20. Nucleophilic 4-exo-dig Products Can Be Pyrroles can be obtained directly from the anionic 5-endo-dig Obtained upon Trapping or Sufficiently Stabilizing the cyclization of o-ethynylanilines upon reaction with a suitable Vinyl Anion base. The choice of base and particularly the counterion was found to be critical for the reaction success (NaH, 60 °C, <5%: KH, 25 °C, 72%).103 An alternate pathway to form aromatic heterocyclic rings would be the cyclization of a carbanion onto a heteroatom-substituted alkyne. Johnson and Subramanian re- ported that aryl anion 3.103 regioselectively attacks the ortho- ethynyl ether (generated in situ by elimination/substitution of the corresponding 2,2,2-trifluoroethyl ether) and, upon work up, gives the substituted benzofuran 3.104 in 40% yield. The authors were able to form thianaphthenes and indoles using this method in up to 60% (Scheme 22).104 5-endo-dig cyclization can also occur if the 4-exo pathway is sufficiently destabilized through strain. As discussed by Baldwin,4

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Scheme 22. Aromatic Products Obtained Directly via a Scheme 24. (Top) No Cyclization Observed when the 5-endo-dig Closure of Heteroatom- or Carbon-Centered Amine Was Attached to the Most Electron-Poor Position in Anions the Ring, whereas Efficient Cyclization Occurs when the Amine Is in the Most Electron-Rich Position (Bottom)

Scheme 23. Selective 5-endo Pathway in a Strained Polycyclic System

Scheme 25. Acid-Catalyzed Transformation of γ-Alkynyl-ss- a hydroxy-r-amino Esters to the Corresponding Pyrroles

when compound 3.105 is exposed to n-BuLi, the resulting carbanion closes regioselectively in a 5-endo-dig fashion. The deformation necessary for annealing the highly strained four- a The possible proton-coordination is shown in red. membered ring at the peri-positions105 shifts the balance in favor of the 5-endo pathway (Scheme 23).20 A more detailed study is needed to shed the light on this topic, An interesting example of electronic control of 5-endo-dig but this lack of cyclic products is presumably due to the higher cyclization of o-ethynyl substituted heteroaromatic amines was themodynamic stability of the acyclic cations relative to that of reported by Vasilevsky et al.106 The authors could not force the the cyclic vinyl cations. 5-endo-dig closure in 4-phenylethynyl-5-amino pyrazole 3.107 where electronic properties of the substituents were mis- Scheme 26. Neither 4-exo nor 5-endo Products Are matched (the fifth position in pyrazoles where the nucleophile Observed upon Generation of Either Primary Carbocations is attached is the most electron poor whereas the fourth 3.114A/B or Oxycarbenium Ion 3.115 position is electron rich). In contrast, the cyclization proceeded smoothly in 3.109 where the two substituents are switched (Scheme 24). Knight et al. obtained 5-endo pyrrole products in 7686% yields in the reaction of γ-alkynyl-ss-hydroxy-R-amino esters 3.111 with 0.5 equiv of p-toluene sulfinic (or sulfonic) acid (Scheme 25).107 It has been suggested that intramolecular coordination of alkyne with the protonated propargylic alcohol 3.112 assists the cyclizations, in analogy to similar 5-endo-dig cyclizations promoted by electrophiles such as I .108 3.2.4. Effect of Metal/External Electrophiles on 4-exo/ 2 111 3.2.3. Electrophilic Cyclizations. As discussed above, the 5-endo Regioselectivity. As has been shown by Toste and 112 4-exo/5-endo competition is much closer than it is for the 3-exo/ Iwasawa using Au(I) and W(CO)5(L) catalysts, respectively 4-endo and 5-exo/6-endo pairs of cyclizations, owing largely to (Scheme 27), enolates exhibit complete 5-(C-allylexo)-endo-dig the strain destabilization of only one (the four-membered) of regioselectivity without the need for built-in bond polarization, the two products. However, the situation changes in cationic such as the carbonyl group in Scheme 21. A variety of oxygen closures where the 5-endo product would be highly strained as nucleophiles undergo 5-endo-dig closure as well when exposed 113 114 115 well because of the inclusion of an sp-hybridized cationic to I2, Cu(I), and Zn(II) salts. A number of regioselec- center in the ring. The instability of vinyl cations is the likely reason tively 5-endo-dig cyclizations has been reported for nitrogen why electrophilic 4-exo/5-endo closures are not described in the nucleophiles in the presence of soft Lewis acids.116 literature and several reactions which could potentially follow these 3.2.5. Summary of 4/5. DFT calculations illustrated in paths were found to give different products. For example, Hanack Figure 16 suggest that the radical 4-exo-/5-endo-dig competition reported that no cyclic products were observed in the solvolysis of is delicately poised. For the parent C-, N-, and O-centered primary triflates 3.114,109 whereas Rychnovsky and co-workers have radicals, the difference between 4-exo- and 5-endo-dig activation found that the formation of oxycarbenium intermediates did not energies lies with the expected computational margin of error. lead to either 4-exo- or 5-endo-dig cyclizations (Scheme 26). 110 Although there is currenly not enough experimental data to fully

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Scheme 27. Selection of 5-endo-dig Cyclizations of Carbon, EAN closures provide a way to overcome the intrinsic exo pre- Oxygen, and Nitrogen Nucleophiles with a Variety of External ference and obtain 5-endo products in good yields. A variety of soft Electrophiles Lewis acids can be used to fine-tune these processes, accounting for their increased practical utility. Neither 4-exo- nor 5-endo-dig cationic closures are known. Several attemps to accomplish such cyclizations led to the formation of only acyclic products. This is probably associated with the greater thermodynamic stability of isomeric acyclic cations and very low barriers for the ring-opening.

3.3. 5-exo/6-endo Cyclizations

Figure 17

This section represents the most fully studied and understood class of cyclizations involving alkynes. Both 5-exo- and 6-endo-dig closures are favorable and their competition is often controlled by subtle structural modifications. As will be seen below, radical closures have been thoroughly investigated both computationally and experimentally and many examples clearly reveal the under- lying stereoelectronic effects governing regioselectivity. 3.3.1. Radical Cyclizations (Table 17). Recent computa- tional data for the 5-exo- and 6-endo-dig cyclizations of parent C-, N-, and O-radical species are assembled in Tables 18 and 19. Stalinski and Curran have thoroughly examined the cycliza- tions of the parent system (motif A) for a series of mono- or dihalo-4-phenylhex-1-ynes. With a rate constant of 2.19 107 M 1 s 1 for closure onto a terminal alkyne, complete 5-exo regioselectivity was observed with high yields (up to 99%).117 The relatively fast 5-exo-dig closure matches the fairly low Ea for this process well (Scheme 28). In agreement with the calculated activation barriers for substituted alkynes (Table 19), substitution of the alkyne does not alter the regioselectivity. For example, Zhou and co-workers obtained good yields of cyclic products from phenyl, butyl and TMS- substituted alkynes. Radicals were generated via chemoselective reduction of a primary bromide with SmI2.Presence Figure 16. Electronegativity effects on the M05-2X/6-31+G** potential of an acceptor substituent at the alkyne slightly decreases the yield of energy surfaces for the 4-exo-/5-endo-dig anionic and radical cycliza- cyclic products, e.g. 41% for the N,N-diethylamide derivative. Due tions of C-, N-, and O-centered anions (black dashed, bold) and radicals to a competing reduction pathway, no cyclic products were observed (red solid, italics, underlined) with terminal alkynes. (*) denotes radical/ 118 anion. when R = CO2Me (3.136,Scheme28). Tributyltin radicals can also be used to generate radical species for selective 5-exo-dig closure onto alkyl-substituted alkynes (Scheme 28).119 test these predictions, the available data suggest that the nature of Martinez-Grau and Curran found that 5-exo closure is sensi- the radical does play a role in the cyclizations selectivity. Simple tive to substitution at the interior propargylic position for silyl radicals seem to prefer slightly the 4-exo-dig closure but this ether 3.140. However, even when the detrimental effect of preference can be overcome by structural and electronic factors. substituents stops exocyclic closure, no 6-endo-dig products Primary carbanions regioselectively close in a 4-exo-dig fashion. were observed (Scheme 29).120 The cyclizations proceeded especially efficiently when the alkyne 5-exo-dig radical cyclizations have been used for the preparation is substituted with a terminal group bearing a σ,p,orπ acceptor of interesting polycyclic systems. Both spiro (3.145)121 and fused σ π 122 ( *CI,nB,or *CdO, Scheme 20). If the polarity is reversed, that (3.148) compounds have been synthesized in high yields is, a carbonyl group replaced the interior propargylic methylene, following regioselective 5-exo closure onto terminal alkynes enolates have been shown to close in a 5-endo-dig fashion (Scheme 30). It is possible to include 5-exo-dig closures into (Scheme 21). Benzylic or aryl anions, like the radical examples, furthercascadesasillustratedbytheefficientl trapping of the resulting also preferentially underwent 5-endo-dig closure in the few vinyl radical in a subsequent 5-exo-trig closure (Scheme 30).123 available literature examples (Scheme 23). Aromaticity facilitates However, Marco-Contelles et al. reported that the 6-endo-dig closure a number of heterocyclic 5-endo closures (Scheme 22). becomes possible when a strained fused [3.3.0] bicyclic system is

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Table 17. Literature Examples of 5-exo/6-endo-dig Radical Table 18. Activation, Reaction, and Intrinsic Energies Closure with Respect to the Environment of the Radical (kcal/mol) for the Parent 5-exo- and 6-endo-dig Radical a Center Cyclizations at the B3LYP/6-31+G(d,p) and M05-2X/6-31 c +G(d,p) Levels of Theory

a B3LYP/6-31+G(d,p) and M05-2X/6-31+G(d,p) levels of theory. The M05-2X data are given in parentheses.24 b B3LYP/6-31G** level.135 c The M05-2X data are given in parentheses. Corresponding motifs are a x marks denote gaps in the literature. Motif structures are given in given and the ring-closing bond is shown in red. Scheme 1. Motif B is unknown. The sensitivity of radical cyclizations to the nature of substit- present in the reactant, possibly due to the lower strain in the 6-endo uents of the triple bond increases when the radical center is a part product (Scheme 30, 3.155).124 of a conjugated system. While Zhou et al. found that primary Further accumulation of strain, for example, via annealing of a carbon radicals close regioselectively (5-exo) whether the alkynyl 125 trans-fused 5-membered cycle, completely reverses the 5-exo/ substituent was aromatic or aliphatic (Scheme 28),118 Choi and ff 6-endo selectivity in favor of the larger cycle. Ho mann and Hart observed that carbon-radicals R to the nitrogen of a lactam co-workers have shown that the trans-fused ring does not have to undergo relatively inefficient but regioselective 6-(π-vinylendo)- be preinstalled but can be synthesized as part of a cascade. The endo-dig closure (motif E) onto sterically hindered alkynes (R = secondary carbon radical initially underwent a 5-exo cyclization Me, 27% in addition to 61% of the reduced product). Only in the at the adjacent alkene or alkyne, giving either an alkyl or a vinyl presence of bulkier groups such as TMS, t-Bu C(CH ) OMe, at radical, respectively. Interestingly, the reactivity of these two 3 2 the alkyne terminus is the 5-exo-dig selectivity restored. Medium- radicals was drastically different. The alkyl radical was converted ffi 126,127 sized groups (i-Pr and n-Pr) gave mixtures with the 5-exo/6-endo into a tricyclic product via an e cient 6-endo-dig closure. ∼ By substituting the relay olefin for a 1-cyclopentenyl group, ratio correlating with the steric bulk of the substituents ( 2:1 and ∼5:4, respectively, Scheme 32).128 Carbamoylmethyl radicals, (both the yield can be increased to 78%. In contrast, the analogous 129 130 vinyl radical underwent neither 5-exo- nor 6-endo-dig closure C-allylendo2 and C-allylexo, Scheme 32) also undergo selective (Scheme 31).126 Although this difference in reactivity suggests 5-exo-dig cyclizations with terminal and TMS-substituted alkynes, that dig-cyclizations of vinyl radicals are more sensitive to respectively. ffi strain effects than analogous cyclizations of alkyl radicals, Benzylic radicals (motif H)closee ciently despite being con- numerous examples of vinyl and aryl radicals undergoing jugated with the aromatic system, as shown by the regioselective 5-exo-/6-endo-dig closure are known in less strained systems 5-exo closure of an R-pyridyl radical onto the alkyl-substituted alkyne. (vide infra). The resulting vinyl radical was trapped via hydrogen abstraction from

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Table 19. Activation, Reaction, and Intrinsic Energies Scheme 30. Formation of Bi- and Polycyclic Products by (kcal/mol) for the Parent 5-exo- and 6-endo-dig Radical Regioselective Radical 5-exo-dig Cyclizations and Erosion of Cyclizations at the B3LYP/6-31+G(d,p) and Regioselectivity Because Increased Strain in a [3.3.0] System a M05-2X/6-31+G(d,p) Levels of Theory

a The M05-2X data are given in parentheses.24 All cyclizations corre- spond to Motif A and the ring-closing bond is shown in red. Scheme 31. Strain-Controlled Radical 6-endo-dig Cycliza- tions in Cyclic trans-Fused Systems Scheme 28. Regioselective 5-exo-dig Cyclization of Primary Carbon Radicals onto a Variety of Substituted Alkynes

Scheme 32. Cyclizations of Conjugated 2° and 3° Carbon Radicals Corresponding to Motifs EG

Scheme 29. Effect of Substitution at the Interior Propargylic Position on the Yield of 5-exo-dig Product

the silyl group. Subsequent 5-exo-trig closure completed the cascade and yielded the final tricyclic product (Scheme 33).131 While polarization controls the regioselectivity of anionic cycliza- 5-exo-dig closure for silyl, aryl alkyl substituted alkynes instead of tions effectively (Scheme 21 and Scheme 53), Weavers et al. observed radical conjugate addition (RCA)132 which would provide the 6-endo

6534 dx.doi.org/10.1021/cr200164y |Chem. Rev. 2011, 111, 6513–6556 Chemical Reviews REVIEW products.133 In a similar way, conjugation with a β-pyridine moiety Table 20. Activation Barriers, Reaction Energies, and does not affect the exocyclic regioselectivity either (Scheme 34).134 Intrinsic Barriers (kcal/mol) for 5-exo-dig and 6-endo-dig 2 Because of the stereoelectronic features of the alkyne moiety, the Cyclizations of sp -Radicals with a Saturated Bridge between the Vinyl and a Terminal Alkyne Moieties incipient radical in these two examples remains orthogonal to the a internal π-systems in the transition state and, thus, the 6-endo-dig (B3LYP/6-31G** Level) closure does not receive any conjugative assistance. Scheme 33. Regioselective 5-exo-dig Cyclizations of Benzylic Radical

Scheme 34. Regioselective 5-exo-dig Cyclizations of Internal Alkynes with Acyclic Carbon Radicals

a Arrows overlaid with the SOMOs of parent vinyl radicals (motif B, C) show projection of the radical orbital in space.135 Ring-closing bonds are shown in red.

As with the smaller rings (4-exo/5-endo cyclizations, Table 10),83 Scheme 35. Regioselective 5-(σ-Vinylexo)-exo-dig Cycliza- the closures of sp2-hybridized radicals (motifs B, C) have lower tions of Carbon-Centered Radicals activation barriers due the higher exothemicity of the conjugated products formation (Table 20) relative to the parent systems (Table 18). However, while the exo/endo barriers are close for 4-exo/5-endo pair, a clear stereoelectronic 5-exo preference is observed for σ-vinylexo and σ-vinylendo closures, despite these processes being less exothermic than their 6-endo counter- parts.135 The slight differences observed for motifs B and C are due to the greater stability of endocyclic alkenes and trans-dienes relative to exocyclic alkenes and cis-dienes136 (Table 20). The 5-exo barriers are relatively insensitive to structural changes (Table 20, entries 1, 3, 5), while the 6-endo barriers vary significantly. As the result, the kinetic preference for the discussed in this section, TMS-substitution facilitates regio- formation of 5-exo products significantly decreases in motif B selective 5-exo attack (54% yield, Scheme 35).137 Journet and compared to motif C. It is interesting that the intrinsic barriers for Malacria published an efficient cascade initiated by a similar both the 5-(σ-vinylendo)-exo and 6-(σ-vinylendo)-endo cycliza- regioselective closure onto an alkyl-substituted triple bond 138 tions (motif C) are ∼2 kcal/mol higher than for the respective (Scheme 35). “σ-vinylexo” cyclizations. Although these differences are consis- Sha and co-workers have found that both R-andβ-vinyl radicals tent with the orientation of radical orbitals in the two reagents (motif C) in an enone system undergo clean 5-(σ-vinylendo)- (the radical orbital for the σ-vinylexo radical is tilted outward, exo-dig cyclizations onto TMS-substituted alkynes. Both [4.3.0] and which should facilitate attack at the alkyne’s terminal carbon, [3.3.0]-bicyclic ring systems, as well as heterocycles, are formed in see red arrows in Table 20), it is not clear whether this is a 7089% yields (Scheme 36).139 It is noteworthy that in the second determining factor. Because of the unfavorable orientation of the example, even when n = 1, the cyclization is regioselective for radical orbital in the reactant, locking the reacting vinyl group in a exocyclic closure onto the TMS substituted alkyne, forming the benzene ring (motif C) leads to a further increase in the 6-endo 55 bicyclic system (Scheme 36).140 barrier. Five-membered heterocycles can also be efficiently and regio- Starting from the vinyl bromide (motif B), Montevicchi selectively synthesized using aryl radicals (motif C, Scheme 37).141 and co-workers found that, as with the other cyclizations The experimental data are in good agreement with the DFT analysis

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Scheme 36. Regioselective Cyclizations of Enone Radicals Scheme 38. Regioselective Closure of Aryl Radicals onto onto TMS-Capped Alkynes Ynones and Ynamides

Scheme 37. 5-exo-dig Cyclizations of Aryl Radicals with an Aminomethylene Bridge between the Acetylene and Aryl a Moieties

Scheme 39. 5-exo-dig Cyclizations of Aryl Radicals with Saturated Linkers

a SOMO of reacting radical and comparison of calculated 5-exo and 6-endo activation barriers (B3LYP/6-31G(d,p), energies in kcal/mol). performed by Alabugin and Manoharan, who found that incorpora- tion of the nitrogen atom lowers the barrier with respect to the all- carbon analog and confirms that 5-exo path is kinetically favored.135 The apparent selectivity and efficiency are independent of whether the nitrogen atom is attached to the benzene ring or to the triple bond. Connection through the nitrogen of the amide (ynamide) provides two more possibilities for structural variation, with the carbonyl inside or outside the formed ring. Experimentally, abstraction from the silane and subsequent 5-endo-trig clo- σ higher yields for 5-( -vinylendo)-exo closure onto ynamides sure. Introduction of the third sp2-carboninthebridgeinnaphthyl were obtained when the carbonyl was inside the formed cycle, radical 3.215 did not change the observed 5-exo selectivity.131 particularly for terminal alkynes. Introduction of an electron- However, in the absence of this trap, pyridyl radical 3.218 has been withdrawing carboxyl group at the alkyne terminus lowered the shown to yield a 10:1 mixture of 5-exo and reduced products in an 142 yield; however, all cyclizations were regioselective for the exo- overall 84% yield. No 6-endo product was obtained.144 cyclic closure. The 5-exo/6-endo competition is more complicated when the Brunton and Jones connected a TBDMS-capped triple bond bridge is fully unsaturated and, thus, the cyclization can produce to the carbonyl of the amide and attained, upon reductive completely conjugated molecules. In the case of 6-endo closure, dehalogenation, the 5-exo-dig product in 62% yield (3.204, aromaticity of the products renders it much more exothermic Scheme 38). No cyclization was observed with terminal than 5-exo-dig. The strong thermodynamic contribution selec- alkynes due to competing hydrostanylation.143 Alabugin tively decreases the 6-endo-dig activation barrier for the cycliza- and Manoharan showed that introduction of an amide moiety tion of the parent conjugated 1,3-hexadiene-5-yn-1-yl radical significantly lowers the cyclization barriers and renders them (Figure 10, Table 18), which is considered as the possible key more exothermic.135 step in the formation of polycyclic aromatic hydrocarbons Phenyl and napthyl radicals close efficiently and regioselec- (PAH)145 during combustion of hydrocarbons.146 Most recently, tively onto alkyl-substituted propargylic silyl ethers (Scheme 39), Olivella and Sole147 carefully studied the kinetic competition similar to the sp3-radicals discussed earlier (Scheme 33). The between 5-exo and 6-endo cyclizations in this system using resulting vinyl radical is effiently trapped via hydrogen both DFT and high level multiconfigurational (CASSCF and

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Figure 18. Reactant SOMO (left) and transition state geometries for 5-exo-dig (center) and 6-endo-dig (right) cyclizations of the 1,3-hexadien-5-yn-1- yl radical. (CASSCF/6-31G(d)). Reproduced with permission from refs 135 and 147. Copyright 2005 and 2000 American Chemical Society.

RCCSD(T)) calculations and found that the 5-exo activation Scheme 40. Regioselective 5-exo-dig Cyclizations in Conju- barrier is only 1.4 kcal/mol lower than the 6-endo barrier (at gated Systems the ZPVE-corrected RCCSD(T)6-311+G(3df,2p)//CASSCF/6- 31G(d) level): a noticeable leveling in comparison to the difference between the respective digonal cyclizations of motifs B and C.148 Even still, the authors suggested that the lowest energy pathway for the formation of phenyl radical involves the rearrangement of the 5-exo product via bicyclo[3.1.0]hex-3,5-dien-2-yl radical intermedi- ate instead of direct 6-endo cyclization. The difference between the reaction energies of 5-exo and 6-endo cyclizations is close to the difference in the stabilities of benzene and fulvene. Interestingly, the incipient C 333C bonds in the fully conjugated radicals are 0.30.6 Å shorter than in radicals with a saturated bridge. This trend, along with the high exothermicities, accounts for very early transition states for motif C digonal cyclizations (Figure 18).135 The majority of the literature examples agree with the calculated intrinsic 5-exo preference for the addition of vinyl radicals to triple bonds in conjugated systems. For example, K€onig, Schreiner and co-workers149 reported an example of the 5-exo-dig cyclization of an enediyne promoted by TEMPO (2,2,5,5-tetramethyl-4-piperidin-1-oxyl) radical (Scheme 40). Alabugin and co-workers found that Bu3Sn-initiated cycliza- tions of diaryl substituted enediynes proceed through the same 150 pathway but with considerably improved yields, thus provid- Scheme 41. Selective 6-endo-dig Cyclizations ing a convenient synthetic approach to substituted fulvenes and indenes (Scheme 40).151 Schmittel et al. found that triplet diradicals formed photochemically from enyne-carbodiimides (Scheme 40) and enyne-ketenimines undergo exclusively 5-exo-dig cyclization.152 Similar to the examples discussed pre- viously (Scheme 39), aryl radicals (made by abstraction of a bromine atom) also close regioselectively in a 5-exo-dig fashion in conjugated systems.153 However, this “intrinsic preference” is not absolute and aromaticity-driven 6-endo cyclizations in conjugated systems can compete with the 5-exo pathway.154 For example, Anthony and co-workers153,155 reported that initial 5-exo-dig closure is followed by a surprisingly efficient 6-endo cyclizations in several constrained enediyne systems (Scheme 41). Matzger et al.156 also described thermal cycloaromatization of tri- and tetraynes Moreover, in many cases, the ratio of 5-exo- and 6-endo-dig where, following the 5-exo-dig closure dicussed above (Scheme 40), products is sensitive to the substitution pattern, for example, in R 157 formation of the final product may potentially include, among other the cyclizations of -Bu3Sn-imidoyl radicals 3.238 reported possibities, a selective 6-endo-dig closure (Scheme 41). by Rainier and Kennedy (Scheme 42).158 As with the previous

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Scheme 42. Regioselectivity of Ring Closure Involving Aryl not only increases the thermodynamic favorability of endocyclic Isocyanides Is Dependent upon the Conditions closure but also lowers its activation barrier to the extent where the 5-exo/6-endo selectivity can be fine-tuned by a number of factors, such as the higher sensitivity of the 5-exo pathway to strain. As the result, one reaches a crossover in selectivity: the 6-endo cyclization is kinetically favored in smaller (and strained) bicycles, whereas the 5-exo cyclization has lower barriers when the reactive centers are fused with a larger ring. In particular, strain becomes an especially important factor in cascade radical cyclizations, where rigid polycyclic frameworks are created as the result of sequential cyclizations. Strain effects were estimated by annealing a cyclopentene ring at all possible positions (3.249, 3.251, 3.252). Remarkably, independent of the exact pattern in Figure 19, such a structural change leads to an inversion of selectivity in comparison to the acyclic systems and renders the 6-endo cyclization the kinetically preferred pathway. Because 5-membered rings are more strained than 6-mem- bered rings, annealing the bridge alkene to a cyclopropene examples, the TMS-capped alkyne reacts selectively in a 5-exo-dig introduces ∼34 kcal/mol of strain in the 5-exo product but only fashion. The simple alkyl substituted (R = Bu) and terminal 19 kcal/mol for 6-endo product. Differences between the acyclic alkyne, however, showed a preference for 6-endo-dig closure. and cyclobutene systems are still significant: 19 (5-exo) versus The regioselectivity is altered when thermal initiation/stannyl 7 kcal/mol (6-endo). As a result, the product strain should create radicals are replaced by photolytic cleavage of diphenyl ditellur- a 5-exo f 6-endo crossover in selectivity and render the 6-endo ide. Under these conditions, Ogawa and coworkers found that pathway kinetically favored in the more strained systems. This only the 6-endo-dig product was obtained for both alkyl and observation is of practical value in the design of selective radical aromatic substituted reagents in 2882% yields, while the 164 159 processes and in understanding available experimental results. bulkier TMS and t-Bu groups resulted in no reaction. This For example, it readily rationalizes the switch in selectivity from is in contrast to the findings of Rainier and Kennedy and may be 160 5-exo to 6-endo in strained systems illustrated in Scheme 31 and the result addition of the Te radical to the alkyne, followed by Figure 19. regioselective closure at the carbon of the isocyanide. Another intriguing example is provided by the topologi- cally related diradicals produced in the course of Bergman and MyersSaito cyclizations (Scheme 43). Although Bergman and co-workers reported only the formation of naphthalene product (>10%) in the “double cycloaromatization” of (Z,Z)- deca-3,7-diene-1,5,9-triyne,161 Vollhardt and Matzger found both the 5-exo (19%) and the 6-endo products (2.5%) in a similar system.162 Moreover, Wu and co-workers reported that, depending on the substitution, didehydrotoluene diradicals formed by the MyersSaito cyclization yield either exclusively the 6-endo product (18%) or a mixture of 5-exo and 6-endo products in a ∼4:1 ratio and a 63% combined yield.163 Figure 19. Activation barriers for 5-exo-dig and 6-endo-dig cyclizations of conjugated vinyl radicals fused with rings of varying size (B3LYP/ Scheme 43. Examples of Competing 5-exo-dig/6-endo-dig 6-31G** level). Cyclizations of Conjugated Radicals Other structural modifications besides strain can perturb the relatively close competition between the two cyclizations of motif C.165 For example, as with the parent system (Table 19), one can further differentiate the two cyclizations via introduction of aryl substituents at the terminal carbons. This modification imposes a number of effects on the cyclization (Table 21). For example, 5-exo cyclizations of the isomeric radicals in entries 1 and 3 are accompanied with gain or loss of benzylic conjugation, respectively, and thus have very different thermodynamic com- fi In a detailed theoretical study aimed at providing a uni ed ponents. In contrast, even when the reactant radical is stabilized description of digonal radical cyclizations, Alabugin and Manoharan by benzylic conjugation, the conjugation is invariably lost in the addressed the question whether the basic stereoelectronic 6-endo process. Additionally, the double substitution at the requirements for these reactions (exemplified by the Baldwin termini further disfavors the 6-endo process for R,ω-disubstituted rules) are absolute or can be attenuated or even reversed by substrates (Table 21) because of the significant steric destabiliza- thermodynamic contributions to the reaction barriers.135 They tion caused by the repulsion of two Ph-substituents in the concluded that although the 5-exo pathway usually has a lower naphthalene product. The products of 5-exo cyclization do barrier, the formation of a new aromatic ring (in conjugated systems) not suffer from this steric repulsion between the terminal

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Table 21. SOMOs for the Reacting Radicals, Activation Scheme 44. 5-exo-dig/6-exo-dig Radical Cascade Initiated by Barriers, Reaction Energies, and Intrinsic Barriers Regioselective Tributyltin Radical Addition to the Center Triple (in kcal/mol) for 5-exo-dig and 6-endo-dig Bond a Cyclizations of Phenyl-Substituted Vinyl Radicals

Bu3Sn radical at the central triple bond. A vinyl radical, produced in the intermolecular step, is trapped selectively 5-exo-dig cycliza- tion. This step is critical for the initiation of the cascade and is completely regioselective: no cyclic products derived from the 6-endo closure of the initial radical has been observed. The result- ing vinyl radical is trapped by the third alkyne in a 6-exo-dig cyclization. In the case of phenyl, p-tolyl, and p-anisyl, the fourth step of the cascade is proposed to be cyclization upon the aromatic ring followed by a 1,5 H-translocation and aromatization to give a the final polycyclic structure. When the triyne is capped with TMS, All values in kcal/mol and ring-closing bonds are shown in red (B3LYP/6-31G** level). the fourth step consists of hydrogen abstraction from a silyl methyl and subsequent 5-endo-trig cyclization and aromatization to yield the final product. substituents and are still stabilized by benzylic conjugation. Here, Another interesting radical cascade cyclization results from the both steric and thermodynamics combine to further decrease the reaction of an aryl isothiocyanate with an o-phenylethynyl aryl 5-exo barrier, accounting for the 5-fold increase in the kinetic radical (created from the corresponding diazonium tetrafluoro- 168 pereference for this pathway (>6 kcal/mol) relative to the borate). Higher yields were attained when the arene ring of the competing 6-endo-dig closure in comparison with the preference radical species is with a cyano group substituted para- to the for the entries 3 and 5 (∼1.3 kcal/mol). radical (Scheme 45). The resulting carbon-centered radical Note that for the last two cases (Table 21), intrinsic barriers do cyclizes in a 5-exo-dig fashion, which outcompetes the R- not change and calculated barriers are only affected by different fragmentation of the aryl sulfanyl radical. Unlike the previous reaction thermodynamics. The intrinsic barriers for 5-exo cycli- examples, the 5-exo closure, rather than the 6-endo, provides an zations (entries 3 and 5) are identical and differences in the aromatic product and, accordingly, no 6-endo products were overall activation barriers are solely due to the thermodynamic detected. component (loss of benzylic conjugation in the first case). In contrast, the 6-endo intrinsic barrier increases for the latter case Scheme 45. Formation of Isomeric Quinoline Structures Resulting from a Radical Cascade Initiated by Addition of an which suggests that steric interaction between the terminal substituents is already present at the TS stage. Aryl Radical to the Carbon Sulfur Double Bond Interestingly, the intrinsic barriers for entries 2 and 4 are also similar, suggesting that the deactivating effect of benzylic con- jugation is compensated by the difference in hybridization and geometry. Aryl-substituted radicals have very little s-character and almost linear geometry at the radical center, whereas simple vinyl radicals have significant amount of s-character and are noticeably bent. Besides the usual consequences for chemical reactivity and orbital energies, hybridization also controls 3.3.2. Anionic Cyclizations (Table 22). As with the smaller molecular geometry and determines the direction in which analogs, 5-exo-/6-endo-dig closures of the parent anionic sys- the radical orbitals are projected in space (the valence angles), tems exhibit lower intrinsic and activation barriers for exocyclic as well as the relative size of the two lobes of a nonbonding closure. Unique to this system, however, are the similar exother- orbital.166 Such differences in the projection trajectory should micities for both exo- and endocyclic closure. While the conver- have stereoelectronic consequences for the attack at the acetylene sion of a weaker bond into a stronger bond (π-bond f σ-bond) π-system (see section 2.5.2). and the concomitant transformation of an alkyl anion into a more On the basis of the above results, Alabugin et al. developed a stable vinyl anion makes carbanionic closure effectively irrever- radical cyclization cascade transforming polyynes into conju- sible, closure of oxygen anions, however, are either thermo- gated structures similar to those present at the tip of carbon neutral or weakly endothermic (Figure 20 and Table 23).24 nanotubes. When triyne molecules are capped with either phenyl, The 5-exo trajectory of carbanionic closure approaches that of p-tolyl, or trimethylsilyl groups, the radical cascade proceeded the intermolecular angle of attack, and because of the longer smoothly in ∼70% yields (Scheme 44).167 The success of the linking chain within this system, the endocyclic transition state cascade relies upon the regioselective intermolecular attack of the now attains an obtuse trajectory (Table 24).

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Table 22. Literature Examples of 5-exo/6-endo-dig Anionic Table 23. Activation, Reaction, and Intrinsic Energies (kcal/ a Closure with Respect to the Environment of the Anionic Center mol) for the Parent 5-exo- and 6-endo-dig Radical Digonal Cyclizations at the B3LYP/6-31+G(d,p) and M05-2X/6-31 a +G(d,p) Levels of Theory

a The M05-2X data are given in parentheses and the ring-closing bond is shown in red.

so for the analogous H, Me, and TMS-substituted alkynes. The most important effect of the anion-stabilizing terminal phenyl group is that its presence renders this 5-exo-dig closure >12 kcal/mol more exothermic than the other 5-exo-dig closures in (Table 23, Table 24). Marcus theory readily demonstrates that the effect of this additional product stabilization should be sufficient to make the reaction barrier disappear. Indeed, once the reaction energy and the intrinsic barrier169 for this reaction are substituted to the Marcus eq 1, the reaction barrier vanishes.24 The cyclizations of alkyl lithium reagents, generated from alkyl iodides170 and connected to an alkyne via a fully saturated linker, proceeds exclusively via the 5-exo-dig pathway (motif a x marks denote gaps in the literature. Motif structures are given in A). Bailey and co-workers have analyzed this anionic competi- Scheme 1, and D E do not apply to anionic closures. tion comprehensively and found no evidence for the formation of 6-endo-dig products. For alkyl substituted alkynes, the cyclization is relatively sluggish at the room temperature, in a full agreement with the measured activation parameters (a half- q q life of ∼7minat∼29 °C, ΔH =23( 0.9 kcal/mol, ΔS =+4( 3.3 eu). The relatively high activation barriers are likely to reflect the effects of aggregation, solvation as well as nature of the counterions. The phenyl-substituted analogue cyclizes much faster (a half-life ∼6minat51 °C, suggesting ∼106 times acceleration at the low temperatures).171 TMS-substi- tuted alkyne also shows complete 5-exo regioselectivity and ∼95% yield (Scheme 46).96,172 Stereoselective syn-addition is observed, suggesting that the Li atom is transferred intramole- cularly to the developing carbanionic center. Physical basis for these results has been suggested to lie in the stereochemical requirements of the ring closure transition state. This intramo- ff Figure 20. Electronegativity e ects on the M05 2X/6-31+G** poten- lecular coordination could not occur in the 6-endo-dig transi- tial energy surfaces for the 5-exo-/6-endo-dig anionic cyclizations of tion state and may be one of the factors that aid in the complete C- (black solid, bold), N- (blue dashed, italics), and O- (red dashed, 24 underlined) centered anions with terminal alkynes. regioselectivity observed. With a bulky group at the pro- pargylic carbon, the well-defined TS allows for stereoselective According to DFT calculations, carbanionic 5-exo-dig closure synthesis of chiral cyclopentanoid building blocks in 7099% is barrierless in the case of the Ph-substituted alkyne but not yields (Scheme 46).173

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Table 24. Transition State Geometries, NICS (0) Values, and Scheme 47. sp3-Nucleophiles with Two sp2 Centers in the LUMO Plots for 5-exo/6-endo Carbanionic Cyclizations for Chain Linking the Nucleophile with the Alkyne the Me-Substituted Alkyne Calculated at the M05-2X/ c 6-31+G** Level

Although the analogous cyclizations of σ-vinylexo anions (motif B) are still fully 5-exo-dig selective, the reactions are much slower (sp2-hybridized carbanions are less reactive) and simple alkyl substituted alkynes mostly give the products result- ing from intermolecular capture of the intermediate acyclic vinyl anion (Scheme 48). This limitation notwithstanding, the cyclizations of aryl or silylated alkynes proceed smoothly (8394%).172b,174

Scheme 48. Nucleophilic 5-(σ-Vinylexo)-exo-dig Ring Closure of Vinyl Lithiums

Negishi and co-workers have shown that simple σ-vinylendo anions (motif C) also undergo selective 5-exo-dig cyclizations172b a (Scheme 49). Later, Myers and co-workers have utilized such Energies are given relative to the near-attack conformations (NAC). The anti-anti conformation is ∼45 kcal/mol stable than regioselective closure of reactive species formed via Br Li the NACs. b This cyclization is barrierless. c Bond lengths given in Å. exchange at an endocyclic vinyl bromide adjacent to an ethynyl Activation, reaction, and intrinsic energies (kcal/mol) for the moiety in the development of synthetic approaches toward parent 5-exo- and 6-endo-dig anionic cyclizations at the B3LYP/ Kedarcidin and related natural products. These examples of 6-31+G(d,p) and M05-2X/6-31+G(d,p) levels of theory. M05-2X 5-(σ-vinylendo)-exo-dig cyclizations gave the desired product in data are given in parentheses and the ring-closing bonds are shown up to 52% (Scheme 49)175 At the reported experimental condi- in red. tions (78 °C in THF), this reaction is believed to proceed 176 through a carbanionic pathway.172b, σ Scheme 46. sp3-Anionic 5-exo-dig Closures with Completely Scheme 49. Regioselective 5-( -Vinylendo)-exo- Saturated Linkers dig Cyclizations

Using a thiazole bridge, Arcadi et al. have proposed that an imine intermediate is what undergoes a 6-(σ-vinylendo)-endo-dig The regioselectivity of alkyl lithium reagents for TMS- cyclization onto aromatic- and aliphatic-substituted alkynes in substituted alkynes is unaffected by two sp2 carboninthe 7495% yields (Scheme 50).177 Wu and co-workers found that bridge, affording the 5-exo-dig closure in excellent yields when an iminyl anion is attached to a benzene ring, the (94100%, Scheme 47).172b regioselectivity can be tuned based on the nature of the alkynyl

6541 dx.doi.org/10.1021/cr200164y |Chem. Rev. 2011, 111, 6513–6556 Chemical Reviews REVIEW substituent.178 Upon addition of methoxide to the nitrile, the Scheme 52. 5-exo-dig Product, Trapped through Elimina- nitrogen anion regioselectively attacked in a 6-endo fashion when tion of a Fluoride Ion, Is Formed Regioselectively, although the alkyne was terminated with an alkyl group. Conversely, when the 6-endo-dig Product would be Aromatic R was an aromatic group, the ring closure was exclusively 5-exo (Scheme 50).

Scheme 50. Regioselective N-Centered 6-(σ-Vinylendo)- endo-dig Closure with a Thiazole Linker Regardless of the a Nature of the Alkynyl Substituent

examples should have an effect on the observed reactivity as well. Enolendo substrates ((C-allylendo2), motif G), with the carbonyl in the exterior propargylic position, react similarly to the re- spective enolexo nucleophiles.182 a Scheme 53. Anionic 5-exo-dig Closures Controlled by Benzene-linkers allow for tunable cyclizations based on substitution. Polarization of the Triple Bonds Zhu et al. have found that when the nitrile moiety is replaced by an isonitrile (formed in situ by the dehydration of o-ethynyl formamides), exclusive formation of the 6-endo-dig product 179 3.290 is observed when exposed to n-Bu4Cl. Interestingly, while excellent yields were obtained for both alkyl and aromatic substituents, the TMS derivative resulted in no cyclic product while the sterically similar t-Bu group closed efficiently (Scheme 51). The radical version of the same TMS derivative resulted in an 82% yield of the 5-exo product (Scheme 42). Scheme 51. Carbanions Derived from Isonitriles Close ffi σ E ciently and Regioselectively in a 6-( -Vinylendo)-endo- While the above allylexo examples are chemoselective for dig Fashion closure through the carbon atom of the enol, Arcadia and co- workers have observed an interestingly solvent dependence for the chemoselectivity of allylendo closures. While closure via the carbon nucleophile (C-allylendo2) is observed in a protic solvent, when an aprotic solvent is used, furans are obtained exclusively by 5-(O-allylendo2)-exo-dig closure (Scheme 54). The same chemo- and regioselectivity is observed for oxygen attack onto terminal and aryl-substituted alkynes (vide infra, Scheme 57).182

Aryl carbanions conjugated to the alkyne moiety can form the Scheme 54. Chemoselectivity of 5-(Allylendo)-exo-dig σ nonaromatic product (5-( -vinylendo)-exo-dig) if the acetylenic Closure Controlled by the Nature of the Solvent group has a leaving group, which West and co-workers utilized for the first preparation of a 1-silaallene moiety in near quanti- tative yield.180 One has to note, however, that steric effects im- posed by the bulky silyl groups are likely to play substantial role in this example as well (Scheme 52). An interesting comparison, which illustrates the potentially useful effect of alkyne polarization on the regioselectivy of ring closure, is provided in Scheme 53. Trost and co-workers have shown that enolates (C-allylexo) regioselectively undergo 1,4- Michael addition onto ester-substituted alkynes (Scheme 53).181 When the polarization of the alkyne is reversed, Lavallee and co- workers have shown that enolate closure follows the 6-(C-allylexo)- endo-dig pathway. The 6-endo Michael addition products are formed for terminal and internal alkyl-substituted alkynes in 4789% yields.100 One has to note, of course, that the different Solvent can also modify the observed regioselectivity. For example, nature of nucleophiles, with regards to stability, in these two in nucleophilic cyclizations of motif H for oxygen nucleophiles

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(O-allylendo3), Miranda and co-workers183 found that the “anti- Scheme 57. Base-Catalyzed 5-exo-dig Cyclizations of Pri- a Michael” 5-(O-allylendo3)-exo-dig product is formed in 79% yield mary and Secondary Alcohols onto Terminal Triple Bonds when using a protic solvent (EtOH). However, in acetone, the major product derives from the formal 6-(O-allylendo3)-endo- dig closure. These observations suggest that the 5-exo cycliza- tion is kinetically favorable and gives the product as long as the cyclized carbanion is quickly and irreversibly trapped by proton- ation. In an aprotic solvent, the initially formed 5-exo-dig vinyl anion has enough time to rearrange to the more stable 6-endo-dig product, as has been suggested in similar systems (Scheme 55).184,56 Tietze and co-workers have used this strategy for six-membered ring formation in their syntheses of several anthrapyran natural products.185 Scheme 55. Solvent-Dependent Cyclizations of Oxygen Anions with Three sp2-Atoms in the Linking Chain

a Benzylic alcohols also close regioselectively onto phenyl-substituted acetylenes. group derived from addition of guanidine to the carbonyl moiety of peri-substituted acetylenic anthraquinones 3.324.Thepresence of several nucleophilic and electrophilic centers in this group A formal 6-(O-allylendo2)-endo-dig cyclization has been accounts for the multichannel mode of its interaction with the 186 reported by Padwa et al. (Scheme 56). However, the authors adjacent alkyne and several reaction cascades potentially originating do not exclude the initial formation of a 5-exo product which from alternative cyclization modes. Interestingly, the nature of sub- could rearrange in the six-membered benzopyran ring under stituent R has the ability to control partitioning between these workup conditions, similar to an analogous rearrangement cascades through modulation of the polarization of the triple bond. reported by them for similar benzylic alcohols (vide infra, Presence of an acceptor substituent at the β-carbon decreases Scheme 57). electron density at the R-carbon, thus facilitating favors the 5-exo attack of the oxygen atom in the hemiacetal intermediate Scheme 56. Formal O-6-(enolendo)-endo Cyclization (Scheme 4). Subsequent transformations in this cascade lead Closure onto Aryl-Substituted Alkynes to a remarkable transformation that is is formally equivalent to the full cleavage of the triple bond and insertion of a nitrogen atom between the two acetylenic carbons. Scheme 58. Diverging Mechanistic Pathways and Factors Responsible for the Multichannel Character of Reactions in Adducts of Peri-Substituted Acetylenyl-9,10-anthraquinones and Guanidine

Cyclizations of other oxygen nucleophiles corresponding to motif A are also common. As expected based on the above cal- culations (Table 23), base-catalyzed cyclizations of aliphatic alcohols exclusively follow the 5-exo path, the vinyl anion serving as the base for another acyclic alcohol. When a secondary allylic alcohol187 is used as opposed to a primary alcohol,188 gem-dimethyl groups are required to facilitate the regioselective transformation. Trost and Runge found that reactions of secondary allylic alcohols with elec- tron deficient alkynes were inefficient(<30%)butledtothetetra- hydrofuran through the formal 1,4-Michael addition (aka 5-exo-dig closure) to the polarized alkyne bond.189 The incorporation of additional sp2 atoms in the bridge does not change 5-exo-dig selectivity for oxygen nucleophiles (Scheme 57).186 Vasilevsky, Alabugin, and co-workers sought a deeper under- Activation of the alkyne moiety has been suggested to be standing of the factors controlling exo/endo selectivity in cycliza- important for weaker O-nucleophiles such as benzoates. tions of alkynes through analysis of the possible cyclization path- Kanazawa and Terada192 proposed that the conjugate acid of ways in the system shown in Scheme 58.190 This system combines the base facilitates formation of the exocyclic vinyl anion and an activated alkyne moiety with a polyfunctional hemiaminal quickly traps the cyclic product through protonation.191 193 The

6543 dx.doi.org/10.1021/cr200164y |Chem. Rev. 2011, 111, 6513–6556 Chemical Reviews REVIEW majority of the aromatic-substituted alkynes exclusively gave The involment of Cu-π-complexes and the role of EPN processes in the five-membered ring with high yields (8099%). However, these reactions is unexplored. appreciable amounts of 6-endo-dig products were observed for o-MeO-C6H4 (Scheme 59), which is possibly the result of a “ ” Scheme 61. Cuprate Coupling and Subsequent Regioselec- 6-membered coordination with the acid activating position 6 tive 6-endo-dig Cyclizations of Carboxylic Acids Where the (3.333). Interestingly, while n-pr showed only a slight preference Two Functional Groups Are Fused to a 5-Membered Ring for 5-exo cyclization (5/6 = 58:36), 2-propenyl substitution gave only 5-exo-dig closure. The authors also note that the introduction of an electron-withdrawing group para to the alkyne (Ac) “markedly retards the (5-exo) cyclization” and leads to the formation of 8% of the 6-endo-dig product (Scheme 64). The regioselectivity for closures of this system is reversed, however, under acidic conditions (see section 3.3.3).

Scheme 59. Weaker Oxygen Nucleophiles (Benzoates), un- der Catalytic Amine-Base Conditions, Observe a Loss in 5-exo Regioselectivity with Certain Alkyne-Substituents

The questions of 5-exo/6-endo selectivity in digonal cycliza- Castro and co-workers showed that the condensation of tions of N-nucleophiles (motif G) have been studied by Vasilevsky, o-halobenzoic acids with substituted copper acetylides in DMF 56 or pyridine leads, in most cases, to 5-membered lactones. Only in Alabugin and co-workers. Alkyl substituents at the alkyne terminus the case of n-propylacetylide has some of the 6-endo product favor the 6-endo-dig closure, whereas aryl groups greatly fascilitate been observed (phthalide:isocoumarin ratio 2:1).194 The analo- the alternative 5-exo-dig path. gous cyclization of o-ethynylbenzoic acid also afforded the The competing cyclization pathways were fully analyzed com- γ 195 putationally. Both the decreased 5-exo-dig activation energies -lactone product of 5-exo-dig closure (Scheme 60). The fi involvement of Cu-π-complexes and the role of EPN processes and increased stability of the 5-exo products for R = Ph con rm in these reactions is unexplored. that the Ph group steers the cyclization selectively down the 5-exo path by providing benzylic stabilization to the anionic Scheme 60. Cyclizations of Benzoic Acids, Following center in the product. In contrast, the competition between the Cuprate Addition, Prefers the 5-exo-dig Pathway 5-exo- and 6-endo-dig closures is close for alkyl substituted acetylenes. For R = Me, the values of the cyclization barriers are within 1 kcal/mol from each other and thus, both cyclizations can proceed with comparable rates. Although the 5-exo

Scheme 62. Fine-Tuning of the Regioselectivity of N-Amide Nucleophilic Closures via Electronics of the Alkyne Moiety

Interestingly, the 5-exo-dig preference observed for the benzoic acid derivatives can be completely overruled when a more strained five-membered heterocyclic core is used. A variety of N-containing heterocycles, shown in Scheme 61, exhibit complete 6-endo-dig selectivity.195,196 These observations are consistent with the earlier discussed role of strain on the competition between closely matched radical cyclization (section 3.3.1 on 5-exo/6-endo-dig radical).

6544 dx.doi.org/10.1021/cr200164y |Chem. Rev. 2011, 111, 6513–6556 Chemical Reviews REVIEW cyclization has a 0.6 kcal/mol lower barrier than the 6-endo case where only 5-exo product has been observed for a benzene- closure in the gas phase, introduction of solvation reverses this derived substrate (Scheme 65). This observation is likely to have preference. Moreover, the 5-exo-dig cyclization is predicted to be its origin in the same strain effects as those discussed previously endothermic and readily reversible in solution, whereas the for radical closures (Figure 19). O-attack via a 6-exo or 7-endo 6-endo-dig closure is ∼10 kcal/mol exothermic. The higher closure was not observed.199 computed activation barriers for both 6-endo and 5-exo cycliza- tions of alkyl substituted alkynes are consistent with experimental Scheme 65. Switch in the 5-exo/6-endo Selectivity As the observations (Scheme 62).56 Function of Annealed Ring Size These anionic cyclizations lack a significant thermodynamic driving force because the gain in stability due transforma- tion of a weak π-bondintoastrongerσ-bond is offset by the transformation of a stable nitrogen anion into an inherently less stable carbanionic center. Formation of the finalproductsisnego- tiated through several proton shifts, ultimately leading to the most stable tautomeric anion as a thermodynamic sink (Scheme 63).56 Scheme 63. Full Potential Energy Surface for the Competing 6-endo and 5-exo Cyclizations of Hydrazide Anions at B3LYP/6-31+G(d,p) Level of Theory 3.3.3. Electrophilic Cyclizations (Table 25). Unlike the 3-exo/4-endo and 4-exo/5-endo pairs, electrophilic 5-exo/ 6-endo cyclizations are relatively well studied. The electrophilic closure of carbocations (motif A) and oxonium ions (π-vinylexo/ endo, motifs D, E) are particularly well represented. The latter processisreferredtoasthe“Prins-type” closure. Cyclizations onto diazonium salts (σ-vinylendo, motifs B, C), called the Richter cyclization, have also been investigated.

Table 25. Literature Examples of 5-exo/6-endo-dig Electrophilic Closure with Respect to the Environment a of the Electrophilic Center

In contrast, aryl amides cyclize under basic conditions into the 6-membered products even with a phenyl-substituted alkyne (73%, Scheme 64).197 However, when the linking chain is saturated, the cyclizations of β-alkynyl amides proceed exclusively through the 5-(N-allylendo2)-exo-dig pathway (Scheme 64).198

Scheme 64. Regioselectivity of Anionic Cyclizations of β- Alkynyl Amides Is Influenced by the Nature of the Linking Carbons

a x marks denote gaps in the literature. Motif structures are given in The regioselectivity of anionic closure of o-ethynyl-benzene- Scheme 1. Motifs B and FH are unknown. hydroxamic acids has been found to depend on the nature of the aromatic linker. Interestingly, change to a pyrazolyl core again The regioselectivity of the parent carbocationic system leads to the switch from 5-exo to 6-endo selectivity, even in the is dictated, as with the 3/4 analogs, by the substituent on

6545 dx.doi.org/10.1021/cr200164y |Chem. Rev. 2011, 111, 6513–6556 Chemical Reviews REVIEW the alkyne (NPEC). Upon solvolysis in acid, primary tri- Scheme 68. 5-(π-Vinylexo)-exo and 6-(π-Vinylexo)-endo- flates109 and secondary tosylates200 exhibit complete endo- dig Electrophilic Cyclizations of Oxocarbenium Ions cyclic regioselectivity in cyclizations with terminal alkynes. Likewise, when a strongly stabilizing group such as a phe- nyl caps the triple bond, complete exo regioselectivity is observed.201 Unlike homopropargylic cations, where methyl substitution resulted in almost exclusive formation of the 4-endo-dig product (Scheme 7, Scheme 8), both primary and secondary carbocations yield a mixture of the 5-exo- and 6-endo-dig products, favoring the exocyclic pathway (Scheme 66).109,200 Scheme 66. Regioselectivity of 1° and 2° Carbocationic Closure Is Dictated by the Alkynyl Substituent

Scheme 69. Selective 6-endo-dig Closure in the Prins-Type Cyclization of Homopropargylic Alkynes Tertiary carbocations behave similarly, yielding the regio- selective formation of spirocyclic202 or bicyclic203 ketones resulting from the 5-exo-dig closure onto phenyl-substi- tuted alkynes. The cyclization is equally successful under acidic solvolysis of 3° alcohols or protonation of an olefin (Scheme 67).

Scheme 67. Tertiary Carbocations Close Efficiently and of a dihydropyranyl cation.209 While the TMS-containing cyclic Regioselectively onto Phenyl-Substituted Alkynes cation is a shallow minimum whose formation is 5.4 kcal/mol endothermic, the parent dihydropyranyl cation is not even an energy minimum but exists only as a TS for the Cope rearrangement TS q (ΔE ≈ 7 kcal/mol, Figure 21). The alternative 5-exo-dig direction has not been considered and it is not clear whether the 5-exo product may be formed transiently and rearrange to the dihydropyrane.

Harding and King described the formation of 5-exo and 6-endo products (π-vinylexo, motif D)in∼55:45 ratio upon the exposure 204 of hept-6-yn-2-one to BF3Et2OorHCl. However, when bicyclic products are formed, the regioselectivity can be efficiently controlled through substitution of the triple bond. The exclusive formation the 6-(π-vinylexo)-endo-dig product upon reaction with terminal al- kynessuggeststhatthestabilityofthe intermediate vinyl cation plays the decisive role in regioselectivity of this ring closure.205 These results are in accord with earlier findings by Keirs et al., who observed 6-(π-vinylexo)-endo-dig closure for terminal alkynes. In the latter case, the cyclic vinyl cation was trapped through intramo- lecular hydride transfer (Scheme 68).206 Exocyclic closure has been Figure 21. Relative stability of the cationic intermediates of the Prins- observed for internal alkynes.205 type cyclization at the B3LYP/6-31G(d) level. The Prins-type cyclization, resulting from homoallylic alcohols and aldehydes has been shown to favor the 6-endo products.207 In a seeming conflict with this computational data, terminal Homopropargylic alcohols also undergo this transformation via a alkynes also react regioselectively in a 6-endo-dig fashion in 6-(π-vinylendo)-endo-dig product when exposed to a Lewis acid, Prins207 and aza-Prins reactions210 promoted by Fe(III) halides 208 for example FeCl3 (Scheme 69). (Scheme 70). It should be noted however, as discussed by DFT analysis (B3LYP/6-31G(d) level) revealed that the Martín, Padron, and co-workers, FeX3 not only activates the electronic effect of the TMS group is crucial for the formation carbonyl moiety as a Lewis acid but also participates in “forming

6546 dx.doi.org/10.1021/cr200164y |Chem. Rev. 2011, 111, 6513–6556 Chemical Reviews REVIEW alkyne-iron complexes that may be an initial step in further Scheme 72. Effects of Lewis Acid/Nucleophile upon the chemical events.”211 Regioselectivity of Prins-Type Cyclizations of Homopro- pargylic Alcohols Scheme 70. Prins-Type Closure of Terminal Alkynes

The presence of the external nucleophile also plays a critical role in the cyclizations of these stabilized acyclic cations. Over- man and Sharp examined the NPE cyclizations of a series of aza- Prins cyclizations, observing a lack of cyclic products in the absence of external nucleophile and chemoselective 6-exo clo- sure onto an alkyne in the presence of a pendant alkene capable of Scheme 73. In situ Formation of Diazonium Salt, Trapped by undergoing 5-exo-/6-endo-trig closure. While exocyclic closure is 6-endo-dig Closure upon Intermolecular Attack of a Chlorine observed in the 6/7 pair for terminal and internal alkynes, electro- Anion philic cyclization proceeded exclusively in a 6-endo-dig pathway upon exposure to either bromide or iodide (Scheme 71).32,33

Scheme 71. Nucleophile-Promoted Electrophilic Closures of Iminium Ions with Alkynes in the Presence of Strong a Nucleophiles

in up to 53 and 93% yields for the chloro- and bromo-derivatives, respectively.217 The effect of temperature is also critical to the products obtained. ° When alkyne 3.433 istreatedwithHBr(aq) at 95 C, exclusive formation of 6-endo-dig product 3.436 is observed;218 however, at room temperature the major product was that of 5-exo-dig cyclization (3.435,Scheme74).219

Scheme 74. Effects of Temperature on Product Distribution of a HX = camphorsulfonic acid. p the Richter Cyclization with ( -MeOC6H4)-Substituted Alkynes

Aside from facilitating the cyclization, the external nucleophile, as well as the Lewis acid, can modify or even control the regioselectivity of the cyclization. While the above FeCl3-induced closures were all endo selective, a mixture of products favoring 5-(π-vinylendo)-exo- 110 dig closure is observed for SnBr4 or BF3 3 OEt2. Cho and co- workers have shown that, through two subtle modifications (a 2° benzylic homopropargylic alcohol as opposed to a 2° aliphatic and using TMSOTf as a Lewis acid) the regioselectivity can be completely tuned toward 5-(π-vinylendo)-exo-dig closure (Scheme 72).212 A highly selective and efficient 5-exo-dig ring closure of a Ph-substituted alkyne, which may proceed through a similar oxocarbenium intermediate, is also known.213 NPEC can also occur between “two” triple bonds (CtC and NtN), as exemplified by the Richter reaction,214 where cyclization between a vicinyl alkyne and diazonium salt is observed only in the presence of a suitable nucleophile (motif C, Scheme 73). Initial studies observed the formation of hydroxy- cinnoline derivatives, where simultaneous attack of a water The nature of the cyclic core also has a significant influence on molecule on the interior carbon of the alkyne and C Nbond the regioselectivity of cyclization. The effects of temperature can 215 formation was proposed. Vasilevsky and Tretyakov found be superseded by those of strain, as shown by Vasilevsky et al., that nucleophilic attack by a less nucleophilic halogen anion where no formation of the 5,5-bicyclic product was observed can outcompete that of water at room temperature, giving (Scheme 75).216 When 2-acetylenic anthraquinone-1-diazonium halogenated 6,6 (cinnolines) and 5,6 (pyrazolopyridazines)216 salts are exposed to similar conditions at room temperature,

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Scheme 75. Effects of Aromatic Core on Regioselectivity of nucleophiles (Scheme 57) close regioselectively onto terminal or Cyclization alkyl-substituted triple bonds in a 6-endo-dig fashion in the presence of an external electrophile223,224 (Scheme 76). Interestingly, the regioselectivity of oxygen nucleophiles derived from addition to, or tautomerization of, a ketone (using a Au cat.) depends on the substitution at the bridge carbon as well as the nature of solvent (Scheme 76).225 When a nonmetal external electrophile is used such as I2 or PhSeBr, hemiacetates derived from benzaldehyde undergo addition and subsequently close regioselec- tively onto phenyl or alkyl-substituted alkynes in a 6-endo-dig fashion. When the aldehyde was exchanged for a methyl ketone, however, only the 5-exo-dig product was obtained.226 sp2-Hybridized nitrogen nucleophiles undergo efficient and regio- selective 6-(σ-vinylendo)-endo (imines,227 hydrazides,228 oximes229) and 6-(σ-vinylexo)-endo (azides230) -dig closure in the presence of 231 external electrophiles such as I2,Pd,orAg (Scheme 77).

Scheme 77. Regioselective 6-(σ-Vinylendo)- and 6-(σ- vinylexo)-endo-dig Closures of Nitrogen Nucleophiles in the Scheme 76. Electrophile-Induced Nucleophilic Cyclizations Presence of External Electrophiles of Carbon and Oxygen Species

Formation of [2.2.2]-bicyclic structures from stabilized enolates via a selective 6-endo fashion has been reported to occur in up to 89% yield in the presence of Au(I) salts (Scheme 78).232 Endo-233 and exocyclic enamines were reported to close differently in the presence of a gold catalyst234 (Scheme 78). The formation of aromatic products directs the Cu(II) cyclizations of 3.475 and 3.476, resulting from regioselective O-centered235 5-exo- and N-centered236 6-endo-dig closures, respectively (Scheme 78). Contrary to several examples discussed above (Scheme 61), the ring-closure of carboxylic acid derivatives, whether attached to a 5- or 6-membered ring, regioselectively close in a 6-endo-dig fashion when exposed to Cu(I) and (II) salts,237 Ir(III) hydrides,238 239 or I2 (Scheme 79). When benzamides are exposed to a variety of external nonmetal electrophiles, only modest to good selectivity for 5-exo-dig closure is observed.240 3.3.5. Summary of 5/6. The parent carbon-centered radicals and anions close regioselectively in a 5-exo fashion, matching the calculated activation barriers (Figure 22). However, the exo/ endo barriers for carbon radicals are less than 3 kcal/mol apart and if exclusive formation of the NPE-5-exo-dig product is observed for 220 the linking chain is a trans-fused 5-membered ring, increased strain terminal as well as alkyl- and aryl-substituted alkynes. in the smaller ring selectively directs the radical closures (motif A) 3.3.4. The Effect of Metal/External Electrophiles on along the 6-endo-dig path (Scheme 31). The effects of fused rings 5-exo/6-endo Regioselectivity. Representative examples σ 221 on the regioselectivity of ( -vinylendo, motif C) radicals has been provided in this section illustrate that, in contrast to the examined computationally (Figure 19). Regardless of the alkynyl uncatalyzed cyclizations of carbon nucleophiles which usually substitution or the possibility of the formation of an aromatic prod- proceed with a 5-exo-dig regioselectivity, formation of the 6-endo uct, the majority of σ-vinyl radicals close in an exocyclic fashion. product is common in cyclizations promoted by coordination of Similarly, anions also are generally regioselective for the 5-exo-dig an external Lewis acid, particularly when an aromatic product is mode of closure, including primary and vinyl (σ-vinylexo/endo) car- formed (Scheme 76).222 In a similar manner, sp3-hybrized oxygen banions (Scheme 46-Scheme 49), primary, secondary, and benzylic

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Scheme 78. Regioselective Closures of Enols, Enamines, and Aniline Derivatives in the Presence of Metal Species

Figure 22. Electronegativity effects on the M052X/6-31+G** poten- tial energy surfaces for the 5-exo-/6-endo-dig anionic and radical cycliza- tions of C-, N-, and O-centered anions (black dashed, bold) and radicals (red solid, italics, underlined) with terminal alkynes.

strongly stabilizing group (Scheme 68). Carbocations close regioselectively in a 5-exo fashion onto phenyl substituted alkynes (Scheme 67). The same regioselectivity is not always observed, however, for nitrogen electrophiles (Richter cyclizations, Scheme 74, Scheme 75). 4. CONCLUSIONS: REVISED RULES FOR ALKYNE CYCLIZATIONS Literature reports of cyclization modes predicted to be unfavorable together with the lack of several cyclizations modes Scheme 79. EIN Closure of Benzoic Acid and Benzamide predicted to be favorable by the original rules, (for example, Derivatives anionic/radical 4-endo-dig closures) call for a revised set of rules for alkyne cyclizations. We propose several modifications. First, we suggest to modify the classification system and expand the types of cyclizations to favored (green in Table 26), borderline (yellow), and disfavored (red). This “middle ground” was added to describe a select number of examples, where a varying degree of assistance is required to attain the desired product (e.g., adjacent leaving groups, strongly delocalizing and stabilizing substituents, thermodynamical stabilization of the product by aromaticity etc.). In addition, “favorability” has two components: intrinsic stereo- electronics that originate from the differences in the orbital overlap patterns, and full activation barriers which combine the intrinsic barriers with thermodynamic components. From the fundamental and didactical perspectives, the first definition is valuable but the second is more useful in practice. Based on the first criterion with oxygen nucleophiles (Scheme 57) aswellashydrazides(Scheme63). regards to anionic and radical closure (Table 26), one can clearly The regioselectivity of the respective enolate closures can be tuned classify all exo-dig cyclizations as favorable. However, because of the based on the polarity of the alkyne; when a carbonyl group is in inherent strain of 3- and 4-membered rings, these closures are less the exterior propargylic postion, enolates close in a 5-exo fashion. kinetically favorable241 than closures with normal thermodynamic When the polarity is reversed, so is the regioselectivity (Scheme 53). driving forces and require careful experimental design, justifying Finally, while benzamides have been shown to close regioselectively their classification as “borderline”. The formation of 3- and (6-endo, Scheme 64), the cyclizations of aromatic hydroxamic acids 4-membered rings via endocyclic closure is unfavorable. Under are more sensitive to the size of the aromatic core (6-membered certain conditions and structural modifications, 5- and 6-endo-dig rings result in 5-exo cyclization, 5-membered rings yield the 6-endo closure of anions can be obtained regioselectively and as such have products, Scheme 65). been labeled “borderline”. Because of the differences in the stabiliz- The regioselectivity of NPE 5-exo/6-endo closures, as with ing interactions of the LUMO and SOMO with alkynes, radical the 3/4 series, depends upon the nature of the Lewis acid and 6-endo cyclizations are more favorable than their anionic alkynyl substitution. Exclusive formation of 5-membered rings counterparts.242 is observed for Prins-type closures using TMSOTf (Scheme 72), With respect to electrophilic closures, the following rules can be while only 6-endo-dig products are obtained using FeCl3 suggested on the basis of a still rather limited data set (Table 27). As (Scheme 69, Scheme 70). Mixtures are formed when either with the cyclizations of anionic/radical intermediates, 3-endo-dig SnBr4 or BF3 3 OEt2 (Scheme 72) is used, as well as for closure is a disfavored reaction. Products resulting from nucleophilic non-Prins-type oxycarbenium closures in the absence of a attack (NPE) onto 3-center, 2-electron nonclassic cation (3-exo/

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Table 26. Revised Baldwin Rules for Digonal Cyclizations of AUTHOR INFORMATION a Anions and Radicals Corresponding Author *E-mail: [email protected].

BIOGRAPHIES

a Red squares correspond to disfavored, yellow squares to borderline/ problematic, and green to favored modes of ring-closure.

Table 27. Revised Baldwin Rules for Digonal Cyclizations of a Cationic Intermediates

a Red squares correspond to disfavored, yellow squares to borderline/ problematic, and green to favored modes of ring-closure. Kerry Gilmore was born in 1984 in Brewster, Massachusetts. He received B.S.s in Biology and Chemistry from Roger Williams 4-endo pair), under the right conditions can proceed efficiently and University in 2006 working under the direction of Prof. Dan von even be obtained regioselectively, and these closures are deemed Reisen. After that, he began his doctoral studies at Florida State “borderline”. While there are no examples of electrophilic 4-exo- and University under the direction of Prof. Igor Alabugin. He is also a 5-endo-dig closures in the literature, we predict these cyclizations to 2011 Fulbright scholar, working in Bologna, Italy under the be difficult but potentially achievable given the appropriate substitution/ direction of Dr. Chrys Chatgilialoglu. His Ph.D. studies include conditions. Finally, both 5-exo and 6-endo products can be discovery of new cyclizations of alkynes, incorporation of these obtained regioselectively, depending upon substitution and the processes into cascade transformations, as well as the dissection nucleophile, and are classified as favorable. and reevaluation of the structural and electronic effects involved In summary, the combination of computational, theoretical in nucleophilic, radical, and electrophilic ring closure processes. and experimental data presented herein has clearly shown that both anionic and radical endo-dig cyclizations are intrinsically less favorable than the competing exo-dig closures. The origin of this preference lies in the greater magnitude of stabilizing bond-forming interactions for the obtuse angle of nucleophilic (and to a lesser extent, radical) attack. This stereoelectronic preference is similar to the well-established B€urgiDunitz trajectory for the cyclizations of alkenes. Intrinsic stereoelectronic preferences for exo-dig closure can be overshadowed by additional factors, such as polarization of the π-system and thermodynamic effects (e.g., strain in one of the prod- ucts and aromaticity in the other), which can tip the balance in favor of the endo products. The cationic dig-cyclizations have limited importance and are essentially unknown for the 3-exo/4-endo and 4-exo/5-endo pairs, unless they proceed via a nucleophile-assisted path. A more important and increasingly popular approach to the formation of endo adducts involves electrophile-promoted Igor V. Alabugin was born in Novokuznetsk, Russia, in 1969. nucleophilic cyclizations, where the symmetry of the alkyne LUMO He received his undergraduate degree in 1991 and his Ph.D. is reversed by coordination with a suitable soft Lewis acid and endo- degree in 1995 from the Moscow State University under the dig closure of nucleophilic species becomes possible. These cycliza- supervision of Professors N. S. Zefirov, N. V. Zyk, and V. K. Brel. tions are not included in the present sets of rules. After a postdoctoral study at the University of Wisconsin- Modern organic synthesis deals with molecular targets of ever Madison with Professor H. E. Zimmerman, he joined the increasing complexity and new synthetic methods continue to Department of Chemistry and Biochemistry of the Florida State emerge. The progress of organic chemistry leads to birth, aging, University in 2000, where he is currently a Full Professor. and death of a number of concepts dealing with chemical struc- His research interests are at the intersection of photochemistry ture and reactivity. However, after the redesign and expansion and organic synthesis with biochemistry and materials science described in this manuscript, the basic stereoelectronic concepts including the design, discovery and development of: photochemi- embodied by the Baldwin rules will continue to serve the broad cal double-stranded DNA cleavage agents with built-in selectivity chemical community. to cancer cells, pH-gated DNA binding and modification, new

6550 dx.doi.org/10.1021/cr200164y |Chem. Rev. 2011, 111, 6513–6556 Chemical Reviews REVIEW radical cyclizations, cascade transformations of alkynes for the (21) (a) Strozier, R. W.; Caramella, P.; Houk, K. N. J. Am. Chem. Soc. construction of graphene nanoribbons, electronic and conforma- 1979, 101, 1340. See also: (b) Houk, K. N.; Strozier, R. W.; Rozeboom, tional control of the Bergman cyclization, conformationally gated M. D.; Nagaze, S. J. Am. Chem. Soc. 1982, 104, 323. cyclization/fragmentation pathways which provide a potential bio- (22) Houk, K. N.; Rondan, N. G.; Schleyer, P. v. R.; Kaufmann, E.; chemical autoprotection mechanism from DNA-damaging cy- Clark, T. J. Am. Chem. Soc. 1985, 107, 2821. cloaromatization, metal-free conversion of phenols into esters (23) (a) Elliott, R. J.; Richards, W. G. THEOCHEM 1982, 87, 247. (b) Perkins, M. J.; Wong, P. C.; Barrett, J.; Shalival, G. J. Org. Chem. and amides of aromatic carboxylic acids, as well as studies of stereo- ff 1981, 46, 2196. (c) Ersenstein, O.; Procter, G.; Dunitz, J. D. Helv. Chim. electronic and rehybridization e ects in organic and supramole- Acta 1978, 61, 1538. (d) Dykstra, C. E.; Arduengo, A. J.; Fukunaga, F. T. cular chemistry. J. Am. Chem. Soc. 1978, 100, 6007. (e) Klimenko, N. M.; Bozhenko, K. V.; Strunina, E. V.; Rykova, E. A.; Temkin, O. N. THEOCHEM 1999, 490, 233. ACKNOWLEDGMENT (24) Alabugin, I. V.; Gilmore, K.; Manoharan, M. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja203191f. I.V.A. is funded in part by the National Science Foundation (25) The intrinsic barriers were estimated via removal of thermonamic (CHE-0848686) and Petroleum Research Fund, administered contribution to the activation barrier using Marcus theory (vide infra). by the American Chemical Society (Award 47590-AC4). A (26) (a) Tomooka, K.; Yamamoto, H.; Nakai, T. J. Am. Chem. 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(d) Shibata, Izv. Akad. Nauk SSSR, Ser. Khim. 1978, 1175. (b) Vasilevsky, S. F.; T.; Ueno, Y.; Kanda, K. Synlett 2006, 3, 411. Gerasimov, V. A.; Shvartsberg, M. S. Izv. Akad. Nauk SSSR, Ser. Khim. (223) Experimental studies: (a) Ramana, C. V.; Mallik, R.; Gonnade, 1981, 902. (c) Prikhodko, T. A.; Kurilenko, V. M.; Vasilevsky, S. F.; R. G.; Gurjar, M. K. Tetrahedron Lett. 2006, 47,3649.(b)Trost,B.M.; Shvartsberg, M. S. Izv. Akad. Nauk SSSR, Ser. Khim. 1990, 134. Ashfeld, B. L. Org. Lett. 2008, 10, 1893. (c) Schuler, M.; Silva, F.; Bobbio, C.; (197) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles 1988, Tessier, A.; Gouverneur, V. Angew. Chem., Int. Ed. 2008, 47, 7927. 27, 2225 and cited refrences therein. (224) Computational analysis: Sheng, Y.; Musaev, D. G.; Reddy, S.; (198) Koseki, Y.; Kusano, S.; Ichi, D.; Yoshida, K.; Nagasaka, T. McDonald, F. E.; Morokuma, K. J. Am. Chem. Soc. 2002, 124, 4149. Tetrahedron 2000, 56, 8855. (225) (a) Belting, V.; Krause, N. Org. Biomol. Chem. 2009, 7, 1221. (199) (a) Knight, D. W.; Lewis., P. B. M.; Malik, A.K.M.; For select examples of Pd catalyzed closures of similar systems, see: Mshvidobadze, E. V.; Vasilevsky, S. F. Tetrahedron Lett. 2002, 43, 9187. (b) Nakamura, H.; Ohtaka, M.; Yamamoto, Y. Tetrahedron Lett. 2002, (b) Vasilevsky, S. F.; Mshvidobadze, E. V.; Elguero, J. Heterocycles 2002, 43, 7631. (c) Bacchi, A.; Costa, M.; Della Ca, N.; Gabriele, B.; Salerno, 57, 2255. G.; Cassoni, S. J. Org. Chem. 2005, 70, 4971. For a comparison of AuBr3 ff (200) Peterson, P. E.; Kamat, R. J. J. Am. Chem. Soc. 1969, 90, 4521. and PtClx catalysts and their di ering regioselectivities, see: (d) Oh, (201) Closson, W. D.; Roman, S. A. Tetrahedron Lett. 1966, 48, 6015. C. H.; Lee, S. L.; Lee, J. H.; Na, Y. J. Chem. Commun. 2008, 5794. (202) Jin, T.; Himuro, M.; Yamamoto, Y. Angew. Chem., Int. Ed. (226) Yue, D.; Della Ca, N.; Larock, R. C. Org. Lett. 2004, 6, 1581. 2009, 48, 5893. (227) (a) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, (203) (a) Johnson, W. S.; Hughes, L. R.; Kloek, J. A.; Niem, T.; 67, 3437. (b) Dai, G.; Larock, R. C. Org. Lett. 2001, 3, 4035. (c) Roesch, Shenvi, A. J. Am. Chem. Soc. 1979, 101, 1279. (b) Johnson, W. S.; K. R.; Larock, R. C. J. Org. Chem. 1998, 63, 5306. Hughes, L. R.; Carlson, J. L. J. Am. Chem. Soc. 1979, 101, 1281. (228) (a) Ding, Q.; Chen, Z.; Yu, X.; Peng, Y.; Wu, J. Tetrahedron (c) Lansbury, P. T.; Demmin, T. R.; DuBois, G. E.; Haddon, V. R. Lett. 2009, 50, 340. (b) Chen, Z.; Yang, X.; Wu, J. Chem. Commun. J. Am. Chem. Soc. 1975, 97, 394. (d) Abad, A.; Agullo, C.; Arno, M.; 2009, 3469. (c) Ghavtadze, N.; Fr€ohlich, R.; W€urthwein, E.-U. Eur. J. Domingo, L. R.; Rozalen, J. Can. J. Chem. 1991, 69, 379. Org. Chem. 2010, 1787. (204) Harding, C. E.; King, S. L. J. Org. Chem. 1992, 57, 883. (229) Huo, Z.; Tomeba, H.; Yamamoto, Y. Tetrahedron Lett. 2008, (205) Balog, A.; Curran, D. P. J. Org. Chem. 1995, 60, 337. 49, 5531.

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(230) (a) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 4764. (b) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2008, 130, 15720. (c) Niu, Y.-N.; Yan, Z.-Y.; Gau, G.-L.; Wang, H.-L.; Shu, X.-Z.; Ji, K.-G.; Liang, Y.-M. J. Org. Chem. 2009, 74, 2893. (231) Alvarez-Corral, M.; Munoz-Dorado,~ M.; Rodríguez-García, I. Chem. Rev. 2008, 108, 3174. (232) Ito, H.; Makida, Y.; Ochida, A.; Ohmiya, H.; Sawamura, M. Org. Lett. 2008, 10, 5051. (233) Abbiati, G.; Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. J. Org. Chem. 2003, 68, 6959. (234) Binder, J. T.; Crone, B.; Haug, T. T.; Menz, H.; Kirsch, S. F. Org. Lett. 2008, 10, 1025. (235) Sakai, N.; Uchida, N.; Konakahara, T. Tetrahderon Lett. 2008, 49, 3437. (236) (a) Gabriele, B.; Mancuso, R.; Salerno, G.; Ruffolo, G.; Plastina, P. J. Org. Chem. 2007, 72, 6873. The regioselectivity of Pd- cat. closures for similar aniline systems can be switched to 5-exo in the presences of CO, see: (b) Gabriele, B.; Mancuso, R.; Salerno, G.; Lupinacci, E.; Ruffolo, G.; Costa, M. J. Org. Chem. 2008, 73, 4971. (237) Mellal, M.; Bourguignon, J.-J.; Bihel, F. J.-J. Tetrahedron Lett. 2008, 49, 62. (238) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett. 2005, 7, 5437. (239) Mehta, S.; Waldo, J. P.; Larock, R. C. J. Org. Chem. 2009, 74, 1141. (240) Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432. (241) The current exception to this is Malacria’s example of a carbon-centered radical closing onto a terminal alkyne in a 4-exo-dig fashion, which was trapped via a 1,5-H atom transfer from the methyl of a silyloxy group (see Scheme 9, ref 75and 76). (242) Note that the 6-endo-dig closure is particularly favored by more electrophilic O-centered radicals. See Figure 22.

NOTE ADDED AFTER ASAP PUBLICATION An error in Table 15 was discovered in the version published on 8/23/2011. This was corrected in the version published on 9/16/2011.

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DOI: 10.1002/anie.200601872 Natural Product Synthesis Cascade Reactions in Total Synthesis K. C. Nicolaou,* David J. Edmonds, and Paul G. Bulger

Keywords: cascade reactions · domino reactions · natural products · tandem reactions · total synthesis

Angewandte Chemie

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The design and implementation of cascade reactions is a challenging From the Contents facet of organic chemistry, yet one that can impart striking novelty, elegance, and efficiency to synthetic strategies. The application of 1. Introduction 7135 cascade reactions to natural products synthesis represents a partic- 2. Nucleophilic Cascades 7137 ularly demanding task, but the results can be both stunning and instructive. This Review highlights selected examples of cascade 3. Electrophilic Cascades 7144 reactions in total synthesis, with particular emphasis on recent applications therein. The examples discussed herein illustrate the 4. Radical Cascades 7150 power of these processes in the construction of complex molecules 5. Pericyclic Cascades 7155 and underscore their future potential in chemical synthesis. 6. Transition-Metal-Catalyzed Cascades 7167

1. Introduction 7. Summary and Outlook 7174

Cascade reactions constitute a fascinating branch of organic chemistry, and one which has been the subject of intense research in recent years, as witnessed by the number seminal work in this field.[4] Subsequent classic examples of reviews that have appeared covering various aspects of include the cationic polyolefin cyclization approach to these processes.[1] The undeniable benefits of cascade reac- progesterone (11, Scheme 2) developed by Johnson and co- tions are well established, having been recounted on numer- ous occasions, and include atom economy,[2] as well as economies of time, labor, resource management, and waste generation. As such, cascade reactions can be considered to fall under the banner of “green chemistry”,[3] as the savings involved when one carries out several transformations in one synthetic operation can be considerable. For example, only a single reaction solvent, workup procedure, and purification step may be required to provide a product that would otherwise have to be made over the course of several individual steps. Such considerations will become increasingly important in years to come, as both chemists and society in general strive for evermore effective and responsible methods for the management of Earths precious resources. Target-oriented synthesis provides the ultimate test of reaction design and applicability. The design of cascades to provide specific targeted molecules of considerable structural and stereochemical complexity poses a significant intellectual challenge and can be one of the most impressive activities in natural product synthesis. Cascade reactions therefore con- tribute immeasurably to both the science and art of total synthesis, bringing not only improved practical efficiency but also enhanced aesthetic appeal to synthetic planning. The recognition of these dual benefits is, of course, by no means an Scheme 2. The total synthesis of ( )-progesterone (11) involving a exclusively modern phenomenon. Indeed, cascade reactions polyolefin cyclization (Johnson et al., 1971).[5] (either as designed sequences or serendipitous discoveries) have attracted the attention of organic chemists since the formative years of total synthesis, with Robinsons one-pot [*] Prof. Dr. K. C. Nicolaou, Dr. D. J. Edmonds, Dr. P. G. Bulger synthesis of tropinone (4, Scheme 1) in 1917 standing as the Department of Chemistry and The Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA) Fax : (+1)858-784-2469 E-mail: [email protected] and Department of Chemistry and Biochemistry University of California, San Diego Scheme 1. Robinson’s seminal total synthesis of tropinone (4).[4] 9500 Gilman Drive, La Jolla, CA 92093 (USA)

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workers[5] on the basis of the Stork–Eschenmoser hypoth- esis,[6] the “endiandric acid cascade” (Scheme 3) proposed by Black and co-workers[7] and reduced to practice by the Nicolaou group,[8] and the radical-based synthesis of hirsutene (22, Scheme 4) and other triquinane natural products by Curran and co-workers.[9,10] As masterful as each of the syntheses illustrated in Schemes 1–4 is, they should by now be familiar to most

Scheme 4. A radical cyclization cascade in the total synthesis of ( )- hirsutene (22; Curran and Chen, 1985).[10]

students of organic chemistry. Therefore, rather than dwell further on the triumphs of the past, this Review will highlight and discuss a selection of more recent examples of cascade reactions employed in the total synthesis of natural products, offering fresh evidence for the utility of these types of processes in chemical synthesis. We do not aim to present a comprehensive survey of the literature, but rather to highlight a broad variety of strategies developed for the construction of complex molecules using cascade reactions. Where possible, we have tried to avoid duplicating the content of previous reviews, although some examples are covered again in cases where they serve to illustrate a particular reaction class or strategy. Of course, in selecting only representative examples from the extensive literature in the field, and then further restricting the candidate pool to applications in the total synthesis of natural products, we will inevitably be omitting discussion of a wealth of impressive cascade processes, such as

the landmark rational chemical synthesis of C60 (24, Scheme 5) by L. T. Scott et al.[11] Apologies are therefore due in advance to those whose work has been omitted. The very nature of cascade reactions, which often involve many distinct steps, can at times make them rather hard to classify. For convenience, we have grouped the examples that follow into five sections: nucleophilic, electrophilic, radical- mediated, pericyclic, and transition-metal-catalyzed process- es. This classification scheme is rather arbitrary, particularly in the case of examples that feature more than one class of Scheme 3. The endiandric acid cascade (Nicolaou et al., 1982).[8] reaction, but we have tried to place each cascade according to

K. C. Nicolaou, born in Cyprus and educated David J. Edmonds was born in Glasgow in England and the United States, is cur- (UK) in 1980. He received his MSci in rently Chairman of the Department of Chemistry with Medicinal Chemistry from Chemistry at The Scripps Research Institute, the University of Glasgow in 2001. He was where he holds the Darlene Shiley Chair in awarded a University Scholarship for post- Chemistry and the Aline W. and L. S. Skaggs graduate research, and carried out his PhD Professorship in Chemical Biology. He is also work at Glasgow under the supervision of Professor of Chemistry at the University of Dr. D. J. Procter on the application of California, San Diego, and Program Director samarium(II)-mediated reactions to total at the Chemical Synthesis Laboratories at synthesis. In early 2005, he joined Professor Biopolis, A*STAR, Singapore. His series K. C. Nicolaou’s group, supported by a Euro- “Classics in Total Synthesis”, which he has pean Merck Postdoctoral Fellowship, where co-authored with Erik J. Sorensen and he has continued to pursue his research Scott A. Snyder, is used worldwide as a teaching tool and source of interests in the total synthesis of natural inspiration for students and practitioners of chemical synthesis. products..

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[11] Scheme 5. The total synthesis of C60 (24; Scott et al., 2002). what can be argued as being the major theme of the sequence. Within each section, we have ordered the examples so as to provide a continuous discussion, rather than in chronological fashion. On the basis of space considerations, we shall not discuss the important class of enzyme-catalyzed cascade reactions,[12] except to highlight the current “gold standard” in this field by the group of A. I. Scott; namely the conversion of 5-aminolevulinic acid (25) into hydrogenobyrinic acid (26, Scheme 6) by treatment with a genetically engineered 12- enzyme cocktail in a process that involves 17 steps and the formation of nine stereocenters in a single reaction vessel![13] Scheme 6. The enzymatic synthesis of hydrogenobyrinic acid (26; Afurther four chemical transformations enable the elabo- [13] [14] Scott et al., 1994). ration of hydrogenobyrinic acid to vitamin B12 (27). Before tackling the chosen examples, however, some discussion regarding the terminology and organization of this Review is warranted. Different authors use varying defini- however, exclude multidirectional reactions (also sometimes tions as to what constitutes a cascade process. Avariety of termed “tandem” reactions) in which two or more reactions terms, including “cascade”, “domino”, “tandem”, and occur on the same substrate, but essentially in isolation of one “sequential”, are used in the literature, often seemingly another. interchangeably and with liberal abandon, although efforts Many of the examples highlighted here are based on the have been made to restore order to this area of reaction use of biosynthetic considerations to guide synthetic strategy terminology.[1b,c] For our subjective purposes, we shall employ (biomimetic synthesis), a paradigm that has witnessed a the term “cascade” to encompass all of the above descriptors. renaissance in recent years.[15] Others feature novel strategies We have also adopted a rather inclusive attitude in order to by combining several known reactions that would normally be capture as broad a spectrum of creative reaction design as executed independently into a single-pot cascade, or by possible. For example, the strictest definition of a cascade developing completely new reaction pathways altogether. process would discount any example in which the reaction Nevertheless, the common feature of all these examples is conditions are altered during the process; we will include not their inspired use of cascade reactions to generate molecular only these but also sequences in which further reagents are complexity in a concise fashion. It is hoped that this Review added at various points (“one-pot” transformations). We will, will serve not only to put into perspective recent accomplish- ments in the field but also to provide further impetus and Paul G. Bulger was born in London (UK) in inspiration for the implementation of new cascade strategies 1978. He completed his MChem degree in of broader generality and scope in the future. 2000 at the University of Oxford, where he carried out undergraduate research under the supervision of M. G. Moloney. He 2. Nucleophilic Cascades remained at the University of Oxford for his graduate studies, obtaining his DPhil in Chemistry in 2003 for research conducted In defining a nucleophilic cascade, we have adopted a under the supervision of Professor Sir J. E. policy whereby the key step in each case involves a Baldwin. In late 2003, he joined Professor nucleophilic attack. This section includes a variety of con- K. C. Nicolaou’s group at The Scripps jugate addition reactions, which are often employed in Research Institute as a postdoctoral conjunction with other reactions.[16] Also included here are researcher. His research interests encompass several organometallic addition processes, which are followed reaction mechanism and design, and their application to complex natural by pericyclic or anionic rearrangements, such as the anionic product synthesis and chemical biology. oxy-Cope reaction or Brook rearrangement.

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The polyketide ionophore natural product tetronasin (31, Scheme 7) is of commercial importance as an antibiotic, antiparasitic, and growth-promoting agent for use in rumi- nants. The interesting structure of tetronasin, which includes

Scheme 7. An anionic cyclization cascade in the total synthesis of tetronasin (31; Ley et al., 1998).[18]

Scheme 8. Total synthesis of (+)-harziphilone (38) via a nucleophile- tetronic acid, tetrahydrofuran, tetrahydropyran, and cyclo- catalyzed cycloisomerization (Sorensen et al., 2004).[20] hexane rings, prompted the groups of Ley and Staunton to investigate its biosynthesis. They proposed that both the tetrahydropyran and cyclohexane six-membered rings might form the cyclohexane ring, followed by a 6p-electrocycliza- be formed in a single step, and with the correct configuration, tion of a dienone to generate the pyran ring. This second step through a nucleophilic cascade triggered by the addition of an was based on precedent from work by Büchi and Marvell on alcohol group to a suitably disposed activated triene.[17] The the cycloisomerization of cis-dienones.[21] Thus, treatment of

intriguing question of whether this process could be repli- enone 32 with DABCO (33, 10 mol%) in CHCl3 at ambient cated in the laboratory was also answered by Ley and co- temperature led to the initial formation of enolate 34 in a workers, who developed a biomimetic total synthesis of process resembling the first step of the Baylis–Hillman tetronasin incorporating the proposed biosynthetic cycliza- reaction.[22] Subsequent conjugate addition of enolate 34 tion cascade (Scheme 7).[18] They found that exposure of the onto the proximal triple bond established the cyclohexane putative cascade precursor 28 to potassium hexamethyldisi- ring (34!35), and was presumably followed by proton lazide (1.1 equiv) in toluene at 08C indeed led to efficient transfer to give the isomeric enolate 36. Afurther cyclization cyclization to give 30 in a respectable yield of 67%. This process then generated the target natural product 38 and cyclization is thought to proceed via potassium salt 29,in concomitantly liberated a molecule of DABCO (33), which which the oxygen-based functional groups coordinate to the could then re-enter the catalytic cycle. Two mechanistic metal center in a manner resembling the ionophoric charac- pathways can be envisaged for this second ring formation. The teristics of the natural product, orienting the reacting groups first involves a single step, intramolecular substitution of the in a favorable manner for cyclization. The structural order in quaternary ammonium ion by the ketone carbonyl oxygen this intermediate led to formation of 30 as a single diastereo- atom (path a). Alternatively, elimination of DABCO from 36 isomer, in which three of the newly formed stereogenic would give cis-dienone 37, which would be expected to centers (at C5, C10, and C13) were installed with the required undergo a facile 6p-electrocyclization (path b).[21] Interest- configuration as found in the natural product 31. Although ingly, model studies indicated that the cyclization cascade the stereogenic center at C4 was formed with the incorrect proceeded significantly faster in substrate 32, which bears an R configuration, this site was readily epimerized to the unprotected 1,2-diol, as opposed to one in which the diol natural S configuration in the closing stages of the syn- group was protected as the corresponding acetonide. This thesis.[19] disparity may be due to activation of the enone to 1,4-addition The group of Sorensen recently reported the nucleophilic by intramolecular hydrogen bonding. catalysis of a cascade reaction in the enantioselective total The growing family of bisanthraquinone natural products synthesis of harziphilone (38, Scheme 8).[20] They devised a includes a number of dimeric structures, such as rugulosin (47, clever strategy for the construction of the required bicyclic Scheme 9), in which the monomeric anthraquinone units are ring system of the target molecule through the conjugate united by between one and four single bonds to form cagelike addition of a ketone enolate onto an acetylenic ketone to skeletons. Following the biosynthetic proposals and prelimi-

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Scheme 9. The total synthesis of (+)-rugulosin (47) through an oxidative coupling/Michael reaction cascade (Nicolaou et al., 2005).[26]

[23] nary experimental results of Shibata and co-workers, the Et3N to the reaction mixture at this point, followed by gentle groups of Nicolaou[24] and Snider[25] independently developed warming to 458C, not only facilitated the final intramolecular biomimetic approaches to this class of natural products by Michael reaction to establish the complete core structure employing cascade sequences to prepare model systems and (45!46) but also hindered further oxidative carbon–carbon analogues. Amajor obstacle to the preparation of the natural bond formation between the enol groups. In earlier model compounds is the presence of b-hydroxy or alkoxy ketone studies,[24] Nicolaou et al. observed a related oxidative bond groups in both the monomeric tricyclic units (such as 39) and formation in the absence of Et3N to form the strained product the dimeric intermediates, as these motifs are very prone to 48, which comprises the carbon framework of the related elimination and subsequent aromatization of the resulting natural product rugulin. With compound 46 in hand, acidic cyclohexenone ring. The conditions developed by Nicolaou hydrolysis of the hydroxy-protecting groups then completed et al. proved to be mild enough to overcome this hurdle and the total synthesis of (+)-rugulosin (47). If so desired, any one allowed for the preparation of (+)-rugulosin (47) in a highly of 43, 44,or45 could be isolated at the appropriate stage. In efficient cascade process.[26] It was found that the complete this case, however, the rugulosin structure 46 was the desired polycyclic architecture of the target compound, 47, could be endpoint, and it transpired that it was, in fact, more efficient prepared from readily available ketone 39 in a single reaction to conduct the whole seven-step sequence (39!46) in one pot vessel through a sequence of oxidative, bond-forming and rather than to adopt a stepwise approach to bond construc- bond-breaking events (Scheme 9). Exposure of monomeric tion. ketone 39 to MnO2 in CH2Cl2 resulted in oxidation to the The facile dimerization of the alkaloid avrainvillamide corresponding anthraquinone, 40, followed by dimerization to (49) has been exploited by the groups of Myers and Baran in give heptacyclic compound 43. Although 43 is formally the their total syntheses of stephacidin B (51, Scheme 10).[27] Both product of a hetero-Diels–Alder reaction between two groups observed that 49 dimerized upon treatment with molecules of the corresponding enolized species 41 of triethylamine at room temperature. The interconversion of 49 anthraquinone 40, compound 43 is believed to be formed and 51 was also observed during preparative TLC or upon via sequential inter- and intramolecular Michael reactions concentration or dissolution. Aplausible mechanism for this (i.e. 40!41!42!43), as the use of the bulkier TBS hydroxy- dimerization involves the nucleophilic attack by the amide protecting group (R = TBS) allows for the isolation of the first nitrogen atom of one molecule of 49 onto the a,b-unsaturated Michael adduct (corresponding to 42). Oxidative bond nitrone group of another to give 50, with conjugate addition of cleavage (43!44) and Michael reaction steps then led to the resulting hydroxyenamine onto the other a,b-unsaturated the formation of doubly bridged structure 45. Addition of nitrone then forming the second bond.[27a,28] An alternative

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Scheme 10. Dimerization of (+)-avrainvillamide (49) to give (À)-stephacidin B (51) through a double conjugate addition (Herzon and Myers, 2005; Baran et al., 2005).[27]

mechanism in which the two bonds are formed in the reverse generation followed by hydrogen-atom abstraction from the order has also been proposed,[29] however, this seems less bis-allylic methylene site in 52 to generate cyclohexadienyl likely in light of the observations by Myers and Herzon radical 54. The latter species fragments through the enthalpi- regarding the electrophilicity of the a,b-unsaturated nitrone cally and entropically favored loss of a molecule of toluene to functionality.[30] give acyl radical 55;6-exo-trig cyclization and expulsion of a The groups of Myers and Baran both also employed phenylsulfinyl radical then furnished the desired tetracyclic cascade reactions in their respective routes to avrainvillamide product 56 in good overall yield (62%). Fusion of the (Scheme 11 and Scheme 12). The synthesis by Herzon and remaining three rings of the avrainvillamide structure onto Myers (Scheme 11),[27a] which led to the unnatural enantio- compound 56, over the course of five more steps, then mers (À)-avrainvillamide (57) and (+)-stephacidin B (58), completed the synthesis of the monomeric unit 57.[32] featured a radical cyclization cascade approach to the The synthesis of (+)-avrainvillamide (49) by Baran et al. diazabicyclooctane ring system. Acyl radical 55 was generated involved a deprotection–cyclization cascade initiated by from cyclohexadienyl carboxamide 52 by employing a method heating of 59 at 2408C (Scheme 12).[27b,33] The first step is developed by Walton and co-workers.[31] Heating of a mixture the loss of the Boc protecting group from the indole nitrogen of amide 52 and peroxide-based initiator 53 resulted in radical atom, which occurs by a retro-ene mechanism under thermal

Scheme 11. Acyl radical generation and cyclization in the total synthesis of (À)-avrainvillamide (57) and (+)-stephacidin B (58; Herzon and Myers, 2005).[27a]

Scheme 12. The total synthesis of (+)-stephacidin A (63) and (+)-avrainvillamide (49) by a thermal cascade (Baran et al., 2005).[27b]

7140 www.angewandte.org 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 7134 –7186 Angewandte Cascade Reactions Chemie conditions with the extrusion of isobutene and carbon dioxide different types of human cancer.[37] Inspired by its promising to afford 60. At the elevated temperature of the reaction, a biological activity, scarcity, and intriguing molecular structure, formal ene reaction between the indole ring and the the Corey group initiated investigations that culminated in isopropenyl group of 60 then ensues, yielding spirocyclic the efficient total synthesis of ecteinascidin 743 (72).[38] A imine 61 as a fleeting intermediate, which then undergoes a prominent feature of the route was the ingenious method selective 1,2-shift of the more highly substituted alkyl group devised for the installation of the unusual bridging 10- to give (+)-stephacidin A( 63). This material was converted membered sulfur-containing ring, as shown in Scheme 13. into the natural enantiomers of avrainvillamide (49) and Advanced hexacyclic intermediate 64 was prepared from two stephacidin B (51), thus establishing their absolute configu- amino acid derivatives through a series of iminium ion rations as those shown in Scheme 10.[34] cyclizations. This set the stage for the introduction of the Ecteinascidin 743 (72, Scheme 13) is a marine-derived bridging sulfide through the 1,4-addition of a thiolate anion to natural product isolated from the Caribbean tunicate Ectei- an intermediate ortho-quinone methide (67).[39] This highly nascidia turbinata.[35, 36] It is a potent antitumor agent and has reactive species was generated by treatment of hydroxy entered clinical trials for the treatment of a number of ketone 64 with a Swern-type reagent to generate the O- dimethylsulfonium ion intermediate 65. Triflic anhydride was used in place of the more conventional oxalyl chloride in order to avoid any interference by chloride ions during

subsequent steps. The addition of an amine base (iPr2NEt) led to the cyclo-elimination of DMSO, via ylide species 66,to afford ortho-quinone methide 67. Following the addition of tBuOH to quench any excess Swern reagent, a guanidine base 68 was used to release a thiolate anion from the fluorenyl sulfide moiety. The liberated thiolate anion 69 was then trapped by the ortho-quinone methide to give the 10- membered sulfide ring. This intramolecular conjugate addi- tion was rendered irreversible by the addition of acetic anhydride, to trap the resulting phenolate 70 as the corre- sponding acetate 71. This amazing one-pot cascade proceeded in excellent overall yield (79%) and, significantly, without the need for isolation of any of the sensitive intermediates along the pathway. Asimilar cascade sequence has since been employed in an efficient semisynthesis of ecteinascidin 743 (72), thereby securing the supply of larger quantities of this previously scarce compound.[40] Multicomponent reactions offer means to construct com- plex and structurally diverse compounds rapidly from rela- tively simple building blocks.[41,42] The Ugi reaction is a powerful four-component coupling reaction and one of several such processes that employ an isocyanide as one of the reactants.[43] Although popular in the field of combinato- rial synthesis,[44] applications of Ugi reactions in total syn- thesis are comparatively rare.[45] One of the most advanced applications of an Ugi reaction to date can be found in the total synthesis of ecteinascidin 743 (72) by Fukuyama and co- workers, who employed this four-component process to couple two major fragments, whilst simultaneously incorpo- rating the remaining three carbon atoms needed for the hexacyclic core structure of the target.[46] Amine 73, carbox- ylic acid 74, isocyanide 75, and acetaldehyde (76) were heated in methanol to give amide 80 (Scheme 14). Reversible acid- catalyzed iminium ion formation (73 + 76!77) is followed by nucleophilic attack of the isocyanide component and capture of the resulting nitrilium ion 78 by the carboxylate anion to generate neutral intermediate 79. This species then undergoes a rapid O!N acyl transfer to afford 80 as the observed product. Amide 80 was formed in high yield (90%), albeit as a mixture of epimers at the newly generated C4 stereocenter. Scheme 13. ortho-Quinone methide generation and trapping in the Indeed, satisfactory control of the stereochemistry of the total synthesis of ecteinascidin 743 (72; Corey et al., 1996).[38] newly formed stereocenter in the Ugi reaction remains an

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Scheme 14. The Ugi four-component coupling reaction in the total synthesis of ecteinascidin 743 (72; Fukuyama et al., 2002).[46]

unresolved problem in general. In the context of this syn- thesis, however, this lack of stereocontrol was immaterial, as the planned route required the subsequent destruction of this stereocenter followed by its later reinstallation with the required configuration.[47] Triquinane natural products, such as hypnophilin (91), coriolin (92), and ceratopicanol (93, Scheme 15) have been, and continue to be, popular targets for total synthesis endeavors, inspiring the development of a number of cascade processes.[48] The Paquette group has exploited the squarate ester cascade[49] for the total syntheses of all three of the aforementioned targets, as shown in Scheme 15.[50] This anionic cascade is triggered by the addition of two vinyl- Scheme 15. The squarate ester cascade as used in the total synthesis lithium species to the squarate ester 81, and can proceed by of ()-hypnophilin (91) and ( )-coriolin (92), and the structure of two pathways, depending on whether the second nucleophile ( )-ceratopicanol (93; Paquette and Geng, 2002).[50] adds in a cis or trans fashion relative to the first. With a cis mode of addition, favored by chelation between the incoming nucleophile and the ketal oxygen atoms, the 1,5- diene-dialkoxide 84 is formed. This undergoes a facile vinyllithium species are substituted on the distal end of the dianionic oxy-Cope rearrangement, via a boatlike transition olefin, it is possible to distinguish between these mechanisms state, to form cyclooctatriene species 85. Alternatively, a and, to some extent, control which pathway is followed.[49] In trans mode of addition, favored by steric considerations, leads this case, it is likely that both modes are operative, each giving to dialkoxide 86, which, on stereoelectronic grounds, cannot the same final product. From dianion intermediate 85, the undergo a [3,3] sigmatropic reaction. Instead, a charge-driven cascade continues with the b-elimination of one of the ketal 4p-conrotatory electrocyclic ring opening occurs, with elec- oxygen groups by the adjacent enolate, leading to regiose- trostatic repulsion favoring rotation of the two alkoxide lective formation of ketone 88. An intramolecular aldol oxygen centers away from each other. The resulting octate- reaction between this ketone and the remaining enolate, traene 87 then converges on cyclooctatriene intermediate 85 followed by hydrolysis, then gave tricyclic product 90, which through an 8p-conrotatory ring closure. In cases where both could be converted into hypnophilin (91) or coriolin (92) over

7142 www.angewandte.org 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 7134 –7186 Angewandte Cascade Reactions Chemie several more steps. Asimilar cascade led to the total synthesis of ceratopicanol (93).[50b] Paquette and Geng employed a related approach for the preparation of the angular triquinane pentalenene (100, Scheme 16).[51] In this cascade, the second nucleophile is an acetylide anion and the trans addition route dominates, generating the highly strained 1,2,4,6-cyclooctatetraene inter- mediate 97. As expected, this species was formed with high stereoselectivity due to the more facile 8p-conrotatory electrocyclic ring closure of conformer 96, in which the cyclopentane methyl substituent is on the exterior of the helical pitch of the dienolate. In this case, there is no leaving group available to differentiate the two enolate groups, but relief of strain favors the selective protonation of the allenoate to give ketone 98. Atransannular aldol reaction then gives the product 99, which was elaborated to give the target natural product 100.[52] In their approach to (+)-CP-263,114 (phomoidride B, 112), Shair and co-workers also employed an organometallic addition/Cope rearrangement strategy.[53a] Their variant involved the addition of Grignard reagent 101 to b-keto ester 102 (Scheme 17). The addition proceeds with complete selectivity for the desired diastereoisomer 103 under chela- tion control. 1,5-Diene 103 then undergoes a facile oxy-Cope rearrangement upon warming to room temperature to give the cyclononene enolate 104. Interestingly, the use of organo- lithium or organocerium reagents in model studies of this Scheme 16. The total synthesis of ( )-pentalenene (100) using the addition step failed to give the desired products.[53b] The final squarate ester cascade (Paquette and Geng, 2002).[51] step in this cascade is the transannular Dieckmann cyclization of 104 to form ketone 105 and generate the characteristic

Scheme 17. Anionic oxy-Cope/Dieckmann cascade and Fries-like rearrangement in the total synthesis of (+)-CP-263,114 (112; Shair et al., 2000).[53]

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strained bicyclic core of the target compound. Following the ality to give iminobutenolide 116. Subsequent tautomeriza- advancement of ketone 105 to b-ketoester 106, a novel tion, oxidation, and hydrolysis steps afforded maleic anhy- electrophilic cascade was effected by treatment of this dride 121 via intermediates 117–120. Several further func-

material with TMSOTf (2.0 equiv) and HC(OMe)3 tional group manipulations then completed the syntheses of [56] (2.0 equiv) in CH2Cl2 to give lactone 111 in over 90% yield. both CP-225917 (122) and CP-263114 (112). Aplausible mechanism for this transformation is shown in The dithiane lynchpin strategy,[57] developed by the Smith Scheme 17 and commences with the initial ionization of the group based on precedent noted by Tietze et al.,[58] makes use enol carbonate with TMSOTf to provide silylketeneacetal of the Brook rearrangement[59] to regenerate a lithiated 108, a species poised for reaction with the liberated acylium dithiane, following the opening of an epoxide by a lithiated ion, leading to the assembly of 109. Lewis acid mediated silyl dithiane nucleophile. The new lithiated dithiane can then deprotection of the MOM groups and hydrolytic workup then capture a second, different electrophile, provided that the gave the product 111. In addition to providing an interesting timing of migration of the silyl group can be controlled. Smith solution to the problem of generating the g-lactone cage and Kim recently extended this strategy to the synthesis of the structure, the concomitant unveiling of the carboxylic acid poison frog alkaloids (À)-indolizidine 223AB and (À)-205B group at C14 during the conversion of 106 into 111 provided a (129, Scheme 19) by using an aziridine electrophile in the convenient handle for the installation of the one remaining second step.[60] Thus, lithiation of silyl dithiane 123 with tBuLi carbon atom required to reach the target structure 112 in diethyl ether and addition of epoxide 124 led to lithium through a modified Arndt–Eistert protocol. Subsequent alkoxide 125 (Scheme 19). Aziridine 126 was then added in a studies by Shair and co-workers of this addition/Cope mixture of THF and DME, the polar solvent triggering a 1,4- rearrangement strategy using related systems revealed the Brook rearrangement to generate lithiated dithiane 127. potential for retro-aldol/aldol equilibration of the organome- Nucleophilic opening of the aziridine then gave the sulfona- tallic addition product (corresponding to magnesium alkoxide mide product 128, which was subsequently converted into 103), with implications for the dynamic kinetic resolution of alkaloid (À)-205B (129).[61] substrates with chiral all-carbon quaternary stereocenters.[54] Nicolaou et al. also employed a cascade reaction in their total synthesis of CP-225,917 (phomoidride A, 122) and CP- 3. Electrophilic Cascades 263,114 (phomoidride B, 112).[55] This cascade was used to introduce the challenging maleic anhydride moiety from The first synthesis described in this section could equally nitrile precursor 114. In preparation for the cascade process, have been included in the previous section, as it includes both 113 was selectively mesylated on the primary alcohol group. nucleophilic and electrophilic cascades. The approach of Mesylate 114 was then exposed to mildly basic conditions, Corey and co-workers to the dimeric triterpene (+)-a- which initiated the presumed chain of events delineated in onocerin (137, Scheme 20) involved a sequential addition/ Scheme 18. Base-induced epoxide formation (114!115)is dimerization, four-component coupling sequence to assemble followed by fragmentation to give an intermediate alkoxide, a precursor for a two-directional electrophilic tetracycliza- which immediately closes onto the proximal nitrile function- tion.[62] Addition of vinyllithium to acyl silane 130 gave

Scheme 18. Construction of the maleic anhydride unit during the total synthesis of the CP molecules (Nicolaou et al., 1999).[55] Substituents in intermediates 115–120 are omitted for clarity.

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chelated Z-allylic lithium intermediate 133 through the 1,2- Brook rearrangement of alkoxide 131 followed by allylic rearrangement (132!133).[63] Addition of iodine gave the dimer 134 in excellent yield (74%). Conversion of the silyl enol ether groups into the corresponding enol triflates was accomplished in a single operation through the action of cesium fluoride and phenyl ditriflimide, and was followed by Negishi coupling to give dimeric allylsilane 135 in 66% yield

from 134. Exposure of 135 to MeAlCl2 (2.5 equiv) in CH2Cl2 at À948C followed by treatment with TBAF (to cleave any TMS ethers of 137 which may have been present) then gave (+)-a-onocerin (137, 63% yield from 135). In addition to the desired tetracyclic product, which arose from the chair–chair

transition-state arrangement 136, a minor non-C2-symmetric product (not shown) was also formed in 9% yield, presum- ably as a result of one cyclization proceeding through a chair– boat transition state. This remarkable synthesis demonstrates the great power of cascade reactions in the rapid construction Scheme 19. Dithiane linchpin coupling through a 1,4-Brook rearrange- of complex molecules; indeed, the two cascades described ment, as applied to the total synthesis of poison-frog alkaloid (À)- here enabled the formation of four rings, nine carbon–carbon [64] 205B (129; Smith and Kim, 2005).[60] bonds, and six new stereogenic centers in just four steps. The opening of epoxide rings under (Brønsted or Lewis) acidic catalysis forms the basis of many spectacular cascade processes. Corey and Xiong used a two-directional epoxide-

opening cascade in their total synthesis of the C2-symmetric pentacyclic tetrahydrofuran natural product glabrescol (142), in an endeavor which also served to determine the true stereochemical identity of the natural material.[65] They had previously prepared several meso isomers, including that originally proposed for the natural product, and found that the original structure was incorrect.[66] All the isomers were prepared by using cascade cyclizations of polyepoxides; the cascade used to prepare natural glabrescol is illustrated in Scheme 21. The tetra-epoxide precursor 138 was prepared by oxidative dimerization and epoxidation using the protocol of Shi and co-workers.[67] Treatment of 138 with camphorsulfonic acid gave the desired tetracyclic product 139 in good overall

Scheme 20. Application of the 1,2-Brook rearrangement and a two- directional epoxy-olefin cyclization in the total synthesis of (+)-a- Scheme 21. Poly-epoxide cyclizations in the total synthesis of glabres- onocerin (137; Corey et al., 2002).[62] col (142; Xiong and Corey, 2000).[65]

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yield. At each site, opening of the corresponding epoxide ring nucleophilic solvent 1,1,1,3,3,3-hexafluoro-2-propanol was occurred at the more substituted terminus, a corollary of the chosen for its ability to stabilize such charged species without stereoelectronic preference for five-membered-ring forma- interfering in the progress of the reaction. Fusion of the tion, and with inversion of configuration. Selective mono- oxepane Aring onto intermediate 146 followed by the mesylation of 139, followed by treatment with acetic acid gave appropriate side-chain manipulations then completed the [72] the desired C2-symmetric product 142 by the double-inversion total synthesis. mechanism shown (140!141!142). The use of acetic acid, a The pinacol-terminated Prins cyclization was developed good ionizing solvent, combined with the steric shielding by the group of Overman as an effective technology for the around the secondary mesylate group, discourages the direct synthesis of natural products.[73] One such application is found

SN2-type displacement by the hydroxy group (which would in their general approach to the cladiellin family of diterpene form the undesired product stereochemistry as the result of a metabolites, as represented by the synthesis of the revised single inversion), and enables neighboring-group participa- structure of sclerophytin A( 153, Scheme 23.[74] The sequence tion from the vicinal ether oxygen to form epoxonium ion intermediate 141. This species is then opened in a kinetically favored 5-exo mode by the pendant hydroxy group. Compar- ison of synthetic 142 and natural glabrescol revealed the two materials to be identical.[68] Abiomimetic electrophilic cascade [69] was employed by Holton and co-workers in their total synthesis of hemibreve- toxin B (147, Scheme 22).[70] Their plan of attack called for the

Scheme 23. The Prins-pinacol reaction in the total synthesis of sclero- phytin A (153; Overman et al., 2001).[74]

begins with the Lewis acid catalyzed condensation of diol 148 with aldehyde 149 to form oxocarbenium ion 150. It is not necessary to specifically control which alcohol group engages Scheme 22. Total synthesis of hemibrevetoxin B (147) using an epoxy-olefin the aldehyde in this step, as only 150 can participate in the [70] cyclization (Holton et al., 2003). Prins cyclization reaction and all the possible condensation products are in equilibrium. The Prins cyclization of 150 formation of the B and C rings of the target structure through proceeds stereoselectively, with the approach of the oxocar- the double cyclization of a suitable hydroxy epoxide pre- benium ion dictated by the bulky isopropyl substituent. The cursor.[71] They eventually settled on epoxy alkene 143 as a cyclization generates stabilized allylic carbocation 151, which suitable substrate, with the alkene serving as a trigger for the undergoes a pinacol rearrangement to give the bicyclic cascade upon activation by an electrophile. In the event, product 152 in 79% isolated yield. Tetrahydrofuran 152 treatment of 143 with N-phenylselenophthalimide led to proved to be a versatile platform for the synthesis of various sequential ring closure to give the advanced intermediate 146 members of this class of natural products, including sclero- in 83% yield and as a single stereoisomer. This cyclization is phytin A( 153), its originally proposed structure, deacetox- thought to proceed through attack of the epoxide oxygen yalcyonin acetate, and cladiell-11-ene-3,6,7-triol.[74–76] atom on the epi-selenonium ion of intermediate 144 to Oxocarbenium ion species are commonly employed in generate a bicyclic epoxonium ion 145. Subsequent attack by total synthesis as intermediates in the preparation of acetal the hydroxy group then proceeds selectively to give the trans- and ketal protecting groups, and also in the formation of fused oxepane product 146. The highly polar but non- spiroketal structural units.[77,78] The construction of such

7146 www.angewandte.org 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 7134 –7186 Angewandte Cascade Reactions Chemie motifs using cascade processes is exemplified by two synthe- ing groups, and the formation of three rings, with the ses of the trioxadispiroketal ABCD-ring fragment of the thermodynamically favored anomeric configuration at the shellfish toxin azaspiracid-1 (156, Scheme 24). In their C10 and C13 positions, to give 155 in 65% yield.[80] In a second-generation synthesis of the azaspiracids, Nicolaou conceptually different approach to the ABCD-ring fragment, et al. prepared bis-spiroketal 155 from precursor 154 in a one- Forsyth and co-workers prepared acetylenic ketone 158, [79] step deprotection–cyclization cascade sequence. Treatment which, upon exposure to TsOH·H2O (1.0 equiv) in toluene at of 154 with excess TMSOTf at low temperature effected room temperature, underwent cleavage of the two TES removal of the TES ether, acetonide, and dioxolane protect- protecting groups followed by a double intramolecular conjugate addition.[81] The use of acid catalysis under equilibrating conditions ensured the formation of the desired, thermodynamically favored ketal 159, which was isolated as a single stereoisomer in 55% yield from alcohol 157.[81–83] Heathcock and co-workers famous one-step syn- thesis of dihydro-proto-daphniphylline (168), the pro- posed biogenetic precursor to the Daphniphylum polycyclic alkaloids, is perhaps the most striking example of a cascade involving iminium ion inter- mediates.[84] The process begins with dihydrosqualene dialdehyde 160 (Scheme 25) and represents the culmi- nation of several years of careful development com- bined with a chance discovery.[85] Treatment of acyclic di-aldehyde 160 with methylamine and warm acetic acid gave the target compound 168 in 65% yield through a process that formed five new rings and installed eight new stereogenic centers in a completely diastereoselective fashion. The first step in the cascade involves the condensation of methylamine with the most reactive aldehyde group to give secondary enamine 161. Intramolecular Michael addition of enamine 161 onto the enal group establishes the first carbon–carbon bond and ring of the sequence (161! Scheme 24. a) Use of a deprotective polycyclization en route to the total synthesis of azaspiracid-1 (156; Nicolaou et al., 2006).[79] b) Construction of the 162), and is followed by further condensation and azaspiracid-1 ABCD ring framework through an acid-catalyzed nucleophilic cyclization events to form iminium ion 164. Aformal addition cascade (Forsyth et al., 2004).[81] hetero-Diels–Alder reaction then gives tetracyclic

Scheme 25. Biomimetic synthesis of dihydro-proto-daphniphylline (168; Heathcock et al., 1992).[84]

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iminium ion 165, although this step most likely proceeds in a the opposite face of the molecule. The stereochemistry of the stepwise manner through a Prins cyclization to form the resulting spirocyclic intermediate 173 then governs the facial second five-membered ring, followed by ring closure between selectivity in the attack of the allylsilane substituent[87] on the the resulting enamine and tertiary carbocation species. The newly formed iminium ion to generate the pentacyclic system final ring is then formed by another Prins cyclization to 174. Following completion of this cascade, sodium cyanobor- generate carbocation 166. A1,5-hydride shift from the methyl ohydride was added to effect reduction of the enamine group group of the tertiary amine to the carbocation, followed by to give 176, which was converted into aspidophytine.[88] hydrolysis on workup, completes the synthesis of dihydro- The total synthesis of (+)-vinblastine (184, Scheme 27) by proto-daphniphylline (168). When ammonia is used in place Fukuyama and co-workers makes use of an electrophilic of methylamine, the dehydro product with an isopropenyl side aromatic substitution reaction for the late-stage coupling of chain in place of the isopropyl group, is formed in a rather the “northern” and “southern” halves of the target (178 and lower yield. Thus, in addition to differentiating what would be 181, respectively), along the lines of the biosynthesis of this one of three similar olefins in the polycyclic product, the use of methylamine also aids the progress of the cascade as the substituted imine and enamine intermediates are more stable. Another example of the power of iminium ions as intermediates in cascade reactions can be found in the highly efficient and convergent synthesis of aspidophytine (177, Scheme 26) by Corey and co-workers. Reductive con- densation of tryptamine derivative 169 and chiral di-aldehyde 170 gave pentacyclic amine 176 with the formation of three new rings, three new stereogenic centers, and four new sigma bonds.[86] This transformation proceeds through condensation of primary amine 169 with dialdehyde 170 to give the cyclic iminium ion 172, presumably via enamine 171. APictet– Spengler cyclization generates the pyrrolidine ring and the new quaternary stereocenter. The stereocontrol obtained in this step is notable and may arise through interaction between the iminium ion carbon atom and the ester carbonyl oxygen atom of 172, leading to preferential attack by the indole from

Scheme 27. The total synthesis of (+)-vinblastine (184) through elec- trophilic aromatic substitution (Fukuyama et al., 2002).[89]

clinically important anticancer drug.[89] Treatment of indole

178 with tBuOCl in CH2Cl2 led to the initial formation of imine 179, followed by tautomerization to the corresponding chloroindolene species 180. Exposure of a mixture of chloroindolene 180 and synthetic indole 181 (itself a natural product, (À)-vindoline, which had previously been synthe- [90] sized by the Fukuyama group) in CH2Cl2 to excess TFAled to the formation of the desired adduct 183 as a single regio- and stereoisomer in remarkable yield (97% for the two steps from “northern” indole 178) by addition of the vindoline aromatic nucleus to the highly reactive electrophilic species 182.[91] The stereochemical outcome of the coupling was anticipated not only on the basis of precedent provided by model studies from Schill and co-workers,[92] but also by Scheme 26. The total synthesis of (À)-aspidophytine (177) through a molecular modeling calculations, which suggested that the 11- series of iminium ion cyclizations (Corey et al., 1999).[86] membered ring of intermediate 182 would preferentially

7148 www.angewandte.org 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 7134 –7186 Angewandte Cascade Reactions Chemie adopt the conformation shown. Attack of (À)-vindoline (181) from the convex face of this ring would then lead to the formation of coupled product 183 with the correct stereo- chemistry at the C16 position as required for the target natural product 184.[93] Fukuyama and co-workers have also applied this strategy to the synthesis of the related alkaloid (+)-vincristine (185).[94] The Padwa group has employed a Pummerer/Pictet– Spengler cascade reaction,[95–97] involving both thionium and iminium ion intermediates, in the preparation of the alkaloid jamtine (191, Scheme 28).[98] This synthesis also serves to demonstrate the versatility of sulfoxides in total synthesis. Treatment of sulfoxide 186 (as a 4:1 mixture of Z/E isomers) with CSAin refluxing toluene generated sulfonium ion 187, which underwent cyclization to form N-acyl iminium ion 189. This species was then intercepted by the electron-rich aromatic ring in a Pictet–Spengler cyclization to form the tricyclic core of the target natural product 191. This cycliza- tion cascade in fact led to the formation of a 5:2:1:1 mixture of diastereoisomers in an overall yield of 88%, with the major product being the desired diastereoisomer 190. To rationalize the preferential formation of tricyclic stereoisomer 190, Padwa et al. suggested that a 4p-Nazarov-type electrocycli- Scheme 28. The total synthesis of ( )-jamtine (191) through a Pum- zation controls the direction of ring closure from the a- merer/Pictet–Spengler cascade (Padwa and Danca, 2002).[98] acylthionium ion intermediate (i.e. 188!189). The subse- quent Pictet–Spengler step involves attack of the aromatic ring from the less hindered side of the iminium ion frame- polycyclic alkaloid jamtine (191) from simple building work. The resulting sulfide group in cascade product 190 was blocks.[99] put to further use later in the synthetic route to introduce the Two distinct cascade reactions involving carbocationic trisubstituted alkene through the thermal elimination of a intermediates can be found in the total syntheses of sceptrin sulfoxide. This strategy allowed the rapid construction of the (197) and ageliferin (202, Scheme 29), reported by Baran and

Scheme 29. The total synthesis of (À)-sceptrin (197) and (À)-ageliferin (202) by a controlled quadricyclane fragmentation and cationic ring expansion (Baran et al., 2006).[103]

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co-workers. In their synthesis of racemic sceptrin,[100] they recent total synthesis campaigns, with the aim of highlighting made use of the fragmentation of a 3-oxaquadricyclane a broad scope of radical processes. The use of carbon- and system, first reported by the groups of McInnes[101] and heteroatom-centered radicals is exemplified, as are a range of Nelson,[102] to prepare the required all-trans-tetrasubstituted methods for radical generation, including single electron cyclobutane ring. The problem of preparing enantiopure transfer and photochemical processes in addition to the more sceptrin by an analogous route was far from simple, especially traditional AIBN/tin hydride protocols. in light of the poorly understood mechanism of the quad- In their synthesis of (À)-morphine (208, Scheme 30), ricyclane fragmentation. Indeed, initial attempts to prepare Parker and Fokas used a cascade radical process to form two non-racemic cyclobutanes from enantiomerically enriched rings and install the all-carbon quaternary stereocenter in a chiral 3-oxaquadricyclanes resulted in significant loss of single step. Treatment of bromide 203 with tri-n-butyltin enantiopurity. However, by employing monobenzylamide hydride and AIBN in refluxing benzene gave tetracyclic 193, prepared in situ by irradiation of non-racemic diene 192, Baran et al. were able to access tetrasubstituted cyclo- butane 196 with clean transfer of chirality (Scheme 29).[103] They proposed a mechanism involving initial cleavage of the oxygen bridge to give cyclopropyl carbocation 194.The regioselectivity of this step is crucial to the transfer of chirality during the cascade and is correlated with the greater stability of amide enols as compared to ester enols.[104] Addition of a molecule of water to 194 yields cyclopropanol 195, which subsequently undergoes retroaldol fragmentation, driven by relief of ring strain, to give cyclobutane 196. Interestingly, the product of this cascade has the cis,trans,trans configuration, in contrast to that observed earlier using meso-quadricyclanes. Fortunately, a facile epimerization gave the correct all-trans arrangement required for natural (À)-sceptrin (197).[105] Suspecting that (À)-sceptrin (197) may be the true natural precursor of the related natural product (À)-ageliferin (202), rather than a product of a divergent pathway, Baran et al. began to investigate the rearrangement of 197 to 202. After screening a number of conditions, they discovered that the required transformation could be achieved by brief heating of an aqueous solution of 197 under microwave irradia- tion.[106, 107] The most direct route from 197 to 202 would involve a concerted [1,3]-sigmatropic shift followed by tautomerization, but the possibility of this pathway occurring can be excluded on the basis that it would require inversion of À configuration at the migrating center, whereas retention is Scheme 30. Radical cyclizations in the total synthesis of ( )-morphine [110] observed experimentally. Several other more plausible mech- (208; Parker and Fokas, 2006). anisms for the conversion of 197 into 202 can be envisioned, including the one illustrated in Scheme 29 which features a series of 1,2-shifts. Initial enamine–imine tautomerization of product 207 in moderate yield.[110] The reaction proceeds by (À)-sceptrin (197) gives 198, which undergoes the first alkyl the initial generation of aryl radical 204, which cyclizes onto 1,2-shift to give 5,5-spiro carbocation 199. Ahydride shift the tethered cyclohexene to form the dihydrobenzofuran followed by a second alkyl 1,2-shift gives cyclohexane 201, system and the quaternary center. The approach of the aryl and a final tautomerization affords (À)-ageliferin (202)in radical to the lower face of the alkene (as drawn in 204)is moderate overall yield (40% from 197). The synthesis by governed by the stereochemistry of the ether linkage. Baran et al. of (À)-sceptrin (197) and (À)-ageliferin (202) Secondary radical 205 then cyclizes in a 6-endo-trig fashion served to highlight a new possibility for the biosynthetic to generate benzylic radical 206. The geometric constraints relationship of these natural products and to define the imposed by the tricyclic framework of 205 discourage the absolute stereochemistry of natural (À)-ageliferin. alternative, and otherwise generally kinetically favored, 5- exo-trig mode of cyclization. Finally, elimination of phenyl- sulfinyl radical forms the olefin required for completion of 4. Radical Cascades this formal total synthesis of morphine.[111] Notably, a model substrate that lacks the vinylic 2-aminoethyl substituent The reactivity profiles of organic radicals[108] are well underwent an analogous radical-based cyclization to generate suited to the development of cascade reactions, and a wide the corresponding tetracyclic system in a much improved variety have been designed and executed.[109] In this section, yield of 85%, illustrating the difficulties often encountered in we will discuss a selection of radical-based cascades from the installation of congested all-carbon quaternary centers.

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Zard and co-workers have developed a mild method for 214, which was converted into 13-deoxyserratine (215) in just the generation of nitrogen-centered amidyl radicals from O- a few more steps. The yield for this cascade is impressive if it is acyl hydroxamic acids.[112] This technology was central to their considered that two vicinal quaternary stereocenters are synthesis of the Lycopodium alkaloid 13-deoxyserratine (215, formed in a single step from a relatively simple starting Scheme 31).[113] Treatment of benzoate 209 with tri-n-butyltin material. Zard and Sharp have recently applied a similar strategy to the total synthesis of the alkaloid aspidospermi- dine.[115] The use of radical rearrangements and fragmentations can allow for the construction of complex systems in remarkable ways, providing that the timing of the elementary steps in the cascade can be controlled in the desired manner.[109] One instructive example can be found in the synthesis of lubiminol (223, Scheme 32) by Crimmins et al.[116] The synthetic strategy called for a radical fragmentation/ring expansion of a tricyclic cyclobutane such as 216. This plan allowed for the formation of the spirocyclic system, including the challenging C5 quaternary center, by a stereocontrolled [2+2] photocycload- dition. Indeed, the cyclobutane substrate 216 could be prepared as a single diastereoisomer in this manner. Treat- ment of 216 with tri-n-butyltin hydride and AIBN led to fragmentation of the thiocarbamate to give secondary radical 218. This process is driven by the affinity of tin for the sulfur Scheme 31. Nitrogen-centered radical cyclization in the total synthesis atom of the thiocarbonyl group and the formation of a of 13-deoxyserratine (215; Zard et al., 2002).[113] stronger C=O bond in place of the C=S linkage. Strain-driven fragmentation of the cyclobutane ring in 218 then proceeded regioselectively to give the primary radical 219. This species hydride and the radical initiator 1,1’-azobis(cyclohexanecar- then underwent a Dowd–Beckwith ring expansion,[117] involv- bonitrile) led to generation of amidyl radical 211. This species ing 3-exo-trig cyclization onto the ketone carbonyl group underwent sequential 5-exo-trig and 6-endo-trig cyclizations, followed by fragmentation of the resulting oxygen-centered followed by hydrogen abstraction from tri-n-butyltin hydride, radical 220, with regioselective cleavage giving the observed to furnish a tetracyclic intermediate (211!212!213). In this cyclohexanone product 222 after reduction of 221. Ketone 222 reaction, the vinyl chloride substituent acts as a disposable was then converted into ( )-lubiminol (223).[118] Amore directing group.[114] Substrate 210, which lacks this control direct approach to this target would involve the radical element, was found to give the product arising from two 5- fragmentation of substrate 224, in which the required C10 exo-trig cyclizations. The chlorine atom encourages the methyl substituent has already been installed. Surprisingly, desired switch in regiochemical outcome by disfavoring the under the conditions that worked so effectively for 216, 5-exo-trig ring closure on steric grounds and by stabilizing the cyclobutane 224 failed to give any cyclohexanone prod- radical that results from the 6-endo cyclization. The overall ucts.[116] The reason for the dramatic and deleterious effect of efficiency of the synthesis does not suffer as a result of this this seemingly benign methyl group on the radical process is tactic, as no extra step was required for the introduction of the not clear. It may be that the Dowd–Beckwith fragmentation chlorine substituent and it is cleanly removed in situ to give step is disfavored by the increased steric hindrance imposed

Scheme 32. The total synthesis of lubiminol (223) through a cyclobutane fragmentation/ring-expansion cascade (Crimmins et al., 1998).[116]

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by the methyl group, or that intramolecular hydrogen-atom enabled the diastereoselective formation of three rings and transfer from this group is a competing process. However, as four stereocenters in a single maneuver. From tetracyclic another substrate bearing the epimeric 10S-methyl-substi- compound 231, a simple two-step procedure then led to ( )- tuted center also failed to proceed efficiently through the estrone (232).[125] The low overall yield of this cascade can be cascade, more subtle conformational effects may also be at attributed largely to the difficulty in achieving the initial work. macrocyclization step. The relatively slow rate of macro- The chemical synthesis of steroids has been a central cyclization allows side reactions, such as simple quenching of feature of organic chemistry research for much of the last primary radical 226 by tri-n-butyltin hydride, to compete. century.[119] The rigid steroid framework has inspired a Indeed, the major product of this reaction was the reduced number of elegant and inventive cascade reactions, from the species 233, which was isolated in 52% yield. However, once landmark biomimetic synthesis of progesterone (11)by the macrocyclization event had occurred, the remaining steps Johnson and co-workers (see Scheme 2),[5] and the cobalt- of the cascade were comparatively efficient. catalyzed synthesis of estrone (232) by Vollhardt and co- Radical cascades can also be initiated by treating suitable workers,[120] to more recent accomplishments, including the substrates with various single-electron-transfer reagents. palladium-catalyzed sequences developed by the groups of Samarium(II) iodide has been employed as a mild and Tietze[121] and Negishi,[122] and Grubbs and co-workers enyne selective reductant in many cascade reactions, in which it can metathesis cascade.[123] Pattenden et al. recently completed a mediate both radical and anionic processes.[126] Kilburn and short synthesis of ( )-estrone (232) using an imaginative co-workers employed this reagent in the synthesis of paeo- radical cascade (Scheme 33).[124] Radical precursor 225 was nilactone B (239, Scheme 34),[127] which featured a cascade

Scheme 34. The use of a SmII-mediated cyclization/fragmentation cascade in the total synthesis of paeonilactone B (239; Kilburn et al., 2001).[127]

cyclization involving a methylene cyclopropane group. Treat- Scheme 33. Total synthesis of ( )-estrone (232) through a radical ment of ketone 234 with samarium(II) iodide in the presence [124] cascade cyclization (Pattenden et al., 2004). of HMPAand tBuOH results in one-electron reduction to give ketyl radical anion 235.A5-exo-trig cyclization of 235 treated with AIBN and tri-n-butyltin hydride to give the onto the methylene cyclopropane unit generates cyclopropyl tetracyclic steroid precursor 231. This reaction proceeds by carbinyl radical 236, which undergoes a facile ring-expanding the initial macrocyclization of the primary radical 226 to give fragmentation to give homoallylic radical species 237. Sub- tertiary radical 227 (note that, in contrast to carbanion sequent 5-exo-dig cyclization of 237, followed by hydrogen- chemistry, carbon-centered radicals generally tolerate oxy- atom capture, gives the bicyclic product 238 in good yield genated functionality in the b-position). Fragmentation of the (63%) as a 10:1 mixture of diastereoisomers at the hydroxy- cyclopropane ring (227!228) then serves to move the radical substituted center (only the major diastereoisomer is shown in site to the benzylic position. Two sequential transannular Scheme 34). Elaboration of bicyclic product 238 over a short cyclizations (228!229!230) followed by quenching of the sequence of steps then completed the total synthesis.[128] The resulting secondary radical (230) then gave 231. Although the relatively high level of diastereoselectivity observed in the overall yield of this cascade was very modest, it nevertheless conversion of 235 to 236 was found to be critically dependent

7152 www.angewandte.org 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 7134 –7186 Angewandte Cascade Reactions Chemie on the reaction solvent mixture. The use of the highly coordinating cosolvent HMPAwas crucial, with the selectivity thought to result from the bulky solvated samarium alkoxide adopting a pseudoequatorial position in the cyclization of 235.[129] Radical species can also be generated oxidatively by one- electron transfer from the substrate to a metal center. Lee et al. employed the MnIII–CuII system in their total synthesis of the guaianolide sesquiterpene (À)-estafiatin (247, Scheme 35).[130] Treatment of allylic chloromalonate 240 with a mixture of manganese(III) acetate and copper(II) acetate in ethanol at 808C led to a stereoselective 5-exo-trig,7- endo-trig radical cyclization cascade, which gave tricyclic product 246 in 65% yield. The chloride substituent was specifically incorporated into cascade precursor 240 in order to prevent further oxidation of product lactone by the excess manganese(III) acetate and was easily removed during the subsequent completion of the total synthesis of (À)-estafiatin (247).[131] The radical cyclization proceeds by ligand exchange to generate the manganese(III) enolate 241 in the rate- determining step.[132] Arapid redox reaction then generates the electrophilic radical 242, which undergoes a 5-exo-trig cyclization to generate primary radical 243. This species then undergoes a selective 7-endo-trig cyclization to afford tertiary radical 244. The generally moderate intrinsic endo selectivity found in related reactions[133] is enhanced in this case by the presence of the vinylic methyl substituent, which hinders the trajectory of approach required for 6-exo cyclization and encourages the 7-endo pathway. Areluctance towards formation of a more strained trans-fused 6,5-ring system Scheme 35. Total synthesis of (À)-estafiatin (247) through an oxidative may also contribute to the high endo selectivity in this case. In radical cyclization cascade (Lee et al., 1997).[130] the final step, tertiary radical 244 is oxidized by the copper(II) acetate to give the tertiary carbocation 245, which loses a proton to give the exo-methylene product 246. naphthazarin unit of hybocarpone (256) through photoeno- The lanthanide salt, cerium(IV) ammonium nitrate lization of benzaldehyde derivative 248 in the presence of (CAN), is another single-electron oxidant that is widely acrylate 249. Thus, irradiation of 248 generated ortho- used in organic synthesis.[126, 134] Nicolaou and Gray employed quinodimethane enol 250, which was trapped in situ by CAN to effect the key dimerization step in their total dienophile 249 to give the cyclohexanol product 251 in high synthesis of hybocarpone (256).[135] Their approach involved yield.[136] Alcohol 251 was then converted into quinone 252 in the use of two separate cascade sequences, as shown in preparation for the crucial dimerization event. After screen- Scheme 36. The first was used to prepare the monomeric ing a range of electron-transfer agents, it was discovered that

Scheme 36. Total synthesis of hybocarpone (256) through photochemical enolization/Diels–Alder and oxidative coupling cascades (Nicolaou and Gray, 2001).[135]

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brief treatment of 252 with CAN at low temperature effected through the oxidative cyclization of peptidic precursor 257.

the desired carbon–carbon bond-forming reaction. Oxidation Thus, treatment of 257 with PhI(OAc)2 and LiCl in

of 252 by CAN is believed to lead to tertiary radical 253, CF3CH2OH gave the desired macrocycle 261 in moderate

which undergoes stereoselective dimerization to give the C2- yield (20–25%), accompanied by lesser amounts of the symmetric diketone 254. Quenching of the reaction with base diastereomeric product 262 (7–8%) and a mixture of epimeric completed the process by triggering hydration of the 1,4- spirodienones 263 (ca. 15%). Anumber of mechanistic diketone to give pentacyclic product 255. Hydrate 255 was pathways could be invoked to explain this result,[139] but a formed along with a minor quantity of an unsymmetrical likely pathway[140] involves the reaction of the phenol group stereoisomer, as predicted by molecular modeling studies, with the iodoso species to generate 258, which fragments with which could be epimerized to give 255 on treatment with mild the loss of acetate and iodobenzene to give phenonium ion acid. Global deprotection of 255 with aluminum bromide and intermediate 259. Reaction of 259 through path b benzene thiol gave hybocarpone (256).[137] (Scheme 37) involves attack of the amide group at C4 of the Harran and co-workers employed a photochemically phenonium ion, leading to spirocycle 263. Alternatively, initiated radical coupling in the total synthesis of the revised attack of the nucleophilic indole (path a) gives macrocyclic structure of diazonamide A( 270, Scheme 37).[138] They also intermediate 260, which re-aromatizes with concomitant ring made use of an oxidative annulation reaction of a phenol closure to generate the required aminal ring system in 261. precursor, mediated by a hypervalent iodine(III) reagent. The The minor diastereomeric product 262 arises from attack of core architecture of diazonamide A( 270) comprises two the indole ring and subsequent ring closure occurring on the macrocyclic domains: the “left-hand” macrolactam peptide- opposite face of the indole C2ÀC3 double bond to that containing portion and the “right-hand” heterocyclic sector. depicted in Scheme 37. The observed stereocontrol in the The macrolactam portion of the target was prepared first, formation of the macrocyclic products is thought to be relayed

Scheme 37. Oxidative phenolic coupling and photolytic aromatic coupling reactions in the total synthesis of (À)-diazonamide A (270; Harran et al., 2003).[138]

7154 www.angewandte.org 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 7134 –7186 Angewandte Cascade Reactions Chemie from the two backbone stereocenters, which endow precursor 257 with a helical character. This helical character also brings the phenol and indole rings into close proximity to one another, enabling macrocyclization to dominate over an ostensibly more favorable five-membered ring closure to afford spirodienones 263. After separation from the accom- panying by-products, macrocycle 261 was elaborated to give bromide 264, in preparation for the photochemical macro- cyclization event. Treatment of compound 264 with aqueous lithium hydroxide in acetonitrile served to cleave the phenolic acetate group and afford phenolate anion 265. Irradiation of this solution then triggered the crucial Witkop cyclization[141] to generate macrocyclic product 269 in 72% overall yield. This process involves a photoinduced electron transfer between the phenoxide group and the less electron-rich bromoindoline aromatic ring. Loss of bromide from the resulting radical anion 266 then gives a radical pair 267, which couples (267!268) and tautomerizes (268!269) to generate the required biaryl linkage in high yield and complete the macrocyclic framework.[142] These two very different cycliza- tion procedures therefore provided both elegant and creative solutions to the synthesis of the respective macrocyclic domains of diazonamide A( 270). Having reached the advanced staging area represented by compound 269 in this concise manner, Harran and co-workers were able to complete the total synthesis of this fascinating target in short order.[143]

5. Pericyclic Cascades

Pericyclic reactions are perhaps the most common pro- cesses encountered in cascade reactions. This broad class includes cycloadditions, sigmatropic rearrangements, and Scheme 38. Knoevenagel/hetero-Diels–Alder reaction cascade in the electrocyclic reactions, all of which have been employed in total synthesis of hirsutine (280; Tietze and Zhou, 1999).[145] cascades en route to natural product targets. This section begins with cascades that incorporate Diels–Alder reac- [144] tions, coupled with a variety of other pericyclic and non- (84%). In a second cascade step, treatment of 278 with K2CO3 pericyclic processes, in both inter- and intramolecular settings. in methanol followed by hydrogenation under palladium Several other cascades that hinge upon sigmatropic and catalysis led to methanolysis of the lactone, loss of the PMB electrocyclic transformations then follow. Additionally, a and Cbz protecting groups, iminium ion formation, and finally number of pericyclic reactions can be found throughout this reduction to form tetracyclic amine 279, a precursor to Review as components of other cascades. hirsutine (280).[147] The first example in this section is taken from the total Another cascade sequence involving a hetero-Diels– synthesis of the indole alkaloid hirsutine (280, Scheme 38) by Alder reaction can be found in the total synthesis by Nicolaou Tietze and Zhou.[145] As with several of the reactions covered et al. of the veterinary antibiotic thiostrepton (289, in this Review, this process is rather difficult to classify, as it Scheme 39),[148] the most structurally complex member of combines several individual reaction types in an elegant the thiopeptide class of natural products.[149] Inspired by the cascade. The first step in this three-component coupling biosynthetic proposals of Floss and co-workers,[150] Nicolaou reaction is the Knoevenagel condensation of chiral aldehyde et al. began investigating the [4+2] dimerization of azadienes 271 with Meldrums acid (272), which proceeds under very for the construction of the dehydropiperidine core structure mild conditions.[146] The resulting alkylidene intermediate 274 that lies at the heart of the target natural product. It was found then reacts with enol-ether 273 in an intermolecular hetero- that treatment of thiazolidine 281 with silver(I) carbonate and Diels–Alder reaction to give dihydropyran 275 with excellent a catalytic amount of DBU in pyridine led to a formal diastereoselectivity. This is then followed by a retro- elimination of hydrogen sulfide to generate the highly [4+2] cycloaddition reaction to expel a molecule of acetone reactive aza-diene 282. The Diels–Alder dimerization of 282 and generate a reactive ketene intermediate 276. Hydration then proceeded through an endo transition state to give the of 276 gives a new 1,3-diacid derivative 277, which undergoes dihydropiperidine system 283 with excellent control of thermal decarboxylation to form 278 in excellent overall yield stereoselectivity at the newly formed piperidine C5 and C6

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Scheme 39. aza-Diels–Alder dimerization and aza-Mannich reactions in the total synthesis of thiostrepton (289; Nicolaou et al., 2004).[148]

stereocenters. However, the reaction was not influenced by product 285 (60%), along with a similar quantity of aldehyde the remote stereocenters of the substrate, so 283 was formed 286, which could be recycled for the synthesis of thiazolidine as a 1:1 mixture of 5R,6S/5S,6R diastereoisomers (283 and 281.[152,153] 284, respectively). In the initial investigation of this reaction, The complex polycyclic architectures of the bisorbicilli- the addition of water to the reaction mixture at the end of the noids belie their considerably simpler biosynthetic precursor. cascade sequence, with the intention of hydrolyzing the The groups of Nicolaou and Corey have investigated the exocyclic imine group of 283, led to a low yield (20%) of the biosynthesis and total synthesis of a number of these desired amine product 285. Under these conditions, the major fascinating fungal metabolites.[154,155] Quinol 291 reaction product was found to be the interesting bicyclic imine (Scheme 40) was identified as a potential precursor to several 288, which presumably arises as the result of tautomerization of these natural products, however, such a compound was of the initial [4+2] adduct 283 to the corresponding enamine anticipated to be highly unstable.[156] Therefore, acetate 290 species 287, followed by a highly stereoselective aza-Mannich was prepared through oxidation of the corresponding phenol [151] cyclization (path a). Fortunately, inclusion of benzylamine using Pb(OAc)4 in AcOH to serve as a more stable precursor in the reaction mixture successfully diverted the course of the to the required quinol species 291. It was anticipated that reaction in favor of the desired imine lysis pathway (path b). hydrolysis of the acetate group, under either basic or acidic Thus, imine hydrolysis, through initial aminolysis (283! conditions, could then lead to the formation of reactive 284!285), gave a good yield of the dihydropiperazine intermediate 291 in situ. As shown in Scheme 40, acid-

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The conditions under which acetate 290 is hydrolyzed and the resulting quinolate anion is neutralized have a dramatic impact on the product distribution. The groups of Corey and Nicolaou have both used 290 as a precursor to the intricate pentacyclic cage structure of trichodimerol (302, Scheme 41).

Scheme 41. A Michael reaction and ketalization cascade to form trichodimerol (302; Nicolaou et al., 1999; Corey and Barnes-Seeman, 1999).[154,155]

Scheme 40. Diels–Alder dimerization and base-catalyzed isomerization Basic hydrolysis of the acetate, followed by careful neutral- reactions to form (+)-bisorbicillinol (293) and (+)-bisorbibutenolide ization with sodium dihydrogen phosphate, gave the target (297; Nicolaou et al., 1999).[154] natural product 302. The yield of trichodimerol (302) isolated from this sequence may seem low (10–16%), but should be judged in light of the great molecular complexity generated; catalyzed hydrolysis of 290 led to the Diels–Alder dimeriza- the sequence forms four new sigma bonds and generates eight tion of quinol 291 to give 292, tautomerization of which new stereocenters (six of which are quaternary). Under these afforded (+)-bisorbicillinol 293 in 43% yield.[154] Under basic reaction conditions, quinol 291 enters a sequence of Michael conditions (10 equiv KOH, 9:1 THF/H2O), the potassium salt additions and ketalizations rather than a Diels–Alder process. of 291 could be observed by 1H NMR spectroscopy, and only Addition of enol tautomer 291 to keto tautomer 298 initially dimerized to give 293 on acidification, indicating the yields dimeric species 299. Aketalization event then provides increased stability of the quinoxide. Nicolaou et al. also tricyclic intermediate 300, which is poised for a succession of found that (+)-bisorbicillinol (293) could be converted into Michael addition (300!301) and further ketalization steps another member of this class through a base-mediated ring- (301!302) to afford the target product 302. In addition to the contraction sequence. Deprotonation of 293 using KHMDS formation of trichodimerol (302), Nicolaou et al. also isolated (1.1 equiv) in THF at room temperature led to intramolecular a similar proportion of bisorbicillinol (293) from the reaction attack of the alkoxide group of anion 294 onto the ketone mixture, indicating the degree of crossover between the group, followed by a retro-aldol fragmentation to give competing Michael addition/ketalization and Diels–Alder butenolide anion 296. Protonation of this species upon dimerization pathways. quenching the reaction mixture with 1n aqueous HCl then AubØ and co-workers have designed a number of cascade furnished (+)-bisorbibutenolide (297). The conversion of processes based on sequential Diels–Alder and intramolecu- bisorbicillinol (293) into bisorbibutenolide (297) is attended lar Schmidt reactions, using either keto-azides or azido-dienes by a significant relief in the ring strain and overall steric under Lewis acid catalysis.[157] They applied this strategy for crowding present in the former compound, which provides nitrogen heterocycle construction to the total synthesis of the the necessary driving force for this transformation. Stemona alkaloid stenine (310, Scheme 42). Their first-

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product 309, accompanied by the corresponding diastereo- isomer 308 (which results from the minor endo mode of [4+2] cycloaddition), in 3:1 ratio and a combined yield of 70%. After the separation of 308 and 309, the latter could be converted into stenine (310) through a short sequence of steps.[161] In their approach to the same target, Padwa and Ginn employed an intramolecular Diels–Alder reaction of a 2- methylthio-5-amido-substituted furan to fuse the 6,5-bicyclic system onto a preexisting seven-membered ring.[162] The required activated furan system was prepared in situ as part of an impressive cascade reaction (Scheme 43), which also included the rearrangement of the Diels–Alder product. The sequence begins with dithioacetal 311, which was treated with DMTSF to form furan 316. Methylsulfenylation of 311 by DMTSF gives methylthiosulfonium ion 312, which fragments to give sulfonium ion 313. APummerer cyclization of 313 with the nearby amide group, followed by loss of a proton and elimination of acetic acid, gives the required furan ring (314! 315!316).[163] The electron-rich furan group then undergoes Scheme 42. Total synthesis of stenine (310) through a Diels–Alder/ an intramolecular Diels–Alder reaction with the pendant Schmidt cascade (Zeng and AubØ, 2005).[159] olefin[164] to generate tetracyclic intermediate 317. Interest- ingly, this Diels–Alder reaction proceeded smoothly at room temperature, while the reaction of the corresponding six- generation approach to this target employed an intramolec- membered lactam substrate required heating at 1108C. The ular Diels–Alder/Schmidt reaction sequence,[158] however, not rate difference can be explained by the greater flexibility of only was the cascade precursor difficult to prepare, but the the seven-membered lactam, which allows the furan to adopt cascade itself generated several undesired by-products, limit- a reactive conformation at ambient temperature.[165] Opening ing its efficiency. In their second-generation synthesis,[159] a of the strained oxygen bridge (317!318), assisted by the Lewis acid catalyzed intermolecular Diels–Alder reaction was nitrogen atom, is accompanied by a 1,2-shift of the methylthio utilized to couple azido-diene 303 with cyclohexenone 304 to substituent onto the activated iminium ion species to give give cis-decalin 306, as shown in Scheme 42. The moderate tricyclic enamide 319, a species which now comprised much of exo selectivity of this reaction was ascribed to unfavorable the structural and stereochemical complexity of the target steric interactions between the cyclic dienophile and the natural product 310.[166] bulky TMS enol ether of the diene (only the exo mode of Boger et al. have developed a number of cascade pro- [4+2] cycloaddition is depicted in Scheme 42). Subsequent cesses based on the hetero-Diels–Alder reactions of aza- attack of the tethered azide onto the ketone proceeded dienes.[167] Recent examples of this work can be found in their stereoselectively due to the constraints of the fused ring use of 1,3,4-oxadiazoles in the total syntheses of several system to give 307.[160] Selective migration of the carbon– alkaloid natural products, including that of vindorosine (324, [168] carbon bond antiperiplanar to the equatorially aligned N2 Scheme 44) described here. 1,3,4-Oxadiazoles had previ- leaving group in 307 led to formation of the desired tricyclic ously been employed in Diels–Alder reactions with olefins to

Scheme 43. A heterocyclization/Diels–Alder reaction/rearrangement cascade in the total synthesis of stenine (310; Ginn and Padwa, 2002).[162]

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precursor 320 is achiral, hexacyclic product 323 was formed as a racemate; however, it could be resolved by HPLC on a chiral stationary phase, thus providing access to (À)-vindor- osine.[171] Besides vindorosine, Boger and co-workers have used analogous cascades to prepare a number of other members of this class of alkaloids.[173,174] Several groups have prepared the class 1 Galbulimina alkaloid himbacine (334) by means of an intramolecular Diels–Alder reaction.[175] In an extension of this approach, Baldwin et al. designed and executed a biomimetic cascade to install three of the four rings of the target molecule in a single step (Scheme 45a). They postulated that reductive condensa- tion of diketone 326 with an appropriate amine would generate a cyclic unsaturated iminium ion 327, which would undergo a Diels–Alder reaction to form the tetracyclic structure (Scheme 45b).[176, 177] With this hypothesis as both

Scheme 44. Diels–Alder and [3+2] cycloadditions in the total synthesis of vindorosine (324; Boger et al., 2006).[168] produce bicyclic intermediates. These intermediates lose nitrogen to generate 1,3-dipoles, which undergo a second cycloaddition with another equivalent of the olefin to give symmetrical 2:1 adducts.[169] Boger and co-workers have extended this technology by developing cascade processes in which 1,3,4-oxadiazoles are employed in intramolecular cycloadditions, giving access to nonsymmetrical products.[170] Work by Padwa and Price had demonstrated that vindorosine (324) and related alkaloids could be accessed through the 1,3- dipolar cycloaddition of a carbonyl ylide species and a tethered indole dipolarophile.[171] By tethering both the olefin and the indole ring to a suitably substituted 1,3,4- oxadiazole, Boger and co-workers found that the pentacyclic skeleton of vindorosine (324) could be accessed rapidly from the relatively simple precursor 320 in a single step.[172] Heating of a solution of 320 in triisopropylbenzene at 2308C led to its slow, but efficient, conversion into hexacyclic product 323 (Scheme 44). An inverse-electron-demand Diels–Alder reac- tion between the oxadiazole ring and the tethered enol ether substituent leads to the initial formation of 321, followed by extrusion of nitrogen to form carbonyl ylide intermediate 322. Astereoselective 1,3-dipolar cycloaddition then ensues, to give the desired product 323. In all, three rings, four carbon– carbon bonds, and six stereocenters (four of them quaternary) are formed in this cascade. The endo selectivity observed in this case,[172] and also in the work of Padwa and Price,[171] is attributed to the conformational preference of the tethered dipolarophile. Interestingly, the efficiency of this cascade sequence was found to be strongly dependent on the concentration of the reaction mixture, with dilute solutions giving the best results. The use of the corresponding E-enol ether 325 (which led to the formation of the undesired Scheme 45. Cyclization/cycloaddition cascades in the total synthesis of 17S epimer of hexacyclic product 323) gave higher yields in himbeline (333) and himbacine (334): a) biomimetic approach; b) pro- the cascade sequence at higher reaction concentrations. As posed biosynthesis (Baldwin et al., 2005).[176]

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their guide and inspiration, the team prepared tetraene 328,in the undesired endo adduct.[181] This was successfully overcome which the chiral secondary amine was already incorporated in in their synthesis by the use of a chiral auxiliary, however, this

a protected form. Exposure of 328 to TFAin CH 2Cl2 effected strategy would not be possible in the context of a transannular the cleavage of the Boc protecting group and catalyzed the cycloaddition. Roush and co-workers combined the use of a formation of the cyclic iminium ion 329. Conjugation with the fully functionalized macrocyclic substrate with a bromide iminium ion species served to activate the adjacent diene stereodirecting substituent on the diene to achieve excellent system (through the lowering of the LUMO energy) towards stereocontrol in favor of the correct isomer. As shown in intramolecular Diels–Alder reaction with the other diene Scheme 46, the cascade begins from the linear precursor 335, unit, forming tetracyclic species 330. Brief treatment of the which undergoes an E-selective Horner–Wadsworth– reaction mixture with sodium cyanoborohydride then gave Emmons macrocyclization[182] to give pentaene 336. This amine 331. While the Diels–Alder event was highly diaste- intermediate spontaneously undergoes a transannular Diels– reoselective, forming a single 6,6,5-tricyclic system, the final Alder reaction to form 337, with the correct stereochemistry reductive quench of iminium ion 330 displayed no facial for spinosyn A( 338). Steric repulsion between the vinylic selectivity, with amine 331 produced as a 1:1 mixture of bromide and the C9 alkoxy substituent helps to ensure that epimers at the C12 position. Separation of this epimeric 336 reacts through the conformation shown,[183] while the mixture was postponed until after Boc protection of the overall conformation of the macrocyclic ring improves the secondary amine and selective hydrogenation of the trisub- selectivity through the influence of distant stereogenic stituted olefin to give 332, along with its C12 epimer, in centers, such as that at C21. This highly efficient conversion modest overall yield from 328. Amine 332 was converted into (335!337) facilitated the completion of the total synthesis of himbeline (333) and then himbacine (334) through standard (À)-spinosyn A( 338). procedures. The other epimer of the cascade product, (12S)- The total synthesis of the antitumor polyketide (À)- 332’, could similarly be transformed into another member of FR182877 (344, Scheme 47) was completed by the groups of this class of natural products, namely himandravine (not Sorensen and Evans, with both employing a transannular shown), the C12 epimer of himbacine (334).[178] Diels–Alder cascade sequence. Sorensen and co-workers Transannular Diels–Alder reactions have been used proposed that the polycyclic ring system of (À)-FR182877 widely in the synthesis of complex natural products. The (344) could be formed through two Diels–Alder processes conformational constraints imposed by the macrocyclic nature of the substrates often provide a high degree of stereocontrol in these processes. This area was the subject of a recent review by Deslongchamps, a pioneer of the transannular Diels–Alder reaction.[179] Two strik- ing examples that have appeared in the literature since that survey are included here to demonstrate the power of the reaction in cascade sequences. The first is the total synthesis of the insecticide spinosyn A( 338, Scheme 46) by Roush and co-workers.[180] In their total synthesis of this target, Evans and Black had previously observed that the natural conformational preference of an intra- molecular Diels–Alder substrate favored formation of

Scheme 46. Total synthesis of spinosyn (338) using a macrocycliza- Scheme 47. Transannular Diels–Alder cascades in the total synthesis of (À)- tion/transannular Diels–Alder cascade (Roush et al., 2004).[180] FR182877 (344; Sorensen et al., 2002; Evans and Starr, 2002).[188,189]

7160 www.angewandte.org 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 7134 –7186 Angewandte Cascade Reactions Chemie and a condensation event to form a large ring,[184] a hypothesis that was supported by the isolation and biosynthetic inves- tigation of the related natural product hexacyclinic acid.[185] Their initial synthetic studies focused on a sequence involving an intramolecular Diels–Alder reaction followed by forma- tion of a macrocycle and eventual hetero-Diels–Alder reaction.[186] Ultimately, their successful synthetic plan was based upon the construction of a polyketide macrocycle, which would undergo transannular Diels–Alder and hetero- Diels–Alder reactions to form the complex pentacyclic framework of the target compound. Their first total synthesis of FR182877 yielded the unnatural (+)-enantiomer,[187] how- ever, their optimized sequence gave the natural (À)-antipode 344 (Scheme 47a).[188] The efficiency of the transannular Diels–Alder cascade hinged on the selectivity of the oxidation reaction used to introduce the crucial C2ÀC3 double bond into precursor 341. In the absence of this element of unsaturation, macrocycle 339 did not undergo transannular cycloaddition, as the dienophile is not activated by conjuga- tion. It was found that selenation of keto-ester 339, using phenyl selenium chloride and sodium hexamethyldisilazide in diethyl ether at room temperature gave a 10:1 ratio of selenide products in favor of the desired epimer. Oxidation led to facile selenoxide elimination to generate pentaene 341. Warming of the reaction mixture to 458C triggered the cycloaddition sequence (341!342!343), giving a good over- all yield of the desired pentacyclic stereoisomer 343.The selenoxide elimination step also formed a smaller amount of Scheme 48. a) Diene formation/Diels–Alder reactions in the synthesis À the alkene with a Z-configured C2=C3 bond (not shown), of ( )-colombiasin A (350; Nicolaou et al., 2001; Jacobsen et al., 2005).[194,195] b) Proposed biosynthesis of elisabethin A (349) and (À)- which in turn followed its own divergent cycloaddition colombiasin A (350) from bicyclic compound 348. pathways, yielding by-products which account for most of the mass balance in this reaction. Nevertheless, this optimized route allowed the Sorensen group to prepare multigram quantities of advanced intermediate 343, ensuring a reliable been proposed to involve the stepwise formation of the supply of the natural product 344. bridged bicyclic system from bicyclic compound 348 through Evans and Starr also identified a Diels–Alder cascade as a initial C1–C9 cyclization to give elisabethin A( 349) followed potential route to (À)-FR182877 (344).[189] They prepared a by subsequent C2ÀC12 bond formation.[190] The concomitant similar precursor, 345, which underwent oxidation to 346 and isolation of 348,[191] 349,[192,193] and 350,[190] all produced from the transannular Diels–Alder cascade in an efficient one-pot the same organism (Pseudopterogorgia elisabethae), lends procedure (Scheme 47b). Their advanced cascade product credence to this hypothesis (although, of course, not con- 347 was formed as a single diastereoisomer in good yield. As stituting definitive proof for it). both groups of researchers had observed poor selectivity in Jacobsen and co-workers were keen to investigate a more intramolecular Diels–Alder reactions of related substrates, direct method for the formation of the C1ÀC9 and C2ÀC12 Evans and Starr calculated the effect of the macrocycle on the bonds from a precursor such as 348, and to this end they selectivity of the cascade sequence. They found that the C6- prepared advanced intermediate 352 (Scheme 48a). Heating

C7-C8 stereotriad alone had little effect on the facial a mixture of this material and MgSO4 in benzene to reflux selectivity of the cycloaddition, even within a macrocyclic initiated a tandem dehydration/endo-intramolecular Diels– environment, due to its local symmetry. However, including Alder reaction (352!353!354) to assemble the tetracyclic either of the C18 or C19 stereocenters in the calculations led framework of the target natural product in 77% yield. to a preference for the desired selectivity. The reinforcing Barton–McCombie reduction of the xanthate ester group to effect of having both stereocenters present was shown to be the corresponding alkane (nBu3SnH/cat. AIBN) followed by responsible for the excellent selectivity observed in the initial demethylation of the C16 hydroxy group (AlCl3, PhNMe2) transannular cycloaddition, further emphasizing the ability of then completed the concise total synthesis of (À)-colombia- a macrocyclic framework to transmit stereochemical control sin A( 350).[194] Arelated intramolecular Diels–Aldercascade from seemingly remote stereocenters. approach had previously been employed by Nicolaou et al. in Highlighting the various syntheses of (À)-colombiasin A their approach to the same target.[195] In this case, the in situ (350, Scheme 48–Scheme 50) serves to illustrate a compen- generation of diene 353 was achieved through the cheletropic [196] dium of pericyclic cascade processes. As shown in extrusion of SO2 from sulfone 355. Note that the initial Scheme 48b, the final stages in the biosynthesis of 350 have masking of the sensitive diene as the corresponding sulfone

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was essential in order to enable the generation of the quinone appended. In another highly original approach, Harrowven portion of the cascade precursor 355. et al. introduced the quinone ring at a late stage in the The most recently reported total synthesis of (À)-colom- synthetic sequence through the domino process illustrated in biasin A( 350) came from Davies et al., who deployed their Scheme 50.[200] Heating of a solution of squarate derivative combined CÀH insertion/Cope rearrangement methodol- ogy[197] as one of the defining transformations.[198] Slow addition of methyl vinyl diazoacetate (358, 3.0 equiv) to a solution of racemic dihydronaphthalene 359 and chiral rhodium(II) catalyst 360 (2 mol%) in 2,2-dimethylbutane at room temperature triggered the sequence of events shown in Scheme 49. Initial rhodium carbenoid formation (358!362) was followed by enantioselective intermolecular CÀH inser- tion to give b,g-unsaturated ester 363 as a fleeting intermedi- ate which, under the conditions of the reaction, underwent Cope ([3,3] sigmatropic) rearrangement to form 364 (pre- sumably via the expected chairlike transition conformation shown). Isolation of the cascade product was postponed until after hydrogenation of both alkenes and reduction of the ester group to the corresponding primary alcohol to give 365 in 34% overall yield from dihydronaphthalene 359 and, perhaps more significantly, as a single diastereoisomer and with over 95% ee! Three new stereogenic centers were therefore formed in a single operation from achiral starting materials employing only 2 mol% of a chiral catalyst, which demon- strates the enormous potential of this CÀH activation methodology. The CÀH functionalization step (359!363)is particularly noteworthy as a result of the discrimination between the two enantiomers of dihydronaphthalene 359 by the chiral rhodium carbenoid 362. Thus, while the (S)- Scheme 50. Electrocyclization reactions in the synthesis of (À)-colom- À dihydronaphthalene enantiomer undergoes the desired C H biasin A (350; Harrowven et al., 2005).[200] insertion, the corresponding R enantiomer preferentially undergoes cyclopropanation to give 366 in 36% yield and with over 95% ee following hydrogenation and ester reduc- 367 in THF to 1108C under microwave irradiation[107] tion. As such, the conversion of racemic 359 into enantio- triggered a Moore rearrangement,[201] involving sequential merically enriched 364 can be regarded as a kinetic resolu- 4p-electrocycloreversion (367!368), 6p-electrocyclization tion.[199] (368!369), and tautomerization (369!370) steps to deliver The syntheses of (À)-colombiasin A( 350) by the groups the fully substituted aromatic derivative 370 as a single of Nicolaou, Jacobsen, and Davies all began with the same regioisomer. Following the complete conversion of 367 into quinone starting material, 351 (Scheme 48), onto which the 370, exposure of the crude reaction mixture to air resulted in remainder of the polycyclic architecture was cleverly facile oxidation to form quinone 371, which was isolated in

Scheme 49. Enantioselective CÀH insertion/Cope rearrangement cascade in the synthesis of (À)-colombiasin A (350; Davies et al., 2006).[198]

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80% overall yield from cyclobutenone 367. With 371 in hand, by Harrowven and co-workers on the related tert-butyl ether intramolecular Diels–Alder reaction followed by cleavage of 370, to give (À)-elisapterosin B (375) in 71% yield.[200] the tert-butyl protecting group was all that was required to For the sake of completeness, we shall conclude our foray complete the total synthesis of this intriguing marine natural into the chemistry of gorgonian diterpene metabolites by product. highlighting the elegant biogenetically inspired synthesis of The close structural relationships between various mem- (+)-elisapterosin B (385, Scheme 52a) by Rawal and co- bers of this family of marine-derived diterpenes was under- scored by the conversion of (À)-colombiasin A( 350) into (À)-elisapterosin B[202] (375, Scheme 51) reported by Jacob-

Scheme 51. Conversion of (À)-colombiasin A (350) into (À)-elisapter- osin B (374) by a retro-Diels–Alder/[5+2] cycloaddition cascade (Jacob- sen et al., 2005),[194] and formation of (À)-elisapterosin B from a quinone precursor (Rychnovsky and Kim, 2003; Harrowven et al., 2005; Davies et al., 2006).[198,200, 204]

Scheme 52. a) Pinacol-type rearrangement and oxidative cyclization cascades in the total synthesis of (+)-elisapterosin B (385; Rawal [205] sen and co-workers.[194] One plausible mechanistic rationale et al., 2003). b) Structures of the nonsteroidal anti-inflammatory drugs ibuprofen (386) and naproxen (387). for this transformation invokes a retro [4+2] cycloaddition to give quinone 372, followed by Lewis acid catalyzed [5+2] cycloaddition[203] to generate the rearranged carbocy- clic framework in a remarkable yield of 94%. Proof of the workers that features a conceptually different approach to validity of the [5+2] cycloaddition step had already been formation of the bridged bicyclic system.[205] Treatment of provided in the pioneering total synthesis of (À)-elisapter- tricyclic compound 381 (ent-2-epi-elisabethin A), in which the osin B (375) by Rychnovsky and Kim,[204a] who converted C1ÀC9 bond is already in place, with CAN in acetonitrile at quinone 376 into the natural product 375 in 41% yield by 08C resulted in oxidative cyclization (possibly by the pathway [206] treatment with a large excess of BF3·OEt2 (25 equiv) in shown) to create the final ring junction and install the À CH2Cl2 at 788C. By analogy with Lewis acid catalysis of the remaining two stereocenters, leading to the formation of Nazarov cyclization,[204b] Rychnovsky and Kim proposed that triketone 384. At this point, addition of pyridine and triethyl- coordination of the boron species to the quinone generates a amine to the reaction mixture, followed by gentle warming to 4p-electron pentadienyl cation intermediate (e.g. 373) which 508C, resulted in enolization to give (+)-elisapterosin B (385, can undergo a thermally allowed cycloaddition with the the enantiomer of the natural product) in 84% overall yield pendant alkene. Asimilar protocol was subsequently applied from 381. Akey step in the synthesis of tricyclic compound

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381 was the pinacol-type ketal rearrangement of mesylate 378 The challenge of reducing these biosynthetic hypotheses to give a-aryl ester 380, involving migration of the electron- to practice inspired a number of groups to tackle the total rich aryl ring (with inversion of stereochemistry at the C9 synthesis of these natural products. Hayashi and co-workers position) via bridged phenonium ion 379. This type of were the first to disclose their route to the epoxyquinols,[211] rearrangement, initially developed by Tsuchihashi and co- followed shortly thereafter by the groups of Porco,[212] workers,[207] provides a potentially useful stereocontrolled Mehta,[213] and Kuwahara.[214, 215] Each of these elegant syn- entry to the a-aryl alkanoic acid class of compounds, which theses featured a different route to the monomeric precursor includes the widely used nonsteroidal anti-inflammatory 388, but all then successfully employed the key oxidation/ drugs ibuprofen (386) and naproxen (387) shown in electrocyclization/Diels–Alder cascade.[216] Scheme 52b.[208] Studies by the groups of Hayashi[217] and Porco[218] also As demonstrated by the syntheses of the endiandric acids culminated in the enantioselective synthesis of epoxytwinol A (Scheme 3) and (À)-FR182877 (344, Scheme 47), the linking (394). For the sake of brevity, however, we shall highlight only of sequential pericyclic processes into a single cascade can the results from Porco and co-workers, as summarized in lead to rapid and dramatic increases in molecular complexity. Scheme 53 and Scheme 54. Selective oxidation of the primary Another example is provided by the novel anti-angiogenic hydroxy group in diol 388 using conditions developed by

fungal metabolites epoxyquinols A( 392) and B (393, Semmelhack et al. (cat. TEMPO, cat. CuCl, 1 atm O2, DMF, Scheme 53). These molecules have been proposed, by 258C)[219,220] provided a 9:1 equilibrium mixture of 2H-pyran Osada and co-workers, to arise through oxidation of quinol epimers 390/391 and aldehyde 389. Stirring this crude

388 to give dienal 389, followed by 6p-electrocyclization to oxidation product mixture in CH2Cl2/MeOH (100:7) at give a mixture of diastereomeric 2H-pyrans 390 and 391 and room temperature triggered the various modes of dimeriza- subsequent intermolecular cycloaddition.[209] Epoxyquinol A tion, to give epoxyquinols A( 392, 16% yield from 388) and B (392) would be formed through an endo-Diels–Alder hetero- (393, 21%) and epoxytwinol A( 394, 10%). The fact that dimerization between one molecule of 390 and one molecule these oxidation/dimerization cascades occur spontaneously of 391, while the formation of epoxyquinol B requires a under ambient conditions suggest that they need not be [4+2] homodimerization between two molecules of 390 in an enzyme-controlled. exo alignment. Interest in this class of compounds was Detailed mechanistic studies by Hayashi and co-workers heightened by the isolation, at a later date, of epoxytwinol A indicate that the particular transition-state arrangements [210] (394) from the same fungus. This C2-symmetric pentake- leading to epoxyquinols A( 392) and B (393) are favored tide dimer would arise from a formal [4+4] cycloaddition not only by approach of the larger methyl substituents anti to between two molecules of 390. one another, but are also stabilized by intermolecular hydro-

Scheme 53. Pericyclic and Michael reaction cascades in the total synthesis of epoxyquinols A (392) and B (393) and epoxytwinol A (394; Hayashi et al., 2002; Porco et al., 2002).[211,212, 218]

7164 www.angewandte.org 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 7134 –7186 Angewandte Cascade Reactions Chemie gen-bonding interactions as shown.[221] The [4+2] homodime- mediate such as 397 (Scheme 54), which is stabilized by both rization of two molecules of 2H-pyran epimer 391 is hydrogen bonding and interaction of the oxygen anion and apparently very unfavorable, and was not observed by carbonyl oxygen center with the electropositive silicon atoms, Porco and co-workers.[222] could facilitate the initial Michael addition in the [4+4] path- Of particular interest is the dimerization pathway leading way. Whatever the precise mechanistic basis, this innovative to epoxytwinol A( 394). [4+4] Cycloaddition reactions are use of a silanol as a directing group provided an elegant electronically forbidden processes under thermal conditions solution to the problem at hand. and are generally conducted under photochemical irradia- The total syntheses of the immunosuppressant agents tion[223] or with transition-metal catalysts.[224,225] Astepwise, SNF4435 C (399) and D (400, Scheme 55), reported inde- ionic mechanism for the formation of epoxytwinol A( 394) pendently by the groups of Parker,[229] Baldwin,[230] and has therefore been invoked.[218] Intermolecular Michael Trauner,[231] represent an “endiandric acid cascade” for the reaction between two molecules of 390 initially gives zwitter- 21st century.[232] By analogy with the endiandric acids, the ionic intermediate 395, which then undergoes rotation about bicyclo[4.2.0]octadiene core of SNF4435 C (399) and D (400) the newly formed carbon–carbon bond to enable subsequent would be derived from sequential 8p-conrotatory and 6p- ring closure of the dienolate species onto the oxonium ion. disrotatory electrocyclizations of the appropriately config- Whilst the cascades described above provided a concise ured tetraene precursor 401.[233] In comparing the three total approach to the target natural products (392, 393, and 394), syntheses, one of the most striking observations is their Porco and co-workers were still interested in developing common reliance on palladium-catalyzed cross-coupling reaction conditions which would favor [4+4] cycloaddition reactions to assemble the tetraene backbone. These processes over the predominant [4+2] Diels–Alder pathways. As shown compare favorably with the more laborious preparation of the in Scheme 54, it was found that the use of an alkoxysilanol endiandric acid cascade precursor 13 (Scheme 3) more than twenty years earlier (when such cross-couplings were still a nascent technology) through a classical Glaser acetylene coupling[234,235] followed by several further manipulations (a route which in any case would not be amenable to the production of methyl-substituted derivatives of tetraene systems such as 13). Parker and Lim effected the Stille coupling of vinyl iodide 402 with stannane 403 to furnish the putative tetraene intermediate 401, which, under the conditions of the reaction, spontaneously underwent the electrocyclization cascade to afford a 3.8:1 mixture of SNF3345 C (399) and D (400). Trauner and Beaudry subsequently coupled the complemen- tary reaction partners 404 and 405 under modified Stille conditions[236] to provide the target products (399 and 400)in an improved overall yield. Baldwin and co-workers extended the proposed biosynthesis of SNF back a further step by speculating that the Z,Z,Z,E-tetraene 401 arises from isomer- ization of the corresponding Z,E,E,E-configured precursor 406,[237] itself a natural product (named spectinabilin) isolated from the same actinomycete strain (Streptomyces spectabi- lis).[238] To their delight, they found that this extended cascade (406!401!399 + 400) could indeed be triggered by heating a solution of synthetic spectinabilin 406 (prepared through Scheme 54. Silanol-promoted formal [4+4] dimerization reaction for Suzuki coupling of 407 and 408 followed by a Negishi [226] the selective formation of epoxytwinol A (394; Li and Porco, 2004). coupling to install the remaining vinyl methyl group) in DMF at 708C. The modest overall yield for this isomerization/ electrocyclization cascade is counterbalanced by the more protecting group on the secondary alcohol redirected the straightforward synthesis of the key cross-coupling fragments inherently favored [4+2] dimerization pathway to a 407 and 408, compared to that of 402 and 403 or 404 and 405. [4+4] manifold to exclusively generate the epoxytwinol The ratio of synthetic SNF4435 C (399) and D (400) molecular architecture in respectable overall yield.[226] The formed in these cascades (3.0–3.8:1.0) closely parallels that of reasons behind the choice of a seemingly rather exotic silanol the compounds found in nature.[239] The origin of this protecting group[227, 228] are twofold: 1) the Diels–Alder reac- diastereoselectivity lies in the conrotatory 8p-electrocycliza- tions to form 392 or 393 (Scheme 53) place the hydroxy tion of tetraene 401, which can proceed through either of the group(s) in more sterically encumbered positions than helical transition states 410 or 412;[240,241] the former is required in the corresponding [4+4] pathway, thus bulky evidently favored to a degree, because in this arrangement protecting groups might be expected to discourage the the bulky pyrone substituent is orientated away from the [4+2] cycloadditions, and 2) formation of a templated inter- interior of the helix. Related 8p-/6p-electrocyclization

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Scheme 55. Total syntheses of SNF4435 C (399) and D (400) through electrocyclization cascades (Parker and Lim, 2004; Baldwin et al., 2005; Trauner et al., 2005).[229–231]

domino processes have been applied in the total syntheses of related compounds gambogin[248] (420) and 1-O-methyllateri- several other structurally intriguing natural products.[242–244] florone (421, Scheme 56b).[249] Further proof, if any were needed, of the value of The aza-Cope rearrangement/Mannich reaction cascade biomimetically inspired synthetic strategies towards natural provides a useful access to 3-acylpyrrolidine systems products is provided by the total syntheses of 1-O-methyl- (Scheme 57a), which are a common substructure of a diverse forbesione (418, Scheme 56) reported by Nicolaou and Li[245] collection of alkaloids.[250] Overman and co-workers and by Theodorakis and co-workers.[246] Heating a solution of employed this process in their recent synthesis of the Stemona readily available xanthone derivative 414 in DMF to 1208C alkaloids didehydrostemofoline (429) and isodidehydroste- initiated the Claisen rearrangement/Diels–Alder/Claisen mofoline (430, Scheme 57b).[251,252] Identification of an aza- rearrangement cascade, illustrated in Scheme 56a, to form Cope/Mannich cascade as a key operation en route to the four new stereogenic centers and two new rings to directly rather unusual polycyclic framework of the target compounds provide the target natural product (418) in 51–63% yield. 429 and 430 is aided by their retrosynthetic simplification to Most of the mass balance of this reaction comprised the common precursor 428, in which a 3-acylpyrrolidine motif is regioisomeric polycyclic structure 419, which results from the more clearly visible as part of the tricyclic skeleton. Despite initial [3,3]-sigmatropic rearrangement of the C5, as opposed being itself a formidable synthetic target, ketone 428 could be to C6, allyloxy group, followed by the corresponding intra- prepared in a single operation from the more readily available molecular Diels–Alder reaction. Claisen rearrangement of bicyclic compound 425. Treatment of compound 425 with an the C3 allyloxy group was site-selective, with migration excess of paraformaldehyde in toluene/MeCN (3:1) at 808C occurring exclusively towards the C4 terminus. Circumstantial led to the initial formation of iminium ion 426, which then evidence provided by both groups justifies the sequence of underwent a (reversible) charge-accelerated [3,3]-sigmatropic events being as depicted in Scheme 56a, in which the Claisen/ arrangement[253] to afford enol 427, with a subsequent Diels–Alder cascade of ring C precedes the Claisen rear- irreversible and highly exothermic intramolecular Mannich rangement of ring A. This biomimetic route to the 4- reaction terminating the sequence. This cascade proceeded in oxatricyclo[4.3.1.0]decan-2-one system, first proposed by a remarkable overall yield of 94%, with the stereochemical Quillinan and Scheinmann in 1971,[247] provides access to information in bicyclic precursor 425 being transferred with this formidable cagelike structure with an unrivalled elegance high fidelity to the more structurally complex rearranged and efficiency, and has found use in the synthesis of the product 428. Overman and co-workers have been instrumen-

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Scheme 57. The aza-Cope/Mannich cascade approach to 3-acylpyrroli- dine structures: a) general principles and b) application to the total synthesis of didehydrostemofoline (429) and isodidehydrostemofoline (430; Overman et al., 2003).[251]

many of the well-rehearsed criteria required to be labeled “atom-economical transformations”.[2] Additionally, whilst many of the cascades described so far have been predicated on the use of biomimetic strategies, transition-metal-cata- Scheme 56. a) A Claisen/Diels–Alder/Claisen cascade in the total syn- lyzed processes provide synthetic chemists with tools for bond thesis of 1-O-methylforbesione (418; Nicolaou and Li, 2001; Theodor- construction for which there are no direct parallels in nature. akis et al., 2004).[245,246] b) Structures of gambogin (420) and 1-O- An enormous variety of transition-metal-mediated cascades methyllateriflorone (421). have been developed in recent years, but our self-imposed restriction to applications in total synthesis will limit our discussion here to exemplars of just some of the more widely tal in the design and development of the aza-Cope/Mannich used processes. cascade[254] and have demonstrated the utility of this method- It would certainly be hard to overstate the impact that the ology in the synthesis of a number of other structurally development of palladium-catalyzed cross-coupling reactions complex targets, including strychnine,[255] dehydrotubifo- has had on synthetic organic chemistry. Within the last line,[256] and 16-methoxytabersonine.[257] 25 years, these processes have blossomed into extraordinarily powerful tools for carbon–carbon and carbon–heteroatom bond formation, and research in this field continues apace.[261] 6. Transition-Metal-Catalyzed Cascades Awide variety of highly inventive palladium-catalyzed cascades have been applied in total synthesis, but we shall The development of new transition-metal-catalyzed reac- limit our discussion here to just a few instructive examples. tions is one of the most vibrant areas of chemical research, For more details on this topic, the reader is directed to several and one which is likely to become increasingly important in more specific reviews.[262] years to come.[258] Together with organocatalytic reactions[259] Amongst the palladium-catalyzed carbon–carbon bond- and enzymatic processes,[260] transition-metal-mediated reac- forming reactions, the Heck reaction[263] has undoubtedly tions offer the potential for generating molecular complexity, found the most applications in cascade processes. In partic- and often in an enantioselective fashion, by employing only ular, the utility of the intramolecular Heck reaction for the catalytic amounts of mediators. In doing so, they also meet generation of tertiary or quaternary stereocenters (in both a

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diastereo- and enantioselective fashion) and multiple-ring counterion followed by alkene p oordination then yields systems, even in sterically crowded environments, has been cationic complex 436. That the chiral binap ligand 442 well documented.[264] Keay and co-workers employed an remains anchored to the metal center through both the asymmetric polyene Heck cyclization in their enantioselective alkene coordination event and subsequent 1,2-insertion step synthesis of (+)-xestoquinone[265] (440, Scheme 58), in which to generate s-alkylpalladium(II) intermediate 437 ensures a higher level of enantioselectivity. Once formed, intermediate 437 can then undergo another migratory insertion reaction (437!438) followed by b-hydride elimination to deliver pentacyclic compound 439 and regenerate the Pd0 catalyst. Formation of the 5-exo product 441 during the second 1,2- insertion is apparently disfavored by the greater strain energy of the resulting ring system, to the extent that the 6-endo mode of ring closure predominates. In contrast, reaction of aryl bromide 432 presumably requires partial dissociation of the diphosphine ligand from the palladium center in the corresponding oxidative addition complex 435, due to the lower lability of the PdÀBr bond, in order to generate a vacant coordination site for the pendant alkene. This can lead to the substantially diminished enantioselectivity observed experi- mentally.[271–273] The Stille reaction has become a well-established method for effecting both intermolecular fragment couplings and intramolecular cyclizations of highly functionalized substrates under mild conditions.[274] The combination of these two processes into a single operation results in a Stille “stitching cyclization” cascade for the generation of macrocyclic struc- tures. Pioneered by Nicolaou et al. in the total synthesis of rapamycin,[275] a more recent application of the stitching cyclization cascade can be found in the synthetic route to the novel ansamycin antibiotic mycotrienin I[276] (447, Scheme 59a) developed by Panek and co-workers.[277] Having overcome a number of unanticipated synthetic hurdles en route to bis-E,E-vinyl iodide 443, the team was gratified to find that the most daring step in the whole sequence was to proceed with remarkable efficiency. Thus, sequential addition of bis-iodide 443, enedistannane 444[278]

(1.2 equiv), and iPr2NEt (1.5 equiv) to a solution of [PdCl2-

(MeCN)2] (20 mol%) in DMF/THF (1:1) at room temper- Scheme 58. Use of a catalytic asymmetric Heck polyene cyclization in ature led to the formation of macrocyclic triene 445 over the [266] the total synthesis of (+)-xestoquinone (440; Keay et al., 1996). course of 24 h. Treatment of macrocycle 445 with TsOH in MeOH then resulted in the selective cleavage of the C11 TIPS protecting group (an outcome anticipated by the authors on achiral aryl triflate 431 was converted in a single step into the basis of earlier model studies, and a maneuver which pentacyclic compound 439 under the conditions shown.[266,267] would subsequently allow for the installation of the amino Although the enantioselectivity of this reaction was not acid derived side chain on the correct hydroxy group) to give optimal, the conversion of 431 into 439 nevertheless provided alcohol 446 in 90% overall yield from bis-iodide 443.The an elegant solution to both the problems of generation of the crucial stitching cyclization therefore served to incorporate imposing polycyclic ring structure and the installation of the the missing C6ÀC7 unit, generate the complete macrocyclic isolated all-carbon quaternary stereocenter. This polyene structure, and form the C4–C9 triene with the required E,E,E cyclization was originally attempted using aryl bromide 432, geometry, all in a single operation![279] which led to the formation of 439 with poor enantioselectivity Aconceptually similar stitching cyclization cascade had (13% ee or less). Identification of the corresponding aryl been employed by Smith et al. two years earlier in their triflate 431 as the optimal substrate for this reaction followed approach to the structurally related trienomycin family of from insights provided by Hayashi and co-workers[268] and metabolites,[280,281] in this case employing Wittig reactions as Cabri et al.[269] on the mechanism of Heck reactions of aryl the key carbon–carbon bond-forming processes. As shown in triflates employing diphosphine ligands.[270] As shown in Scheme 59b for the synthesis of (+)-trienomycin A( 451), bis- Scheme 58, oxidative addition of a Pd0 species into aryl olefination of dialdehyde 448 with phosphonium salt 449[282] triflate 431 initially generates PdII complex 434. Owing to the provided the macrocyclic E,E,E-triene in 21% yield, accom- kinetic lability of the PdÀOTf bond, dissociation of the triflate panied by a mixture of other triene isomers in a combined

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Scheme 59. a) A Stille “stitching cyclization” cascade in the total synthesis of (+)-mycotrienin I (447; Panek et al., 1998).[277] b) A Wittig “stitching cyclization” cascade approach to (+)-trienomycin A (451; Smith et al., 1996).[280] yield of 34%. This case illustrates one potential advantage of 459 and magnesium acetylide 460, respectively. Subsequent cross-coupling reactions for the synthesis of polyene systems addition of [PdCl2(PPh3)2] (5 mol%) and heating to 658C over more traditional olefination procedures, namely the triggered a Kumada cross-coupling reaction[293,294] to give (generally) reliable and predictable formation of alkene ortho-alkynylphenolate intermediate 461. At this point, systems of well-defined geometry. dilution of the reaction mixture with DMSO, addition of An alternative Stille-based cascade approach to macro- vinyl bromide 462, and further heating to 808C promoted the cyclic structures, pioneered by Baldwin et al. in 1992[283] and exemplified by the synthesis of elaiolide (456, Scheme 60) by Paterson et al., involves the one-pot cyclodimerization of an a-iodo-w-stannane monomeric precursor.[284] As illustrated in Scheme 60, treatment of ester 452 with copper(I) thiophene- 2-carboxylate (10 equiv) in NMP (Liebeskind “palladium- free” Stille coupling conditions)[285, 286] led to the formation of the 16-membered C2-symmetric macrolide 455 in an impres- sive 80% yield. Note that the reaction proceeded to completion within 15 minutes at room temperature with no trace of the presumed intermediate 454 being isolated. Geometric constraints preclude intramolecular cyclization of precursor 452, while intramolecular cyclization of the open- chain dimerization intermediate 454 is evidently faster than competing oligomerization processes, at least at the particular concentration used.[287] This one-step cyclodimerization approach to macrolides offers an appealing alternative to conventional esterification/macrolactonization strategies.[288] One of the most widespread and versatile uses of palladium in organic synthesis is in the generation of heterocyclic ring systems.[289] Flynn and co-workers reported an interesting palladium-catalyzed multicomponent coupling approach to benzo[b]furan structures,[290,291] and subsequently applied this methodology to the synthesis of the norsesqui- terpenoid frondosin B (467, Scheme 61).[292] This well-orches- trated sequence of events began with the treatment of a mixture of readily available ortho-bromophenol 457 and alkyne 458 with MeMgBr (2.1 equiv) in THF, leading to the Scheme 60. A “palladium-free” Stille dimerization/macrocyclization initial formation of the corresponding magnesium phenolate approach to the synthesis of elaiolide (456; Paterson et al., 1999).[284]

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the industrial production of a variety of polymers, can in a sense be viewed as the pinnacle of metathesis-based cas- cades.[302] In the context of total synthesis, however, a number of elegant cascades triggered by the initial ring-opening metathesis of a strained ring system have also been devel- oped. Selected examples include ring-opening metathesis/ sigmatropic rearrangement processes,[303] ring-opening/cross- metathesis cascades,[304–306] and, in particular, ring-opening/ ring-closing metathesis (“ring-rearrangement metathesis”) strategies.[307] In their recent synthesis of (+)-cyanthiwigin U (477, Scheme 62), Phillips and Pfeiffer employed an elegant

Scheme 61. A palladium-catalyzed multicomponent coupling approach to benzo[b]furan structures in the synthesis of ()-frondosin B (467; Flynn et al., 2004).[292]

heteroannulation cascade, via the presumed intermediacy of species 463 and 464, to afford the 2,3-disubstituted benzo[b]- furan product 465 in 48% overall yield.[295–297] Minor by- products concomitantly formed in this reaction were the protocyclized material 468 (12% yield) and tetracyclic compound 469 (11% yield); whilst the former would derive from the direct cyclization of ortho-alkynylphenolate inter- Scheme 62. Total synthesis of (+)-cyanathiwigin U (477) via a two- mediate 461, the latter was speculated to arise from cascade directional ring-opening/ring-closing olefin-metathesis cascade [308] product 465 by a further sequence consisting of an antarafa- (Pfeiffer and Phillips, 2005). cial 1,7-hydrogen shift followed by conrotatory 8p-electro- cyclization.[298] Despite these competing side reactions, the two-directional ring-opening metathesis/ring-closing meta- multicomponent coupling cascade enabled the preparation of thesis tandem reaction to fashion the tricyclic core structure tricyclic compound 465 in just two steps from commercially of the targeted natural product.[308] Achiral-auxiliary-medi- available starting materials, with only a further three oper- ated asymmetric Diels–Alder reaction[309] was used to con- ations required to reach the complete framework of frondo- struct bicyclic dialdehyde 470 in enantiopure form, treatment sin B (467), as represented by the phenolic methyl ether 466. of which with vinylmagnesium bromide and subsequent Deprotection of 466 to give the target natural product 467 had Dess–Martin oxidation gave bis-enone 471. Exposure of 471 previously been reported by Danishefsky and co-workers[299] to ruthenium carbene 472[310] in refluxing toluene under an and by Trauner and Hughes[300] in their respective total atmosphere of ethylene[311] led to the desired rearrangement, syntheses. giving tricyclic compound 476 in 43% overall yield from Over the last 15 years, metathesis-based reactions have dialdehyde 470. Tricyclic product 476 has the correct relative made the transition from emerging methodologies to estab- and absolute stereochemistry at the four contiguous stereo- lished synthetic techniques in the research laboratory, genic centers around the crowded cyclohexane ring required although, as with palladium-catalyzed cross-couplings, the to complete the total synthesis, which was then achieved in field is still far from maturity.[301] The ring-opening metathesis only five further steps. There are several possible mechanistic polymerization of cyclic olefins, a well-established method for scenarios for the conversion of 471 into 476, of which only one

7170 www.angewandte.org 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 7134 –7186 Angewandte Cascade Reactions Chemie is illustrated in Scheme 62. Note that all the steps in the cleanly generated the desired 22-membered macrocyclic catalytic cycle are, in principle, reversible, but this reaction compound 489 within two hours at 208C in 72% yield and benefits from a powerful thermodynamic driving force with as a single E,E isomer. The same transformation could also be favorable contributions from both enthalpic (release of ring effected by using the Grubbs second-generation carbene 472 strain) and entropic (release of ethylene) terms. This example (15 mol% catalyst, benzene, 408C, 27 h, 58% yield). Two is illustrative of a key enabling ability of ring-rearrangement further steps then completed the total synthesis of (À)- metathesis, namely the transfer of easily installed stereo- cylindrocyclophane F (490). To rationalize this remarkable chemical information on a precursor molecule (in this case metathesis cascade, the researchers performed molecular 471) to a polycyclic product (476) in which such chiral modeling calculations, which revealed that the observed information would be difficult to encode with equal facility. product 489 was the thermodynamically most stable entity Cascade reactions figure prominently in the masterful amongst the possible seven cyclic dimers of 486 (including synthesis of (À)-cylindrocyclophane F (490, Scheme 63) head-to-head [8,6]-cyclophanes and Z-configured isomers). reported by Smith et al. in 2000.[312,313] Having already This suggested that the dimerization/macrocyclization of 486 synthesized this target through conventional stepwise actually proceeds through a cascade of reversible olefin approaches,[314] they turned to the far more challenging, but metatheses,[319] which drives the reaction towards formation inherently more tantalizing, prospect of effecting the syn- of the thermodynamically most stable product, E,E-[7,7]- thesis of the [7,7]-paracyclophane core structure through paracyclophane 489. Lending weight to this rationale was the olefin-metathesis dimerization. Specifically, cross-metathesis observation that either the E or Z isomer of the tail-to-tail between two molecules of functionalized rescorcinol mono- dimer 491 could be employed as a metathesis substrate, giving mer 486, in a head-to-tail fashion, followed by a ring-closing only the E,E-[7,7]-paracyclophane head-to-tail product 489. metathesis event could afford the complete [7,7]-cyclophane This second-generation metathesis-based approach almost skeleton, as represented by 489, in a single operation. halved the number of steps (11 versus 20), and proceeded in Monomeric precursor 486 was prepared by the thermal nearly three times the overall yield (22% versus 8%) combination of silyloxyacetylene 478 and cyclobutenone 479 compared to the original stepwise strategy, once again to give phenol 484, followed by routine protecting-group highlighting the potential of cascade processes for the adjustments. This initial annulation reaction, first developed streamlining of synthetic routes.[320,321] by Danheiser et al.,[315] presents a convenient regiocontrolled The spectacular results of the application of ruthenium approach to highly substituted aromatic compounds,[316] and carbine based systems such as 472 as olefin- and enyne- proceeds through a cascade of four pericyclic reactions, as metathesis catalysts over the last decade has, to a certain illustrated in Scheme 63.[317] To their delight, Smith et al. degree, overshadowed the concomitant development of a found that treatment of a solution of precursor 486 in benzene number of other useful ruthenium-catalyzed carbon–carbon with the Schrock molybdenum carbene 487[318] (30 mol%) bond-forming reactions.[322] One such reaction is the ruthe-

Scheme 63. Selective olefin cross-metathesis/ring-closing metathesis in the synthesis of (À)-cyclindrocyclophane F (490; Smith et al., 2000).[312]

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nium-catalyzed intermolecular coupling of alkynes and ter- precatalyst 497 is followed by ligand exchange and coordina- minal alkenes to give 1,4-dienes (Scheme 64a) developed by tion of the alkene and alkyne components (498!499), Trost et al.[323] Through the judicious placement of appropri- oxidative cyclization to generate ruthenacyclopentene 500, ate functional groups on the alkene and alkyne partners, this syn-b-hydride elimination (500!501), and then reductive elimination to extrude 1,4-diene 502 and regenerate catalyst 498.[327] Diene 502 is suitably arranged to undergo lactoniza- tion to give butenolide 503 as the observed product. Simple manipulations of the 1,2-disubstituted alkene then completed the synthesis of the target natural products 504 and 505.[328] The regioselectivity of butenolide formation is set during the coordination and cyclization steps of the catalytic cycle and is dictated primarily by coordination and steric effects, rather than electronic factors. This reaction provides a concise approach to the target butenolide ring system, a structural motif present in a large number of biologically active natural products.[329] In a more general context, the ruthenium- catalyzed alkene–alkyne coupling offers a mild, highly chemoselective, and atom-economical method for effecting fragment couplings.[330] It is significant that the uncatalyzed reaction of simple alkenes with alkynes to give 1,4-dienes (Scheme 64a), a formal variant of the Alder-ene reaction, generally only occurs under forcing conditions (T> 1508C) and has con- sequently found little application in the synthesis of complex molecules.[331] Indeed, a notable feature of transition-metal catalysis is that it offers the potential for effecting a variety of pericyclic processes which would be difficult, if not impos- sible, to achieve under purely thermal conditions.[332] In particular, a litany of higher-order and multicomponent [m+n+o…(+x)] cycloaddition reactions (where m, n, etc. refer to the number of atoms of each component participating in the reaction), many of which were unimaginable before the advent of transition-metal catalysis, have been, and continue to be, developed.[333] Classic examples include the [2+2+1] carbocyclization of an alkene, alkyne, and CO to generate cyclopentenones (the Pauson–Khand reaction),[334] and the [2+2+2] cyclotrimerization of alkynes to form benzenoid rings.[335–338] Wender et al. have been the key instigators in the development of a homologue of the venerable Diels–Alder reaction for the synthesis of seven- membered rings, namely the formal [5+2] cycloaddition between vinylcyclopropanes (VCPs) and p systems. Origi- nally described as the intramolecular cyclization of alkynes Scheme 64. Ruthenium-catalyzed alkene–alkyne coupling: a) general ! [339] principles and b) application to butenolide formation in the total and VCPs (e.g. 506 507, Scheme 65a), the scope of this synthesis of (+)-squamocin E (504) and (+)-squamocin K (505; Trost reaction has subsequently been extended to include et al., 1997).[326] alkenes,[340] allenes,[341] and even intermolecular processes.[342] Given the prevalence of seven-membered rings in a wide range of natural and designed molecules,[343] it is perhaps coupling reaction has been extended to the one-step synthesis unsurprising that this versatile reaction has begun to find of substituted butenolides.[324,325] Trost et al. showcased this application in target-oriented synthesis, an example of which methodology in the total synthesis of squamocins E (504) and being the approach to the bicyclo[5.3.0]decane skeleton of the K(505, Scheme 64b),[326] whereby heating a solution of tremulane sesquiterpenes recently reported by Martin and alkene 495 (1.0 equiv), g-hydroxyalkynoate 496 (1.0– Ashfeld.[344] Exposure of alkyne 508 to dimeric rhodium 1.6 equiv), and ruthenium complex 497 (5 mol%) in MeOH species 509 (10 mol%) in refluxing toluene triggered the at 608C led to the formation of butenolide 503 as a single sequence of events depicted in Scheme 65b, leading to the regioisomer and in yields of up to 98%! The mechanism of formation of two new rings and two new stereocenters in a this protecting-group-free transformation is believed to completely diastereoselective fashion and generating bicyclic proceed through the sequence shown in Scheme 64b. For- aldehyde 514 in 85% yield. The initial steps in the mechanism mation of the presumed active ruthenium species 498 from bear close parallel to the ruthenium-catalyzed alkene–alkyne

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core structure in this manner, Martin and Ashfeld were then able to complete the enantioselective syntheses of tremule- nediol A( 515) and tremulenolide A( 516) over the course of several more steps.[348–350] The final class of transition-metal-catalyzed reactions that we shall highlight involves the formation and subsequent reactivity of metal carbenoid species from a-carbonyldiazo compounds. Coordination to the metal center (usually a RhII or CuI species) tempers, to a degree, the generally high reactivity associated with free carbenes and allows for potentially selective further transformations.[351] From a practical synthetic perspective, such metal carbenes undergo three main types of reaction, as summarized in a very simplistic form in Scheme 66a. Cyclopropanation with alkenes and CÀH insertion reactions are both areas that have witnessed spectacular advances in recent years, partic- ularly with regards to intermolecular and asymmetric pro- cesses, and have been extensively reviewed.[352,353] An exam- ple of each was illustrated in the synthesis of (À)-colombiasin

Scheme 65. Rhodium-catalyzed [5+2] cycloadditions: a) first examples (Wender et al., 1995)[339] and b) application to the total syntheses of tremulenediol (515) and tremulenolide A (516; Martin and Ashfeld, 2005).[344] coupling discussed above (but this time occurring through a RhI$RhIII manifold), that is, formation of a coordinatively unsaturated RhI species followed by complexation of the alkene and alkyne groups (508!510) and oxidative cycliza- tion to give RhIII metallacyclopentene 511.[345] In this case, however, intermediate 511 can undergo a strain-driven cyclo- propane cleavage reaction to form the ring-expanded metal- lacycle 513 and, finally, reductive elimination to provide bicyclic product 514.[346] Importantly, note that cyclopropane cleavage from the initially formed metallacyclopentene 511 requires rotation about the C5ÀC6 bond to give the alter- native conformer 512 (i.e. 511!512!513). This ensures the correct alignment of not only the carbon–rhodium and carbon–carbon bonds required for concerted ring expansion, but also of the C5 hydrogen and C6 methyl substituents required for formation of the Z-configured C5ÀC6 double bond. The net result is that only one of the cyclopropyl carbon–carbon bonds undergoes cleavage to form 514 as a Scheme 66. a) Formation and fate of metal–carbene species 518 single regio- and diastereoisomer, an outcome anticipated by derived from a-carbonyl diazo compounds 517. b) A tandem carbonyl Martin and Ashfeld on the basis of elegant mechanistic ylide formation/1,3-dipolar cycloaddition approach to the total syn- studies by Wender et al.[347] Having assembled the bicyclic thesis of (À)-colchicine (526; Schmalz et al., 2005).[355]

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(350) by Davies et al. (Scheme 49). However, the electro- philic character of the metal-bound carbon atom also renders this site susceptible to nucleophilic attack to generate a variety of ylide species, which, in turn, can undergo subse- quent reactions. Anumber of elegant cascades have been designed on the basis of this sequence,[354] one of which was employed by Schmalz and co-workers in an enantioselective synthesis of (À)-colchicine (526, Scheme 66b) reported in 2005.[355,356] Colchicine (526) has proven to be a tempting target for generations of synthetic chemists and has inspired the development of many ingenious syntheses over the last 50 years.[357] However, a common feature of these routes is that they all adopt a stepwise linear approach to the construction of the tricyclic ring system (i.e. A!AB! ABC, A!AC !ABC, etc.), with the regiocontrolled syn- thesis of the tropolone C ring often being a particularly thorny issue.[358] As illustrated in Scheme 66b, Schmalz and co-workers employed a Rh-triggered cycloaddition cascade of a-diazoketone 522 to generate both the seven-membered B and C rings in a single step, and with complete control of Scheme 67. Carbonyl ylide generation and cycloaddition in the total diastereoselectivity, in a unique A!ABC ring approach. The synthesis of zaragozic acid C (532; Hashimoto et al., 2003).[362] mechanism of this transformation[359] begins with the gener- ation of electrophilic rhodium carbene 523, followed by intramolecular cyclization of the proximal Lewis basic carbonyl group to form a reactive carbonyl ylide 524, which then undergoes intramolecular 1,3-dipolar cycloaddition onto 7. Summary and Outlook the tethered alkyne to give the observed product 525 in 64% yield.[360] The elevated temperature (1108C) at which this The enormous benefits associated with cascade reactions reaction was run was crucial to the success of this venture, as have ensured that they continue to be developed and at ambient temperature the uncyclized enol ether 527, exploited in organic synthesis. That most of the beautiful formally derived from carbonyl ylide 524 via a 1,4-hydrogen and ingenious examples described in this Review have been shift, was the exclusive product. In addition to establishing the reported within only the last five years serves to emphasize complete carbon skeleton of the target natural product 526, this point. Of course, in highlighting only successful applica- this sequence also regioselectively installed oxygen function- tions from total synthesis, we neglect a great many cascades ality at the C9 and C10 positions in what would become the developed for other applications, or without a natural product tropolone C ring, thereby allowing the completion of the total target in mind. Additionally, countless examples of cascades synthesis in short order.[361] that have gone awry or failed altogether have been omitted. An intermolecular variant of this cycloaddition cascade The synthesis of the cascade precursors themselves may also was applied by Hashimoto and co-workers en route to their be far from trivial, and considerable experimental skill (and second-generation synthesis of zaragozic acid C (532, perseverance) is often required to unearth suitable conditions Scheme 67).[362] Slow addition of a solution of the d-tartrate- under which the desired cascade can be effected with success. derived a-diazoester 528 to a solution of alkyne 529 There are currently relatively few examples of catalytic (3.0 equiv) and rhodium(II) acetate dimer (5 mol%) in enantioselective cascade reactions, and it is likely that refluxing benzene led to the formation of bicyclic compound asymmetric catalysis of cascade processes will become 530 as a single stereoisomer in 72% yield. The stereoselec- increasingly prominent in years to come, with enzymatic, tivity of this reaction is dictated by approach of the alkyne organocatalytic, and transition-metal-catalyzed processes at dipolarophile to the top face of carbonyl ylide intermediate the vanguard of this movement. With the increasing pressures 530 (as drawn in Scheme 67), so as to avoid steric interactions to fashion diverse and increasingly complex molecular with the pseudoaxial OTMS group at C4. The regioselectivity architectures rapidly through efficient and economical of the cycloaddition can be rationalized in terms of frontier means, cascade reactions are destined to assume an integral molecular orbital theory,[363] assuming that the dominant position in many synthetic endeavors. In order to push the electronic interaction is between the ylide HOMO and alkyne state of the art of these sequences, contemporary as well as LUMO.[364] This cycloaddition provides an concise approach future generations of synthetic practitioners will require an to the densely functionalized 2,8-dioxabicyclo[3.2.1]octane increasingly precise understanding of the mechanism and core structure of the zaragozic acids, and avoids some of the kinetics of organic transformations. Gains in this fundamental potential problems associated with the formation of this motif knowledge, combined with a large dose of intellectual through intramolecular acid-catalyzed ketalization of an flexibility and creativity, will undoubtedly lead to even more open-chain 1,3-diol precursor.[365–367] spectacular applications of cascade reactions in the future.

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Abbreviations rewarding and enjoyable. We also thankDr. David M. Shaw for proofreading this manuscript. We gratefully acknowledge Ac acetyl the National Institutes of Health (USA), the Skaggs Institute ACCN 1,1’-azobis(cyclohexanecarbonitrile) for Chemical Biology, the George E. Hewitt Foundation, AIBN 2,2’-azobis(2-methylpropionitrile) Amgen, Merck, Novartis, and Pfizer for supporting our BINAP 2,2’-diphenylphosphino-1,1’-binaphthyl research programs. D.J.E. thanks Merck for postdoctoral Bn benzyl fellowship support. Boc tert-butyloxycarbonyl CAN ammonium cerium(IV) nitrate Received: May 11, 2006 Cbz benzyloxycarbonyl CSA10-camphorsulfonic acid 2,2-DMB 2,2-dimethylbutane [1] a) L. F. Tietze, G. Brasche, K. Gericke, Domino Reactions in DBU 1,8-diazabicyclo[5.4.0]undec-7-ene Organic Synthesis, Wiley-VCH, Weinheim, 2006, p. 672; b) L. F. 4-DMAP 4-dimethylaminopyridine Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137 – 170; Angew. DME ethylene glycol dimethyl ether Chem. Int. Ed. 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