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The Art and Science of REVIEWS

The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century**

K. C. Nicolaou,* Dionisios Vourloumis, Nicolas Winssinger, and Phil S. Baran

Dedicated to Professor E. J. Corey for his outstanding contributions to

At the dawn of the twenty-first cen- of the most exciting and important covery and invention of new synthetic tury, the state of the art and science of discoveries of the twentieth century in strategies and ; and explo- total synthesis is as healthy and vigor- , biology, and medicine, and rations in through ous as ever. The birth of this exhilarat- continues to fuel the drug discovery molecular design and mechanistic ing, multifaceted, and boundless sci- and development process with myriad studies. Future strides in the field are ence is marked by Wöhlers synthesis processes and compounds for new likely to be aided by advances in the of in 1828. This milestone eventÐ biomedical breakthroughs and appli- isolation and characterization of novel as trivial as it may seem by todays cations. In this review, we will chroni- molecular targets from nature, the standardsÐcontributed to a ªdemysti- cle the past, evaluate the present, and availability of new and syn- fication of natureº and illuminated the project to the future of the art and thetic methods, and information and entrance to a path which subsequently science of total synthesis. The gradual automation technologies. Such advan- led to great heights and countless rich sharpening of this tool is demonstrated ces are destined to bring the power of dividends for humankind. Being both a by considering its history along the organic synthesis closer to, or even precise science and a fine art, this lines of pre-World War II, the - beyond, the boundaries defined by discipline has been driven by the con- ward and Corey eras, and the 1990s, nature, which, at present, and despite stant flow of beautiful molecular archi- and by accounting major accomplish- our many advantages, still look so far tectures from nature and serves as the ments along the way. Today, natural away. engine that drives the more general total synthesis is associated field of organic synthesis forward. with prudent and tasteful selection of Keywords: drug research ´ natural Organic synthesis is considered, to a challenging and preferably biologically products ´ synthetic methods ´ total large extent, to be responsible for some important target ; the dis- synthesis

1. Prologue more or less useful, are constantly discovered and investi- gated. For the determination of the structure, the architecture ªYour Majesty, Your Royal Highnesses, Ladies and Gentle- of the , we have today very powerful tools, often men. borrowed from . The organic of In our days, the chemistry of natural products attracts a very the year 1900 would have been greatly amazed if they had lively interest. New substances, more or less complicated, heard of the methods now at hand. However, one cannot say that the work is easier; the steadily improving methods make [*] K. C. Nicolaou, D. Vourloumis, N. Winssinger, P. S. Baran it possible to attack more and more difficult problems and the Department of Chemistry ability of Nature to build up complicated substances has, as it and The Skaggs Institute for Chemical Biology The Scripps Research Institute seems, no limits. 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA) In the course of the investigation of a complicated and substance, the investigator is sooner or later confronted by Department of Chemistry and the problem of synthesis, of the preparation of the substance University of California, San Diego by chemical methods. He can have various motives. Perhaps 9500 Gilman Drive, La Jolla, CA 92093 (USA) Fax: (‡1) 858-784-2469 he wants to check the correctness of the structure he has E-mail: [email protected] found. Perhaps he wants to improve our knowledge of the [**] A list of abbreviations can be found at the end of the article. reactions and the chemical properties of the molecule. If the

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000 1433-7851/00/3901-0045 $ 17.50+.50/0 45 REVIEWS K. C. Nicolaou et al. substance is of practical importance, he may hope that the The synthesis of a complicated molecule is, however, a very synthetic compound will be less expensive or more easily difficult task; every group, every must be placed accessible than the . It can also be desirable to in its proper position and this should be taken in its most modify some details in the molecular structure. An literal sense. It is sometimes said that organic synthesis substance of medical importance is often first isolated from a is at the same time an exact science and a fine art. Here microorganism, perhaps a mould or a germ. There ought to nature is the uncontested master, but I dare say that exist a number of related compounds with similar effects; they the prize-winner of this year, Professor Woodward, is a good may be more or less potent, some may perhaps have second.º[1] undesirable secondary effects. It is by no means, or even With these elegant words Professor A. Fredga, a member of probable, that the compound produced by the microorgan- the Committee for Chemistry of the Royal ismÐmost likely as a weapon in the struggle for existenceÐis Swedish Academy of Sciences, proceeded to introduce R. B. the very best from the medicinal point of view. If it is possible Woodward at the Nobel ceremonies in 1965, the year in which to synthesize the compound, it will also be possible to modify Woodward received the prize for the art of organic synthesis. the details of the structure and to find the most effective Twenty-five years later Professor S. Gronowitz, then a mem- remedies. ber of the Nobel Prize Committee for Chemistry, concluded

K. C. Nicolaou D. Vourloumis N. Winssinger P. S. Baran

K.C. Nicolaou, born in Cyprus and educated in England and the US, is currently Chairman of the Department of Chemistry at The Scripps Research Institute, La Jolla, California, where he holds the Darlene Shiley Chair in Chemistry and the Aline W. and L. S. Skaggs Professorship in Chemical Biology as well as Professor of Chemistry at the University of California, San Diego. His impact on chemistry, biology, and medicine flows from his works in organic synthesis described in nearly 500 publications and 70 patents as well as his dedication to chemical education, as evidenced by his training of over 250 graduate students and postdoctoral fellows. His recent book titled ªClassics in Total Synthesisº,[3] which he co- authored with Erik J. Sorensen, is used around the world as a teaching tool and source of inspiration for students and practitioners of organic synthesis.

Dionisios Vourloumis, born in 1966 in Athens, Greece, received his B.Sc. degree from the University of Athens and his Ph.D. from West Virginia University under the direction of Professor P. A. Magriotis, in 1994, working on the synthesis of novel . He joined Professor K. C. Nicolaous group in 1996, and was involved in the total synthesis of A and B, eleutherobin, sarcodictyins A and B, and analogues thereof. He joined Glaxo Wellcome in early 1999 and is currently working with the Combichem Team in Research Triangle Park, North Carolina.

Nicolas Winssinger was born in Belgium in 1970. He received his B.Sc. degree in chemistry from Tufts University after conducting research in the of Professor M. DAlarcao. Before joining The Scripps Research Institute as a graduate student in chemistry in 1995, he worked for two years under the direction of Dr. M. P. Pavia at Sphinx Pharmaceuticals in the area of molecular diversity focusing on . At Scripps, he joined the laboratory of Professor K. C. Nicolaou, where he has been working on methodologies for -phase chemistry and combinatorial synthesis. His research interests include natural products synthesis, molecular diversity, molecular evolution, and their application to chemical biology.

Phil S. Baran was born in Denville, New Jersey in 1977. He received his B.Sc. degree in chemistry from New York University while conducting research under the guidance of Professors D. I. Schuster and S. R. Wilson, exploring new realms in fullerene science. Upon entering The Scripps Research Institute in 1997 as a graduate student in chemistry, he joined the laboratory of Professor K. C. Nicolaou where he embarked on the total synthesis of the CP molecules. His primary research interest involves natural product synthesis as an enabling endeavor for the discovery of new fundamental processes and concepts in chemistry and their application to chemical biology.

46 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS his introduction of E. J. Corey, the 1990 Nobel prize winner, mentioned. The labeling of these eras is arbitraryÐnot with the following words: withstanding the tremendous impact Woodward and Corey ª...Corey has thus been awarded with the Prize for three had in shaping the discipline of total synthesis during their intimately connected contributions, which form a whole. time. As in any review of this kind, omissions are inevitable Through and introduction of new and we apologize profusely, and in advance, to those synthetic reactions, he has succeeded in preparing biologically whose brilliant works were omitted as a result of space important natural products, previously thought impossible to limitations. achieve. Coreys contributions have turned the art of synthesis into a science...º[2] This description and praise for total synthesis resonates today with equal validity and appeal; most likely, it will be 2. Total Synthesis in the Nineteenth Century valid for some time to come. Indeed, unlike many one-time discoveries or inventions, the endeavor of total synthesis[3±6] is The birth of total synthesis occurred in the nineteenth in a constant state of effervescence and . It has been on the century. The first conscious total synthesis of a natural product move and center stage throughout the twentieth century and was that of urea (Figure 1) in 1828 by Wöhler.[8] Significantly, continues to provide fertile ground for new discoveries and this event also marks the beginning of organic synthesis and inventions. Its central role and importance within chemistry will undoubtedly ensure its present preeminence into the OH future. The practice of total synthesis demands the following O O HO O OH virtues from, and cultivates the best in, those who practice it: NH NH Me OH HO 2 2 OH ingenuity, artistic taste, experimental skill, persistence, and urea character. In turn, the practitioner is often rewarded with acetic [8] [9] [12] discoveries and inventions that impact, in major ways, not [Wöhler, 1828] [Kolbe, 1845] [Fischer, 1890] only other areas of chemistry, but most significantly material Figure 1. Selected nineteenth century landmark total syntheses of natural products. science, biology, and medicine. The harvest of touches upon our everyday lives in myriad ways: medicines, high-tech materials for computers, the first instance in which an inorganic substance and transportation equipment, nutritional products, , (NH4CNO: ) was converted into an or- cosmetics, , clothing, and tools for biology and ganic substance. The synthesis of from elemental .[7] by Kolbe in 1845[9] is the second major achievement in But why is it that total synthesis has such a lasting value as a the history of total synthesis. It is historically significant that, discipline within chemistry? There must be several reasons for in his 1845 publication, Kolbe used the word ªsynthesisº for this phenomenon. To be sure, its dual nature as a precise the first time to describe the process of assembling a chemical science and a fine art provides excitement and rewards of rare compound from other substances. The total syntheses of heights. Most significantly, the discipline is continually being alizarin (1869) by Graebe and Liebermann[10] and indigo challenged by new structural types isolated from natures (1878) by Baeyer[11] spurred the legendary German dye seemingly unlimited library of molecular architectures. Hap- industry and represent landmark accomplishments in the pily, the practice of total synthesis is being enriched constantly field. But perhaps, after urea, the most spectacular total by new tools such as new reagents and catalysts as well as synthesis of the nineteenth century was that of (‡)-glucose analytical instrumentation for the rapid purification and (Figure 1) by E. Fischer.[12] This total synthesis is remarkable characterization of compounds. not only for the complexity of the target, which included, for Thus, the original goal of total synthesis during the first part the first time, stereochemical elements, but also for the of the twentieth century to confirm the structure of a natural considerable stereochemical control that accompanied it. product has been replaced slowly but surely with objectives With its -containing monocyclic structure (pyranose) related more to the exploration and discovery of new and five stereogenic centers (four controllable), glucose chemistry along the pathway to the target molecule. More represented the state-of-the-art in terms of target molecules recently, issues of biology have become extremely important at the end of the nineteenth century. E. Fischer became the components of programs in total synthesis. It is now clear that second winner of the Nobel Prize for chemistry (1902), after as we enter the twenty-first century both exploration and J. H. vant Hoff (1901).[13] discovery of new chemistry and chemical biology will be facilitated by developments in total synthesis. In this article, and following a short historical perspective of total synthesis in the nineteenth century, we will attempt to 3. Total Synthesis in the Twentieth Century review the art and science of total synthesis during the twentieth century. This period can be divided into the pre- The twentieth century has been an age of enormous World War II Era, the Woodward Era, the Corey Era, and the scientific advancement and technological progress. To be 1990s. There are clearly overlaps in the last three eras and sure, we now stand at the highest point of human accomplish- many more practitioners deserve credit for contributing to the ment in science and technology, and the twenty-first century evolution of the science during these periods than are promises to be even more revealing and rewarding. Advances

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 47 REVIEWS K. C. Nicolaou et al. in medicine, computer science, communication, and trans- portation have dramatically changed the way we live and the way we interact with the world around us. An enormous amount of wealth has been created and opportunities for new enterprises abound. It is clear that at the heart of this technological revolution has been science, and one cannot deny that basic research has provided the foundation for this to occur. Chemistry has played a central and decisive role in shaping the twentieth century. Oil, for example, has reached its potential only after chemistry allowed its analysis, fractiona- tion, and transformation into myriad of useful products such as kerosene and other fuels. Synthetic is perhaps the most expressive branch of the science of chemistry in view of its creative power and unlimited scope. Figure 2. Selected landmark total syntheses of natural products from 1901 To appreciate its impact on modern humanity one only has to to 1939. look around and recognize that this science is a pillar behind pharmaceuticals, high-tech materials, , fertilizers, pesticides, cosmetics, and clothing.[7] The engine that drives forward and sharpens our ability to create such molecules 3.2. The Woodward Era through chemical synthesis (from which we can pick and choose the most appropriate for each application) is total In 1937 and at the age of 20 R. B. Woodward became an synthesis. In its quest to construct the most complex and assistant professor in the Department of Chemistry at challenging of natures products, this endeavorÐperhaps Harvard University where he remained for the rest of his more that any otherÐbecomes the prime driving force for life. Since that time, total synthesis and organic chemistry the advancement of the art and science of organic synthesis. would never be the same. A quantum leap forward was about Thus, its value as a research discipline extends beyond to be taken, and total synthesis would be elevated to a providing a test for the state-of-the-art. It offers the oppor- powerful science and a fine art. Woodwards climactic tunity to discover and invent new science in chemistry and contributions to total synthesis included the conquest of some related disciplines, as well as to train, in a most rigorous way, of the most fearsome molecular architectures of the time. One young practitioners whose expertise may feed many periph- after another, diverse structures of unprecedented complexity eral areas of science and technology.[6] succumbed to synthesis in the face of his ingenuity and resourcefulness. The following structures (some are shown in Figure 3) are amongst his most spectacular synthetic achieve- ments: quinine (1944),[22] patulin (1950),[23] cholesterol and 3.1. The Pre-World War II Era cortisone (1951),[24] lanosterol (1954),[25] lysergic acid (1954),[26] (1954),[27] reserpine (1958),[28] chlorophyll a (1960),[29] The syntheses of the nineteenth century were relatively colchicine (1965),[286] cephalosporin C (1966),[30] prostaglan- [31] [32] simple and, with a few exceptions, were directed towards din F2a (1973), B12 (with A. Eschenmoser) (1973), benzenoid compounds. The starting materials for these target and erythromycin A (1981).[33] Some of these accomplishments molecules were other benzenoid compounds, chosen for their will be briefly presented in Section 3.5. resemblance to the targeted substance and the ease by which Woodward brought his towering intellect to bear on these the synthetic could connect them by simple function- daunting problems of the 1940s, 1950s, and 1960s with alization chemistry. The twentieth century was destined to distinctive style and unprecedented glamour. His spectacular bring dramatic advances in the field of total synthesis. The successes were often accompanied by appropriate media pre-World War II Era began with impressive strides and with coverage and his lectures and seminars remained legendary increasing molecular complexity and sophistication in strat- for their intellectual content, precise delivery, and mesmeriz- egy design. Some of the most notable examples of total ing style, not to mention their colorful nature and length! synthesis of this era are a-terpineol (Perkin, 1904),[14] What distinguished him from his predecessors was not just his (Komppa, 1903; Perkin, 1904),[15] (Rob- powerful intellect, but the mechanistic rationale and stereo- inson, 1917; Willstätter, 1901),[16±17] haemin (H. Fischer, chemical control he brought to the field. If Robinson 1929),[18] pyridoxine hydrochloride (Folkers, 1939),[19±20] and introduced the curved arrow to organic chemistry (on paper), equilenin (Bachmann, 1939)[21] (Figure 2). Particularly im- Woodward elevated it to the sharp tool that it became for pressive were Robinsons one-step synthesis of tropinone teaching and mechanistic understanding, and used it to (1917)[16] from succindialdehyde, , and explain his science and predict the outcome of chemical and H. Fischers synthesis of haemin[18] reactions. He was not only a General but, most importantly, a (1929). These total syntheses are among those which will be generalist and could generalize observations into useful highlighted below. Both men went on to win a Nobel Prize for theories. He was master not only of the art of total synthesis, Chemistry (Fischer, 1929; Robinson, 1947).[13] but also of structure determination, an endeavor he cherished

48 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

H H OH N CO2H O Me O Me H O O H Me N OH H NMe HO Me H H Me N MeO H H H O HO O OH H Me H [23] O O HN Me N patulin (1950) cortisone (1951)[24] strychnine (1954)[27] lysergic acid (1954)[26] lanosterol (1954)[25] quinine (1944)[22]

NMe2 OMe H H MeO N H OH N N MeO O O NH2 N Mg H H H H OH OMe N N OH OH O O O MeO2C H OMe 6-demethyl-6-deoxytetracycline (1962)[285] MeO reserpine (1958)[28] NHAc MeO OMe O MeO C O O 2 HO [286] H2N colchicine (1965) NH2 O O Me Me [29] CO2H H H chlorophyll a (1960) O Me OHC H2N O H N CN HO H OH HO O Me N N NH 2 H H H [31] H Me OH N PGF α (1973) H Co H3N N S 2 O H2N O O N N Me CO O N OAc N [288] H Me 2 marasmic acid (1976) O O H O O Me CO2H O Me NH [287] Me Me O Me 2 [30] isolongistrobine (1973) cephalosporin C (1966) Me N OH NH H H HO OH Me R N Me N OH OMe OMe S HO OMe Me Me HO H OHC R' O O NMe2 Me O H MeO O N O O N O Me P O O O OMe O CO2H O H H [290] Me Me penems (1978) OH OH HO O O CO H HO O O O [32] 2 Me vitamin B12 (1973) [289] [289] [289] erythromycin A (1981)[33] [with A. Eschenmoser] illudalic acid (1977) illudinine (1977) illudacetalic acid (1977) Figure 3. Selected syntheses by the Woodward Group (1944 ± 1981). throughout his career. He clearly influenced the careers of not Urbana-Champaign. His dynamism and brilliance were to only his students, but also of his peers and colleagues, for make him the natural recipient of the total synthesis baton example, J. Wilkinson (sandwich structure of ), K. from R. B. Woodward, even though the two men overlapped Block ( ), R. Hoffmann (Woodward and for two decades at Harvard. Coreys pursuit of total synthesis Hoffmann rules), all of whom won the Nobel Prize for was marked by two distinctive elements, retrosynthetic chemistry.[13] analysis and the development of new synthetic methods as His brilliant use of rings to install and control stereo- an integral part of the endeavor, even though Woodward chemical centers and to unravel functionality by rupturing (consciously or unconsciously) must have been engaged in them is an unmistakable feature of his syntheses. This theme such practices. It was Coreys 1961 synthesis of longifolene[34] appears in his first total synthesis, that of quinine,[22] and that marked the official introduction of the principles of appears over and over again as in the total synthesis of retrosynthetic analysis.[4] He practiced and spread this concept [28] [3, 32] reserpine, vitamin B12 , and, remarkably, in his last throughout the world of total synthesis, which became a much synthesis, that of erythromycin.[33] Woodwards mark was that more rational and systematic endeavor. Students could now of an artist, treating each target individually with total be taught the ªlogicº of chemical synthesis[4] by learning how mastery as he moved from one structural type to another. to analyze complex target molecules and devise possible He exercised an amazing intuition in devising strategies synthetic strategies for their construction. New synthetic toward his targets, magically connecting them to suitable methods are often incorporated into the synthetic schemes starting materials through elegant, almost balletlike, maneu- towards the target and the exercise of the total synthesis vers. becomes an opportunity for the invention and discovery of However, the avalanche of new natural products appearing new chemistry. Combining his systematic and brilliant ap- on the scene as a consequence of the advent and development proaches to total synthesis with the new tools of organic of new analytical techniques demanded a new and more synthesis and , Corey synthesized hun- systematic approach to strategy design. A new school of dreds of natural and designed products within the thirty year thought was appearing on the horizon which promised to take period stretching between 1960 and 1990 (Figure 4)Ðthe year the field of total synthesis, and that of organic synthesis in of his Nobel Prize. general, to its next level of sophistication. Corey brought a highly organized and systematic approach to the field of total synthesis by identifying unsolved and important structural types and pursuing them until they fell. 3.3. The Corey Era The benefits and spin-offs from his endeavors were even more impressive: the theory of retrosynthetic analysis, new syn- In 1959 and at the age of 31 E. J. Corey arrived at Harvard thetic methods, asymmetric synthesis, mechanistic proposals, as a full professor of chemistry from the University of Illinois, and important contributions to biology and medicine. Some of

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 49 REVIEWS K. C. Nicolaou et al.

Figure 4. Selected syntheses by the Corey Group (1961 ± 1999).

50 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS his most notable accomplishments in the field are highlighted unprecedented challenges and opportunities. To be sure, the in Section 3.5. final decade of the twentieth century proved to be a most The period of 1950 ± 1990 was an era during which total exciting and rewarding period in the history of total synthesis. synthesis underwent growth as evidenced by inspection of the primary chemical literature. In addition to the Woodward and Corey schools, a number of other groups 3.4. The 1990s Era contributed notably to this rich period for total synthesis[3±5] and some continue to do so today. Indeed, throughout the The climactic productivity of the 1980s in total synthesis second half of the twentieth century a number of great boded well for the future of the science, and the seeds were synthetic chemists made significant contributions to the field, already sown for continued breakthroughs and a new as natural products became opportunities to initiate and focus explosion of the field. Entirely new types of structures were major research programs and served as ports of entry for on the minds of synthetic chemists, challenging and presenting adventures and rewarding voyages. them with new opportunities. These luring architectures Among these great chemists are G. Stork, A. Eschenmoser, included the such as and dynemicin, and Sir D. H. R. Barton, whose sweeping contributions began the polyether neurotoxins exemplified by brevetoxins A and with the Woodward era and spanned over half a century. The B, the immunosuppressants cyclosporin, FK506, rapamycin, Stork ± Eschenmoser hypothesis[35] for the stereospecific and sanglifehrin A, taxol and other tubulin binding agents, course of biomimetic ± cation cyclizations, such as the con- such as the epothilones eleutherobin and the sarcodictyins, version of into steroidal structures, stimulated much ecteinascidin, the manzamines, the glycopeptide antibiotics synthetic work (for example, the total synthesis of progester- such as vancomycin, the CP molecules, and everninomicin one by W. S. Johnson, 1971).[36] Storks elegant total syntheses 13,384-1 (see Section 3.5). (for example, , , tetracyclins)[37±39] dec- Most significantly, total synthesis assumed a more serious orate beautifully the chemical literature and his useful role in biology and medicine. The more aggressive incorpo- methodologies (for example, chemistry, anionic ring ration of this new dimension to the enterprise was aided and closures, radical chemistry, tethering devices)[40±43] have found encouraged by combinatorial chemistry and the new chal- important and widespread use in many and lenges posed by discoveries in genomics. Thus, new fields of industrial settings. investigation in chemical biology were established by syn- Similarly, Eschenmosers beautiful total syntheses (for thetic chemists taking advantage of the novel molecular architectures and biological action of certain natural products. example, colchicine, corrins, vitamin B12 , designed nucleic )[44±47] are often accompanied by profound mechanistic Besides culminating in the total synthesis of the targeted insights and synthetic designs of such admirable clarity and natural products, some of these new programs expanded into the development of new synthetic methods as in the past, but deep thought. His exquisite total synthesis of vitamin B12 (with Woodward), in particular, is an extraordinary achieve- also into the areas of chemical biology, solid phase chemistry, ment and will always remain a classic[3] in the annals of and combinatorial synthesis. Synthetic chemists were moving organic synthesis. The work of D. H. R. Barton,[48] starting deeper into biology, particularly as they recognized the with his contributions to conformational analysis and bio- timeliness of using their powerful tools to probe biological genetic theory and continuing with brilliant contributions phenomena and make contributions to chemical and func- both in total synthesis and synthetic methodology, was tional genomics. Biologists, in turn, realized the tremendous instrumental in shaping the art and science of natural products benefits that chemical synthesis could bring to their science synthesis as we know it today. Among his most significant and adopted it, primarily through interdisciplinary collabo- contributions are the Barton reaction, which involves the rations with synthetic chemists. A new philosophy for total photocleavage of [49] and its application to the synthesis as an important component of chemical biology synthesis of aldosterone-21-acetate,[50] and his began to take hold, and natural products continued to be in reactions and related radical chemistry,[51] which has found the center of it all. In the next section we briefly discuss a numerous applications in organic and natural product synthesis. number of selected total syntheses of the twentieth century. It seemed for a moment, in 1990, that the efforts of the synthetic chemists had conquerred most of the known 3.5. Selected Examples of Total Syntheses structural types of secondary metabolites: prostaglandins, steroids, b-lactams, macrolides, polyene macrolides, polyeth- The chemical literature of the twentieth century is adorned ers, , porphyrinoids, endiandric acids, palitoxin with beautiful total syntheses of natural products.[3±5] We have carboxyclic acid, and gingkolide; all fell as a result of the chosen to highlight a few here as illustrative examples of awesome power of total synthesis. Tempted by the lure of structural types and synthetic strategies. other unexplored and promising fields, some researchers even thought that total synthesis was dead, and declared it so. They Tropinone (1917) were wrong. To the astute eye, a number of challenging and beautiful architectures remained standing, daring the syn- Perhaps the first example of a strikingly beautiful total thetic chemists of the time and inviting them to a feast of synthesis is that of the (Æ)-tropinone (1 in Scheme 1) discovery and invention. Furthermore, several new structures reported as early as 1917 by Sir R. Robinson.[5, 16] In this were soon to be discovered from nature that offered elegant synthesisÐcalled biomimetic because of its resem-

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 51 REVIEWS K. C. Nicolaou et al. a) prior to elimination of the latter functionalities. In contrast to Me the rather brutal reagents and conditions used in this N CO2H CHO s synthesis, the tools of the ªtradeº when Wood- O + + NMe H2NMe O ward faced chlorophyll a, approximately thirty years later, O CHO Mannich reaction CO2H were much sharper and selective. 1: tropinone 2 3 4 b) H Me O N Equilenin (1939) - H2O NMe H2NMe NMe +H2O CHO CHO O The first sex hormone to be constructed in the laboratory by H OH 2: succin-dialdehyde 5 6 7 total synthesis was equilenin (1 in Scheme 3). The total H O synthesis of this first steroidal structure was accomplished in [intermolecular Mannich reaction] O2C CO2

Me Me Me Me N N a) N N Me O HCl CO2H CO2H CO2H Dieckmann cyclization -2 CO2 O O O H HO O O H CO2H CO2H H CO2H 1 10 9 8 HO MeO [intramolecular Mannich reaction] 1: equilenin 4: Butenandt's Scheme 1. a) Strategic bond disconnecions and retrosynthetic analysis of (Æ)-tropinone and b) total synthesis (Robinson, 1917).[16] Me Me CO2Me CO2H H blance to the way nature synthesizes tropinoneÐRobinson CO2H CO2Me H utilized a tandem sequence in which one molecule of HO HO succindialdehyde, methylamine, and either acetone dicarbox- 2 3 Arndt-Eistert reaction Reformatsky ylic acid (or dicarboxylate) react together to afford the natural reaction substance in a simple one-pot procedure. Two consecutive a. (CO2Me)2, MeONa Me b) CO2Me CO2Me Mannich reactions are involved in this synthesis, the first one b. 180 ¡C, glass MeI, MeONa (90%) (92%) in an inter- and the second one in an intramolecular fashion. O O O MeO MeO MeO In a way, the total synthesis of (Æ)-tropinone by Robinson was 4 5 6 quite ahead of its time both in terms of elegance and logic. [Reformatsky reaction] a. BrZnCH2CO2Me With this synthesis Robinson introduced aesthetics into total [dehydration] b. SOCl2, py synthesis, and art became part of the endeavor. It was left, [saponification] c. KOH, MeOH Me a. CH2N2 Me Me Me H CO H however, to R. B. Woodward to elevate it to the artistic status CO2 b. NaOH CO2 2 d. Na-Hg that it achieved in the 1950s and to E. J. Corey to make it into c. SOCl2 H H (39% overall) CO2H CO2H the precise science that it became in the following decades. MeO O Cl MeO MeO 8 3a 7 (84% overall) [Arndt-Eistert a. CH2N2 reaction] b. Ag O, MeOH [-N ] [Dieckmann cyclization- Haemin (1929) 2 2 sequence] Me Me Me O CO2Me CO2Me Haemin (1 in Scheme 2), the red pigment of blood and the a. MeONa carrier of oxygen within the human body, belongs to the H H b. HCl, AcOH H porphyrin class of compounds. Both its structure and total MeO O : MeO CO2Me HO (92%) synthesis were established by H. Fischer.[5, 18] This combined 9 10 1: equilenin program of structural determination through chemical syn- Scheme 3. a) Strategic bond disconnections and retrosynthetic analysis of [21] thesis is exemplary of the early days of total synthesis. Such equilenin and b) total synthesis (Bachmann et al., 1939). practices were particularly useful for structural elucidation in the absence of todays physical methods such as NMR 1939 by Bachmann and his group at the University of , , and X-ray . Michigan.[21, 52] This synthesis featured relatively simple In the case of haemin, the molecule was degraded into smaller chemistry as characteristically pointed out by the authors: fragments, which chemical synthesis confirmed to be substi- ªThe reactions which were used are fairly obvious ones...º[21] tuted . The assembly of the pieces by exploiting the Specifically, the sequence involves -type chemistry, a greater nucleophilicity of s 2-position, relative to that Reformatsky reaction, a amalgam reduction, an of the 3-position, led to haemins framework into which the Arndt ± Eistert homologation, and a Dieckmann cycliza- cation was implanted in the final step. Among the most tion ± decarboxylation process to fuse the required cyclo- remarkable features of Fischers total synthesis of haemin are pentanone ring onto the pre-existing tricyclic system of the the fusion of the two dipyrrole components in at starting material. As the last pre-World War II synthesis of 180 ± 1908C to form the cyclic porphyrin skeleton in a single note, this example was destined to mark the end of an era; A step by two CC bond-forming reactions, and the unusual way new epoch was about to begin in the 1940s with R. B. in which the carbonyl groups were reduced to hydroxyl groups Woodward and his school of chemistry at the helm.

52 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

a) Me Me Me Me Me Me Me OHC NH HN N N Me H H N N Me 2 4 5 Fe CO H N N Br Br 2 Me Me NH HN Me Me Me 1: haemin HO C CO H 2 2 Me N CO2Et H HO2C 3 CO2H 6

b) H Me Me HO H Me HO H Me Me Me Me HBr Me H Me Me Me Me Me Me N N NH HN NH HN NH HN NH HN NH HN H H O Me Me Me Me Me Me Me Me H 4 H 5 7 8 9 Br 10 2

CO H 2 HO2C HO2C HO2C HO2C 14 HBr, CO2H EtO2C Me Me OHC Me Me Me Br2 Me Me a. H2SO4 HCO2H Na/Hg H b. ∆ HCl [Knoevenagel] H CO Et CO Et Me CO Et CO Et Me CO2Et CO Et CO2Et Me N 2 Me N 2 N 2 Me N 2 N Me N 2 N H H H H H H H 11 12 13 15 6 16 17

HO2C HO2C HO2C HO2C HO2C

Me Me Me H Me Me

H2O Br HO CO Et CO Et CO2Et CO Et CO2Et N 2 N 2 N N 2 N H H H H H Br δ+ δ- 22 21 20 19 Br Br 18

HO C O O 2 EtO C CO Et 2 2 CO2H HO2C HO2C H Br Me Me NH HN NH HN Me Me δ- δ+ NH HN Br Br Me Me Me Me HO2C HO CO2Et CO2Et H N N O Ð [CO2] H H CO2H HO2C CO H CO H 22 23 24 2 25 2 HO2C 26 CO2H Me Me Me Me

Me Me Me Me NH HN NH HN NH HN NH HN H H 2 Br Br Br Me Br Br Me H H NH HN NH HN NH HN NH HN Me Me Me Me Me Me Me Me [fusion in succinic acid]

29 28 27 CO2H 3 CO2H HO2C CO2H CO2H HO2C CO2H HO2C [oxidation]

Me O Me HO Me Me a. Fe3 Me b. Ac2O, AlCl3 Me Me ∆ Me N HN N HN N HN a. /H N N O KOH,EtOH, ∆ OH c. H [dehydration] Fe [Friedel-Crafts ] [reduction] b. Fe3 Cl NH N NH N NH N N N Me Me Me Me Me Me Me Me

HO2C CO2H O2C CO2 30 31 32 1: haemin

CO2H HO2C HO2C CO2H Scheme 2. a) Strategic bond disconnections and retrosynthetic analysis of haemin and b) total synthesis (Fisher, 1929).[18]

Before we close this era of total synthesis and enter into a system in order to accomplish his goal. The issue new one, the following considerations might be instructive in of of the two was probably left atempting to understand the way of thinking of the pre-World open to chance in contrast to the rational approaches towards War II chemists as opposed to those who followed them. The such matters of the later periods. Connecting the chosen rather straightforward synthesis of equilenin is representative starting material 4 with the target molecule 1 was apparently of the total syntheses of pre-World War II eraÐwith the obvious to Bachmann, who explicitly stated the known nature exception of Robinsons unique tropinone synthesis. In of the reactions he used to accomplish the synthesis. contemplating a strategy towards equilenin, Bachmann must Since the motivations for total synthesis were strongly tied have considered several possible starting materials before to the proof of structure, one needed a high degree of recognizing the resemblance of his target molecule to confidence that the proposed transformations did indeed Butenands ketone (4 in Scheme 3). After all, three of to the proposed structure. Furthermore, the limited arsenal of equilenins rings are present in 4 and all he needed to do chemical transformations did not entice much creative devia- was fuse the extra ring and introduce a onto the tion from the most straightforward course. This high degree of

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 53 REVIEWS K. C. Nicolaou et al. confidence that synthetic chemists had in their designed structural chemists for a rather long time. Its gross structure strategies was soon to decrease as the complexity of newly was revealed in 1946[54] and was subsequently confirmed by discovered natural products increased, thus catalyzing the X-ray crystallographic analysis.[55] In 1952, Sir Robert Rob- development of novel strategies and new chemistry in inson commented that strychnine: ªFor its molecular size it is subsequent years. In addition, advances in theoretical and the most complex substance known.º[56] This estimation had mechanistic organic chemistry as well as new synthetic tools not, apparently, escaped R. B. Woodwards attention who had were to allow much longer sequences to be planned with a already been fully engaged in strychnines total synthesis. In heightened measure of confidence and considerable flexibility 1948 Woodward put forth the idea that oxidative cleavage of for redesign along the way. -rich aromatic rings might be relevant in the bio- genesis of the strychnos alkaloids.[57] This provocative idea was implemented in his 1954[27] synthesis of strychnine, which Strychnine (1954) established Woodward as the undisputed master of the art at As the most notorious poison[53] of the Strychnos the time. The total synthesis of ()-strychnine by Woodward species, strychnine (1 in Scheme 4) occupied the minds of (Scheme 4) ushered in a golden era of total synthesis and

Scheme 4. a) Strategic bond disconnections and retrosynthetic analysis of ()-strychnine and b) total synthesis (Woodward et al., 1954).[27]

54 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

installed unprecedented confidence in, and respect for, the introduced as a drug during World War II and saved countless science of organic synthesis. Although several of its steps were lives. Its molecular structure containing the unique and beautifully designed and executed, perhaps the most striking strained b-lactam ring was under the cloud of some contro- feature is its reliance on only the simplest of reagents to carry versy until Dorothy Crowfoot-Hodgkin confirmed it by X-ray out what seemed to be rather complex chemical transforma- crystallographic analysis.[64] tions. With its challenging molecular structure, the molecule Not surprisingly, immediately became a highly of strychnine continued to occupy the minds of several priced synthetic target attracting the attention of major subsequent practitioners of the art and several other total players in total synthesis of the time. Finally, it was Sheehan syntheses have since appeared in the literature.[58, 59] and Henery-Logan[65] at the Massachusetts Institute of Technology who delivered synthetic penicillin V by total synthesis of the ªenchantedº molecule, as Sheehan later Penicillin (1957) called it.[66] Their synthesis, reported in 1957 and summarized Few discoveries of the twentieth century can claim higher in Scheme 5, was accompanied by the development of the notoriety than that of penicillin (1 in Scheme 5). Discovered phthalimide and tert-butyl protecting groups and the in 1928 by Alexander Fleming[60] in the secretion of the mold introduction of an aliphatic as a condensing Penicillium notatum, penicillin was later shown to possess agent to form bonds andÐin the eventÐpenicillins remarkable antibacterial properties by Chain and Florey.[61] fragile b-lactam ring. With this milestone, another class of Following a massive development effort known as the natural products was now open to chemical manipulation and Anglo ± American penicillin project[62, 63] the substance was a new chapter in total synthesis had begun.

a) Reserpine (1958) Amide formation Ring formation PhtN Reserpine (1 in Scheme 6), a constituent of the Indian H H H N PhtN O Me PhO S Me S Me HS snakeroot Rauwolfia serpentina Benth., is an alkaloid sub- + Me O N Me tBuO2C HN Me OH O [67] O HCl¥H N CO H stance with curative properties for the treatment of hyper- CO H 2 2 Lactamization 2 CO2H [68] 1:penicillin V 2 3 4 tension, as well as nervous and mental disorders. Reserpine was isolated in 1952 and yielded to structural elucidation in b) Me Me Me O O [69] ClCH2COCl Ac2O, 60 ¡C 1955 (Schlittler and co-workers) and to total synthesis in CO2H CO2H Me Me Me O Me [28] (72-80%) (75%) 1958 (Woodward et al.). The first total synthesis of reser- NH HN O N O 2 H pine (Scheme 6), considered by some as one of Woodwards 5: valine 6 7 Cl Cl greatest contributions to synthesis, inspires admiration and

OAc respect by the manner in which it exploits molecular SH conformation to arrive at certain desired synthetic objectives. Me O Me O Me O Me O [isomerization] H During this synthesis, Woodward demonstrated brilliantly the Me O Me O Me O Me O N N N N power of the venerable Diels ± Alder reaction to construct a 11 Me 10 9 Cl 8 Cl highly functionalized 6-membered ring, to control stereo- (75%) H2S, NaOMe [Michael addition] chemistry around the periphery of such a ring, and most Me Me Me O Me O OMe HS Me S importantly, to induce a desired epimerization by constraining Me OMe Me H a. HCl, H2O O Me Me Me HS O HS O b. Me2CO N the molecule into an unfavorable conformation by intra- Me N CO2Me (100%) H CO2H N N H molecular tethering. All in all, Woodwards total synthesis of 12 Me 13 Me 14 15 reserpine remains as brilliant in strategy as admirable in HCO2H (74%) [70] a. brucine Ac2O execution. It was to be followed by several others. b. resolution Me Me The synthesis of reserpine appropriately represents Wood- a. tBuONa HS Me c. HCl, H2O S b. tBuOCHO Me d. HCl Me Me O O + wards approach to total synthesis. Even though Woodward N N N CHO HCl¥H2N CO2H O CO2H did not talk about retrosynthetic analysis, he must have O O H tBuO2C tBuO2C 4: D-penicillamine practiced it subconsciously. In his mind, reserpine consisted of 17 3a hydrochloride 16 three parts: the (the AB unit, see Scheme 6), the NaOAc PhOCH2COCl, trimethoxybenzene system, and the highly substituted E-ring O Et3N O H a. N2H4 H (70%) H H N HCl¥H N cyclohexane. Given the simplicity of the first two fragments S Me 2 S Me N S Me O b. HCl, H2O PhO and their obvious attachment to fragment 3, Woodward tBuO2C HN Me tBuO2C HN Me tBuO2C HN (82%) Me concerned himself primarily with the stereoselective con- CO2H CO2H CO2H 2 18 19 struction of 3 and the stereochemical problem encountered in a. HCl (100%) b. py, acetone, H2O completing the architecture of the CD ring system. He a. KOH (1.0 equiv) O H H H H brilliantly solved the first problem by employing the Diels ± N b. DCC, H2O, dioxane N S PhO S Me Me Alder reaction to generate a cyclic template onto which he (12%) PhO O N Me HO2C HN Me O installed the required functionality by taking advantage of the CO2K CO2H [ of 1] 20 special effects of ring systems on the stereochemical outcomes Scheme 5. a) Strategic bond disconnections and retrosynthetic analysis of of reactions. He addressed the second issue, that of the last penicillin V and b) total synthesis (Sheehan et al., 1957).[65] to be set at the junction of rings C and D, by

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 55 REVIEWS K. C. Nicolaou et al.

a) cleverly coaxing his polycycle into an unfavorable conforma- Lactamization MeO tion (through intramolecular tethering), which forced an A MeO A B C N B isomerization to give the desired stereochemistry. N N N formation H H O C-C bond H D H D H These maneuvers clearly constituted unprecedented so- formation O H E OMe H E phistication and rational thinking in chemical synthesis MeO2C O MeO2C OAc design. While this rational thinking was to be further OMe OMe OMe advanced and formalized by Coreys concepts on retrosyn- 1: reserpine OMe 2 O Esterification thetic analysis, the stereocontrol strategies of this era were to O O H H dominate synthetic planning for some time before being + Diels-Alder MeO2C O reaction H H E complemented and, to a large degree, eclipsed by acyclic MeO C OAc O CO2Me MeO2C 2 stereoselection and asymmetric synthesis advances which H OMe 6 5 4 3 emerged towards the end of the century.

b) [Meerwein-Pondorff-Verley reduction] O [Diels-Alder H H O Al(OiPr) , OH reaction] 3 Br H iPrOH H H 2 H O H ∆ O O O O H H H Chlorophyll a (1960) MeO2C H H H H H O O Br 5+6 4 7 8 CO2Me Chlorophyll a (1 in Scheme 7), the green pigment of

NaOMe and the essential molecule of , is distinguished Zn [elimination-conjugate addition] MeOH from its cousin molecule haemin by the presence of two extra Zn Br Br Br H H H H O H O HO NBS (and, therefore, two chiral centers) in one of H Zn H H H Cr O H H H H H O O 2 2 7 O H2SO4 O its pyrrole rings, the presence of the phytyl side chain, and the AcOH H O O H O H AcOH O H 2 O H encapsulation of a cation rather than an iron H H H H HO H O H O H O H [29] OMe OMe OMe OMe cation. Its total synthesis by R. B. Woodward et al. in 1960 12 11 10 9 represents a beautiful example of bold planning and exquisite a. CH2N2 b. Ac2O execution. This synthesis includes improvements over Fisch- MeO A c. OsO4 B ers routes to porphyrin building blocks and, most important- O O N d. HIO4 O N H e. CH2N2 H H D H ly, a number of clever maneuvers for the installment of the

MeO2C H E H E NH2 H E three stereocenters and the extra five-membered ring residing OH A B HO2C MeO2C OAc MeO2C OAc on the periphery of the chlorin system of chlorophyll a. The H MeO N OMe OMe H OMe 13 3 14 2 chemical synthesis of chlorophyll a is a significant advance NaBH4, MeOH [18] [reductive -lactamization] over Fischers total synthesis of haemin, and must have POCl 3 given Woodward the confidence, and prepared the ground, for

MeO MeO A MeO A A his daring venture towards vitamin B12 in which he was to be B C B C B N N N N N N Cl joined by A. Eschenmoser (see p. 61). H H H H D H H D H D NaBH4

H E H E H E

MeO2C OAc MeO2C OAc MeO2C OAc OMe OMe OMe 17 16 15

H a. KOH, MeOH H Longifolene (1961) N H b. DCC, py N H H H H H N OAc The publication of the total synthesis of longifolene (1 in OMe O N R MeO R H MeO HN HN Scheme 8) in 1961 by Corey et al.[34] is of historical signifi- O R = CO2Me OMe 17 18 19 cance in that in it Corey laid out the foundation of his OAc systematic approach to retrosynthetic analysis. Our thinking OMe tBuCO2H, ∆ OMe [isomerization] about synthetic design has been profoundly affected and MeO A shaped by the principles of retrosynthetic analysis ever since, B C H N N H N and the theory is sure to survive for a long time to come. H D H NaOMe, MeOH, ∆ H [34] O H Coreys longifolene synthesis exemplifies the identification H E MeO HN MeO2C OH O and mental disconnection of strategic bonds for the purposes 21 OMe 20 O of simplifying the target structure. The process of retrosyn- OMe OMe py Cl [esterification] thetic analysis unravels a retrosynthetic tree with possible 22 OMe MeO A MeO A pathways and intermediates from which the synthetic chemist OMe B C B C a. MeOH/CHCl3 can choose the most likely to succeed and/or most elegant N N (+)-CSA N N H H D H b. resolution H H D H strategies. The total synthesis of longifolene itself, shown in O c. 1 N NaOH O H E H E OMe OMe Scheme 8, involves a , an tetroxide- MeO2C O MeO2C O OMe OMe mediated dihydroxylation of a , a ring expansion, OMe OMe 23 1: (Ð)-reserpine OMe OMe and an intramolecular Michael-type to construct Scheme 6. a) Strategic bond disconnections and retrosynthetic analysis of the longifolene skeleton. This synthesis remains a landmark in reserpine and b) total synthesis (Woodward et al., 1958).[28] the evolution of the art and science of total synthesis.

56 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

a) reaction Me H2N Me Me OHC N N Me Mg HN Me Me Me N N NH OH Me Me Me Me + + Me H HN H Dieckmann cyclization Me Me NH O H 4: phytol O Me CO2Et CO2Me O O Me Me Me Me

CO2Me MeO C Ester Me 2 formation 1: chlorophyll a 2 3

b) H3N H2N NC CN OHC Me Me Me O H2N NH OHC Me SHC NC CN Me Me a. MeO2C Cl HN NH NH HN Me Me HN Me HN Me a. EtNH2, b. NaOH Me MeO C NaBH4 2 CO Et Me AcOH c. CH2N2 2 HN NH HBr NH NH HN b. H S HN HN HCl Me Me Me Me 2 Me Me O O Cl CO Et [thioaldehyde CO Et CO Et 2 formation] 2 2 5 MeO2C 6 MeO2C 2 9 3 8 7 CO2Me CO2Me HCl

H3N AcHN AcHN AcHN

N Me Me Me Me Me

Me Me Me Me NH HN Me Me NH HN a. I [oxidation] N NH NH HN N NH Me 2 Me Me Me b. Ac2O, py AcOH, ∆ air NH HN NH HN (50% overall) NH N NH HN Me Me Me Me Me Me Me Me [oxidation] NH N O Me Me

CO2Me H CO2Me CO2Me H CO2Me CO2Me

CO2Me CO2Me CO Me CO2Me CO Me CO Me CO2Me 2 2 CO2Me 2 CO Me 2 CO2Me 10 11 12 13 14

AcHN AcOH/∆

Me Me Me Me [] Me [highly specific [Hofmann Me Me Me photochemical Me elimination] Me NH N NH N NH N NH N NH N Me a. resolution Me Me cleavage of the Me a. HCl, Me with quinine a. KOH, MeOH cyclopentadiene ring] MeOH b. CH2N2 Me N HN b. NaOH, H2O Me N HN Me N HN b. Me2SO4, Me N HN O2, hv Me N HN Me Me Me Me NaOH Me H H H [photooxygenation] H H

H H CO2Me CO2Me CO Me CHO CO2Me HO2C MeO2C O CHO MeO2C MeO2C 2 O O HO MeO C MeO2C MeO C CO2Me 19 18 2 17 16 2 15

HCN, Et3N [cyanohydrin formation]

Me Me Me Me a. NaOH, H2O a. Zn, AcOH Me Me Me b. H , 4 Me NH N b. CH N NH N NH N N N Me 2 2 Me Me Me NaOH, py c. Mg(OEt)2 c. MeOH, HCl Mg Me N HN [reduction] Me N HN [Dieckmann Me N HN Me N N Me Me cyclization] Me [ester exchange- Me H [] H H magnesium H [methanolysis] insertion sequence] H H H CO Me H H H O 2 1: chlorophyll a NC O MeO2C O O CO2Me MeO2C CO2Me CO2Me CO2Me 20 21 22 O O Me Me Me Me

Me Scheme 7. a) Strategic bond disconnections and retrosynthetic analysis of chlorophyll a and b) total synthesis (Woodward et al., 1960).[29] The locking of 2 and 9 together through formation of a schiff forces the cyclization to proceed with the desired .

Lycopodine (1968) features a unique ªaza-annulationº strategy which utilizes the Lycopodine (1 in Scheme 9), first isolated in 1881, is the Stork enamine methodology[73] (a generally useful strategy to most wildly distributed alkaloid from the genus lycopodi- generate and trap regiospecifically) to construct um.[71] In addition to the great challenge of synthesizing this quinolone systems, a stereospecific cationic cyclization to novel polycyclic framework in a stereocontrolled manner, one establish the C13 quaternary center, and a series of functional must effectively address the challenge posed by the C13 group manipulations to elaborate the resulting aromatic ring quaternary center, which is common to all four rings. Gilbert into ring D. Several syntheses of lycopodine have since Stork was one of the first to successfully complete the total appeared,[74] each featuring a unique strategy complementary synthesis of lycopodine.[72] This masterfully executed synthesis to Storks beautiful synthesis.

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 57 REVIEWS K. C. Nicolaou et al.

a) Alkylation a) Allylic Me H Me Me Michael OMe Me Me Me H oxidation addition O O H H O O N CHO H Olefination Me H H N O Me O O 1: longifolene 2 Me H 3 CO2Me O N Me Lactamization Cl3C H Cationic Stork enamine 1: lycopodine cyclization 3 O O O pinacol O Me Me rearrangement Me 2

O OMe OMe Me O OH H Me 5: Wieland-Miescher OTs 3 MeO 4 CO2Et ketone 6 + Conjugate HO addition b) a. OH O O Me pTsOH, ∆ a. OsO , py O OMe EtO2C Me 4 O N CH 7 O 3 b. Ph3P=CHMe b. pTsCl, py 5 4 Me O O 5 6 4 H b) OMe OMe OTs [Isomerization; a. LiAlH4 [pinacol LiClO , Michael addition] b. MeMgBr, (31% overall) 4 MeO rearrangement] CO2Et a. NaOEt, 7 CuCl2 CaCO3 6 Me b. K2CO3, H2O [conjugate HO OH O OMe O OMe [decarboxylation] addition] O (90%) Et3N , ∆ 2 N HCl, ∆ O O (36%) O O OH O Me (10-20%) 8 9 Me H Me OMe H Me 8 3 7 N [Stork enamine] Ph3CNa; MeI (60%) H Ar Ar N O O Me a. HS Me H Ð Me SH Me Me Me H N BF ¥Et O S a. Na, NH NH , ∆ 2 O 3 2 2 2 H2N b. CrO3, AcOH (20-25% b. LiAlH4, ∆ S O O O N Me of N Me N Me OH H desired 3 ) 10 4 H H H H H Me Me Me [cationic 9 10 2 cyclization] H3PO4:HCO2H (1:1) Me Me Me H Me H Me H a. MeLi, ∆ a. LiAlH4 H H H b. Li-NH3 H H b. SOCl2, py [Birch reduction] H O N O N N Me (49% overall) (55%) c. KOtBu H d. 1: longifolene H O O OMe OMe O OMe 12 Cl O CCl3 13 Scheme 8. a) Strategic bond disconnections and retrosynthetic analysis of 11 Cl3C [34] longifolene and b) total synthesis (Corey et al., 1961). O3, MeOH H Me Me H Me H Me H H H H X H Cephalosporin C (1966) O O SeO2 N O O N N H2O2 N CHO Cephalosporin C (1 in Scheme 10) was isolated from OH (30% O O O O O OH O [75] O O overall) O Cephalosporium acremonium in the mid-1950s and was CO Me 2 CO2Me CO2Me CO2Me Cl3C 16 Cl C 15 14 structurally elucidated by X-ray crystallographic analysis in 3 Cl3C Cl3C 2 a. NaOMe [formate methanolysis] 1961.[76] Reminiscent of the , the cephalosporins b. Zn, MeOH [deprotection of ] represent the second subclass of b-lactams, several of which Me H Me H Me H became legendary antibiotics in the latter part of the H H H twentieth century. Having missed the opportunity to deliver a. LiAlH4 N O N O b. CrO3-H2SO4 N O penicillin, the Woodward group became at once interested in H H H O the synthesis of cephalosporin C and, by 1965, they completed 17 18 1: lycopodine the first total synthesis of the molecule.[30] MeO O This total synthesis of cephalosporin C was the sole topic of Scheme 9. a) Strategic bond disconnections and retrosynthetic analysis of Woodwards 1965 Nobel lecture in Stockholm. Indeed, in a (Æ)-lycopodine and b) total synthesis (G. Stork et al., 1968).[72] move that broke tradition, R. B. Woodward described on that occasion for the first time, and in a breathtaking fashion, the Prostaglandins F and E (1969) elegant synthesis of cephalosporin C. Highlights of this syn- 2a 2 thesis, which is summarized in Scheme 10, include the The prostaglandins were discovered by von Euler in the development of the azodicarboxylate-mediated functional- 1930s[77] and their structures became known in the mid-1960s ization of the group adjacent to the atom of primarily as a result of the pioneering work of Bergström and l-cysteine, the aluminum-mediated closure of the aminoester his group.[78] With their potent and important biological to the b-lactam functionality, the brilliant formation of activities and their potential applications in medicine,[79] these cephalosporins sulfur-containing ring, and the use of the scarce substances elicited intense efforts directed at their b,b,b-trichloroethyloxy moiety to protect the hydroxyl group. chemical synthesis. By 1969 Corey had devised and completed

This total synthesis stands as a milestone accomplishment in his first total synthesis of prostaglandins F2a (1 in Scheme 11) [80] the field of natural product synthesis. and E2. These syntheses amplified brilliantly Coreys

58 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

a) Conjugate CO2H Cyclization O O addition CH2OAc CO CH CCl N NH 2 2 3 H CHO H H S + H2N NH H tBuOC(O)N S Amide bond formation H O H Me Me CO2H O 1: cephalosporin C 2 3

MeO2C OAc MeO C N HO2C 2 3 H H H H H tBuOC(O)N S tBuOC(O)N S H2N SH Me Me Me Me 6: L-(+)-cysteine 5 4

CO Me b) a. acetone 2 HO2C MeO2C N N MeO2C H H b. tBuOCOCl H MeO2C 8 H c. CH N N CO Me H2N SH 2 2 tBuOC(O)N S tBuOC(O)N S N 2

Me Me Me Me CO2Me 6 7 9 OAc

CO2Me CO2Me MeO2C H MeO2C H MeO2C N Pd(OAc)4 N CO2Me H H NH H N NH tBuOC(O)N S tBuOC(O)N S CO2Me tBuOC(O)N S CO2Me N Me Me [oxidation] Me Me Me Me CO2Me 12 11 10

OAc MeO2C H MeO2C MeO2C N N OAc N H N OAc H N H N tBuOC(O)N S CO2Me tBuOC(O)N S CO2Me tBuOC(O)N S CO2Me Me Me Me Me Me Me 13 14 15 OAc

[-N2] MeO C 2 OAc MeO2C OAc MeO2C OAc H H H H + H tBuOC(O)N S tBuOC(O)N S tBuOC(O)N S

Me Me Me Me Me Me 5: major product 17: minor product 16 AcO, MeOH O [reduction of ] MeO2C OH a. MeSO2Cl MeO2C N3 NH H H H b. NaN3 H a. Al/Hg/MeOH H H tBuOC(O)N S tBuOC(O)N S tBuOC(O)N S b. iBu3Al Me Me Me Me [lactamization] Me Me 18 [SN2 with inversion 4 2 of configuration]

H a. CCl CH OH, pTsOH HO CO2CH2CCl3 CO2CH2CCl3 HO CO2H 3 2 b. NaIO4 O O CCl3 ∆ H H H H NaO OH CHO CHO HO2C H O O O O H 19: 20 21 22 3

CO2CH2CCl3 Scheme 11. a) Strategic bond disconnections and retrosynthetic analysis of CO2CH2CCl3 CO2CH2CCl3 O O CHO O CHO N O (Æ)-PGF and b) the total synthesis (Corey et al., 1969).[80] N N TFA 2a H H H H H O a. DCC tBuOC(O)N S NHCO2CH2CCl3 S S N H NHCO2CH2CCl3 H2N H H H [81±83] H CO2H Me Me synthetic work followed the initial Corey synthesis and O CO H 2 25 24 23 CO2CH2CCl3 myriad analogues have since been synthesized, 26 b. CCl3CH2OH, DCC aiding both biology and medicine tremendously. a. BH3 [neutral reducing agent] b. Ac2O, Coreys original strategy evolved alongside the impressive CO CH CCl CO CH CCl py 2 2 3 2 2 3 CO2H O O O CH2OAc CH2OAc CH2OAc developments in the field of asymmetric , many of N N N H H H which he instigated, which culminated by the 1990s, in a NHCO2CH2CCl3 S NHCO2CH2CCl3 S NH2 S N H N H N H H H H H H H refined, highly efficient and stereocontrolled synthesis of the O py O Zn, AcOH CO2H O [84] CO2CH2CCl3 CO2CH2CCl3 prostaglandins. Thus, in its original version, the Corey 27 [equilibration] 28 [reductive removal of 1: cephalosporin C the protecting groups] synthesis of prostaglandins F2a and E2 was nonstereoselective Scheme 10. a) Strategic bond disconnections and retrosynthetic analysis of and delivered the racemate and as a mixture of C15 . cephalosporin C and b) total synthesis (Woodward et al., 1966).[30] Then, in 1975, came a major advance in the use of a to control the stereochemical outcome of the crucial Diels ± Alder reaction to form the bicyclo[2.2.1]heptane retrosynthetic analysis concepts and demonstrated the uti- system in its optically active form.[85] The theme of chiral lization of the bicycloheptane system derived from a Diels ± auxiliaries to control stereochemistry played a major role in Alder reaction as a versatile key intermediate for the syn- the development of organic and natural products synthesis in thesis of several of the prostaglandins. A large body of the latter part of the century. In addition to the contributions

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 59 REVIEWS K. C. Nicolaou et al. of Corey, those of A. I. Myers,[86] D. A. Evans,[87] W. Oppolz- er,[88] and H. C. Brown[89] as well as many others helped shape the field. Finally came the era of catalyst design and here again the prostaglandins played a major role in providing both a driving force and a test. In a series of papers, Corey disclosed a set of chiral aluminum- and -based[90, 91] catalysts for the Diels ± Alder reaction (and several other reactions) that facilitated the synthesis of an enantiomerically enriched intermediate along the route to prostaglandins. And, finally, the problem of at C15 was solved by the introduction of the oxazaborolidine catalyst (CBS) by Corey in 1987.[92] These catalysts not only refined the industrial process for the production of prostaglandins, but also found uses in many other instances both in small scale laboratory operations and manufacturing processes of drug candidates and pharmaceuticals. For a more in-depth analysis of the

Corey syntheses of prostaglandins F2a and E2 and other advances on asymmetric catalysis, the reader is referred to ref. [4] and other appropriate literature sources.

Progesterone (1971) (1 in Scheme 12), a hormone that prepares the lining of the uterus for implantation of an ovum, is a member of the steroid class of compounds that is found ubiquitously in nature. Its linearly fused polycyclic carbon framework is characteristic of numerous natural products of steroidal or triterpenoid structures. A daring approach to progesterones skeleton by W. S. Johnson[93] was inspired by the elucidated -catalyzed conversion[94] of squalene oxide into lanosterol or to the closely related plant triterpen- oid dammaradienol. This biomimetic strategy was also encouraged by the Stork ± Eschenmoser hypothesis, which was proposed in 1955[35] to rationalize the stereochemical outcome of the biosynthetic transformation of squalene oxide to steroid. According to this postulate it was predicted that polyunsaturated molecules with trans CˆC bonds, such as squalene oxide, should cyclize in a stereospecific manner, to furnish polycyclic systems with trans,anti,trans stereochemis- try at the ring fusion. This brilliant proposition was confirmed by W. S. Johnson and his group through the biomimetic total synthesis of progesterone (Scheme 12). A tertiary serves as the initiator of the polyolefinic ring-closing cascade, in this Scheme 12. a) Strategic bond disconnections and retrosynthetic analysis of [93] instance, but other groups have also been successfully progesterone and b) total synthesis (Johnson et al., 1971). employed in this regard (for example, , ). The methylacetylenic group performed well as a terminator of the Woodward in 1965.[96] By 1972 Kishi and his group had cascade in the original work. A number of new terminating published the total synthesis[97] of this highly unusual and systems have since been successfully employed (for example, challenging structure. This outstanding achievement from allyl or propargyl silanes, vinyl fluoride). The work of W. S. Japan was received at the time with great enthusiasm and Johnson was complemented by that of van Tamelen[95] and remains to this day as a classic in total synthesis. The target others[3, 4] who also explored such biomimetic cascades. molecule was reached through a series of maneuvers which included a Diels ± Alder reaction of a quinone with butadiene, a Beckman rearrangement to install the first atom, Tetrodotoxin (1972) stereoselective reductions, strategic oxidations, unusual func- Tetrodotoxin (1 in Scheme 13) is the poisonous compound tional group manipulations, and, finally, construction of the of the Japanese puffer fish and its structure was elucidated by guanidinium system. As a highly condensed and polyfunc-

60 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

Rarely before has a synthetic project yielded so much a) HO O OH C-N Bond H OH H OAc formation CH OH CH2OAc knowledge, including: novel bond-forming reactions and HN 2 NH2 strategies, ingenious solutions to formidable synthetic prob- H2N N O AcHN N H O O AcO lems, biogenetic considerations and hypotheses, and the seeds HO OH H OAc O O trans-Esterification/ of the principles of orbital conservation known as 1: tetrodotoxin 2 epoxide opening [98] formation the Woodward and Hoffmann rules. The structure of Epoxide opening/ vitamin B12 was revealed in 1956 through the elegant X-ray Baeyer-Villiger cyclization H H CH OAc [99] H Me oxidation 2 crystallographic work of Dorothy Crowfoot-Hodgkin. The O O HO O O escalation of molecular complexity from haemin to chloro- H O O AcO OAc phyll a to vitamin B12 is interesting not only from a structural Diels-Alder AcNH AcNH reaction 4 3 point of view, but also in that the total synthesis of each molecule reflects the limits of the power of the art and science b) O O O , SnCl H a. MsCl, Et N H Me 4 Me 3 Me of organic synthesis at the time of the accomplishment. ∆ b. H2O, One of the most notable of the many elegant maneuvers of N (83%) (61%) HO [Lewis acid catalyzed N [Beckmann AcN the Woodward ± Eschenmoser synthesis of vitamin B12 is the Me O O H O Diels-Alder HO Me rearrangement] photoinduced ring closure of the corrin ring from a pre- 5 reaction] 6 7 organized linear system wrapped around a metal template, [regio- and stereoselective reduction] a. NaBH , MeOH 4 (72%) [epoxide-mediated etherification] b. mCPBA, CSA which was an exclusive achievement of the Eschenmoser

a. CrO3, py group. The convergent approach defined cobyric acid (2 in b. BF3¥Et2O, OH H a. SeO2 H H Scheme 14) as a landmark key intermediate, which had Me Me OH b. NaBH4 HO previously been converted into vitamin B by Bernhauser O O (100%) O O HO O 12 c. Al(OiPr)3, iPrOH, ∆ [100] O O H et al. The synthesis of vitamin B12 defined the frontier of AcN AcN d. Ac O, py AcN O H OAc H OAc 2 H (86% overall) research in organic natural product synthesis at that time. For 9 8 4 an in depth discussion of this mammoth accomplishment, the a. mCPBA d. (EtO)3CH, CSA; Ac2O, py [diethylketal formation] ∆ b. Ac2O, py e. [ethyl formation] reader is referred to ref. [4]. c. TFA, H2O; f. mCPBA, K2CO3 [epoxidation] Ac2O, py g. AcOH [epoxide opening and ] (53% overall) O Erythronolide B (1978) H OAc AcO- OAc OAc H a. KOAc, AcOH CH OAc O O mCPBA b. Ac2O, CSA, ∆ OAc 2 O O AcHN The macrolide antibiotics, of which erythromycin is perhaps O (100%) O c. vacuum, H AcO AcN [Baeyer-Villiger O 300 ¡C O the most celebrated, stood for a long time as seemingly H OAc AcO oxidation] AcO AcN OAc [acetate elimination] H H (80%) O unapproachable by chemical synthesis. The origin of the 10 3 11 a. OsO4, py initial barriers and difficulties was encapsulated in the b. (MeO)2CMe2, CSA (65%) following statement made by Woodward in 1956, ªErythro- c. Et3O BF4 , Na2CO3; AcOH O O O O O O mycin, with all our advantages, looks at present hopelessly H H H H H OAc OAc H OAc O O O complex, particularly in view of its plethora of asymmetric CH OAc AcHN OAc CH2OAc S OAc 2 OAc CH2OAc H H H [101] N N H2N centers.º In addition to the daunting stereochemical AcHN H2N H H O H O a. BrCN, NaHCO H O AcO a. Et3O BF4 ; AcO 3 AcO problems of erythromycin and its relatives, also pending was H Ac O, py H b. H2S H O 2 O O 14 b. 13 (100%) 12 the issue of forming the macrocyclic ring. These challenges

a. BF3, TFA (50%) gave impetus to the development of new synthetic technol- b. TFA, H2O ogies and strategies to address the stereocontrol and macro-

HO O HO H cyclization problems. H H OAc a. H5IO6 H OH HO [102] b. NH OH HN CH2OH The brilliant total synthesis of erythronolide B (1 in H2N CH2OAc 4 N H (9% overall) H Scheme 15), the aglycon of erythromycin B, by Corey et al. AcHN H2N N O H O AcO O HO H OH published in 1979, symbolizes the fall of this class of natural H OAc O O products in the face of the newly acquired power of organic 15 1: tetrodotoxin synthesis. Additionally, it provides further illustration of the Scheme 13. a) Strategic bond disconnections and retrosynthetic analysis of tetrodotoxin and b) total synthesis (Kishi et al., 1972).[97] classical strategy for the setting of stereocenters on cyclic templates. The synthesis began with a symmetrical aromatic system that was molded into a fully substituted cyclohexane tional molecule, tetrodotoxin was certainly a great conquest ring through a short sequence of reactions in which two and elevated the status of both the art and the practitioner, bromolactonizations played important roles. A crucial Baey- and at the same time was quite prophetic of things to come. er ± Villiger reaction then completed the oxygenated stereo- center at C6 and rendered the cyclic system cleavable to an open chain for further elaboration. Vitamin B (1973) 12 As was the case in many of Coreys syntheses, the total

The total synthesis of vitamin B12 (1 in Scheme 14), synthesis of erythronolide B was preceded by the invention of accomplished in 1973 by a collaboration between the groups a new method, namely the double activation procedure for the of Woodward and Eschenmoser,[3, 32] stands as a monumental formation of macrocyclic employing 2-pyridinethiol achievement in the annals of synthetic organic chemistry. esters.[103] This landmark invention allowed the synthesis of

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 61 REVIEWS K. C. Nicolaou et al.

Scheme 14. a) Strategic bond disconnections and retrosynthetic analysis of ()-vitamin B12 , b) key synthetic methodologies developed in the course of the [32] total synthesis, c) and final synthetic steps in the Woodward-Eschenmoser total synthesis of vitamin B12 (Woodward ± Eschenmoser, 1973).

62 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

a) O Me I several macrolides including erythronolide B and, most Me Me OBz Me significantly, catalyzed the development of several improve- Me Me Me Me ments and other new methods for addressing the macro- OH HO OBz OH OTBS [104] Me Me O O OTBS cyclization problem. Soon to follow Coreys synthesis of O OH Me Me 3 Me erythronolide B was Woodwards total synthesis of erythro- O OH Functionalization OBz Me Me Me Me Me [33] Me mycin A. C-C bond formation Lactonization BzO O O O 1: erythronolide B 2 Me Alkylation S N Monensin (1979, 1980) Me 4 Baeyer-Villiger [105] Bromolactonization Bromolactonization oxidation Monensin (1 in Scheme 16), isolated from a strain of OH O O OBz Br Streptomyces cinamonensis, is perhaps the most prominent Me Me Me Me Br Me Me Me O Me member of the polyether class of antibiotics. Also known as O O BzO O 8 Me 7 Me 6 Me 5 , these naturally occurring substances have the Me O O O ability to complex and transport metals across membranes, b) OH O O [bromolactonization] O a. BH ¥THF; Br [106, 107] Me Me Me Me 3 Me Me Me thus exerting potent antibacterial action. These struc- Br , KBr NaOMe H2O2, NaOH 2 Me tures are characterized by varying numbers of tetrahydropyr- Br b. CrO3, H2SO4 (96%) O Me (72%) Me Me Me CO H an, , and/or spiroketals. Kishis total synthesis 2 O 8 9 10 7 of monensin,[108] which followed his synthesis of the simpler a. KOH, H2O (98%) b. resolution lasalocid,[109] represents a milestone achievement O O O O nBu3SnH Me Me Me Me AIBN Me Br Me Me in organic synthesis (Scheme 16). This accomplishment dem- Al/Hg Br2, KBr O O Me O (76%) (93%) (91%) onstrates the importance of convergency in the total synthesis HO O O O Me Me Me Me of complex molecules and is one of the first examples of O O O 13 12 6 11 [bromolactonization] stereoselective total synthesis through acyclic stereocontrol, a. H2, Raney-Ni CO2H b. BzCl and elegantly marked the application of the Cram rules within OBz OBz OBz OBz a. LDA a. LiOH the context of natural-product synthesis. By unraveling the Me Me Me Me Me Me Me Me b. MeI b. CrO3, H2SO4 CH3CO3H spiroketal moiety of the molecule Kishi was able to adopt an (75% (80%) (70%) BzO BzO O BzO O BzO O O Me overall) Me Me Me O aldol-based strategy to couple monensins two segments. A CO2H CO2H O O [Baeyer-Villiger series of daring reactions (for example, , Me Me oxidation] Me epoxidations) on acyclic systems with pre-existing stereo- 5 14 15 16 a. Li Ph3P centers allowed the construction of the two heavily substi- a. H2O2, Na2WO4 b. Amberlyst IRC-50 17 b. resolution N S S N (65%) c. ArSO2Cl, py tuted fragments of the molecule which were then successfully c. ClCO Et OBz 2 Me d. Me2CuLi Me I Me Me coupled and allowed to fold into the desired spiroketal upon Me d. NaBH4 OMe O e. TBSCl, imid. Me e. POCl3, f. LDA; MeI deprotection. Kishis beautiful synthesis of monensin also BzO O OMe g. [Cp ZrHCl] O (76% overall) 2 Me O O provided a demonstration of the importance of 1,3-allylic HO2C OTBS Me Me h. I2, CCl4 Me S N strain in acyclic conformational preferences, which in turn can 18 19 3 4 tBuLi, MgBr2 Me OH (90%) be exploited for the purposes of stereocontrolled reactions Me Me OBz OBz (for example, epoxidation). Me Me Me Me Me Me a. AcOH OBz Zn(BH4)2 A second total synthesis of monensin was accomplished in OH HO BzO Me b. LiOH O O OTBS O [110] Me O O OTBS 1980 by W. C. Still and his group (Scheme 17). Just as OH OBz H2O2 Me Me Me Me Me OBz elegant as Kishis synthesis, the Still total synthesis of Me Me Me Me Me Me monensin demonstrates a masterful application of chelation- 21 HO O 2 20 a. KOH d. Amberlyst IRC-50 controlled additions to the carbonyl function. A judicious b. CH2N2 e. KOH c. HBr, choice of optically active starting materials as well as a highly (61% overall) OMe convergent strategy that utilized the same aldol ± spiroketali- OH tBu tBu OH Me Me N N Me Me zation sequence as in Kishis synthesis allowed rapid access to S S Me Me N N Me Me monensins rather complex structure. 23 OH iPr iPr OH Me Ph3P; Me Me OH O O O Me ∆ Me Me Me PhMe, O O O Me (50% ) Me Endiandric Acids (1982) Me HO O 24 22 a. MnO The endiandric acids (Scheme 18) are a fascinating group of 2 (98% ) b. H2O2, NaOH natural products discovered in the early 1980s in the O O a. H2, Pd/C [epoxide reduction] Me Me Me Me Australian plant Endiandra introsa (Lauraceae) by Black b. K2CO3, MeOH 10 [111] [epimerization at C-10] O et al. Their intriguing structures and racemic nature gave Me Me Me Me OH c. HCl OH OH rise to the so called ªBlack hypothesisº for their plant origin, Me Me Me O OH O O Me Me which involved a series of non-enzymatic electrocyclizations O OH O O Me from acyclic polyunsaturated precursors (see Scheme 18). Me Me 1: erythronolide B 25 Intrigued by these novel structures and Blacks hypothesis for Scheme 15. a) Strategic bond disconnections and retrosynthetic analysis of their ªbiogeneticº origin, we directed our attention towards erythronolide B and b) total synthesis (Corey et al., 1978).[102] their total synthesis. Two approaches were followed, a

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 63 REVIEWS K. C. Nicolaou et al.

a) Spiroketalization

HO O H H Et Me Et Me Et Me Me Me Me MeO Me O O O OBn O OH O O Me H H O O Me O Me H H Me H Me H Me H OMe OMe + H H Me HO O Me HO O HO O CO Me CO2H 2 1: monensin 2 3 4 HO Me MeO Me MeO Me

a. Ph3P CO2Et a. O b) (MeO) P CO Me Me OBn a. KH, MeI 2 2 O Me OH OBn OMe O OMe a. nBuLi, MeI b. LiAlH4 BH3; b. H , 10% Pd/C Me CN 2 Me O b. KOH O H c. BnBr, KH KOH, H2O2 O c. resolution O H Me O b. LiAlH4 O c. LiAlH4 Me (66% overall) (85%) Me Me d. PCC Me Me Me Me (73%) OH 5 d. PCC 6 7 BH3 [8:1 mixture] 8 (77% overall) 9 10

(80%) BH3; H2O2 a. mCPBA Me Me Me Me a. MOMBr, Me Me OMe OBn O OMe OBn OMOM OMe OH OH b. KOH aq. 12 steps a. CH2N2 PhNMe2 MeO2C H HO2C b. BnBr, KH c. resolution (35% overall) b. HCl O CO H OH PPh3 O 2 Me Me Me c. PCC Me Me Me c. O3 , MeOH Me Me Me 14 15 12 11 13 2 (33% from 11) [12:1 mixture]

a. PhCHO, CSA CH3C(OEt)3 O b. LiAlH4-AlCl3 (1:4) Et Et Et CH CH CO H, ∆ a. LiAlH4 Et HO OH HO OBn a. PCC 3 2 2 c. resolution b. PCC Ar H EtO2C (93%) b. Et HO OBn [Johnson EtO O OBn OBn H H H c. MeOC6H4MgBr orthoester Claisen MgBr d. CrO3, H2SO4 H rearrangement] 16 17 18 19 20 e. BCl3 21 OH (31% overall) a. pTsCl Me Me O O Me Me b. LiAlH4 Me Me Me Me Me Et Et c. CSA Ar Ar 15 PPh3 Ar OH O Ar NBS Ar d. OsO4, NaIO4 mCPBA O O H O O O OH OH H Et H H Br (57%) H Et H [Wittig reaction] H Et H OH [7:2 mixture] (36%) [hydroxyl-directed 26 [bromoetherification] 25 (78%) 24 23 epoxidation] 22 KO2, [18]crown-6 (47%) DMSO a. NaOMe, MeOH Me Me Me b. (CH3O)3CH Me Me a. Cl3CCOCl, py Me Me Me Me MeOH, CSA b. OsO4, py Li, EtOH Ar OBz MeO OH Ar O c. BzCl, py O O O O O O NH3 (l) O O OH H Et H H H (53% overall) H Et H H H OMe H Et H H H d. CrO , H SO 3 2 4 CCl 4 [Birch reduction] 27 28 O 3

Me Me Me Me Me Me Me Me Me H a. (CH3O)3CH MeMgBr MeOH, CSA Me OH OH MeO OH Me O O O O O O b. O , MeOH O O O MeO OH Et H H H OMe OHC MeO O H Et H H H OMe 3 H Et H H H OMe (22% from 4) OH c. MgBr2 31 30 29 a. O3 , MeOH b. HCl, MeOH c. MeLi OH HO H O Et Me H a. H , 10% Pd/C Et Me iPrNMgBr, 2 Et Me 2 Me Me Me Me Me b. CSA, H2O O O O O O OH OBn OH H O Me H H H O (21%, 92% based on recovered SM) O Me O c. NaOH-MeOH (1:5) Me H H Me H Me H Me H OMe H OMe H Me HO O Me HO O HO O CO2Me CO2Na [8:1 mixture] MeO Me MeO Me HO Me 3 32 1-Na: (+)-monensin sodium salt

Scheme 16. a) Strategic bond disconnections and retrosynthetic analysis of monensin and b) total synthesis (Kishi et al., 1979).[108] stepwise (Scheme 19b) and a direct one-step strategy cules from acyclic precursors from the endiandric acid cascade (Scheme 19c). Both strategies involve an 8-p-electron elec- is remarkable, particularly if one considers the stereospecific trocyclization, a 6-p-electron electrocyclization, and a Diels ± formation of no less than four rings and eight stereogenic Alder-type [4‡2] reaction to assemble the centers in each final product. polycyclic skeletons of endiandric acids. The total synthesis[112] of these architecturally interesting structures demonstrated a Efrotomycin (1985) number of important principles of organic chemistry and verified Blacks hypothesis for their natural origin. In Efrotomycin (1 in Scheme 20; see p. 67), the most complex particular, the ªone-potº construction of these target mole- member of the elfamycin class of antibiotics[113] that includes

64 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

Scheme 17. a) Strategic bond disconnections and retrosynthetic analysis of monensin and b) total synthesis (Still et al., 1980).[110] aurodox, was isolated from Nocardia lactamdurans. [114] Its thesis of efrotomycin, accomplished in 1985 in our laborato- molecular structure, which contains nineteen stereocenters ries,[115] addressed both problems by devising new method- and seven geometrical elements of stereochemistry, presented ologies for the stereoselective construction of glycosides and considerable challenge to the synthetic chemists of the 1980s, . Scheme 20 summarizes this total synthesis particularly in regard to the oligosaccharide domain and the in which the two-stage activation procedure for the synthesis all-cis-tetrasubstituted tetrahydrofuran system. The total syn- of oligosaccharides utilizing thioglycosides and glycosyl

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 65 REVIEWS K. C. Nicolaou et al.

CO2R CO2R

Ph a a Ph a CO2R a CO2R

Ph Ph

RO2C CO2R

CO2R RO2C b Ph Ph b Ph b b Ph

H H H H H H H H Ph CO2H CO2H Ph HO2C Ph Ph HO2C H H H H endiandric acid D endiandric acid E endiandric acid F endiandric acid G Diels-Alder Diels-Alder Diels-Alder Ph Ph H H H HO2C H H H H H Ph H H H H H CO2H H H CO H H H H 2 endiandric acid A endiandric acid B

Scheme 18. The endiandric acid cascade (Black et al., R ˆ Me, H). a) Conrotatory 8-p-electron cyclization; b) disrotatory 6-p-electron cyclization.[111]

Scheme 19. a) Strategic bond disconnections and retrosynthetic analysis of endiandric acids A ± C, b, c) total synthesis, and d) ªbiomimeticº synthesis of endiandric acid methyl esters A ± C (Nicolaou et al., 1982).[112]

66 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

a) OMe OMeMe CCl3 Glycosidation Me O OMe H H O OMe H O O OMe O N H OMe OH OTBS Me O Wittig F HO O 2 O Me Me Glycosidation olefination Me O O Me 5 OH Me O N O Me Me Me O OMe H H Me Me O Me H O PhS OH O N N OMe O Me Me Me O Me O Me TBSO OH Me OH O Me O OH Ph3P HO OH Me OH O OBn Amide Br formation 1: efrotomycin 3 4 6

b)

a. LiCuMe2; TMSCl b. O3; Me2S Me c. OMe O N a. KCH2S(O)CH3 OMe H H Me O O H H OMe H H OTBS O b. TBSCl, imid. O OTBS O H N CuLi O 2 MeO2C MeO2C d. KH, MeI Me Me O OPMB Me Me TMSO OTMS O O O O e. AcOH, H O O O 5, 6 10 7 8 2 9 Me Me Me Me (55%) Me Me

a. H2, 5% Pd/C a. nBu2SnO, ∆ OH OMe b. TBSCl, imid. OMe OMe Me b. BnBr Me Me Me O O c. PhSTMS, ZnI O OMe O OMe c. KH, MeI OMe 2 F a. AgClO , SnCl OMe OH OBn OTBS 4 2 OMe OTBS (90%) d. NBS, DAST b. NBS, DAST 11 O Me MeO MeO 12 (66%) F 2 TBSO O (63%) 15 a. TBAF (80%) b. Ac2O, 4-DMAP OMe Me OMe OMe SPh O OMe OMe a. nBu3SnH, AIBN OMe F OMe O Br O NBS, AIBN O b. TBSCl, imid. O Me OMe OAc Ph HO O HO OBz TBSO OH Me c. PhSTMS, ZnI ; O (100%) 2 AcO O 13 14 K2CO3, MeOH 3 (70%) 16

a. Swern [O] Me Me Me Me a. (-)-DET, Ti(iPrO)4 O a. [Rh], H Me b. tBuOK, Me Me 2 O O HO O OH Me MeO P(O) CO2Me tBuOOH b. LiAlH4 O 3 O O b. BnOC(O)Cl, py a. (MeO)2CMe2, O c. CSA, acetone OH O O c. DIBAL-H c. AlCl ; H O CSA (70%) Me Me Me Me 3 2 Me Me O (85%) (65%) b. K2CO3, MeOH; 17 18 19 20 O CSA c. RuO , NaIO Me 2 4 Me O O a. AcOH, H O (86%) a. AcOH, H2O OH CH3CH2CH2CO2Et, 2 Me OH O OEt O O b. PCC Me Me b. NaOH/EtOH LDA Me Me O O Me O Me Me O Me Me (85%) O CO H O (85%) O c. , nBuLi 2 Me Me Me OH O O Me P(O)Ph2 Me Me Me Me O 4 23 22 21 Me Me (59%) (86%) c. 16, AgClO4, SnCl2 d. K2CO3, MeOH OMe OMe Me Me O O OMe OMe H H OMe OH OMe OH O Me O Me HO O HO O Me Me O O Me OH Me O N O O OMe H H Me Me a. AlMe3, 10 Me H O N O b. HF¥py O Me OH Me c. DDQ, MeOH (26% overall) Me OH O Me Me O OH HO OH 24 1: efrotomycin

Scheme 20. a) Strategic bond disconnections and retrosynthetic analysis of efrotomycin and b) total synthesis (Nicolaou et al., 1985).[115]

fluorides[116] as well as the base-induced zip-type diepoxide exhibits potent inhibition of certain phospha- opening were highlighted as powerful methods for organic tases and is a strong tumor promotor. With its three spiroketal synthesis. Numerous applications and extensions of these moieties and seventeen stereogenic centers, the molecules synthetic technologies have since followed.[117] polycyclic structure presented a serious challenge to synthetic chemistry. The first total synthesis of okadaic acid was achieved in 1984 by the Isobe group in Japan[119] and was Okadaic acid (1986) followed by those of Forsyth[120] and Ley.[121] The Isobe Okadaic acid[118] (1 in Scheme 21) is a marine toxin isolated synthesis of okadaic acid, summarized in Scheme 21, high- from Halichondria Okadai. Besides its shellfish toxicity, lights the use of sulfonyl-stabilized in synthesis, the

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Scheme 21. a) Strategic bond disconnections and retrosynthetic analysis of okadaic acid and b) total synthesis (Isobe et al., 1986).[119]

control of stereochemistry through chelation, and the power amphotericin B[122] (1 in Scheme 22), isolated from Strepto- of the anomeric effect to exert stereocontrol in spiroketal myces nodosus, occupies a high position as a consequence of formation. its complexity and medical importance as a widely used antifungal agent. Its total synthesis[123] in 1987 by our group represented the first breakthrough within this class of com- Amphotericin B (1987) plex molecules. This total synthesis featured the recognition The polyene macrolide family of natural products is a of subtle symmetry elements within the target molecule that subgroup of the macrolide class, which poses formidable allowed the utilization of the same starting material to challenges to synthetic organic chemistry. Among them, construct two, seemingly unrelated, intermediates and the

68 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

a) Horner-Wadsworth-Emmons; - Ester bond formation condensation; ring closure O O (MeO) P OH O 2 MeO Me OTHP Me O OH OBn O O O O OTBS

HO O OH OH OH OH O TBSO 3 Me O 4 Me CO2H H O O Ph Me Me Glycosidation 2 TBSO O NH O O Me OH (EtO) P CO Et NH2 2 2 TBSO 5 Cl C O O Me Phosphonate-aldehyde OH 3 OTBS condensation O 6 7 N3 Ketophosphonate-aldehyde OAc 1: amphotericin B macrocyclization b)

HO TPSO O O O OH OH 7 steps O O a. acetonide OBn O O BnO O O O O OTBS OH formation O (38% overall) 10 (+)-8: (+)-xylose b. TPSCl, imid. 9a 3 NaH, DME a. H2, Pd/C OH c. PhOC(S)Cl, py OTPS O b. L-Selectride (75% overall) O d. nBu3SnH, AIBN O 10 steps OTPS HO c. TPSCl, imid. HO (68% overall) O (32% overall) (MeO) P O O OTBS d. TBAF 2 O HO O e. MsCl, Et N BnO O O O O P(OMe)2 3 O (Ð)-9: (Ð)-xylose 9b 4 f. NaI, acetone g. (MeO)2P(O)H, NaH 11 a. LDA; MeSSMe OR1 OH SMe OMe a. PPTS [cyclization] b. LDA; 5 a. H2, Pd/C O Ph b. NBS, MeOH O Ph c. TBAF b. imid. (63%) AcO O O OR2 OR3 O O BnO O O O O HO O c. TBSOTf c. 5 steps (53%) (67% overall) d. LiOH 13 MeO 12 e. CH2N2 OH f. PDC O 1 2 3 1 2 3 g. CH2N2 mixture of R , R = acetonide, R = TBS and R = TBS, R , R = acetonide a. KSAE

h. K2CO3, b. Red-Al O OR1 c. TBSCl, imid. MeOH OMe O Ph O Ph a. Et AlC CH OTPS BnO HO OTBS 2 2 d. H2, Pd(OH)2/C i. PDC b. NaH, BnBr O TBSO O j. (MeO) P(O)CH Li 2 3 2 2 O O O OR OR O c. TBAF e. PhCH(OMe)2, CSA CO2Me d. Red-Al HO f. SO ¥py TBSO 5 (16% overall) 3 14 19 (47% overall) (MeO)2P (65% overall) O O B(nBu)2 a. (EtO) CH, AcOH a. H2, 10% Pd/C O O 3 H H K2CO3 , O EtO2C OH OH b. LiAlH O OCHO MeOH LiCuMe b. Me2C(OMe)2, CSA 4 BnO PCl5 BnO BnO 2 BnO O N O OEt O c. CSA, MeOH c. BnBr, NaH BnO (86%) BnO OBn OBn OH O Cl (88%) EtO2C Me Me Ph (87%) H H d. PCC Me 15: (+)-diethyl-L-tartrate 16 17 18 20 O 21 22 [Evans' aldol] (72%)

SPh O a. LDA, 6 OTHP a. LiBH4 Me a. Raney Ni OH b. tBuCOCl, py O b. MeOH, PPTS Me OTHP a. LDA, 6 b. DHP, CSA c. TBSOTf, lut. TBSO c. DIBAL-H b. DIBAL-H c. DIBAL-H TBSO d. AcOH, THF, H2O HO TBSO Me Me e. PhSSPh, nBu P Me d. MnO2 Me c. MnO2 d. PCC, NaOAc 3 O O Me Me Me (86% overall) (69%) (60%) (48% overall) Me O OCO2tBu O N Me O 26 25 24 23 Ph

OR1 OMe Me OH Me O OTBS a. K CO , [18]crown-6 TBSO TBSO O O O OR2 OR3 O 2 3 Me Me b. NaBH4 14 CO2Me O Me Me (MeO)2P DCC, 4-DMAP (67% overall) O O 27 (70%) 28 O

OH O MeO OMe Me O OH Me O OTBS a. HF¥py HO O OH OH OH OH O b. HS(CH2)3SHáEt3N TBSO O O O OTBSO O Me CO2H [azide reduction] 7 Me CO2Me H H Me c. MeOH, CSA PPTS (cat.) Me d. LiOH, THF, H2O 1: amphotericin B O O Me [glycosidation] 29 OH OH (40% overall) NH (54% overall) OH 2

Scheme 22. a) Strategic bond disconnections and retrosynthetic analysis of amphotericin B and b) total synthesis (Nicolaou et al., 1987).[123]

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 69 REVIEWS K. C. Nicolaou et al.

employment of the then newly discovered Sharpless asym- a) Epoxidation metric epoxidation reaction[124] to stereoselectively construct Epoxide opening O and lactonization HO HO the 1,3- systems. O O O O O [125] H Oxidation H The Horner-Wadsworth-Emmons process emerged as O Me O tBu tBu O the most valuable reaction of the synthesis, having been HO H Aldol O O H O O reaction utilized five times to construct carbon ± carbon double bonds. 1: ginkgolide B 2 Ring closure

Particularly striking was the application of an intramolecular C-C bond formation ketophosphonate ± aldehyde condensation to construct the MeO OMe 38-membered ring of amphotericin B. A further, notable O Baeyer-Villiger O OMe oxidation feature within this total synthesis is the strategy through which OMe O tBu H Tandem vicinal tBu the moiety was installed stereoselectively on a H di-functionalization H O O H derivative of amphoteronolide B to construct the challenging 5 4 O 3 Intramolecular -olefin b-1,2-cis-glycoside bond of the target molecule. Important in [2+2] cycloaddition this field is also Masamunes elegant synthesis of 19-dehy- droamphoteronolide B.[126] b) a. OMe OMe OMe O 7 OMe a. [tBu2Cu(CN)Li2] O OMe OMe b. 6N HCl b. TMSCl, Et3N N (75%) O TMSO tBu

Ginkgolide B (1988) 6 5 8 O a. TiCl , Ginkgolide B (1 in Scheme 23) is a highly functionalized 4 O O (65%) a. Cy2BH b. LDA; PhNTf2 b. AcOH; H2O2 natural substance isolated from the Ginkgo biloba tree, widely MeO O O MeO MeO c. 1N HCl O [127] O 10 O known for its medicinal properties. The structural eluci- O d. pH 11; pH 3 dation of ginkgolide B in 1967 was a major accomplishment of tBu TfO tBu tBu (86%) [Pd(PPh3)], CuI, nPrNH2 [128] O O [] the Nakanishi group. Its total synthesis by the Corey group O 11 (76-84%) 9 in 1988[129] stands as a landmark achievement in organic 12 CO2H synthesis. Despite its relatively small size, ginkgolide B a. (COCl) proved to be stubborn in its defiance to chemical synthesis, (80%) 2 b. nBu3N, ∆ primarily because of its highly unusual bond connectivity. MeO [Baeyer-Villiger O [ketene-olefin O O Among its most striking structural features are the tert-butyl [2 + 2] oxidation] cycloaddition] group which occurs rather rarely in nature, the eleven Ph3COOH, NaOH tBu tBu tBu stereogenic centers of which two are quaternary, and its six H (86%) H ¥ H H O O five-membered rings. The Corey synthesis of ginkgolide B O 13 O 4 14 a. HS(CH ) SH, TiCl abounds with brilliant strategies and tactics, but most 2 3 4 (75%) b. PDC, AcOH impressive is, perhaps, the intramolecular [2‡2] ketene cyclo-

H OMe MeO , which contributed substantially to the a. LiNEt2 S S Ph O b. a. HIO4, MeOH, H2O construction of the required carbon framework by delivering O N OMe O 16 b. CSA, MeOH PhO2S O H tBu tBu two of the most challenging rings. O H H tBu c. CSA (80%) H (75%) H H O O O O O O 17 3 15 a. NBS, hv

(40%) b. AgNO3 Palitoxin (1989, 1994) c. PPTS, py

O O O Isolated from soft corals of the Palythoa genus, palitoxin (1 O O O Ph3COOH, (68%) tBuO in Scheme 24) is endowed with toxic properties exceeded only H H H O O tBu LDA, HMPA Me O tBu O tBu BnMe3N-OiPr; O [130] O HO by a few other substances known to man. Both its H then (MeO)3P H H O O O O Me O O (72%) tBuO structural elucidation and total synthesis posed formidable 18 2 19 20 challenges to chemists. While the gross structural elucidation CSA (92%) of palitoxin was reported independently by the groups of O [ oxidation] OH [131] [132] HO HO Hirata and Moore in 1981, its total synthesis had to HO a. I2, CaCO3 TBSO a.TBSOTf HO O O O H O O O O b. BF3¥Et2O O b. OsO4, py O await several more years of intense efforts. Finally, after H H H O O (65%) O Me H tBu (89%) Me H tBu Me H tBu heroic efforts from Kishi and his group the synthesis of HO HO HO H O H H palitoxin was published in 1989[133] and that of O O O O O 1: (±)-ginkgolide B 22 21 [134] palitoxin itself in 1994 (see Scheme 24). The synthesis of Scheme 23. a) Strategic bond disconnections and retrosynthetic analysis of palitoxin holds a special place in the history of total synthesis ginkgolide B and b) total synthesis (Corey et al., 1988).[129] in that palitoxin is the largest to be synthesized in the laboratory, both in terms of molecular weight and number of stereocenters. Most importantly, this between iodo-olefins and , a modified, refined mammoth endeavor led to the discovery and development of method for the Suzuki -catalyzed coupling reaction a number of useful synthetic reactions. Amongst them are the leading to conjugated , and a new synthesis of N-acyl improvement of the NiCl2/CrCl2-mediated coupling reaction .

70 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

a) 84 O TBSO OTBS 85 TBSO O O OTBS 84 99 O OH HO OH 85 O O 98 TBSO O HO OH O Wittig 97 93 OTBS 77 99 OH reaction Me 115 O OTBS TBSO OTBS HO B 98 HO 77 O OH OTBS 2 OH Me 76 TEOCNH 115 75 OH HO OH Suzuki coupling NiCl2 /CrCl2 coupling OH H N OH 2 OH OH I Amide bond PMBO 75 formation HO TBS Me PMBO OAc HO OH O O Me O OPMB O O Me HO Me HO OH PMBO OTBS f d a 7 OPMB 2 8 OH OH OTBS MeO 1 7 O HO N c N 1 O e H b H H H OH AcO OAc OPMB O HO HO Me HO HO PMBO OTBS Me 23 NiCl2 /CrCl2 23 OH coupling OTBS OH O OPMB 22 O 22 Me O Me O HO O OPMB Me Me OH Me Me OH OH OMe TBSO 52 H O OTBS O 51 38 O 51 53 OH 37 37 TBSO HO OH BzO OH O OH OBz OTBS HO OH Wittig reactions; BzO hydrogenation OBz MeO H OH Horner-Wadsworth- Emmons reaction 3 53 OTBS 1: O 4

b) PMBO PMBO PMBO TBS OPMB PMBO Me PMBO O Me O Me OPMB 23 PMBO I OPMB 28 8 OPMB PPh3 O Me O H MeO 1 7 O O OPMB H Me THPO OAc OPMB PMBO AcO Me OTBS PMBO O 23 OPMB 37 22 OPMB TBS O 22 5 6 OPMB Me O O Me O Me Me OPMB Me 2 7 OMe MeO 1 I 38 O 51 AcO 11 a. 5, nBuLi, THF, -78 ¡C; then 6 37 (64-46% overall) b. H , 10% Pd/C a. CrCl2, NiCl2, 11 BzO OH O 2 OBz c. TBAF, THF, 25 ¡C b. Ac2O BzO OBz d. MsCl, Et N c. PPTS, MeOH 3 d. [RuCl (PPh ) ] 3 e. NaI, 2- 2 3 3 PMBO f. Ph P, DMF 3 PMBO O Me OPMB PMBO OMe PMBO a. Ketophosponate 10, PMBO O OPMB 38 51 O OPMB NaH; then 3 PMBO O O O BzO 8 H b. LiBH4 THPO 8 OPMB BzO OBz OPMB O OBz Me c. Ac O H PMBO 2 OPMB 8 23 d. DDQ, Ac2O Me PMBO OPMB 23 22 Me O e. HClO4 a. 7, nBuLi, THF; then 8 O OPMB Me OPMB Me 22 f. LiOH Me O 38 OMe O OPMB b. H2, 10% Pd/C O Me 51 g.TBAF I c. PPTS, MeOH PPh 37 h. AcOH 3 d. Swern [O] BzO O O 37 BzO OBz i. py, O 7 (ca. 55% overall 9 OBz HO N NH from 14) H 2 SePh 12 j. camphor sulfonyl 84 O TBSO OTBS 85 TBSO [cis-trans isomerization] k. hv O O OTBS 99 O [Suzuki coupling] O 98 TBSO (7.5% overall) OTBS 77 O a. [Pd(PPh3)4], 2 Me 115 b. LiCH P(O)(OMe) OTBS TBSO OTBS HO B 2 2 84 OTBS OH O TBSO OTBS TEOCNH 85 1: palytoxin TBSO 2 O O OTBS 99 O O 98 TBSO 97 93 OTBS 77 a. CrCl2, NiCl2 O b. PDC Me 115 OTBS TBSO c. Ph3P=CH2 OTBS (72% overall) d. PPTS OTBS OAc e. Swern [O] TEOCNH OTBS f. LiCH[B(OCH2CH2CH2O)]2; OTBS then EtOAc, brine/1N HCl O OTBS OTBS O 84 O TBSO OTBS 85 I TBSO TBSO O O OTBS 99 O OTBS O O TBSO TBSO 98 OTBS O 77 OTBS Me MeO H 115 OTBS OCPh2(C6H4-p-OMe) TBSO OTBS P OTBS 14 MeO OTBS O TEOCNH O 13 10

Scheme 24. a) Strategic bond disconnections and retrosynthetic analysis of palytoxin and b) highlights of the total synthesis (Kishi et al. 1989, 1994).[133, 134]

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 71 REVIEWS K. C. Nicolaou et al.

Cytovaricin (1990) which is endowed with impressive antineoplastic activity and complex molecular architecture. Possessing seventeen stereo- Cytovaricin (1 in Scheme 25) is a 22-membered macrolide, genic centers on its main framework, a spiroketal, and a isolated from Streptomyces diastatochromogenes in 1981,[135] glycoside moiety with four additional stereocenters, cytovar-

Scheme 25. a) Strategic bond disconnections and retrosynthetic analysis of cytovaricin, b) key asymmetric alkylation and aldol reactions, and c) outline of the total synthesis (Evans et al., 1990).[137]

72 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS icin presented a considerable challenge to synthetic chemistry Strychnine (1993) in the 1980s. Its structural elucidation by X-ray crystallo- Although ()-strychnine had succumbed to the ingenuity graphic analysis in 1983[136] opened an opportunity for Evans of Woodward in 1954 (see Scheme 4) it can still be considered et al. to apply their elegant alkylation and aldol methodology a target of choice to demonstrate the application of new for acyclic stereoselection to the solution of the cytovaricin reactions and novel strategies by virtue of its abundant problem. Indeed, by 1990 the group reported a beautiful total stereochemical features densely packed in a heptacyclic synthesis[137] that clearly demonstrated the new concepts of framework. Almost 40 years after Woodwards seminal stereochemical control by acyclic stereoselection as opposed synthesis, Overmans synthesis of strychnine[58] (Scheme 27; to the classical methods applied previously to solve such see p. 76) stands as a testimony to the evolution of organic problems. It is instructive to compare this synthesis to the synthesis. Indeed, powerful palladium-mediated reactions cyclic-template strategy used by Corey,[102] Woodward,[33] and were used to expedite the assembly of the crucial intermediate Stork[138] to achieve stereochemical control in their syntheses 13 (Scheme 27) in a stereospecific fashion, thereby setting the of the erythromycin macrolide framework. This impressive stage for the key tandem aza- and use of acyclic stereocontrol through the use of the Evans Mannich reaction. This tandem reaction proved to be chiral oxazolidone certainly propelled the area of particularly efficient and well-suited to afford an advanced synthesis, a class of compounds that are rather readily tricyclic system with concomitant formation of the quaternary accessible synthetically by todays standards. center stereospecifically, under mild conditions, and in nearly quantitative . The sophisticated sequence of reactions which ultimately led to Overmans ()-strychnine synthesis I Calicheamicin g1 (1992) deserves special mention for its elegance.

I [139] The arrival of calicheamicin g1 (1 in Scheme 26) and its relatives, collectively known as the enediyne anticancer Rapamycin (1993) antibiotics,[140] on the scene in the 1980s presented an entirely new challenge to synthetic organic chemistry. Isolated from Rapamycin (1 in Scheme 28; see p. 77) is an important Micromonespora echinospora ssp calichensis, this fascinating molecule within the field of immunosuppression that was first natural product provided a unique opportunity for discovery isolated in 1975[144] from Streptomyces hygroscopicus, a and invention in the areas of chemistry, biology, and medicine. bacterial strain found in soil collected in Rapa Nui (Easter Its novel molecular structure is responsible for its powerful Island), and structurally elucidated in 1978.[145] Its potent biological properties, which include strong binding to duplex immunosuppressive properties are reminiscent of those of DNA, double-strand cleavage of the genetic material by cyclosporin and FK506, whose biological and medical im- formation of a benzenoid diradical, andÐas a consequenceÐ portance, particularly in the field of organ transplants, became potent antitumor and antibiotic activity. evident in the 1980s.[146] Although the structures of rapamycin I and FK506 possess striking similarities, the former is consid- The structure of calicheamicin g1 is comprised of a carbo- domain and an enediyne core carrying a trisulfide erably more complex and attracted serious attention from the moiety that acts as a triggering device for the cascade of synthetic chemists in the late 1980s and early 1990s. By 1995 [147±150] events which , via a Bergman cycloaromatization,[141] to there were four total syntheses of rapamycin, the first the diradical species and DNA rupture. The oligosaccharide being reported from this group in 1993 (Scheme 28).[147] This I asymmetric synthesis of rapamycin is an example of high domain of calicheamicin g1 is endowed with high affinity for certain DNA sequences, and acts as the delivery system of the convergency and acyclic stereoselection, and is perhaps molecule to its biological target. The highly strained 10- known best for the way in which the macrocyclic ring was membered enediyne system, the novel oligosaccharide frag- formed. A palladium-catalyzed reaction based on Stilles ment, and the trisulfide unit are but some of the unusual and chemistry allowed a ªstitching cyclizationº process to pro- I ceed, to furnish the required conjugated triene system challenging features of calicheamicin g1. Even more challeng- ing, of course, was the chartering of the proper sequence for concurrently as it formed the 29-membered ring of the target assembling all these functionalities into the final structure. molecule.[151] Two groups rose to the challenge, ours (1992)[142] and that of S. J. Danishefsky (1994).[143] I Taxol (1994) Notable features of our total synthesis of calicheamicin g1 (Scheme 26) are the installment of the sulfur atom in the Taxol (1 in Scheme 29; see p. 78), one of the most carbohydrate domain through a stereospecific [3,3]-sigma- celebrated natural products, was isolated from the Pacific tropic rearrangement and the [3‡2] olefin ± oxide yew tree and its structure was reported in 1971.[152] Its arduous cycloaddition reaction employed in the construction of the journey to the clinic took more than 20 years, being approved enediyne core. That a molecule of such complexity could be by the Food and Drug Administration (FDA) in 1992 for the assembled in the laboratory in less than five years after its treatment of ovarian cancer.[153] Synthetic chemists were structural elucidation in 1987 is an accurate reflection of the challenged for more than two decades as taxols complex high level of the state-of-the-art in the early 1990s. Just as molecular architecture resisted multiple strategies toward its impressive is Danishefskys synthesis of calicheamicin, which construction in the laboratory. Finally, in 1994, two essentially can be found in the original literature.[143] simultaneous reports[154, 155] described two distinctly different

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 73 REVIEWS K. C. Nicolaou et al. total syntheses of taxol. These first two syntheses, by our group[154] and that of Holton,[155] were followed by those of Danishefsky,[156] Wender,[157] Mukaiyama,[158] and Kuwaji- ma.[159] All these syntheses, which are characterized by novel strategies and brave tactics, contributed enormously to the advancement of total synthesis and enabled investigations in biology and medicine. Amongst the most notable features of our total synthesis of taxol (Scheme 29) are the boron-mediated Diels ± Alder reaction to construct the highly functionalized C ring, the application of the Shapiro and McMurry coupling reactions, and the selective manner in which the oxygen functionalities were installed onto the 8-membered ring of the molecule. Because of the great drama associated with cancer, this and the other syntheses of taxol received headliner publicity. The art and science of total synthesis was once again brought to the attention of the general public.

Zaragozic Acid (1994) A new natural product with unprecedented molecular architecture often gives impetus to synthetic endeavors directed at its total synthesis. Such was the case with zaragozic acid A (1 in Scheme 30; see p. 79) whose structure was released essentially simultaneously in 1992 by groups from Merck[160] and Glaxo[161] (the latter naming the compound squalestatin S 1).[162] Isolated from a species of fungi, zaragozic acid A exhibits impressive in vitro and in vivo inhibition of cholesterol biosynthesis by binding to squalene synthase.[163] Zaragozic acid A, like its many relatives, possesses an unusual tricarboxylic acid core, whose highly oxygenated nature added to its novelty and complexity as a synthetic target. The distinguishing features of our synthesis[164] of zaragozic acid A (Scheme 30) include the utilization of the Sharpless asymmetric dihydroxylation reaction[165] to install the first two oxygen-bearing stereocenters onto a complex prochiral system and a multi-step, acid-catalyzed rearrangement to secure the zaragozic acid skeleton. The synthesis of zaragozic acid was also accomplished and reported at approximately the same time as ours by the groups of Carreira (zaragozic acid C)[166] and Evans (zaragozic acid C).[167] In addition, Heathcock et al.[168] reported another total synthesis of zaragozic acid A in 1996.

Swinholide A (1994) Swinholide A (1 in Scheme 31; see p. 80), a marine natural product with antifungal and antineoplastic activity, was originally isolated from the Red Sea sponge Theonella swinhoei.[169a] Its structure was fully established in the late Scheme 26. a) Strategic bond disconnections and retrosynthetic analysis of calicheamicin gI and b) total synthesis (Nicolaou et al., 1992).[142] 1980s by X-ray cystallographic analysis.[169b] The structure of 1 swinholide A has C2 symmetry and is distinguished by two conjugated diene systems, two trisubstituted tetrahydropyran and biological action prompted several groups to undertake systems and two disubstituted dihydropyran systems, a 44- synthetic studies towards its total synthesis. Two laboratories, membered diolide ring, and thirty stereogenic centers. Its that of I. Paterson at Cambridge[170] and ours[171] have challenging molecular architecture coupled with its scarcity succeeded in the task.

74 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

Scheme 26. (Continued)

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 75 REVIEWS K. C. Nicolaou et al.

Patersons total synthesis,[170] shown in Scheme 31 (see elucidated (1981).[177] The beauty of brevetoxins molecular p. 80), came first and was accompanied by the development architecture, which accommodates eleven rings and twenty- and application of a number of various types of asymmetric three stereogenic centers, attracted immediate attention from boron-mediated aldol reactions to form key CC bonds. the synthetic community. This neurotoxin, whose mechanism Indeed, this new aldol methodology[172] was utilized to install of action involves the opening of sodium channels, shows three contiguous chiral centers in two steps with high remarkable regularity in its structure. Thus, all rings are trans- diastereoselectivity (9 !12 in Scheme 31), and represents a fused and each contains an oxygen atom. All ring are most welcomed progress in acyclic stereocontrol. Our total separated by a CC bond and each is flanked by two syn- synthesis of swinholide A[171] (Scheme 32; see p. 81) featured arranged hydrogen or methyl substituentsÐexcept for the two relatively new, at the time, methods for CC bond first which carries a carbonyl to its ªleftº and the last which is construction in complex-molecule synthesis, namely the flanked by two anti-oriented . With its imposing Ghosez cyclization[173] to form a,b-unsaturated b-lactones structure, brevetoxin B presented a formidable and daunting from orthoester and , and the dithiane- problem to synthetic organic chemistry. Not only did new stabilized anion opening of cyclic sulfates.[174] The macro- methods need to be developed for the construction of the lactonization was performed by the Yamaguchi [175] in various cyclic ether moieties residing within its structure, but, both strategies. Both total syntheses are highly convergent most importantly, the ªright strategyº had to be devised for and demonstrated the power of the art in acyclic stereo- the global assembly of the molecule. selection and large-ring construction and stand as important After several abortive attempts, brevetoxin B was finally achievements in the field of macrolide synthesis. conquered, and the total synthesis was reported in 1995 from these laboratories (Scheme 33).[178] Along with the accom- plishment of the total synthesis, this twelve-year odyssey[179] Brevetoxin B (1995) yielded a plethora of new synthetic technologies for the Brevetoxin B (1 in Scheme 33; see p. 82), an active construction of cyclic of various sizes. Prominent principle of the poisonous associated with the ªred among them are (see Scheme 33b): a) the regio- and stereo- tideº phenomena,[176] was the first structure of its kind to be selective routes to tetrahydrofuran, tetrahydropyran, and

a) Epoxide Tandem Mannich- O N aza-Cope N opening N rearrangement F COCHN N 3 MeN NMe H TIPSO H H O N N N H H H N I H H H O HO CO Me N H R2N O O 2 OtBu Me3Sn H O lactone NMe Carboxymethylation; 7 1: (Ð)-strychnine formation; 2: Wieland- 3 OH MeN 4 5 6 reduction imine formation; OtBu OtBu Gumlich O aldehyde tautomerization

b) [chemo-and stereo-selective TIPSO a. CrO3, TIPSO TIPSO a. MeOCOCl, py H CO Et reduction] [Pd2(dba)3], Ph3As, CO 2 H2SO4 OH b. NaH, [Pd (dba) ], 2 3 a. NaCNBH3, b. L-Selectride; O O O O TiCl Me3Sn MeN NMe AcO AcO 4 HO then PhNTf2 (80%) 8 EtO2C OtBu 9 10 7 b. DCC, CuCl c. Me Sn , [Pd(Ph P) ] N 11 OtBu 6 2 3 4 R2N (89%) OtBu OtBu I OtBu ÐH2O (78%) c. DIBAL-H 6 a. tBuOOH, d. TIPSCl Triton-B (57%) F COCHN HO 3 b. Ph3P=CH2 tBuO tBuO tBuO [epoxide opening] c. TBAF [3,3] a. NaH, ∆ O O (84%) N [aza-Cope N (CH2O)n, N b. KOH, H2O a. MsCl, iPr2NEt H rearrangement] Na2SO4, (62%) R2N b. LiCl, DMF R2N OtBu OtBu HO HO ∆ HO c. NH2COCF3, NaH

R2N 15 R2N 14 R2N 13 5 (83%) 12

[Mannich reaction] (98%) N N H N N

a. LDA, NCCO2Me H Zn H H ∆ O b. 5% HCl-MeOH, N 10% H2SO4, N N N H [carboxymethylation; H ∆ H H H CO Me MeOH, NMe imine formation; 2 O ZnO OMe MeN tautomerization] OMe OtBu OH OH OH O 4 (70%) 3 Zn: 16 17 H N N N N N [lactamization] [isomerizations] CH2(CO2H)2 a. NaOMe, MeOH H H H ∆ H H Ac2O, b. DIBAL-H N N N (65%) N N H H H H H H H H H H H (65%) H H CO Me O HO2C HO 2 O H O O H OH 18 1: (Ð)-strychnine 20 19 CO2H 2 OH

Scheme 27. a) Strategic bond disconnections and retrosynthetic analysis of ()-strychnine and b) total synthesis (Overman et al., 1993).[58]

76 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

Epoxide a) Me opening Me O O HO OH H OH Amide bond formation Me OTIPS OMe O N Me OMe O OH Stille couplings H 3 HN "stitching macrocyclization" SnnBu3 O I Takai reaction O O I Esterification H nBu Sn O Me OMe 3 2 H O OH Me OMe OTES OTIPS Me O OH Me OTES OTBDPS MeMeO Me Me Me OMe Me Me 1: rapamycin 4 NiII/CrII coupling

a. CSA, MeOH b) Me Me Me Me Me a. nBu3SnH, cat. tBuLi; a. LiI, LiAlH4 b. CF3SO2Cl, Et3N TMS Me TMS TMS TMS TMS Li b. I I Me 2 7 O b. NaH, MeI O c. K2CO3, MeOH O 5 (81%) 6 N 8 O 9 (65%) 10 11 MeO O (80%) OMe O OMe O PmBO O O cat. = [Mo(allyl)Br(CO)2(CH3CN)2] [2-thienylCu(CN)Li] (88%) (70%)

OMe Me Me OH a. HO ,LDA Me Me Me Me Me Me I OH O I a. DDQ I a. TIPSOTf TMS b. LiOH b. Swern [O] b. NIS OMe OTIPS OH O OMe OTIPS O OMe OTIPS PMBO OMe OH PMBO (92%) 3 (68%) 14 13 (95%) 12

O OH OTBS PMBO OTBS Me PMBO OTBS nBuLi, tBuOK; OTBS a. NaHMDS, PMBBr a. CBr4, Ph3P, Zn Me (+)-Ipc B Me Me 2 (+)-Ipc BOMe, (75%) b. O3; Me2S O b. nBuLi; MeI 15 2 16 17 Me Me 18 Me 19 BF3¥Et2O (72%) (98%)

PMBO O Cp2ZrHCl; I2 PMBO HO PmBO OTBS CrCl2, NiCl2, PMBO OTBS (85%) Me Me OMe 21 I a. TIPSOTf Me Me OMe Me Me (93%) [Nozaki-Takai-Hiyama-Kishi reaction] Me Me b. HF¥py 22 20 c. Swern [O] (83%) O O

O O O N PMBO OTIPS OPMB O O O OMe a. [RhCl(Ph3P)3], Et3SiH P(O)(OEt)2 CHO OMe OMe O N b. aq. HF O N Ph Me Me Me OMe Me Me c. TBDPSCI, imid. Ph Me OTBDPS OTBS iPr NEt, LiCl OTBS (75%) Ph Me 2 23 26 25 (96%) 24

[Evans asymmetric aldol reaction] nBu2BOTf, Et3N, (86%)

PMB PMB PMBO OTIPS O OH a. LiBH4 PMBO OTIPS O OH OMe b. pTsCl, Et3N, 4-DMAP OMe

O c. LiEt3BH Me Me OMe Me Me Me Me OMe Me Me Me O OTBDPS OTBDPS O N (81%) a. 27 28 N CO2H Ph Me Me Boc

DIC, iPr2NEt HO OH Boc N b. OsO4, NMO OTIPS Me c. Pb(OAc)4 OMe O N H d. CHI3, CrCl2 a. DDQ O I H O (60%) O b. TESOTf H I OMe O c. 3, DIC, HOBt PMBO OTIPS H Me OMe I Me d. Swern [O] OTES OTIPS (87%) O OTBDPS e. HF¥py Me Me Me OMe Me Me PMB OTBDPS f. Swern [O] OTES 29 g. HF, CH CN Me OMe Me Me 3 Me 30 Me (70%) Me O O SnnBu3 O O O H OH O H OH Me H OH Me OMe O N Me OMe O N nBu3Sn OMe O N 2 I H H SnnBu3 H I [PdCl2(CH3CN)2], iPr2NEt O O O I O (27%) O O H H H Me OMe Me OMe Me OMe O OH O OH O OH Me Me Me O OH O OH O OH 32 Me OMe Me Me Me OMe Me Me Me OMe Me Me [inter- followed by intramolecular 31 Stille couplings] 1: rapamycin

Scheme 28. a) Strategic bond disconnections and retrosynthetic analysis of rapamycin and b) highlights of the total synthesis (Nicolaou et al., 1993).[147]

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 77 REVIEWS K. C. Nicolaou et al.

-induced hydroxy ketone cyclization to oxepanes; a) McMurry coupling Esterification AcO O f) nucleophilic additions to thiolactones as an entry to Ph O OH O Me Me medium and large ring ethers; g) thermal of

Ph N O dimethyl dicarboxylate with cyclic enol ethers as an H Oxetane formation OH O entry to medium size oxocyclic systems; and h) the novel and HO H Oxygenation OBz OAc unprecedented chemistry of dithiatopazine. For a more Shapiro coupling 1: Taxol detailed analysis of this total synthesis, the reader should

TPSO OBn consult ref. [3]. Me Me OTBS TESO Ph + + H N Ph O Dynemicin A (1995) O O NNHSO Ar O O 2 Diels-Alder reaction [180] Diels-Alder reaction Dynemicin A (1 in Scheme 35; see page 84), a dark blue 2 3 4 substance with strong antitumor properties and a member of b) OAc the enediyne class of antitumor antibiotics that includes Me Me OAc Me OH Me OTBS 5 I ∆ KOH, tBuOH a. TBSCl, calicheamicin g1(Scheme 26), possesses a striking molecular Cl (85%) (65%) imid. [140, 181] CN architecture. Isolated from Micromonospora chersina, b. H2NNHSO2Ar [Diels-Alder Cl O NNHSO2Ar CN reaction] (68%) dynemicin includes in its structure a highly strained 10- 6 7 8 3 membered enediyne ring, and a juxtaposition of epoxide, imine, and functionalities. The lure provided O Me O 12 EtO2C O O by this fascinating DNA-cleaving molecule resulted in intense Me O HO OH Me OEt OH 10 O O EtO2C synthetic studies directed towards its total synthesis. In 1993 PhB(OH)2 O [boronate OH B H Ph cleavage] HO Schreiber et al. first reported the total synthesis of di- and OH [Diels-Alder O 9 reaction] 11 13 trimethoxy derivatives of dynemicin methyl ester (1 in [lactone migration] Scheme 34; see p. 84).[182] This synthesis relies on the powerful a. LiAlH4 b. CSA, MeO OMe a. TBSOTf intramolecular Diels ± Alder reaction to construct the com- OBn OBn O OH Me Me b. LiAlH4 Me plex enediyne region of the molecule and a series of selective TBDPSO c. TPAP, NMO TBDPSO c. CSA, MeOH EtO H H H (63% overall) d. TBDPSCl, imid. follow-up reactions to reach the methylated dynemicin O OTBS e. KH, nBu4NI, BnBr OH targets. O O (46% overall) O O O O 4 15 14 Myers et al. reported the first total synthesis of dynemicin Me OTBS itself in 1995.[183] Their synthesis, summarized in Scheme 35, nBuLi (82%) 3 [] highlights a stereoselective introduction of the ene ± diyne 16 Li a. [V(O)(acac)2], a. TBAF bridge, the use of a quinone imine as the dienophile in a regio- TBSO OTBDPS tBuOOH TBSO OTBDPS b. TPAP, NMO HO OH OBn OBn OBn Me Me Me Me and stereoselective Diels ± Alder reaction, and a number of Me b. LiAlH4 Me c. TiCl3•(DME)1•5 c. KH, COCl2 Zn/Cu other novel steps to complete the total synthesis. The second (50%) (17%) O total synthesis of dynemicin was reported from the Danishef- H O O H O [McMurry O H OH coupling] O [184] O O O O sky laboratory (Scheme 36; see p. 85) and features a 17 18 19 O O double Stille-type coupling in its assembly of the enediyne a. Ac2O, 4-DMAP b. TPAP, NMO (48%) grouping. All three syntheses project admirable elegance and • c. BH3 THF; H2O2 sophistication. AcO O a. HCl, MeOH AcO O Me OTES Me OBn Me b. Ac2O, 4-DMAP Me c. H2, Pd(OH)2/C OMs d. TESCl, py OH Ecteinascidin 743 (1996) OH e. MsCl, 4-DMAP O O H O H O OAc (46% overall) O O A marine-derived natural substance, ecteinascidin (1 in O 21 O 20 Scheme 37) possesses an unusual molecular architecture and a. K2CO3, MeOH d. PhLi [selective carbonate opening] b. nBu4NOAc e. PCC [allylic oxidation] (34% overall) extremely potent antitumor properties. Isolated from the c. Ac2O, 4-DMAP f. NaBH4 tunicate Ecteinascidia turbinata, ecteinascidin 743 is com- AcO O AcO O prised of eight rings, including a 10-membered heterocycle, OTES Ph O OH Me Me a. NaHMDS, 2 O Me Me [185] b. HF•py and seven stereogenic centers. Prompted by its attractive HO Ph N O H molecular architecture, impressive biological action, and low OH O O HO H HO H natural abundance, Corey et al. embarked on its total syn- OBz OAc OBz OAc 22 1: Taxol thesis, and in 1996 they published the first total synthesis[186] of Scheme 29. a) Strategic bond disconnections and retrosynthetic analysis of ecteinascidin 743 based on a brilliant strategy (Scheme 37; see taxol and b) total synthesis (Nicolaou et al., 1994).[154] p. 86). The plan was inspired, at least in part, by the proposed oxepane systems employing specifically designed hydroxy biosynthesis of the natural product. Of the many powerful epoxides; b) the -promoted hydroxy dithioketal cycliza- transformations in Coreys total synthesis of ecteinasci- tion to didehydrooxocanes; c) the remarkable radical-medi- din 743, at least three stand out as defining attributes; an ated bridging of bis(thionolactones) to bicyclic systems; d) the intramolecular Mannich bisannulation sequence was instru- photoinduced coupling of dithionoesters to oxepanes; e) the mental in establishing the bridging aromatic core to the

78 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

Scheme 30. a) Strategic bond disconnections and retrosynthetic analysis of zaragozic acid A and b) total synthesis (Nicolaou et al., 1994).[164] ring, which allowed the formation of the desired level of brilliance. This impressive accomplishment also functionality, while two asymmetric Pictet ± Spengler speaks for the efficiency that total synthesis has reached and reactions played key roles in forming the rings. the complex natural product analogues which can be synthe- The centerpiece of the synthesis is, however, the generation sized in large quantities.[187] and biomimetic quinone methide capture by the sulfur atom to construct the 10-membered lactone bridge. The masterful A (1997) use of topology to predict reactivity, inflict asym- metry, and achieve selectivity is amply demonstrated through- Appearing in the mid-1990s, epothilones A (1 in out Coreys synthesis. Scheme 38; see p. 87) and B[188] stimulated intense research Finally, the success in recognizing subtle retrosynthetic activities in several laboratories.[189] The impetus for their total clues left by nature and applying them in the context of a synthesis came not so much from their modestly complex chemical synthesis elevates this total synthesis to a unique macrolide structures but more so from their potent tubulin-

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 79 REVIEWS K. C. Nicolaou et al.

a) OMe OMe

Me O Me Me Yamaguchi Ar O Me Me esterification OH Me OH OH O OH O O OH Me Me Me O OH HO2C Me Me O Dimerization Me TBSO O Brown's OMe OMe Mukaiyama coupling syn-crotylboration MeO MeO O Me Me Me O OTBS tBu O O Me CO2Me Si Me tBu OH O HO OH O O O HO Me Me Me 2 Vinylogous Mukaiyama Me O Ar Yamaguchi Me O Me macrolactonization Me aldol reaction 3 Paterson anti- OMe aldol reaction OMe 1: swinholide A b) [catalytic asymmetric epoxidation] Me a. (+)-DIPT, Ti(OiPr) , a. O ; Me S; HCl Me 4 Me OH 3 2 Me O OMe Me O a. O3; Me2S; HCl Me O CHO tBuOOH b. NaH, MeI H2C=CHCH2TMS b. Ph3P=C(Me)CHO b. Red-Al (79%) TMSOTf (82%) (96%) OH (34%) OH OMe OMe OMe 4 [hydroxy-directed 5 6 7 8 reductive opening of epoxide] Me Me (cC6H11)2BCl, Me Me OBn OBn Et3N O 9 O 10 [-oxidation] B(cC6H11)2 Me Me Me a. thexylborane; Me Me Me Me Me Me Me O OBn Me O OBn a. Me4NBH(OAc)3 Me O OBn H2O2, NaOH b. (imid) C=S b. tBu Si(OTf) O O 2 O O 2 2 OH O a. H2, 10% Pd/C Si c. nBu SnH Si (78%) tBu tBu 3 tBu tBu [Paterson anti-aldol coupling] b. Swern [O] OMe [deoxygenation] OMe OMe (84%) 13 (70%) 12 11 (93%) Me Me Me Me Me Me ]2B Me O a. MeOTf MeO2C MeO C MeO C b. PdCl2, 2 2 O O O TBSO O CuCl, O TBSO O ; H O TBSO O 14 Si 2 24 2 2 23 tBu tBu 25 (74%) [Brown's syn OMe MeO HO O [Wacker oxidation] -crotylboration] Me [stereocontrolled Mukaiyama coupling/ Me Me chelation-mediated 1,3-syn reduction/ [Horner-Emmons reaction] a. (MeO) P(O)CH CO Me, nBuLi 1,3-diol protection sequence] O 2 2 2 b. TBSOTf

a. 25, LiHMDS, TMSCl, Et3N c. K2CO3, MeOH (87%) b. 14, BF3¥OEt2 d. Dess-Martin [O] c. nBu2BOMe; LiBH4; H2O2 Me d. p-MeOC H CH(OMe) , CSA 6 4 2 (80%) OAc e. NaOH, H O, MeOH TMSO 2 TiCl2(OiPr)2 20 O O O Me O OH O Me OTBS BF3¥OEt2 BzO BzO BzO (83%) [vinylogous Mukaiyama 20 21 aldol reaction] 22 HO2C TBSO O [Luche reduction] (85%) a. NaBH , CeCl ¥7H O MeO (97%) 4 3 2 Me b. Ac2O, iPr2NEt tBu O ]2BCl Si Me tBu O Cl O O O O a. , iPr NEt Cl O 16 2 a. CH2N2 Me TMSOTf, O HO b. HF¥py, py Me O Ar iPr2NEt CHO Me Me b. BzO BzO (61%) BzO 17 (94%) 19 18 (56%) 15 OMe [asymmetric aldol reaction] 3 OMe (65%) OMe OMe Me Ar O Me a. TBSCl, Et3N Me Me Me b. HF¥py, py Me O O OH O Me O 2,4,6-Cl C H COCl, Et N, 3; Ar 3 6 2 3 Me c. Ba(OH)2¥8H2O, Me Me OH OH 4-DMAP, 2 OH MeOH O O O OTBS OH OH O OH Me Me Me OMe [Yamaguchi O d. 2,4,6-Cl3C6H2COCl, O esterification] Me Me O Et3N; 4-DMAP Me Me O O OTBS OMe OMe (54%) e. HF/H2O/MeCN CO Me 2 MeO (27%) MeO O Me O Me Me tBu Me O [Yamaguchi O Me macrolactonization] Me 2 tBu Si O O O O OH OH OH OTBS Me HO Me Me Me O Ar Me Me O Me

26 OMe O OMe OMe 1: swinholide A

Scheme 31. a) Strategic bond disconnections and retrosynthetic analysis of swinholide A and b) total synthesis (Paterson et al., 1994).[170]

80 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

a) OMe OMe Enders alkylation Me O Me Yamaguchi Me Dithiane-cyclic Mukaiyama aldol Me esterification Ar O Me OH sulfate coupling OH OH O OH Me Ghosez O O OTBS Me Me lactonization O Me OH Me Me O HO2C OMe Me TBSO O Dimerization OMe MeO O Me Me MeO O OTBS O Me Me CO2Me TMSO OH O HO OH Me HO Me Me TBSO O O 2 Me Yamaguchi Me O Me O Me Ar macrolactonization Me 3

OMe OMe 1: swinholide A a. Ac O, Et N, b) 2 3 Me 4-DMAP Me O OH Me O Me O Me O TiCl , Et N Me 4 3 b. CH2=CHCH2TMS, a. nBu2SnO; CsF, MeI a. O3; NaBH4 b. NaH, CS ; MeI b. I , Ph P, imid. O Me HO OH BF3¥OEt2, TMSOTf HO OH 2 2 3 c. nBu3SnH, AIBN c. LDA, H OH c. NaOMe, MeOH OH OMe N OMe OBn (74%) [selective methylation/ N (68%) 5: L-rhamnose 6 7 OMe 9 O OBn Barton-McCombie deoxygenation Me Me 4 sequence] 8 [aldol condensation] (35%) d. O3 [Enders alkylation] (67%)

Me Me Me a. H2, 10% Pd/C Me Me Me Me Me Me Me O b. SOCl2, Et3N Me O Me O O OBn a. PhCHO, SmI2 OBn c. RuCl3, NaIO4 TBSO OBz O TBSO OBz OBn b. TBSOTf O OH OBn S O (94%) [1,3 anti-reduction; OMe 12 O OMe 11 Evans-Hoveyda modification OMe 10 of the Tishchenko reduction] (77%)

OMe TBSO a. TiCl2(OiPr)2, OMe a. DIBAL-H a. NaH, MeI OMe b. TBSOTf 20 OTMS TMS 17 b. BF3¥OEt2, b. PhSO2 OMe c. K CO , MeOH Me Me 2 3 Me c. BzCl, Et3N Me DMPU, nBuLi; H SO ; OH 2 4 O d. Swern [O] O S O BzO O d. OsO4, NMO; PMBO O O pTsOH; Et3N, DBU PMBO Pb(OAc)4 S OMe OTBS OMe (84%) e. TiCl4, SH SH OMe Me (60%) 18 [Ghosez lactonization] 16 21 f. DIBAL-H 19 a. tBuLi, HMPA; g. TBSOTf K2CO3, MeOH (50%) b. H2SO4 (52% overall) (72%) O a. PMBCO(NH)CCl3, CSA Me Me Me Me Me O OH nBuLi; O O b. DIBAL-H Me O O OTBS HO OMe PMBO CO PMBO c. (+)-Ipc2B(allyl); S S Me Me 2 Me I TBSO OBz OH OMe OTBS NaOH, H2O2 ; 13 (74%) 14 15 OMe 22 I 2 [cleavage of dithiane functionality] a. NBS, AgClO4 [syn 1,3-selective reduction] b. nBu3B; NaBH4; H2O2, NaOH c. p-MeO-C6H4CH(OMe)2, CSA (68% overall) d. DIBAL-H [selective desilylation] e. HF¥py, py

Me Me Me Me Me O OH Me O OMe TBSO OH O O OMe OTBS

OMe Ar 23 Me O Me a. MnO2 [Yamaguchi esterification] Me (92% overall) OH b. (MeO) P(O)CH CO Me, nBuLi a. 2,4,6-Cl C H COCl, Et N, 2, 2 2 2 3 6 2 3 OH OH O OH 4-DMAP Me Me Me Me Me Me b. PPTS, MeOH O Me O O Me Me O CO2Me c. Ba(OH)2¥8H2O OMe TBSO OH O O OMe OTBS d. 2,4,6-Cl3C6H2COCl, Et3N; MeO 2 4-DMAP O Me Me OMe Ar O e. HF/H2O/MeCN Me (82%) a. NaOH, MeOH/THF/H2O b. TMSOTf, iPr NEt [Yamaguchi OH O OH OH 2 HO macrolactonization] Me Me Me Me Me Me (7% overall) Me O Me O O Me CO2H TBSO OTMS O O OMe OTBS OMe 1: swinholide A OMe Ar 3

Scheme 32. a) Strategic bond disconnections and retrosynthetic analysis of swinholide A and b) total synthesis (Nicolaou et al., 1995).[171]

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 81 REVIEWS K. C. Nicolaou et al. binding properties and their potential to overshadow taxol as superior anticancer agents. The first total synthesis of epothilone A came from the Danishefsky laboratories in 1996[190] and was followed shortly thereafter by syntheses from our laboratories[191] and from those of Schinzer.[192] Danishef- skys first total synthesis of epothilone A (Scheme 38) fea- tured a Suzuki coupling reaction to form a crucial CC bond and an intramolecular enolate ± aldehyde condensation to form the 16-membered macrocyclic lactone. This method as well as others allowed the Danishefsky group to synthesize several additional natural and designed members of the epothilone family, including epothilone B,[193] for extensive biological investigations. Chemical biology was also on our minds in devising a solution and a solid-phase total synthesis[194] of epothilone A (1). As shown in Scheme 39 (see p. 87) this new solid-phase paradigm of complex molecule total synthesis relied on a novel strategy.[195] Of special note is the cyclorelease mechanism of this approach by which the 16- membered epothilone ring was constructed with simultaneous cleavage from the resin. Most importantly, this solid-phase strategy allowed the application of Radiofrequency Encoded Chemistry (REC; IRORI technology)[196] to the construction of combinatorial epothilone libraries[197] for chemical biology studies. The power of chemical synthesis of the 1990s in delivering large numbers of complex structures for biological screening was clearly demonstrated by this example of total synthesis, marking, perhaps, a new turn for the science.

Eleutherobin (1997) A marine natural product of some note, eleutherobin (1 in Scheme 40; see p. 88) includes in its structure a number of unique features. Isolated from an Eleutherobia species of soft corals and reported in 1995,[198] this scarce natural product elicited immediate attention from the synthetic community as a result of its novel molecular architecture and tubulin binding properties. Among the challenges posed by the molecule of eleutherobin are its oxygen-bridged 10-membered ring and its glycoside bond. Solutions to these problems were found in our 1997 total synthesis[199] as well as in Danishefskys total synthesis,[200] which followed shortly thereafter. Scheme 40 summarizes our strategy to eleutherobin from (‡)-. Highlights include the intramolecular acetylide ± aldehyde condensation to give the desired 10-membered ring and the spontaneous intramolecular collapse of an in situ generated hydroxycyclodecenone to form eleutherobins bicyclic frame- work. This total synthesis exemplified the power of chemical synthesis in delivering scarce natural substances for biological investigations.

Sarcodictyin A (1997) Scheme 33. a) Strategic bond disconnections and retrosynthetic analysis of Sarcodictyins A and B (1 and 2 in Scheme 41; see p. 88) are brevetoxin B, b) key synthetic methodologies developed for the formation two marine natural products discovered in 1987 in the of polycyclic ethers and fundamental discoveries, and c) total synthesis of Mediterranean stoloniferan coral Sarcodictyon roseum.[201] brevetoxin B (Nicolaou et al., 1995).[178]

82 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

c) Me [Barton-McCombie OH Me a. Swern [O] a. Ac O, py deoxygenation reaction] a. O3; Me2S, Ph3P 2 O OBn OBn CO2Me OBn HO OH b. BF ¥Et O, TMSOTf, a. Im C=S b. AlMe3, Me b. CH2=CHMgBr Me 3 2 O OH 2 HO HO HO TMS b. nBu3SnH, AIBN MgBr2¥Et2O c. TPSCl, imid. a. NaH K HO O K d. O ; Me S, Ph P [Intramolecular c. NaOMe, MeOH c. Amberlyst-15 (61%) 3 2 3 TBDPSO O O O O conjugate addition] OH d. TBDPSCl, imid.; H d. nBu2SnO; BnBr H H e. Ph3P=CHCO2Me H H CSA, OMe TBDPSO TBDPSO TBDPSO TBDPSO 4: D- (35%) (34%) b. DIBAL-H; 5 6 7 8 Ph3P=CHCO2Me (62%) (69%) [6-endo hydroxy OBn OBn H Me H Me OTBS OTBS OBn epoxide O a. DIBAL-H O SEt H Me a. EtSH, Zn(OTf) H Me H H Me cyclization] b. mCPBA O 2 O O HO O O J K J K EtS b. CSA, MeOH 12 steps CSA c. Swern [O] I J K I J K I J K HO O MeO2C O O H TBSO (55%) (71%) H H H H O O c. SO ¥py, Et N, O O O d. Ph3P=CHCO2Me TBDPSO 3 3 H H H TBDPSO TBDPS H H H DMSO H H H MeO2C e. TBAF O 11 TBDPSO 10 9 3 TBDPSO (68%) 12 TBDPSO MeO2C (58%)

a. TBSCl, imid. a. DIBAL-H H Me Me Me b. 9-BBN; Me Me b. mCPBA Me Me H O O O OH HO OH O O OH 10 steps O PPTS O H2O2, NaOH c. SO3¥py O Me O F F F G (49%) d. CH PPh HO (89%) c. Swern [O] Ph O O CO2Et 2 3 H Ph O Ph O OH Ph O O H H H d. Ph P=C(Me)CO Et H H Me e. TBAF H H Me 3 2 TBS 13: 2-deoxy-D- 14 [6-endo ring closure] 15 (77%) 16 f. PPTS 17 (65%) 7 steps (58%) a. Me TBSO PPh3 O b. H , Pd/C O Me Me H Me Me H 2 Me Me H Li O OBn a. 2,4,6-Cl3C6H2COCl, O OBn c. CSA, MeOH O OBn O O E F G Et3N; 4-DMAP F G d. Swern [O] F G 21 Me HO O O OBn b. LiHMDS, HMPA; O OBn e. NaClO , NaH PO TBSO OBn [(2-thienyl)(CN)CuLi] TfO H H Me OH H H Me 2 2 4 H H Me PhNTf2 f. TBAF [Murai coupling] 20 (58%) 19 18 (85%) (83%)

a. LiHMDS, HMPA; PhNTf2 a. PPTS, H2O Me Me Me H Me Me H b. CrCl2, NiCl2, TBSO CHO Me Me H O OBn b. BH3¥THF; H2O2, NaOH H O OBn HO H O OBn 23 Me O E F G c. LiOH, MeOH, H2O O O E F G PivO TBSO E F G R O O D O O [Ni II/Cr II coupling] D O O a. KH, CS2; MeI H H Me d. 2,4,6-Cl3C6H2COCl, H H Me PivO H H H Me H b. nBu3SnH, AIBN Me OBn Et3N; 4-DMAP OBn 21 Me OBn Me 24 (62%) 22 (64%) c. BH3¥THF Me d. TESOTf R = O O a. DIBAL-H (47%) O b. Ph3P=CHCO2Et a. DIBAL-H c. DIBAL-H b. DMP Me Me H Me Me H Me Me H TBS O OBn O OBn Me H H d. (+)-DET, Ti(OiPr)4 H O OBn c. (MeO)2P(O)CH2CO2Me, H O Me H Me O O E F G tBuOOH TBSO O E F G NaHMDS, [18]crown-6 TBSO E F G O C D O O C D O O D O O H H H Me e. SO3¥py H H Me d. CSA, MeOH H H Me O O H PivO H H H OBn f. CH =PPh e. KH TESO Me 2 3 H H Me OBn H Me OBn 27 (72%) CO2Me 26 (74%) 25

a. TBAF a. TBAF

b. PPTS Me Me H b. BrCH2COCl, py Me Me H Me H O OBn Me H O OBn c. TBSOTf H Me H c. (MeO) P H Me H O O E F G 3 O O E F G O d. O3; Ph3P d. iPr2NEt, LiCl B C D O O A B C D O O e. MeMgCl H H Me H H Me TBSO O H [intramolecular O O O H a. DIBAL-H f. DMP H H H OBn H H H OBn Me Horner-Wadsworth-Emmons Me b. BF3¥Et2O, Et3SiH 28 olefination] 29 (69%) c. Li, (l) NH3 (65%) d. pTsCl, py e. NaI TBSO OTBDPS f. TMS-imid. Me K g. Ph3P H O O J H EtS Me Me H AgClO4, H Me O OTMS Me Me H I a. nBuLi, HMPA, 3 H Me H H NaHCO3, Me H O OH Me Me H O H O O E F G EtS I SiO , 4 Å MS H EtS b. PPTS, MeOH O H 2 O O E F G H A B C D O O PPh I G OH H H Me 3 H A B C D O O (75%) O O H H H H H O O O H Me H Me H Me [hydroxy dithioketal H H H Me 2 31 cyclization] 30

O TBSO O HO a. Ph3SnH, AIBN [reductive desulfurization] Me Me K H b. PCC [oxygenation] K H O H O O H O c. TBAF J J [] H H H H d. DMP Me Me H I Me Me H I Me H O Me H O O (42% overall) H O O H a. CH =NMe I H Me H O H H Me 2 2 O O O H O E F G H E F G H b. HF¥py H A B C D A B C D O O O O H H H H Me O O O H Me (76%) O O O H H H H 38 H H H Me Me 1: brevetoxin B

Scheme 33. (Continued)

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 83 REVIEWS K. C. Nicolaou et al. a)

CO2Me Me O Me H OMe O H CO2Me CO2Me OMe O HN O N O O + OCH3 OMe H H OMe Br Diastereoselective Allylic OMe O OMe diazene epoxidation 2 3 OMe Friedel-Crafts rearrangement 1: tri-O-methyl dynemicin A methyl ester HO2C Pd-catalyzed OBz coupling O Me H H N MeO O O N O H N Stereoselective MeO Br imine attack H O 6 OH H MeO 5 4 OMe Pd-catalyzed Me Tandem coupling macrolactonization- Diels-Alder b) a. ClCO2Me, N N [Pd(PPh3)4] BrMg SiR3

SnnBu3 OTBS b. TBAF MeO Br MeO (12%) TBSO Me c. BrCH=CHCO2Me, 6 7 [Pd(PPh ) ] [Stille coupling] Me 3 4 [Sonogashira coupling] (85%) MeO2C OBz

Me O O Me H H H a. KOH H a. LiOH MeO O O N b. 4-DMAP, O b. py, MeO N 9 O O H O Cl Cl N H H Cl OBz O H H O COCl H (82%) H OH Cl MeO 4 8 5 OMe OMe (33%) Me a. CAN [oxidation of C-9] [tandem Yamaguchi b. MeAlCl2; then macrolactonization- O Diels-Alder] S NHNH2 O BzO HO O O(CH ) OBz O Me a. KHMDS, O Me H N 2 3 H OH H N H H MoOPh O H Me N O N b. NaBH N H O 4 OMe c. NaOMe [-N2] O H O d. (Cl3CO)2CO O O H H H H (ca. 50%) O O 9 OMe 10 OMe 11 [allylic diazene rearrangement] (ca. 80%) a. DMP b. NaClO2 (ca. 20%) c. LiOH d. CH2N2 e. NaIO4

CO2Me O Me H CO2Me O N CO2Me O Me OMe O (57%) H O OMe a. AgOTf O N CO2Me MeO O b. K CO O + H 2 3, OH Me2SO4 H OMe [Friedel-Crafts] OMe Br H 2 3 OMe OMe 11 a. MeAlCl2, Et SiH (82%) 3 MeO2C b. SOCl2

O Me CO2Me H Me O CO2Me O OMe O N H CO2Me OMe O N a. TMSOTf OMe COCl b. DDQ OMe H [Friedel-Crafts] H (51%) OMe OH OMe a. mCPBA 13 b. DBU, MeOH OMe 12 OMe

Me Me H [oxidation at a and H CO2Me deprotection at b] CO2Me OMe O HN OMe O HN O a. CAN O OMe b. Cs2CO3, MeI OMe H [reprotection of b] a H b (50%) 3 OMe O OMe OMe OH OMe 1: tri-O-methyl dynemicin A methyl ester 14 Scheme 34. a) Strategic bond disconnections and retrosynthetic analysis of tri-O-methyl dynemicin A methyl ester and b) total synthesis (Schreiber Scheme 35. a) Strategic bond disconnections and retrosynthetic analysis of [183] et al., 1993).[182] dynemicin A and b) total synthesis (Myers et al., 1995).

84 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS a) Ring stitching Their potent antitumor properties are due, at least in part, to Carbonylation their tubulin-binding properties, resembling both eleuthero- Me MOMO Me H [202, 203] CO2H H bin and taxol in this regard. While the structural OH O HN O CO2MOM O N + O similarities of the sarcodictyins to eleutherobin are apparent, OMe O OMe the correspondence of these molecules to taxol is not so H MOMO O H obvious.[203] Nevertheless, the excitement generated from OH O OH 1: dynemicin Oxidation 2 O 3 Diels-Alder their taxol-like properties, coupled with their scarcity, led to the launching of programs directed toward their total syn- thesis. Diels-Alder Stereoselective I Me3Sn imine attack + SnMe Imine formation TMS 3 It is noteworthy that the impetus for the chemical synthesis OH Me Me O MeI OH of these molecules in the 1990s was provided not only from O N O O N O [O] their structural novelty, but also from the desire to apply OH organic synthesis as an enabling technology for chemical H H 6 5 OTBS 4 biology. Thus, the total synthesis of sarcodictyins A and B, TBSO O OTBS Diastereoselective [204] epoxidation accomplished in these laboratories in 1997, went further than delivering the natural substances. It was applied,

b) a. K2CO3, H OH Me particularly in its solid-phase version (Scheme 41; see p. 88), OH Br O O b. NaH, ZnCl to the construction of combinatorial libraries for the purposes CHO 2 CAN O O O CHO Me [203, 205] CO Et (60%) H P 2 (90%) of biological screening. That complex natural products EtO CHO 7 OEt 8 9 H [Diels-Alder] 10 such as the sarcodictyins could be synthesized, at least OMe c. DIBAL-H OMe OMe d. Swern [O] (82%) O partially, on a solid phase is testament to the power and ∆ a. NH4OAc, HOAc, (87%) TIPS b. TBSCl, imid. potential of the recent advances in solid-phase chemistry.

TIPS Me Me Even more telling is the ability of synthetic chemistry at the O Me O a. OsO , NMO N Ph 4 N turn of the century to deliver combinatorial libraries of O BrMg b. Ph2C(OMe)2; N Ph complex natural or designed products such as those synthe- O O TBSCl, imid. OTBS O Cl O (80%) sized in this program and in the one described above for the OTBS TBSO O Ph 12 OTBS 11 OTBS 5 epothilones. Ph

(80%) Resiniferatoxin (1997)

TIPS TIPS A structural relative of phorbol ester,[206] resiniferatoxin (1 [207] Me Me Me in Scheme 43; see p. 92) was isolated from the E. resinifere H a. HCl H a. TBAF H R O R O R OAc N Phb. Swern [O] N Ph b. HCl N cactus species and exhibitsÐunlike phorbol but like capsai- c. Ph P, CBr [208] 3 4 Ph c. NaH, TBSCl cin Ðbinding affinity to the vanilloid receptor present in O Ph O OAc d. nBuLi d. Ac2O, Et3N [Corey-Fuchs (60%) sensory neurons. Besides its potential in biology and medi- OTBS homologation] 13 14 OTBS 15 OTBS (54%) OTBS cine, resiniferatoxin offers opportunities to the synthetic a. [Pd(PPh3)4], O chemist, among which is the application of new methods of b. NaH, O R= O (78%) synthesis to the construction of the molecule. The structure of TMS O Cl [selective triflation at C-5] c. NH3, MeOH resiniferatoxin contains an ABC ring skeleton with two trans a. Tf2O TMS d. mCPBA b. DMP O fusions. The C-ring carries five contiguous stereocenters, three c. CrCl R= Me 2 Me O Me of which bear hydroxyl groups which are engaged in a benzyl H [ H H R CO2MOM R OH R OH N removal] N a. AgNO3, NIS N O O 5 O orthoester system. Following their success with phorbol d. MgBr2, b. [Pd(PPh ) ], OMe OH 3 4 OH [209] Et3N, CO2 ester the Wender group at Stanford reported the total Me Sn H e. MOMCl H 3 H [210] SnMe 17 3 4 synthesis of resiniferatoxin in 1997. This synthesis f. CH2N2 16 (74%) OTBS OTBS OTBS (29%) (Scheme 43) brilliantly blends classical synthetic methods a. TBAF (60%) 2 b. PhI(OAc)2 with modern methodological advances in a strategy that LiHMDS Me [Tamura H stands as a hallmark to the progression of natural product CO2H Me MOMO homophthalic MOMO HN synthesis. Highlights include an intramolecular [3‡2] dipolar H anhydride O CO2MOM O N protocol] OMe O + cycloaddition reaction between an oxidopyryllium and a O H OMe -[CO2] terminal olefin to construct the BC framework, and a H MOMO O MOMO O 3 18 OH 19 -induced ring closure of an eneyne to form O a. PhI(OCOCF3)2, THF b. air, daylight the cyclopentane system (ring A).

Me Me H H CO2H CO2H OH O HN MOMO O HN O O Brevetoxin A (1998) MgBr2, Et2O OMe OMe H (15%) H Within the polluted ªred tideº waters often resides a more OH O OH 1: dynemicin MOMO O OH 20 powerful neurotoxin, and that is brevetoxin A (1 in Scheme 36. a) Strategic bond disconnections and retrosynthetic analysis of Scheme 42; see p. 90). Isolated from the dinoflagellate species dynemicin A and b) total synthesis (Danishefsky et al., 1996).[184] Ptychodiscus brevis Davis (Gymnodium breve Davis), breve-

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 85 REVIEWS K. C. Nicolaou et al.

a) HO 3 Spiro formation NH OMe a. 4 , AcOH, KCN MeO (53%) Esterification HO Me O b. Cs2CO3, allylbromide AcO S H O H OMe OMe Me N Me TBSO OTBS HO OH O N OAllyl AllylO Mannich bisannulation H O H Me O H Me O H OH HN CO2All N CO2All N a. DIBAL-H N 1: ecteinascidin 743 O H O H Fl = b. KF¥2H2O, MeOH O CN O CN OMe c. CH SO H 19 3 3 HO 20 TBSO OTBS [Mannich bisannulation] (55%) OH O OH Me O HO H H O S Fl AllO N NH NH2 OMe OMe NHCO2All H MeO a. Tf NPh, Et N, 4-DMAP O O MOMO Me 2 3 HO OH O O b. TBDPSCl, 4-DMAP 2 3 4 5 OH H AllylO H H c. MOMBr, iPr NEt H Me 2 Me N Me d. [PdCl2(Ph3P)2], nBu3SnH N CO2All N e. formalin, NaBH3CN N O H O H H f. Me Sn, [PdCl (Ph P) ],LiCl O CN 4 2 3 2 O CN b) OMOM a. nBuLi, OMOM OMOM a. CH3SO3H OBn TBDPSO 22 (55% overall) HO 21 TMEDA a. nBuLi b. NaH, Me b. DMF Me CHO Me CHO [position-selective O O b. MeI BnBr angular hydroxylation] O (87%) (64%) (86%) a. (PhSeO) O O O O O 2 O (68%) S O O O O b. TBAF 6 7 8 9 c. EDC¥HCl, 4-DMAP, 2 CO2All N H NH OBn O OMe MOM OMe O O a. piperidine Me OMe MOMO Me O O Me BOPCl; AcOH, 9 O OMe O H Tf2O, DMSO; iPr2NEt; tBuOH; AcO S H OH O OH H H OMe b. [Pd(PPh ) ] OMe (Me2N)2C=NtBu O HO 3 4 Me Me CO2All CO2All OMe O O OH N Me [deprotects ]; Ac2O N Me OMe Et3N/HCO2H 10 11 12 (93%) O 13 N (79%) N H O [tandem quinodimethane formation,O H (PhO)2P(O)N3, [-N2] O CN deprotection and cyclization] O H CN Et3N 23 O 24 OBn O OBn O [Curtius O S Fl a. nBu3SnH, [PdCl2(Ph3P)2] Me OMe rearrangement] Me OMe (70%) O O NHCO All b. O , DBU 2 Me N N OMe [-N2] OMe O C O O N H O HO 25 O 15 O N O 14 NH OMe MOM OMe (93%) BnOH N MeO O HO Me O O Me a. 5 AcO S H AcO S H OBn O [Rh(cod)-(R,R)-dipamp}] BF OBn O O H b. CF3CO2H O H 4 H Me c. AgNO - H O Me Me OMe Me OMe N Me 3 2 N Me O H2 O N N HN O OMe HN O OMe (high yield) [asymmetric O O O hydrogenation] O H H O H OH O H CN O O OBn (97%, 96% ee) OBn 16 17 1: ecteinascidin 743 26

BF3¥Et2O, H2O

O OH O OBn O a. BF3¥Et2O, 4Å MS O Me H Me H b. H2, Pd/C NH (73%) NCO2Bn O O O 3 O 18

Scheme 37. a) Strategic bond disconnections and retrosynthetic analysis of ecteinascidin 743 and b) total synthesis (Corey et al., 1996).[186]

toxin A was structurally elucidated in 1986.[211] With its ten erated from lactones with appropriate appendages to afford fused ring structure and its twenty-two stereocenters, breve- cyclic diene systems[213] suitable for a cycloaddition toxin A rivals brevetoxin B in complexity, but as a synthetic reaction with (24 !26 in Scheme 42). This target it arguably exceeds the latter in difficulty and challenge method provided the crucial turning point in solving the because of the presence of the 9-membered ring. Indeed, with problems associated with the 7-, 8-, and 9-membered rings of rings ranging in size from 5- to 9-membered, all sizes in the target and opened the gates for the final and victorious between included, brevetoxin A can be considered as the drive to brevetoxin A. ultimate challenge to the synthetic chemist as far as medium- sized ring construction is concerned. After a ten-year Manzamine A (1998) campaign, our group reported the total synthesis of brevetox- in A (Scheme 42) in 1998.[212] As in the case of brevetoxin B, Manzamine A (1 in Scheme 44; see p. 93) is a sponge- this program was rich in new synthetic technologies and derived substance (genera Haliclona and Pellina) with potent strategies, which emerged as broadly useful spin-offs antitumor properties. Disclosed in 1986,[214] the structure of (Scheme 42c). Amongst the most important synthetic tech- manzamine A, and those of its subsequently reported rela- nologies developed during this program was the palladium- tives,[215] attracted a great deal of attention from synthetic catalyzed coupling of cyclic ketene acetal gen- chemists. The interest in the manzamines as synthetic targets

86 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS a) Suzuki coupling a) Olefin metathesis/ O Epoxidation O Epoxidation cyclorelease S S S S HO N TBSO N HO N HO N O O O Me Me O Me Me O OH O OTBSO O 2 O OH O O OH O 1: epothilone A 1: epothilone A 2 Aldol reaction

Hetero Diels-Alder reaction S I Me O O BnO S S N H O TBSO H HO Me Me O N N OMe 4 O OH 5 O Me Me Me O Emmons-type Me homologation Esterification O O OMe OH O OTBSO TPS Me Aldol reaction 5 3 4 6 O OTBSO 3

S b) a. DHP. PPTS a. nBuLi, b) a. Li2CuCl4 , O b. TMSÐ ÐLi Ph2(O)P a. TBSCl, imid. TMS N 8 MgBr BF ¥Et O b. NaI, acetone 9 3 2 b. NIS, AgNO3 HO Br TBSO I S c. MOMCl, iPr2NEt c. Cy2BH, AcOH I Me (98%) b. O3 ; Me2S OH Me Me Me Me O d. PPTS, MeOH d. PhSH, BF3¥Et2O (85%) N 7 8 TBSO 10 e. Swern [O] O e. Ac2O, py Me O f. MeMgBr OMOM (34%) a. (+)-Ipc2B(All) a. O3; Ph3P 6 g. TPAP, NMO 7 O 4 H b. TBSOTf b. NaClO2 Me CO H (36%) (73%) (84%) 2 O O O OTBS O OTBS 11 12 6 a. TiCl4,MeO 10 BnO BnO a. DIBAL-H Me Me H a. LiAlH4 H S S S BnO b. CSA O O b. Ph3P=C(Me)CHO (+)-Ipc2B(All) OTMS Me b. Et2Zn, CH2I2 Me O N (88%) N (96%) N O (87%) EtO2C Me Me Me (85%) Me Me [hetero Diels-Alder 13 14 OH 5 reaction] O OH 9 5 11 a. 1,4-butanediol, NaH b. Ph P, I , imid. NIS, MeOH 3 2 NaHMDS; 10 Cl c. Ph3P O O O a. TBSOTf BnO a. nBu3SnH, AIBN BnO (>90%) I PPh3 (>70%) b. DDQ b. TPSCl, imid. H TBSO HO MeO O 15 16 17 c. Swern [O] c. HS(CH2)3SH, TiCl4 Me I Me S S (78%) (61% overall) OTBS Me Me Me Me TPSO S TPSO S OH Me CO2H a. HF¥py O OTBS (ca. 95%) 14 13 12 6 b. Swern [O] a. Ph3P=CHOMe O (59%) b. pTsOH LDA ZnCl2 O c. Ph3P=CH2 d. PhI(OCOCF3)2, MeOH HO (ca. 90%) S (two diastereoisomers) a. 9-BBN, 4; [PdCl2(dppf)], [Aldol reaction] H Me CO2H Me TBSO Cs2CO3, Ph3As TBSO N 18 O OTBS O b. pTsOH OMe O 4 Me Me (ca. 80%) DCC, 4-DMAP, 5 [esterification] [Suzuki coupling] O OMe TPSO O O 15 3 TPS (64%) PCy3 O Cl [Aldol macrocylization] a. KHMDS Ru b. HF¥py, py (47%) S Cl Ph S PCy3 O a. Dess-Martin [O] c. TBSOTf HO N HO N S b. HF¥py S [olefin metathesis c. O O O reaction] O HO N TBSO N Me Me (52%) O O O O O O O O 3 TBS TBS 19 Me (41%) Me O OH O OH O O TFA TBS 4 products [2 from the aldol reaction and (91%) 1: epothilone A 2 2 from the olefin metathesis reaction, ratio 3:3:1:3] CH2Cl2 Scheme 38. a) Strategic bond disconnections and retrosynthetic analysis of epothilone A and b) total synthesis (Danishefsky et al., 1996).[190] O S O O S

HO N Me CF3 HO N

O (85%) O was heightened by a hypothesis put forward by Baldwin et al. Me Me [5:1 mixture of in 1992 for their biosynthesis.[216] By early 1999 two total O OH O diastereoisomers] O OH O 1: epothilone A 2 [217, 218] [219] syntheses of manzamine A and evidence supporting chemistry employed to synthesize the biosynthetic hypothesis had been reported. combinatorial libraries Baldwins intriguing hypothesis for the biosynthesis of the Scheme 39. a) Strategic bond disconnections and retrosynthetic analysis of manzamine alkaloids postulates four simple starting materials epothilone A and b) total synthesis (Nicolaou et al., 1997).[194, 197] and an intramolecular Diels ± Alder reaction as the key process to assemble the polycyclic framework (see Scheme 45). The first total synthesis of manzamine A ap- a photoinduced [2‡2] cycloaddition reaction, a Mannich peared from the Winkler group in 1998,[217] proceeded through closure, and an intramolecular N-alkylation to assemble the ircinal (2 in Scheme 44), itself a natural product, and involved polycyclic skeleton. In early 1999 the Baldwin group provid-

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 87 REVIEWS K. C. Nicolaou et al.

Martin et al. in 1999 (Scheme 46; see p. 94)[218] on the other hand involved an intramolecular Diels ± Alder reaction and two olefin metathesis ring closures to construct the pentacy- clic framework of the target molecule. All three approaches

a) R' R'

O O Me Me H Me trans-Ketalization H Me Cleavage O O OH H O R'' H O 2 Me Me R''' Me Me R''' 1 3 manipulations

Ester or carbonate R' formation OH O Me Linker Me H Me H Me Loading 6 O O + H OH H O Me Me Resin Me Me OTIPS OTIPS 5 7 4 b) a. TIPSOTf OH OTES b. LiHMDS Me Me Me Me H OTES c. Dess-Martin [O] H OH d. Et3N¥3 HF CHO (65%) H H O OH Me Me Me Me OTIPS 8 9

H2, [Rh(nbd)(dppb)]BF4 (>80%) OAc OH Me a. Ac2O, py Me Me Me H HO OH H b. PPTS, 4 11 O O c. Dess-Martin [O] H O O (85%) H OH 4 Me Me Me Me OTIPS 12 OTIPS a. 1,4-butanediol, 10 NaHMDS O NaH Cl 14 13 (>95%) I PPh3 b. Ph3P, I2, OAc imid. OAc Me Me H Me c. Ph3P H Me (>90%) O O

H H O L O O Me Me 4 3 Me Me OTIPS OTIPS 15 15 a. NaOMe b. LG 1 (>81%) O L = O R O c. TBAF 16 1 R1 R O O Me Me Me Me H a. LG R2 18 H O O b. PPTS, H O R3 HO R3 19 H O L Me Me Me Me OH 20 O (42-86%) 17 2 a. (PhO)2P(O)N3, R a. Dess-Martin [O] DEAD, Ph3P b. NaClO 2 b. Ph3P, H2O c. DEAD, Ph P, 3 (49-73%) 5 HO 4 c. LG R R or 25 21 DCC, 4-DMAP, d. PPTS, HO R3 H N 4 2 R 26 1 22 1 R d. CSA, R O HO 3 O Me R Me H Me 23 H Me (46-70%) O O Scheme 40. a) Strategic bond disconnections and retrosynthetic analysis of H O R3 H O R3 X [199] Me Me O Me Me eleutherobin and b) total synthesis (Nicolaou et al., 1997). HN chemistry employed to synthesize 24: X = O, N 4 27 5 R combinatorial libraries R ed[219] evidence for their hypothesis through synthetic studies Scheme 41. a) Strategic bond disconnections and retrosynthetic analysis of culminating in the synthesis, albeit in low yield, of kerama- a solid-phase sarcodictyin library and b) total synthesis (Nicolaou et al., phidin B (Scheme 45; see p. 93). The synthesis reported by 1998).[205]

88 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS are elegant in their conception and brilliant in their execution, guished chapter to the annals of total synthesis and placed the demonstrating once again the ability of organic synthesis to glycopeptide antibiotics on the list of conquests of synthetic swiftly respond to new challenges posed by novel structures organic chemistry. from nature. CP Molecules (1999) Vancomycin (1999) CP-263,114 and CP-225,917 (1 and 2, respectively, in Vancomycin (1 in Scheme 47 and 48; see p. 95), a repre- Scheme 49; see p. 98), isolated from an unidentified sentative of the glycopeptide class of antibiotics,[220] was by Pfizer scientists in 1997,[229] inhibit squalene synthase and isolated in the 1950s and used for over four decades as a ras farnesyl transferase, and as such, represent important new weapon of last resort to combat bacterial disease. Isolated[221] leads for cholesterol-lowering and anticancer drugs. Nature from the actinomycete Amycolatopsis orientalis, vancomycin molded within these structures an exotic display of delicate finally yielded to structural elucidation in 1982.[222] Within a and rare functionalities that beckoned to synthetic chemists few years, it became the subject of synthetic investigations, worldwide. The total synthesis of these compounds was finally primarily as a consequence of its novel molecular architec- accomplished in 1999 in our laboratories after a relentless ture, important biological action and medical applications, campaign through a daunting synthetic labyrinth plagued with and intriguing mechanism of action. As a synthetic target, manifold and unexpected obstacles.[230] This total synthesis is vancomycin offered a unique opportunity to synthetic chem- retrosynthetically blueprinted in Scheme 49 a. A critical ists to develop new synthetic technologies and strategies. disassembly maneuver called upon an intramolecular Among the most intriguing structural features of the molecule Diels ± Alder reaction to simplify the bicyclic structure 6 of were its two 16-membered bisaryl ether macrocycles and its the CP molecules to the open-chain 7. Although this 12-membered bisaryl ring system, each of which is associated retrosynthetic analysis serves as a conceptual overview of the with an atropisomerism problem. The attachment of the two synthesis, it should be noted that it is actually the culmination carbohydrate moieties onto the heptapeptide aglycon system of several unsuccessful retrosyntheses by which the conver- added to the challenge presented by this target molecule. sion of ketone 6 into the CP molecules was planned. By 1998 two groups, that of D. A. Evans[223] and ours,[224] had Commencing with dimethyl malonate (8), the synthesis of reported independent total syntheses of the vancomycin the CP molecules proceeded smoothly through several aglycon and by early 1999 the first total synthesis[225, 226] of intermediates and finally yielded the desired acyclic precursur vancomycin itself appeared in the literature followed by 7 stereoselectively (Scheme 49 b). When compound 7 was [227] another report of the aglycon synthesis by the Boger group. treated with Me2AlCl in dichloromethane at 20 8C, Emanating from these laboratories, the total synthesis of complete conversion to 6 through a Lewis acid catalyzed vancomycin is summarized in Scheme 48 (see p. 96). During intramolecular Diels ± Alder reaction was observed within the vancomycin campaign, a number of new methods and two minutes. The formidable task of stereoselectively instal- strategies were designed and developed, among which, ling the remote stereocenter at C7 was addressed by utilizing perhaps, the triazene-driven biaryl ether synthesis[228] is the dithiane chemistry (6 !15). The reason for such a high level most prominent. The strategy employed modern asymmetric of diastereoselectivity (ca. 11:1) could possibly be a conse- reactions for the construction of the required quence of a shielding effect of the CP skeleton. Indeed, the building blocks, which were then assembled into appropriate surprisingly close proximity of this side chain to the rest of the peptides and cyclized to form the desired framework. While molecule was quite apparent throughout the synthesis. The the two biaryl ether macrocycles were formed by the triazene- stage was now set for the installation of the fused maleic driven cyclization, the bisaryl ring framework was assembled anhydride moiety. The synthesis of this delicate moiety was in by a sequential Suzuki coupling and a macrolactamization itself a great challenge due to unique environment surround- reaction. Finally, the sugar units were sequentially attached ing ketone 15. The development of novel chemistry to onto an appropriately protected aglycon derivative, which construct the anhydride was a result of persistence in the afforded a protected vancomycin system in a stereoselective face of several failed strategies.[231] Thus, ketone 15 was manner from which free vancomycin was obtained. smoothly converted to the enol triflate followed by palladium- The Evans synthesis of vancomycins aglycon, shown in catalyzed carboxymethylation and exchange of the dithiane Scheme 47,[223] featured the stereocontrolled construction of for a dimethoxy ketal leading to the unsaturated ester 16. the amino acid building blocks and assembly to the heptapep- After reduction with DIBAL-H, a Sharpless hydroxyl- tide backbone through a vanadium-mediated CC bond directed epoxidation of the allylic alcohol led to epoxide 17 forming reaction to construct the 12-membered biaryl ring selectively (ca. 10:1). Introduction of this electrophilic species system and two nucleophilic aromatic substitutions activated allowed for the placement of an additional carbon atom with by o-nitro groups to form the two bisaryl ether macrocycles. the correct for the ensuing cascade sequence. The synthesis of vancomycins aglycon[227] by Boger et al. This carbon atom, in the form of a , was added to

(Scheme 50; see p. 100) is distinguished by extensive studies epoxide 17 using Et2AlCN and proceeded with complete to determine the activation energy required to atropisomerize regio- and stereospecificity (see 17b). It was after consider- each macrocycle, thereby allowing selective atropisomeriza- able experimentation that we discovered that it was possible tion of the AB ring system in the presence of the COD to convert diol 18 in one synthetic operation. Thus, selective framework. These total syntheses added yet another distin- mesylation of diol 18, followed by treatment with base and

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 89 REVIEWS K. C. Nicolaou et al.

a) Me H O Me Lactonization A B O H Conjugate addition Dithioketal cyclization O C O O Me Me H H Horner-Wittig coupling Me Me Epoxide opening D H H PPh2 OHC H H O H H OTBS Lactonization O O O Me H H H B C D O O OTBDPS H OH O OMe EtS E F H TPSO G I J O Me H H O O E EtS H O H H H H O H O O H G H I J TrO H H H H O Dithioketal cyclization O O Epoxide opening H H H bis-Lactonization 1: brevetoxin A 2 3

b) OH OBn OBn OBn H H H H a. TBAF a. TBAF; TPSCl, imid. a. 9-BBN; H2O2 e. (+)-DET, Ti(iPrO) HO OH TESO O 4 O b. PPTS 15 steps b. TBSOTf b. SO ¥py, DMSO O J I J 3 tBuOOH O I J c. O3; NaBH4 (17%) [6-endo hydroxy c. MeO C f. SO ¥py HO O O TBSO O 2 PPh3 3 TBSO O d. PPTS, H epoxide cyclization] H H d. DIBAL-H H H OH g. CH2=PPh3 TBDPSO TBDPSO TBDPSO Me2C(OMe)2 4: D-mannose (86%) 6 7 5 (55%) e. TBAF (76%) OTBS O a. PPTS, MeOH O TBS Ph H OBn OBn b. TBSCl, imid. OBn a. SO3¥py, DMSO OBn SEt H H Ph O PPh3I SEt H H Me H H H Me H H H O O O O O 11 EtS O c. TPAP, NMO b. MeO2C PPh3 O O Me Me H EtS H I J H I J d. EtSH, BF ¥Et O H I J H I J nBuLi O 3 2 O c. H2, Raney Ni (W2) O O O O O e. SO ¥py, DMSO O O O O H H H (88%) H H H 3 H H H d. LiAlH4 H H H HO 12 10 (73%) 9 e. TBDPSCl, imid. 8 TBDPSO TBDPSO TBDPSO (81%)

O a. TBAF O O 2 f. K2CO3, MeOH OHC Ph H OBn Ph H OBn a. Zn(OTf)2, EtSH H OTBS SEt H H Me H H g. TPAP, NMO b. AgClO4, NaHCO3 O O b. TBSCl EtS O Me H H O O AlMe O O O c. mCPBA 3 c. Ac2O h. EtSH, Zn(OTf)2; H G H I J H G H I J EtS G H I J [hydroxy dithioketal [acting as PPTS O O O O d. H2, Pd(OH)2/C O O cyclization] H H H Lewis acid and H H H i. SO3¥py, DMSO H H H ] e. TBSOTf (74%) 14 3 13 (48%) TBDPSO (94%) TBDPSO TBDPSO

Me H Me a. Hg(OAc) ; Me H Me a. LiOH O OH O OTBS 2 Me H Me O OTBS O HO 12 steps Li2[PdCl4], CuCl2,O2 b. Li, NH3 (l) C C B C D b. NaHMDS, Tf2NPh MeO2C c. 2,4,6-Cl3C6H2COCl HO OH (18%) BnO OBn CO2Me BnO OBn CO2Me H H c. IZn(CH ) CO Me, H H d. HF¥py O O a. H2, [RhCl(Ph3P)3] OH 2 2 2 H H O O b. H2, 10% Pd/C [Pd(PPh3)4] e. [PhC(CF3)2O]2SPh2 15: D-glucose 16 17 18 (68%) (94%) (70%) Me Me Me nBuLi; Cu-C≡CnPr a. KHMDS, (PhO) P(O)Cl a. hexylborane; Me H Me Me H Me 2 Me H Me O O O TfOCH2CH2OBn b. Me3SnSnMe3, [Pd(Ph3P)4] H2O2, NaOH B C D B C D B C D b. TBDPSCl, imid. (65%) O O (65%) O O (69%) O O c. H2, Pd/C H H OBn H H H H OMe BnO SnMe3 O 21 Me3Sn 20 O 19 d. PPTS, OMe

a. PivCl, 4-DMAP Me Me Me Me H Me c. CSA, MeOH Me H Me a. TPAP, NMO Me Me O H H O H O H O O d. TrCl¥4-DMAP b. Ph3P=(CH2)3CO2Me H B C D H B C D OAc H O TBDPSO B C D e. Ac2O, 4-DMAP TBDPSO c. LiOH TBDPSO a. (PhO)2P(O)Cl, O O O O H H f. TFA O H H OH O O E KHMDS HO H PivO H d. 2,4,6-Cl3C6H2COCl PivO H H H H H H 22 (91%) 23 [Yamaguchi lactonization] 24 b. nBu3SnCH=CH2 (70%) c. O2, hv TBSO Me Me Me Me OH Me Me H a. TBSCl, imid. Me H Me Me H O H H O H Al(Hg) O H a. DIBAL-H O b. TPAP, NMO O O H B C D H H D O b. TrCl¥4-DMAP O B C D B C c. [{Ph3PCuH}6] OH [reductive TBDPSO O TBDPSO O O E TBDPSO E O E c. TPAP, NMO; H H (65% overall) O O cleavage of O H H H H H H H H H H DIBAL-H H endoperoxide] H PivO 27 PivO 26 PivO 25 (70%) Me TBSO O Me a. nBuLi, 3 H Me Me Me H Me PPh2 Me O H H a. CH2=C(OMe)CH3, POCl3 Me H b. KH, DMF TBDPSO B O H H O H O b. Al O O c. AcOH-THF H B C D OH 2 3 H B C D O C O H Me TBDPSO O E c. MsCl TBDPSO OMe H O H H H O O E (49%) H H H H D H H d. Ph2PLi; H2O2 H H TrO H O TrO O H 28 (78%) TrO 2 H E H OTBS EtS Me H H O O Me a. HF¥py Me OH H G H I J H b. Dess-Martin [O] H EtS O Me TBDPSO Me 29 O O B B H H H A O H c. CH =N(Me) I O O O 2 2 H a. AgClO , NaHCO O C O C 4 3 H Me [Eschenmoser's salt] Me H H H b. mCPBA TBDPSO D H (52%) MeO D H H O O H H O O H c. BF3¥Et2O, Et3SiH H OH H d. Dess-Martin [O] E F H E H OTBS Me H H F Me H H e. NaClO O O O O 2 O O H H f. CH2N2 H G H I J H G H I J O (48%) 1: brevetoxin A O O 30 O O OTBDPS H H H H H H

Scheme 42. a) Strategic bond disconnections and retrosynthetic analysis of brevetoxin A, b) total synthesis (Nicolaou et al., 1998),[212] and c) key synthetic methodologies developed in the course of the total synthesis (Nicolaou et al., 1998).[212]

90 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

c) Cyclic ketene acetal phosphates for the construction of medium and large cyclic ethers finally acidic workup afforded the maleic anhydride 5. The course of this dizzying domino sequence undoubtedly Ph O involves formation of the unprecedented carbocyclic imino H O O O Me3Sn O butenolide 21 (a proven intermediate and new chemical H O [Pd(PPh3)4], LiCl (89%) O O Ph O Ph entity isolated for the first time) whereupon facile tautome- OTBS OTBS rization to the electron rich and easily oxidizable 2-amino- 22 occurs. nBu Sn Ph O 3 Stepwise oxidation of the furan 22 followed by nitrogen O KHMDS Ph Ph O H (PhO) POCl H [Pd(PPh ) ], LiCl H O O 2 O O 3 4 O O extrusion leads to anhydride 5. The remarkable efficiency O O H H P(OPh)2 H (90%) O (96%) with which this reaction takes place (56% overall yield, seven transformations in one operation) is a testament to tri-n-butyl(2-ethoxyvinyl)tin hexamethylditin the utility of tandem reactions in organic synthesis. After [Pd(PPh3)4], LiCl [Pd(PPh3)4], LiCl tri-n-butyl(1-ethoxyvinyl)tin (81%) [Pd(PPh ) ], LiCl some brief manipulations, the stage was set (75%) 3 4 (84%) for the aplication of another cascade reaction. It was found Ph O Ph O Ph O H H OEt H that treatment of 23 with Dess-Martin-periodinane in O O O O O SnMe3 O OEt H H H refluxing led to the desired g-hydroxy lactonol in 63% yield. This tandem reaction was based on the simple ring ± chain tautomerization of hydroxy and per- Enol-phosphates and thioketal-mediated etherification for the [232] construction of the EFGH ring skeleton of brevetoxin A mitted the crucial oxidation to take place. OH The next key step involved the one-carbon elongation of O H O a. KHMDS, O H O H O O O Ph (PhO) P(O)Cl Ph Ph 2 a. O2, TPP H intermediate 4 by the classic Arndt ± Eistert reaction. O O O OH H b. nBu3SnCH=CH2, H b. H2, H Because of the extreme steric hindrance of the carboxylic [Pd(PPh3)4] Lindlar's cat. acid derived from 4, a new method specifically tailored for

Ph O the preparation of hindered a-diazoketones was devel- H H [233] O H H O oped. This new synthetic technology was based on the O a. AgClO4 O H H H H H expected extreme reactivity of the acyl mesylate species. In E F O O H EtS O H b. Ph3SnH, AIBN H O Ph EtS the event, acyl mesylate 25 successfully activated the H G H O OH O H hindered carboxylic acid for attack by diazomethane thus H leading to the requisite a-diazoketone for the ensuing Wolff Novel stereocontrolled synthesis of the nonacene ring system of brevetoxin A. Conformational-reactivity effects in nine-membered rings rearrangement. The final stage in the synthesis required conversion of indole 27 into the CP molecules. Although the S H 1,4-diiodobutane I I conversion of 2 into 1 was known, the counterintuitive O THF, ∆ S O S O H H O O conversion of the seemingly robust 1 into its hydrated O O O H O O H counterpart 2 appeared unlikely. We reasoned that LiOH O O Li H H might be useful for effecting this conversion by virtue of its

O unique and reactivity. Not only did this LiOH- O H mediated cascade reaction succeed in hydrolyzing the indole O amide of 27 to the corresponding carboxylic acid, it was also O H able to induce ring opening of the stable pyran motif to provide 2 directly. The conversion of 2 into 1 using acid Synthesis of N-heterocycles via lactam-derived ketene aminal phosphates. catalysis proceeded smoothly, thus completing the total Asymmetric synthesis of cyclic amino acids synthesis of the CP molecules. In summary, the first total syntheses of these (racemic)

N SiMe3 compounds was accompanied by a plethora of fundamental Boc discoveries, cascade reactions, and new synthetic technolo- N N CO2Me Boc CO Ph gies among which the following are, perhaps, most notable a. Me3SiCH2MgCl 2 Ni0 b. CO, Pd0 (see Scheme 49 c, d): 1) the design and execution of a h. PhZnBr MeOH Pd0 cascade reaction involving no less than seven steps travers- ing through previously unknown chemical entities to con- 0 c. nBu Sn g. Et3Al, Pd O 3 struct the fused maleic anhydride moiety;[231] 2) the enlist- N O P(OPh)2 0 N H Pd N Boc R Boc ment of another tandem sequence predicated on the ring ±

f. nBu3Sn chain tautomerization of hydroxy ketones to sculpt the g- d. Me3SnSnMe3 0 Pd Pd0 hydroxy lactone moiety onto the bicyclic skeleton;[232] e. Me3Si CuI, Pd0 3) development of a mild and effective method for the construction of extremely hindered diazoketones using acyl [233] N mesylates (Scheme 49d, top); 4) a new paradigm for the N N SnMe Boc 3 Boc Boc two-step construction of strikingly complex natural-pro- SiMe 3 ductlike heterocycles from commercially available chem- Scheme 42. (Continued) icals (Scheme 49 d, middle);[234] 5) a new method for the

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 91 REVIEWS K. C. Nicolaou et al.

Scheme 43. a) Strategic bond disconnections and retrosynthetic analysis of resiniferatoxin and b) total synthesis (Wender et al., 1997).[210] one-carbon homologation of hindered aldehydes powderÐat least since the Aztec era in parts of Mexico and (Scheme 49d, bottom);[235] and 6) the daring and counter- Central America[236]Ðits complex structure was not elucidat- intuitive conversion of the structurally robust CP molecule 1 ed until 1973 by the groups of M. P. Cava, P. Yates, and D. E. into its hydrated CP derivative 2 passing through a multiply- Zacharias.[237] The first total (enantioselective) synthesis of charged intermediate in yet another cascade sequence.[230] The this molecule was finally completed in 1999 by E. J. Corey and total synthesis of the CP molecules stands as an instructive co-workers and featured a rapid assembly of the aspidophy- example of how total synthesis can act as a driving force for tine core via a novel cascade sequence.[238] The hallmark of the the discovery and development of new concepts and methods synthesis is the tandem sequence uniting dialdehyde 3 and in chemistry. indole 2 in a one flask tandem operation. Also notable is the conversion of acid 9 into lactone 11 by attack of the species 10. It is impressive that all four stereocenters (three Aspidophytine (1999) quatenary) of 1 are derived from one chiral center secured For over 25 years aspidophytine (1 in Scheme 51; see p. 101) early in the synthesis using the CBS reduction (see p. 58). has remained an unanswered challenge for organic synthesis. Aside from developing a breathtaking new domino sequence Best known for its use as an anticockroach/insecticidal to assemble the aspidophytine skeleton, this work raises the

92 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS a) a) CHO Pictet-Spengler cyclization NH N Photoaddition N N H

H H OH N N SN2 Displacement N

N N Mannich closure N exchange H H CHO

H H O H H 1: manzamine A N N N N HN HN OH N N H H N 5 1: manzamin B 2 3 NH2 N H H N Boc O 3 4 2 b) O N H H O N (99%) BocN [Michael addition] N N Boc N HO H 2 3 O 4: keramaphidin B OH 5 O H 7 8 hν H H O N NH3 H O NH3 N HO HO O H H H H O H 8 H BocN 7 BocN O BocN O O 6

N b) a. pTsOH, N N HO H H H I O 8 OTHP 7 Ph3P OH 6 b. KHMDS, 11 9 N CHO py, AcOH a. HCl N 10 b. pTsCl (50%) H CO2Me (77%) c. NaI O O d. NaBH4 H H a. TBSCl H H BocN BocN BocN b. LHMDS, a. mCPBA MeOCOCN N N HO N H N N N b. Tf2O N H (20% overall) c. NaBH4 H d. MsCl (98%) HO e. DBU, C6H6 TBSO 6 12 9 10 (62%) 11 MeOH/ DBU, + pH 7.3 CO Me CO Me CO2Me 2 2 C6H6 a. TBAF H H OH b. pTsCl H H OH H H N N N BocN a. mCPBA BocN N [Diels-Alder] c. TFA b. NaOMe H d. iPr2NEt (69%) N N H N H N (0.2-0.3%) H e. Lindlar's cat. 14 (76%) 13 12 N N TBSO TBSO 5 3 4: keramaphidin B a. DIBAL-H b. Dess-Martin [O] (75%) Scheme 45. a) Strategic bond disconnections and retrosynthetic analysis of manzamine B and b) biomimetic total synthesis of keramaphidin B (Bald- CHO H [219] HN N N N win et al., 1998). H H H H OH N TFA, 4 H H OH DDQ H H OH N (50%) N [239] N [Pictet-Spengler] strain found in a soil sample collected in Malawi. This H (58%) N N molecule was found to display a very strong affinity for H H cyclophillin A (20-fold higher than cyclosporin A) and sig- 15 16 1: manzamine A nificant immunosuppressive activity (10-fold lower than Scheme 44. a) Strategic bond disconnections and retrosynthetic analysis of cyclosporin A). Its mode of action seems to differ from other manzamine A and b) total synthesis (Winkler et al., 1998).[217] cyclophillin binders such as cyclosporin A and thus it raises a high interest for the understanding of immunosuppression mechanisms. standards for the concise synthesis of extremely complex Sanglifehrins chimeric structure is formed by a unique alkaloids from simple starting materials. [5.5]-spirolactam fragment, linked to a 22-membered macro- lactone ring that contains two unusual amino acid residues (piperazic acid and meta-) as well as l-valine. Its Sanglifehrin A (1999) unprecedented molecular features as well as its novel bio- Sanglifehrin A (Scheme 53; see p. 104) was originally iso- logical properties made sanglifehrin A a prime target for total lated by a team of Novartis scientists from an actinomycete synthesis. The first total synthesis of sanglifehrin A was

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 93 REVIEWS K. C. Nicolaou et al.

a) Everninomicin 13,384-1 (1999) Pictet—Spengler cyclization CO2Me H Everninomicin 13,384-1 (Ziracin; 1 in Scheme 52; see N N H [241] H p. 102), a member of the orthosomicin class of antibiot- N Tandem Stille/ [242] H H OH O Diels-Alder ics and currently in clinical trials, is a promising new N reaction NBoc + weapon against drug-resistant including methicillin- N Organolithium Ring-closing H addition resistant Staphylococci and vancomycin-resistant Streptococ- olefin metathesis NH 2 N [243] Wittig H ci and Enterococci. Isolated from Micromonospora carbo- 2 3 1: manzamine A nacea var africana (found in a soil sample collected from the banks of the Nyiro River in Kenya), everninomicin 13,384-1

Br possesses a novel oligosaccharide structure containing two CO2Me CO2Me sensitive orthoester moieties, a 1,1'- bridge, a Br N O nitrosugar, several b-mannoside bonds, and terminates with + NBoc NBoc O two highly substituted aromatic esters.[244] 5 OTBDPS NH OTPS 6 As a consequence of its unusual connectivity and polyfunc- OTBDPS 4 OTBDPS tional and sensitive nature, everninomicin 13,384-1 constitut- ed a formidable challenge to organic synthesis. After several

b) CO2 Na Br a. LHMDS, CO2 generations of glycosylation and protecting group strategies b. NaBH (COCl)2; O 4 CO2Me NBoc c. Na CO 2 3 N OH CO Me N had been explored and new synthetic methodologies were Boc 2 OTBDPS (95%) TBDPSO NBoc 7 O developed, the total synthesis of everninomicin 13,384-1 was 6 Br 5 [245] OTBDPS finally completed in our laboratories in 1999. Highlights of + Et3N 4 TBDPSO NH OTBDPS this synthesis include: 1) the tin acetal-based stereocontrolled (79%) [246] SnnBu3 formation of the 1,1'-disaccharide linkage; 2) the 1,2- [tandem Stille- (68%) [Pd(Ph3P)4], Diels-Alder] , ∆ migration of selenophenyl groups leading to selective or- MeO OMe thoester formation based upon a modification of SinayÈ's CO2Me [allylic oxidation] CO2Me H H H a. DIBAL-H a. CrO3 method;[247] and 3) the stereocontrolled formation of eight b. HCl H b. Dess-Martin [O] H H N + N c. Swern [O] N c. HC(OMe)3,H O unique glycoside bonds using a variety of techniques including d. PPh =CH O d. Li 3 2 N NBoc NBoc sulfur-, selenium-, and ester-based neighboring group partic- [stereocontrolled [double Wittig] O addition] (30%) ipation. 9 (26%) 2 OTBDPS OTBDPS Additional examples of natural products synthesized in the PCy Cl 3 8 Ru [olefin metathesis (67%) twentieth century are given in Figures 5 ± 8 (see pp. 105 ± Cl Ph reaction] [350±458] PCy3 108), but even this listing does not do justice to the [olefin metathesis reaction] science of those whose brilliant contributions are not men- MeO OMe MeO OMe a. N N PCy H Cl 3 tioned here as a result of the limited space available and Ru H H a. KOH, MeOH H H OH Cl Ph H H OH unintentional oversight. For a more complete picture, the N N PCy3 N b. Et3N, O b. HCl reader should consult the primary literature. O O N Cl N c. DIBAL-H N d. Dess-Martin [O] H O (75%) e. TFA,H 10 11 N NH2 1: manzamine A f. DDQ 4. What Have We Learned from a Century of (ca. 5% overall) Organic and Natural Product Synthesis? Scheme 46. a) Strategic bond disconnections and retrosynthetic analysis of [218] manzamine A and b) total synthesis (Martin et al., 1999). During the twentieth century, we have come, through the electronic theory and understanding of the nature of the and mechanistic insights, to adopt the arrow to achieved in our laboratories in 1999.[240] As indicated in designate bond making and bond breaking. During this Scheme 53, the two main domains of the molecule were revolutionary period for organic synthesis, we have also come assembled by an intermolecular Stille coupling. The con- to understand and use conformational analysis, and to use struction of the sensitive iodomacrocycle fragment was pericyclic reactions, anions and cations, as well as performed by an esterification, two peptide couplings, and and radicals in controlled ways to form and break chemical eventually a regioselective intramolecular Stille coupling. The bonds. The Woodward and Hoffmann rules brought under- synthesis of the spirolactam moiety involved the use of standing and generalization to pericyclic reactions such as the Paterson aldol reactions to establish the first five stereo- Diels ± Alder reaction, the photoinduced [2‡2] cycloaddi- centers, while the spirolactam fragment was formed by tions, and the various 1,3-dipolar cycloaddition reactions. intramolecular cyclization of a suitable 9-hydroxy-5-keto- We have discovered new continents of chemistry and an amide precursor. The developed chemistry demonstrated amazing number of synthetic reactions based on heteroatoms once again the power of the Stille coupling reaction in the and organometallic reagents and catalysts. Among the former synthesis of complex molecules and opened the way for the are the chemistries of nitrogen, phosphorous, boron, sulfur, construction of possible libraries for biological screening and silicon. came a long way from purposes. the sodium and Grignard reagents to cuprates and titanium

94 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

SNAr-driven ring closure a) OH NO2 NO2 Cl O O F F OH VOF3, BF3¥Et2O, OH HO Cl OH AgBF , TFA; Cl O 4 Cl O O then NaHB(OAc) H O H H 3 O N NHMe O NHTfa O NHTfa N N N N N O [95:5 ratio of O N H H H H atropisomers] H O H O O NH OBn NH MeHN OH O NH O (65%) MeHN

HO NH2 formation OMe OH OMe MeO OMe MeO OMe OH 1: vancomycin aglycon HO OAllyl 5 19 TBSO OMs a. NaHCO3 S Ar-driven b. 20, HOAt, HATU, collidine (55%) N OAll NO ring closure 2 c. HF¥py O OH F HO2C NHBoc NO 20 OAll 2 OAllyl OH NO2 F HO + O OMs HO OMs Cl Na2CO3; H O H O O H Boc then PhNTf2 N N N N HO HO Cl O NH2 Cl H HO N Me [ca. 5:1 ratio of H H O H H O O O H atropisomers] O N O N NHBoc NHBoc OHN O (79%) O N O N O H NHDdm 3 H NH O Addition of oxygen NH MeHN OH MeHN H MeHN OTf OBn functionality for oxidative biaryl coupling OBn BnO OMe 2 OMe MeO OMe MeO OMe Atropisomerization 22 21

a. Zn, HOAc OPiv a. AlBr ; then EtSH NO2 NO2 3 OAll b. NaNO2, H3PO4,Cu2O O OMs b. MeOH, 55 °C F F HO OMs c. [PdCl2(dppf)]¥CH2Cl2, [atropisomerization and OH Et3N, HCO2H HO transoid to cisoid (54%) HO Cl Cl Cl O d. PivCl isomerization] O H O H O NHTfa e. TFA; then TFAA O N NHTfa [>95:5 ratio of O N O N atropisomers] OPiv NHBoc (68%) O N O O H N H H O OMs H NH OBn NH NH O MeHN MeHN MeHN OH HO Cl 4 Peptide bond formation 5 H O H OMe N N MeO OMe OMe O NHTfa OMe MeO OMe H MeO OMe H O (P)-23 HN Oxidative biaryl coupling O OAll MeHN b) NO2 O OH OH O O O F OH HO HO NO2 a. nBu2BOTf, Et3N Cl O N + OH H O H a. BnBr, Cs2CO3 (M)-24 b. TMGA [N source] N N Br 3 O b. LiSEt F NH2 Bn c. LiOOH HO H H O c. AllBr, Cs2CO3 6 7 (50%) 8 N3 OHN d. LDA O e. LiOH O O O O O a. H2, Pd/C; MeHN (65%) KHMDS; then Boc O N3 2 NHBoc OBn O N then TsN3 O N b. LiOH MeHN OBn OAll BnO 25 NO (78%, 80% de) c. MeNH2, 2 O OH Bn Bn EDC, HOBt F 3 MeO OMe MeO OMe (91%) MeO OMe HO Cl OH 9 10 11 HOAt, EDC O O Boc H O H H Cl F (86%) N N N NMe F N N H H Cl NO2 Cl NO2 H F O H O O O a. Boc2O; then O O HCO H, H O O NH O O O 2 2 2 13 NO2 b. LiOOH O O N MeHN NHDdm Sn(OTf)2 O N (46%) NCS O HO O OBn 26 Bn OBn HN N BnO Bn S Boc O a. CsF [ca. 5:1 ratio of atropisomers] 12 14 15 OAll Cl b. Zn, AcOH O O c. HBF4, tBuONO, CuCl, CuCl2 c) O NO O Boc 2 (62%) HO Cl OH NH2 F TMSEO NMe O O Boc a. EDC, HO H O H H O OH N N N NMe HOBt N N O O H H H b. Ph P-H O 17 H Boc O H O O NHDdm 3 2 N N 16 HO N Me O NH O (53%) H a. HOBt, EDC O b. TBAF O MeHN NHDdm (72%) NHDdm OBn 8 OBn OH 3 BnO Cl 27 O O

NO2 a. N2O4 OH HO2C NHBoc HO Cl F b. LiOOH O O c. [Pd(PPh ) ] morpholine H O H H OBn 3 4 , N N N NHMe TFA OH d. Pd/C, 1,4-cyclohexadiene N N 11 Cl H H H O e. TFA O H O O O NHTfa O NH O a. EDC, OMe O N HOBt 18 H (24%) NH OBn HO MeHN NH2 b. Li2CO3 d. EDC,HOBt OH c. TFA e. TFA; then OH 1: vancomycin aglycon TFAA HO OMe 15 (54%, 6 steps) MeO OMe 5 Scheme 47. a) Strategic bond disconnections and retrosynthetic analysis of vancomycin aglycon, b) key methodology for unnatural amino acid synthesis, and c) total synthesis (Evans et al., 1998).[223]

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 95 REVIEWS K. C. Nicolaou et al.

HO a) BnO O O Cl HO HO H N B(OH) NHBoc OH 2 OH HO a. [Pd(Ph3P)4], O Na2CO3 TBSO MeO OMe (56% plus 28% O O O 7 + (M)-atropisomer) N3 EtO C Glycosidation NHBoc 2 NH2 Triazene MeO BnO O 13 Cl b. (PhO)2P(O)N3, OMe O O DEAD, Ph3P (95%) OMe c. LiOH (99%) MeO (P)-25 OH HO Cl I O O H O H H OMe a. EDC, HOAt N N N NHMe b. TMSOTf (78%) N N N H H H 10 O H O O Cl N Cl O NH O OH N OH Br Br HO TBSO NH2 TBSO OH OH 1: vancomycin O H 18 , EDC, HOAt O HO N NH2 OTBS EtO2C N NHBoc EtO2C N F H (85%) H O O O AcO AcO N3 OH NHCbz AllocO AcO 3 3 OC(NH)CCl3 BnO BnO OMe OMe N OMe OMe Triazene-driven ring closure N Triazene-driven ring closure MeO 27 MeO 26 N Cl O O a. CuBr¥SMe2, b. TBAF py, K2CO3 c. Et3P-H2O d. LiOH TBSO Cl OTBS [1:1 mixture of N N O O Boc H O H H atropisomers] (68%) N N N N N NMe (67%) N N N N O Br H H H H O Br O O O NH O HO TBSO Cl Macrolactamization Cl a. FDPP 4 O H b. TBSOTf BnO H O H NHDdm N N OMe HO2C N NHBoc c. TMSOTf N H NH2 OMe Peptide bond formation (70%) H MeO O O H O Suzuki biaryl coupling NH NH2 (M,P)-28

BnO BnO a. PPh =CH H O 3 2 OMe OMe b) b. AD-β (96% ee) BnO OH nBuLi, BnO O OMe N OMe c. nBu2SnO; B(OMe)3; MeO MeO then BnBr then HCl B(OH) N 29 N Cl (75%) (55%) O Br HO MeO OMe MeO OMe MeO OMe 24 5 6 7 OTBS EDC, HOAt TBSO Cl O O O O O Boc (86%) O H H H NMe NH2 NHBoc NHBoc N N N HO MeO MeO N N H H H a. TMSCl, MeOH a. MeI, K2CO3 O H O O b. Boc2O, K2CO3 b. I2, CF3CO2Ag NH O (93%) (84%) I OH OH OMe BnO NHDdm 8 9 10 OMe OMe 30 OH OBn Cl OH a. BnBr, K2CO3 MeO b. O O a. TBSOTf CuBr¥SMe2, py, K2CO3 N P , KOH b. H2, Pd(OH)2/C [3:1 mixture of (EtO)2 OEt N (P,M,P):(M,M,P)] c. AA c. SO Cl N 2 HO 2 2 TBSO (74%) R (41%, 87% ee) (76%) O O O NHCbz NH2 R1 11 EtO2C 12 EtO2C 13 TBSO Cl OTBS O O Boc H O H H N N N NMe NH2 NH2 a. NaNO2, HCl; N N a. Br2, AcOH , KOH N H H H b. LiAlH Br Br O H O O 4 b. PCC N NH O (93%) c. PPh3=CH2 N Br Br (61%) BnO NHDdm O OMe HO OMe OMe 14 15 MeO N N 16 (P,M,P)-4: R1=Cl, R2=H N a. Ph3P, H2O N ∆ N b. Boc2O, Et3N N [atropisomerization] Br Br c. TBAF a. AD (95% ee) d. TEMPO, NaOCl Br Br b. TBSCl, imid. (M,M,P)-4: R1=H, R2=Cl c. DPPA, DEAD, c. H , Pd/C (52%) a. NaI, I2, TMSCl 2 Ph3P b. MeMgBr, iPrMgBr; then d. MeI, Cs2CO3 TBSO e. Dess-Martin [O]; KMnO HO C NHBoc (66%) B(OMe)3; then H2O2 4 2 N3 f. AlBr3 18 BnO 17 BnO (34%) (21-35%) β a. NaN BnO a. AD- (92% ee) 3 OH b. NosCl, Et N OH b. SnCl2 OH Cl 3 O O (81%) (53%) EtO EtO OH ONos NH2 HO Cl O O 19 CO2Et O 20 O 21 H O H H N N N NHMe O N Cl H H c. NH2 O H O O MeO HO a. EDC, O 23 TBS O NH O 21 HOBt O NHDdm HO b. LiOH c. EDC, HOAt O O Boc NH2 H OH O Boc N NMe (92%) d. TBSOTf 26: vancomycin aglycon NMe HO N OH e. H2, Pd(OH)2/C HO HO O O H f. SO2Cl2 22 g. LiOH 24 (46%) DdmHN

Scheme 48. a) Strategic bond disconnections and retrosynthetic analysis of vancomycin aglycon, b) key methodology for unnatural amino acid synthesis, and c) total synthesis of vancomycin (1) (Nicolaou et al., 1999).[224±226]

96 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

c) OH reagents. Of particular importance are the recent advances Cl O O made in catalysis using transition metals both for the

HO Cl OH formation of carbon ± carbon bonds and for asymmetric O O H O H H N N N NHMe synthesis. The retrosynthetic analysis principles introduced N N H H H O H O O by Corey revolutionized strategy design in total synthesis, O NH O while the many metal-catalyzed processes discovered during HO NH2 the second half of the century facilitated the construction of OH OH 26: vancomycin aglycon complex molecules in impressive ways. Most prominent HO a. TBSOTf c. CbzCl (36%) among these catalytic processes are the various palladium- b. CH N d. Al O ¥KF 2 2 2 3 catalyzed reactions for carbon ± carbon bond formation[248] [249] OH and the olefin metathesis reaction made synthetically Cl O O useful by the Grubbs[250] () and Schrock[251] (mo- TBSO Cl OTBS lybdenum) catalysts. During this period, we have also O O Cbz H O H H [252] N N N NMe witnessed the introduction of as important tools N N H H H [253] O H O O for organic synthesis and of catalytic antibodies as O NH O promising and useful reagents for synthetic and mechanistic MeO NH2 27 studies, and the application of genetic engineering to total TBSO OTBS [254] OTBS a. BF ¥Et O synthesis. O TBSO 3 2 AcO b. nBu3SnH, [Pd(PPh3)4] AcO In terms of stereochemical control, a journey through the AllocO (70%) OC(NH)CCl 3 3 AcO twentieth century reveals the dramatic progress from stereo- AcO chemically random reactions to stereocontrolled processes, OTBS first carried out in a reliable manner on cyclic templates and

HO O later on acyclic systems. Acyclic stereoselection, both via

O internal chiral auxiliaries and external catalysts, brought us Cl O O not only to diastereoselective processes, but also to asym-

TBSO Cl OTBS metric synthesis. Particularly impressive have been the O O Cbz H O H H N N N NMe advances in asymmetric catalysis by which many building N N H H H O H O O blocks and final targets can nowadays be synthesized at will. O NH O Classical optical resolution methods that characterized the MeO NH2 early total syntheses are being replaced by stereoselective OTBS 28 OTBS processes delivering only the desired in high F TBSO BF ¥Et O (84%) O 3 2 enantiomeric excesses. Such processes include the Hajos ± NHCbz AcO Wiechert cycloaldol/ catalyzed by opti- 2 AcO [255] AcO AcO cally active amino acids, the Knowles asymmetric hydro- CbzHN OTBS genation process for the industrial production of l-DOPA O employing soluble rhodium catalysts carrying chiral phos- O O phane ,[256] the Takasago process for the production of O Cl O O l- via an asymmetric catalytic amino ± enamine isomerization employing a rhodium ± BINAP catalyst,[257] the TBSO Cl OTBS O O Cbz H O H H Noyori asymmetric catalytic hydrogenation of ketones ((S)- N N N NMe N N [258] H H H or (R)-[RuBr2(binap)] catalyst), the Katsuki ± Sharpless O H O O O NH O asymmetric catalytic epoxidation ((l)-(‡)- or (d)-()-diethyl [259] MeO tartrate/Ti(OiPr) catalyst), the Sharpless dihydroxylation 29 NH2 4 OTBS reaction (OsO catalyst),[165] the Corey oxazaborolidine- OTBS a. HF¥py c. Raney N: 4 TBSO b. K2CO3 d. LiOH catalyzed reduction of ketones,[92] and the Shibasaki car- (65%) bon ± carbon bond forming reactions employing bimetallic HO HO HO catalysts.[260] H2N OH Cascade reactions in which several transformations are O carried out in one reaction vessel in tandem have assumed O O increasing importance in total synthesis.[261] Such cascades can O Cl O O be defined as one-pot sequences involving fleeting intermedi-

HO Cl OH ates, each of which leads to the formation of the next until a O O H O H H stable product is formed, or pathways marked with distinct N N N NHMe N N H H H intermediates that can be isolated if so desired, but which are O H O O O NH O allowed to proceed to the next stage until the desired product

HO NH2 is obtained. By expanding the definition of cascade reactions OH OH 1: vancomycin one can include the various one-pot reactions in which a HO number of reagents and/or components are added sequen- tially to form a final product without isolation of intermediate

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Scheme 49. a) Strategic bond disconnections and retrosynthetic analysis of the CP molecules (1 and 2) and b) total synthesis (Nicolaou et al., 1999).[230] c) New cascade reactions: the anhydride cascade, which features the first use of a highly unstable 2-aminofuran in the synthesis. The g-hydroxylactonal cascade was developed as a mild method to construct the precursor to the fused g-hydroxylactone moiety, the g-hydroxylactonal. The pyran rupture cascade traverses through a sequence of intermediates, including the tetraanion C. d) New synthetic technologies. (For further information see the text.)

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5. The Impact of Total Synthesis

In tracing the evolution of organic synthesis and total synthesis to its present state, it is instructive to also consider its impact on other scientific disciplines and on society. Simply stated, this impact has been enormous and it boils down to profoundly shaping our world by providing the myriad synthetic materials we have around us today. To be sure, total synthesis has been aided by its own appeal and advances, but also by developments in analytical and purification techniques and spectroscopic methods.

5.1. Driving and Testing the State-of-the-Art in Organic Synthesis

As the flagship of organic synthesis, total synthesis often guides and demands new synthetic methods and strategies. It also becomes the testing ground where new technologies and strategic concepts are tested and judged for their applicabil- ity, efficiency, and practicality. In a way, total synthesis provides the tough and real challenges to new synthetic methods, often before they are passed over to those who use them extensively in their daily research and/or for their manufacturing needs. Indeed, the total synthesis of complex natural products is frequently given as the reason for the need to develop a new synthetic method to achieve a goal unattainable by existing methods. Furthermore, newly ap- pearing synthetic methods become convincingly useful once they have been successfully applied to total synthesis. Examples here include the Diels ± Alder reaction,[266] the Wittig reaction,[267] the hydroboration reaction,[268] the Corey dithiane reaction,[269] the Sharpless asymmetric epoxidation reaction,[259] the various palladium-catalyzed coupling reac- tions,[270] the olefin metathesis reaction,[271] and last but not least, the multitude of protecting groups available to the synthetic chemists.[272] It is important to note that total synthesis not only drives organic synthesis forward in terms of synthetic technologies and strategies, but also frequently leads to fundamental theories and concepts. Thus, it was within the realm of the total synthesis of natural products that the theories of conformational analysis[273] (Barton and Hassel), the Wood- ward and Hoffmann rules,[98] and the Corey principles of retrosynthetic analysis[3, 4, 34] crystallized. Today our desire and ability to make contributions to biology and medicine is driven to a large extent by total Scheme 49. (Continued) synthesis, which can deliver not only scarce natural products but also combinatorial libraries of related substances for biological evaluation purposes. compounds or work-ups. Examples of cascade reactions Total synthesis not only dictates and demands the inven- include the Robinson synthesis of tropinone,[16] the biomi- tion and development of new synthetic strategies, but it also metic synthesis of steroids,[262] the endriandric acid synthe- provides opportunities for the discovery of such methods and sis,[112] the Ugi three-component reaction,[263] the Vollhardt techniques. Such discoveries are made either through rational synthesis of ,[358h] the synthesis of the CP molecules and pursuit or simply by serendipity. Indeed, some of the most the many radical-based[264] and palladium-catalyzed[265] tan- dramatic and influential discoveries of our century are fruits dem sequences for the formation of polycyclic carbon frame- of serendipity. A remark made by Pasteur: ªSerendipity, works. however, appears to be most generous to those positioned to

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S Ar driven ring closure a) OH N OMe Cl O O O OH NHCbz TBSO [Pd2(dba)3], (o-tolyl)3P HO Cl OH Cl MEMO Na2CO3, toluene O O O H O H H H + B(OH)2 N N N NHMe N (88%) N N MeO2C N NHBoc H H H H O H O O O MeO OMe O O NH (M)-15 16 Br HO NH2 Peptide bond formation OMe OH OH 1: vancomycin aglycon OMe E = 30.4 kcal molÐ1 OMe HO a O OH O OH 120 °C TBSO Cl TBSO Cl SNAr driven ring OMe NO2 O O closure F H 3:1 H O OH N N MeO2C N NHBoc MeO2C N NHBoc H H HO Cl + OH O O Boc O Ð1 O H O H H Ea = 25.1 kcal mol N N N NMe NHCbz NHBoc HO N H H MeO NHCbz O H O O MEMO OMe H NH Macrolacta- 2 3 OMe OMe OMEM mization NC MeO (M,P)-16 MeO (M,M)-16 MEMO OMe a. nBu4NF-HOAc OMe MeO b. LiOH (50%) Suzuki biaryl coupling c. H2, Pd/C d. EDC, HOBt OMe NO2 OH b) O F

OMe OMe OMe HO Cl OH O H O Boc BnO OBn BnO OBn H O BnO OBn N N H NHBoc N NMe a. Dess-Martin [O] N AD, BocCl H HO b. NaClO2 O H O H O NH (64%, >99% ee) HO (76%) NHCbz HO2C NHCbz NC 3 4 5 6 MEMO OMe ZrClCp2 OMe OMe MeO 17 N NO OMe a. 2 a. HCO2H NO N (58%) 2 MeO F HO OH b. EDC, HOBt F 9 TBSO OMe NO2 b. TBSOTf O OH F O (45%) MeO2C NH2 HO2C NHBoc OH 8 10 7 HO Cl O O Boc O H H H NMe O O N N N N N a. Boc2O H NH2 NHBoc H H HO b. Br2-py¥HBr HO O H O O c. NaH, MeI NH (43%) NC Br MEMO OMe 18 OH OMe OMe 11 12 MeO CsF, DMSO (65-75%, 6:1 ratio of atropisomers) c)

NO2 NO F 2 OMe OMe NO2 F O O TBSO HO OH TBSO HO Cl OH a. EDC, O O Boc MeO C NH O H H O H H 2 2 HOBt N N N NMe 10 7 N N MeO2C N NHBoc N O b. TBSOTf H H H H EDC, O H O O HOBt O NHBoc (79%) NH HO (91%) NC Br MEMO OMe OMe Br 13 OMe 19 K2CO3, CaCO3 MeO OMe 12 (50-60%) a. H2. Pd/C; tBuONO, d. Dess-Martin [O] OMe OMe HBF4, CuCl2/CuCl e. NaClO NO2 b. CF CONMeTBS 2 OH OH 3 O O c. f. TMSCHN2 (9-11%) O ° g. H2O2, K2CO3 TBSO 140 C TBSO B Br , R h. nBu NF-HOAc O O O 4 H 1:1.1 H i. AlCl , EtSH N N Boc2O 3 MeO2C N NHBoc MeO2C N NHBoc H H OH O O Cl Ð1 O O Ea = 26.6 kcal mol Br Br HO Cl OH O O OMe a. H , Raney Ni OMe H O H H (M)-14 R = NO 2 (P)-14 N N N NHMe 2 b. tBuONO N N (87%) H H O H (M)-15 R = Cl c. CuCl-CuCl2 H O O O NH O

HO NH2 OH OH 1: vancomycin aglycon HO Scheme 50. a) Strategic bond disconnections and retrosynthetic analysis of vancomycin aglycon, b) key methodology for unnatural amino acid synthesis, and c) total synthesis (Boger et al., 1999).[227]

100 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

wishing to pursue the science of drug discovery and develop- a) Oxidation ment process. Cationic NH2 CHO cascade reaction N The pharmaceutical industry applies the knowledge gained OHC O O O + to discovering and manufacturing new drugs for the benefit N MeO O of society. That medicinal and combinatorial chemists have MeO N H OMe Me Me so many tools at their disposal today in their quests for huge OMe 2 3 1: aspidophytine numbers of novel and diverse small molecules is primarily b) the result of the contributions of total synthesis and of O O OAc CeCl3, organic synthesis as a whole. A reminder of the importance Br THF Br a. R-CBS reduction Br TMS b. Na(Hg), MeOH TMS of chemical synthesis as one of the two main arms of the drug TMS MgBr a. LDA, TBSCl, MeO c. Ac2O, Et3N, 4-DMAP -78oC, then ∆ discovery processÐthe other being identification of appro- 4 5 (75%) 6 (82%) b. iPrOH, EDC priate biological targetsÐwill help appreciate total synthesis (57%)

NH2 CHO within a larger perspective. Just as advances in molecular CH3CN, then TFAA, 0°C; NaBH CN OHC biology facilitate drug discovery today by allowing the 3 a. OsO , NMO + O 4 TMS O elucidation of the human genome and proteome, so does b. NaIO4 MeO N O 3 7 OiPr progress in total synthesis, which enables the construction of OMe Me 2 (56%) the molecules needed to bind and modulate the function of N H O N N O H O disease-associated biological targets. OiPr OiPr OiPr The challenging and rewarding features of total synthesis MeO N: MeO N MeO N H invite competition, which, like in any other human endeavor, TMS TMS OMe Me OMe Me OMe Me is both inevitable and healthy. Fortunately, and unlike many H+ other sciences, the creative nature of organic and natural N H O N H O N H O product synthesis allows equal opportunity for brilliant Ð NaOH BH3CN OH OiPr OiPr contributions to all practitioners, whether they are the first (66%) to finish or the last. And there are many things to discover MeO N H MeO N H MeO N H Me Me OMe Me 9 OMe 8 OMe and invent in this science; only our imagination is the limit.

K3[Fe(CN)6], NaHCO3 OH 6. Future Perspectives O N N a. OsO4 N (81%) b. Pb(OAc)4 O O O O O The science and art of organic synthesis attracts many who (71%) MeO N H MeO N H MeO N H practice invention, discovery, and development of new Me Me 11 Me 12 OMe 10 OMe OMe synthetic reactions and reagents for wider use. Such new a. KHMDS, processes and engineered reactions are of paramount N PhNTf2 b. [Pd(PPh3)4], importance to research chemists and manufacturers of O O nBu3SnH (47%) chemical products including pharmaceuticals. Other synthet- MeO N H ic chemists adopt total synthesis as their main endeavor, with OMe Me 1: aspidophytine the aim of designing and executing elegant strategies toward complex targets. In judging such accomplishments, one has to Scheme 51. a) Strategic bond disconnections and retrosynthetic analysis of aspidophytine and b) total synthesis (Corey et al., 1999).[238] give credit not only to the beauty and efficiency of the strategies and tactics, but also to the value of the exercise in providing access to the target molecule and its analogues for, detect and exploit the accidental,º is worthy of remembering. usually but not always, biological studies. Yet, there are Serendipity will, no doubt, continue to be part of our science. others who attempt to combine target-oriented synthesis with the discovery and development of new synthetic technologies. And finally, there are those who aim to incorporate biology into their total synthesis programs as well as methodology 5.2. Drug Discovery and Development development, thus elevating natural products to opportunities for creative science in total synthesis, synthetic methodology, While it is wonderful that total synthesis has made such and chemical biology. great leaps from the beginning of the twentieth century, its All sub-disciplines of organic natural product synthesis are greatest impact has been on the drug discovery and develop- to be equally respected as important to the advancement of ment process.[274] Indeed, the evolution of the drug discovery knowledge and the benefit of humankind. Furthermore, one and development process parallels closely that of total can choose which of these dimensions he or she will adopt in synthesis. The two disciplines must be considered in unison, their research programs, for all three have their place in for they are very synergistic and complementary. Academic science. Indeed, the beauty of total synthesis lies in the research focuses on organic and natural product synthesis, challenge and opportunities that it provides to make creative which provides highly relevant basic knowledge and offers and useful contributions to many other disciplines. It is, superb education and training to young men and women therefore, up to the practitioner to imagine new directions and

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Scheme 52. a) Strategic bond disconnections and retrosynthetic analysis of everninomicin 13,384-1 and b, c)important synthetic methods; b) orthoester formation by 1,2-migration of the phenylselanyl group followed by glycosylation (I !II !III !IV), and ring closure after syn-elimination (V !VI !VII !VIII); c) stereoselective construction of 1,1'-; d) synthesis of the building blocks and completion of the total synthesis of everninomicin 13,384-1 (Nicolaou et al., 1999).[245]

102 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

NH Me Me OMe OBn MeO O O O Me O O nBu O O CCl a. TMSOTf MeO 3 PMBO O O O O O F Sn G D E b. MeI, NaH + HO F G H O nBu O A2 c. NaOH, MeOH PMBO O AllO OBz O O O O Me HO OMe BnO OBn OBn OAc OAc d. BnBr, NaH OAll OBn 28 4 Cl3C NH 5 (55%) 31 OMe OBn a. DDQ OMe OBn (55%) b. TIPSOTf BF3¥Et2O O O OAll O O 3 OCA c.[RhCl(Ph P) ]; OsO Me Me OMe OBn O O F G 3 3 4 F G O Me d. nBu SnO; CACl O MeO O OAll 2 4 OH PMBO O O O PMBO OMe TIPSO OMe O O (69%) D E F G H O OBn 38 OBn 39 O A2 HO O O OMe O O Me BnO OBn OMe OBn OTBS a. 34, SnCl , OR OR OBn PhSe 2

O O 3 OPMB Et2O 48: R = Ac a. NaIO , MeOH OH H 4 (90%) 49: R = H K2CO3, MeOH ∆ F G b. K2CO3, b. O 4 O O MeOH c. nBu4NF TIPSO OMe (75%) BnBr, NaH d. BzCl, E3N OBn 40 Me Me OMe OBn O O (75%) O Me MeO O O O RO O O D E F G H O OMe OBn O A2 OTBS HO O O OMe O O O O O a. nBu4NF, THF Me BnO OBn OBn OBn OBn F H OPMB b. Martin G (73%) O O O sulfurane 50: R = PMB DDQ BzO OMe 51: R = H c. K2CO3, MeOH OBn 41 52: R = CA (CA)2O, Et3N OMe OBn O O O (79%) H2, 10% Pd/C, EtOAc a. TBSCl, NaH F G H OPMB Me Me OMe OH O O (54%) O O Me b. OsO , NMO O O MeO 4 HO OMe CAO O O O c. nBu SnO; BzCl O O 2 OBn 42 D E F G H O O A2 HO O O OMe O O OMe OBn HO OBz Me HO OH OH OH OH O O O a. Dess-Martin [O] 53 F G H OPMB b. Li(tBuO) AlH (78%) O 3 O O a. TBSOTf TBSO OMe c. NaOH, MeOH (55%) b. K2CO3, MeOH OBn 43 Me Me OMe OTBS O O O Me OMe OBn HO OH MeO O O O HO O O O O O D E F G H O a. CH2Br2, NaOH O A2 F G H OPMB HO O O OMe O O b. DDQ O (66%) O O Me TBSO OTBS c. NaH, ArC(O)F TBSO OMe OTBS OTBS OTBS 44 d. nBu4NF, THF OBn 3

Me Me OMe OBn O O O Me OMe O Me Me OMe OTBS O O O O O Me O O O Cl MeO O O O O HO O H O B C F O O F G A A1 E G H O O 2 D F A HO O O BnO Me O O O 2 OMe BnO OBn O BnO SePh HO O O OMe Me TBSO OTBS OBn 5 Cl OTBS OTBS OTBS NO2 O A Me 2 3 O Me OMe O SPh Me O OTIPS O (70%) D + E SnCl2, Et2O O OTBS MeO OTBS Ph Me Me OMe O Me Me OMe OTBS O O OPMB OH O O O Me Cl O MeO O O O 23 26 O B O C O O A E G H O 1 D F A Ph HO O 2 O a.Tf2O, BnO Me O O OMe O O O BnO SePh Me (67%) 2,6-tBuPy Me TBSO OTBS MeO b. DDQ Cl OTBS OTBS OTBS O NO2 O O O A D E Me 54 HO O OTIPS Me OMe a. NaIO , MeOH (65%) 4 OTBS OTBS ∆ 45 b. Me Me OMe OTBS O O a. TPAP, NMO OMe O Me Me O Me pTsO MeO b. MeLi, Et O Me O O O O O O (74%) 2 Cl O O c. H2, 10% Pd/C HO MeO O E G H O O B C D F A d. pTsCl, py O O A1 O 2 D E O O O OMe O O HO BnO Me Me TBSO OTBS O OTIPS O BnO OTBS OTBS OTBS Me Cl OTBS OTBS NO2 55 46 O A Me a. H , 10% Pd/C, NaHCO Me Me a. LiI, DMF (75%) 2 3 Me OMe b. nBu4NF, THF PMBO MeO b. nBu3SnH O O (53%) D E c. nBu2SnO; Me Me OMe OH O O OMe O Me Me O Me HO PMBCl MeO O O O O OTIPS O O O O Me Cl O OTBS OTBS O B O C D E F G H O A1 O A2 47 O O O OMe O O Me Me HO OH a. nBu NF HO Me O HO Me 4 MeO OH OH OH PMBO Cl b. Ac2O O O (69%) NO2 c. nBuNH D E O A 2 HO Me d. CCl3CN O O Me OAc OAc Me OMe 1: everninomicin 13,384-1 4 HN CCl3

Scheme 52. (Continued)

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Scheme 53. a) Strategic bond disconnections and retrosynthetic analysis of sanglifehrin A and b) total synthesis (Nicolaou et al., 1999).[240] to constantly raise the bar to higher and higher expectations for minds of the twentieth century and its impact on society is the art and science of organic and natural products synthesis. paramount, if not fully appreciated by the general public. As Throughout its history the art and science of total synthesis we close the chapter of the twentieth century and move into has demonstrated its nature as an aesthetically appealing the twenty-first century many may be wondering of the fate of endeavor and as a scientifically important discipline. As a total synthesis. The best guides we have are history and the science and an art, it has attracted some of the most creative present state-of-the-art. They both speak volumes of the vigor

104 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

H O HO HO C Me OMe OH 2 MeO NMe2 Me N H H O OH H N OH H N N Me H O H H H MeO HO NH2 H N H H H H H OH MeO Me OH OH O O O O NH HO MeO2C MeO cortisone[351] [352] 6-demethyl-6 lysergic acid[353] OH NHAc N [Woodward, 1951] O -deoxytetracycline[356] [350] [Gates, 1952] [Woodward, 1954] [354] [355] quinine [Sarett, 1952] [Ginsburg, 1954] colchicine [Woodward, 1962] [Kuwajima, 1986] [Julia, 1969] [Woodward, 1944] [Morrison, 1967] [Ramage, 1976] [van Tamelen, 1958] [Echenmoser, 1961] [Muxfeldt, 1965] [Gates, 1970] [Fukumoto, 1990] [Kametani, 1969] [Szántay, 1965] [van Tamelen, 1961] [Oppolzer, 1981] [Nakamura, 1962] OH [Uskokovic, 1970] [Schwartz, 1975] [Rebek, 1984] [Stork, 1972] [Rice, 1980] [Scott, 1965] O [Taylor, 1972] [Ninomyia, 1985] [Kametani, 1975] [Woodward, 1965] [Hanaoka, 1982] [Evans, 1982] [Brown, 1980] [Martel, 1965] MeO [Fuchs, 1987] [Wenkert, 1982] O O OMe [Kaneko, 1968] Me [Parker, 1992] [Ninomiya, 1983] [Tobinaga, 1974] N [Overman, 1993] HO [Martin, 1987] [Kato, 1974] Me HN NH H [Mulzer, 1996] [Tanol, 1994] [Evans, 1981] galanthamine[357] O [Boger, 1986] H H [Magnus, 1987] [Barton, 1962] S CO H MeO [Banwell, 1992] [Kametani, 1969] HO 2 H [Cha, 1998] [Koga, 1977] [358] MeN N estrone biotin N cepharamine[359] OH OH [Torgov, 1963] [Quinkert, 1980] [Review[364]] O H H [Bryson, 1980] HO [Smith, 1963] [Inubushi, 1969] Me [Johnson, 1973] [Saegusa, 1981] [Kametani, 1972] OC [Cohen, 1975] [Ziegler, 1982] H [Wallace, 1979] eburnamine[382] HO OH Me [Danishefsky, 1976] [Jung, 1984] [Schultz, 1998] H H [Money, 1985] Me Me H Me [Harley-Mason, 1968] Me CO2H Me [Kametani, 1977] [Saxton, 1969] [Oppolzer, 1980] [Posner, 1986] gibberellic acid[366] OH [Rao, 1991] H Me [Schlessinger, 1976] [Vollhardt, 1980] [Winterfeldt, 1979] illudol[368] [Oyasawara, 1992] H [Corey, 1970] [Grieco, 1980] HO [Takano, 1985] [Mander, 1980] [Matsumoto, 1971] H H Me Me Me [Fuji, 1987] [Yamada, 1989] [Semmelhack, 1980] H [360] [Vollhardt, 1991] lupeol O O Me Me [Malacria, 1997] O H N OH [Stork, 1971] N N H Me Me O OH O [367] OMe O dendrobine OH H OH OH N H2N H O [Yamada, 1972] [361] N [Inubushi, 1974] fumagillol MeO N OAc H H O H H [Kende, 1974] [Corey, 1972] MeO C OH Me CO2Me 2 HN N [Kim, 1997] [Roush, 1978] OMe O OH OH MeO N OAc NH [Martin, 1991] [Sorensen, 1999] [363] H HN [Taber, 1999] vindoline R CO Me N NH [Williams, 1992] 2 [362] R = Me: [375] OH [Uesaka, 1994] [Büchi, 1975] daunomycinone vinblastine [Kutney, 1978] [375] OH [Sha, 1997] [Wong, 1973] [Hauser, 1981] R = CHO: vincristine [Ban, 1978] [370] [Kende, 1976] [Kimball, 1982] [Potier, 1976] saxitoxin OH [Danieli, 1984] [Swenton, 1978] [Reddy, 1983] [Kishi, 1977] H H [Langlois, 1985] [Kelly, 1980] [Vogel, 1984] OH [Rapoport, 1987] [Jocobi, 1984] Me [Kallmerten, 1980] [Rodrigo, 1984] Me OH S [Kuehne, 1987] [Braun, 1980] [Garland, 1988] HO OH N O O HO HO NH2 O CO H H O H 2 NH2 H Me O O HO O O [371] Me OH thienamycin X Me OMe NH [Christensen, 1978] [Shibasaki, 1985] OH [Hart, 1985] H [376] [Kametani, 1980] H H Me N NH Me ryanodol [Shiozaki, 1980] [Hiraoka, 1986] [Deslongchamps, 1979] [Hanessian, 1982] [Buynak, 1986] hirsutene[374] O [Evans, 1986] X = OMe: mitomycin A[369] [Ikegami, 1982] [Tatsuta, 1979] [Hua, 1985] [Shinkai, 1982] [Fleming, 1986] [Cossy, 1987] [369] HO [Georg, 1987] [Hudlicky, 1980] X = NH2: mitomycin C [372] [Yoshikoshi, 1982] [D. R. Little, 1981] [Lacroix, 1989] cytochalasin B CH2OH [Hatanaka, 1987] [Kishi, 1977] [Koga, 1982] [Mehta, 1981] [Sternbach, 1990] [Fukuyama, 1987] [Stork, 1978] Me [Grieco, 1984] [Ohno, 1988] [Greene, 1990] [Jacobi, 1996] [Magnus, 1981] [Ley, 1985] [Wender, 1982] [Rao, 1990] H [Ley, 1982] [Paquette, 1990] OMe [Cohen, 1992] Me HO [R.D. Little, 1983] O Me H [Curran, 1983] [Fukumoto, 1993] O MeO Cl O Me Me HO OH [Oppolzer, 1994] MeO [377] O MeO aphidicolin HO N Me H H Me [Trost, 1979] H CHO Me Me O O OMe H H [McMurry, 1979] O NMe2 Me [Corey, 1980] HO N Me HO O OH N O [Ireland, 1981] Me O Me HO H [380] [van Tamelen, 1983] O O Me Me MeO quassin MeO H [Bettolo & Lupi, 1983] O O N-methylmaysenine[373] [Grieco, 1980] O OAc Me [Tanis, 1985] OMe O [Watt, 1990] [Holton, 1987] carbomycin B[383] [Corey, 1978] [378] [Meyers, 1979] [Valenta, 1991] [Fukumoto, 1994] delphinine [Nicolaou, 1979] [Isobe, 1984] [Shing, 1998] [Iwata, 1995] [Wiesner, 1979] [Tatsuta, 1980]

Figure 5. Selected natural product syntheses from the twentieth century. of this art and science, and of its potential for further advances will demand new and sharper tools for organic synthesis. and contributions. For one, nature has not yet finished Fueled by these and other industries, the discipline of total revealing its secrets to us, and many more novel, and presently synthesis will be there to attract talented individuals as unimaginable, structures are destined to dazzle our eyes, practitioners and to deliver the new tools needed for yet boggle our minds, and challenge our creativity. Furthermore, higher efficiencies and selectivities. the state of the art is comparatively only in its early stages of Targeting more complex structures will demand more development in light of natures seemingly magical and effective reactions in terms of accomplishing bond construc- powerful biosynthetic schemes. To be sure, the competitive tions and functional-group transformations. The overall nature of the pharmaceutical and biotechnology industries efficiency has to be pushed higher and so does selectivity. and their drive to discover and produce new cures for disease Cascade reactions and other novel strategies will have to be

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Me Me Me OH Me Me Me Me HO O O O H AcO H H O Me O Me Me O OH OH O H MeO OH OH Me O Me O Me H Me Me O Me H O O O O O Me O O B O OH O H H Me O O OH O Me O Me Me Me O O [379] Me NH Me coriolin [365] O OH O [Danishefsky, 1980] quadrone OH [Ikegami, 1980] [Danishefsky, 1980] [Isoe, 1984] [391] O pleuromutilin [Tatsuta, 1980] [Helquist, 1981] [Iwata, 1985] O [389] Me Me [Trost, 1981] [Burke, 1982] [Wender, 1985] O compactin [Gibbons, 1982] [384] [Piers, 1985] O [Sih, 1981] [Boeckman, 1989] aplasmomycin [Mehta, 1982] [Kende, 1982] Me [Schlessinger, 1983] [Funk, 1986] [Hirama, 1982] [Corey, 1982] [Matsumoto, 1982] [387] [Magnus, 1983] [Vandewalle, 1983] [Magnus, 1987] rifamycin S [Girotra, 1983] [White, 1986] [Koreeda, 1983] [Yoshii, 1983] [Liu, 1988] [Kishi, 1980] [Grieco, 1983] MeO [Nakata & Oishi, 1986] [Wender, 1983] [Smith, 1984] [Little, 1990] [Hanessian, 1982] [Heathcock, 1985] [Matsumoto, 1987] [Keck, 1986] HO [Schuda, 1984] Me O MeO [Funk, 1985] [Kozikowski, 1987] O [Little, 1985] [Clive, 1988] O Me Me NHCOCOMe R = H: saframycin B[381] [Danishefsky, 1989] Me [Demuth, 1986] O R O O H [Curran, 1988] [Fukuyama, 1982] [Burke, 1991] H MeO H [Hagiwara, 1995] [Hanessian, 1986] O Me [Weinges, 1993] N [Kubo,1987] [Kuwajima, 1997] [Ley, 1990] [381] [White, 1995] Me N Me R = CN: saframycin A Me Me O O O H [Fukuyama, 1990] R = OH: avermectin B [394] O H 1a [Myers,1998] R = OMe: avermectin A [395] OH O Me [Corey, 1999] 1a O NH2 [Danishefsky, 1987] NH2 H OMe OH OH N NH2 N HO O Me H OH HO H HO O O OH HO R O H H O N N Me O O HO O N H H N O HO N NH histrionicotoxin[402] MeO Me H2N O NH S N O NH H [Kishi, 1985] H N O Me HN O Cl- N 2 O N Me HO Me N S + [Stork, 1990] Br O SMe2 OH H H [Holmes, 1999] OH N O OH O N N Me O N OH H H OMe H O HO HO OMe N O [390] O Me O H O CN neosurugatoxin O OH NH OH OH O MeO [Inoue, 1986] OH N O O Me H HO Me O N N OH Me Me OMe O OH OH Me O NH2 H H O N O OMe O OH [385] HN O FK506[401] bleomycin A2 O HN N [Merck, 1989] [Ohno,1982] [386] N OMe [Hecht, 1982] cyanocycline A H [Schreiber, O [Boger, 1994] [Evans, 1986] fredericamycin A[393] O 1990] [Fukuyama, 1987] [396] [Danishefsky, [Kelly, 1986] [Bach, 1994] CC-1065 1990] [Clive, 1992] [Kelly, 1987] [Reddy, 1994] H [Sih, 1990] [Julia, 1993] [Boger, 1995] [Boger, 1988] O N [Smith, 1994] Me [Kita, 1999] Me [Ireland, 1996] O Me H H Me H H O Et N OHC Me O H O O H HO O CONH2 NH H N Me O Me H H H NH Me O N O NH2 H H Me H [397] O O H HO ikarugamycin H [399] [392] echinosporin[388] [400] [398] daphnilactone A ophiobolin C huperzine [Boeckman, 1989] koumine [Heathcock, 1989] [Kishi, 1989] [Smith, 1989] [Kozikowski, 1989] [Paquette, 1989] [Magnus, 1989]

Figure 6. Selected natural product syntheses from the twentieth century.

devised for delivering complex and diverse structures in single and forthcoming. Indeed, automation technologies are al- operations in order to achieve such goals. New catalysts have ready entering the realm of chemical synthesis laborato- to be invented to bring about otherwise difficult or impossible ries.[281] Finally, a goal of paramount importance for the operations. There is little doubt that we can count on mother ensuing century will undoubtedly involve the development of nature to provide us with the targets and the opportunities to synthetic strategies for the rapid construction of complex invent and develop such methods in the future. natural products that rival or even surpass the efficiency of Solid-phase chemistry[275] is now gathering momentum in nature. natural product synthesis. Traditionally used for the synthesis In addition to natural products and their analogues, of peptides[276] and oligonucleotides,[277] this approach is now synthetic chemists are also beginning to target complex and being applied to construct small organic molecules in large exotic natural productlike structures for the purpose of numbers, particularly for the purposes of drug discovery,[278] biological screening.[282] Such endeavors are clearly related catalyst development,[279] and material science.[280] Again, new to total synthesis and are both inspired and facilitated by techniques, strategies, and tactics are needed to elevate this advances in the latter field. Particularly enabling are those endeavor to a higher level of sophistication, applicability, and contributions that include both new synthetic technologies scope. As we have mentioned above, total synthesis is taking a and novel molecular architectures. Examples of such endeav- leading role in spearheading developments in new technolo- ors include those from the Schreiber group,[283a] Sharpless gies for solid-phase and combinatorial chemistry. With the group,[283b] and our own[283c] (Figure 9; see p. 108). strong foundation provided by such advances, automation of In closing, in surveying the art and science of total synthesis synthetic and combinatorial chemistry should also be possible of the twentieth century, one is left with awe at its accomplish-

106 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

Me H2N OH O OH OH OMe O Me OH Me O Me HO O O O HO OH Me OH N Me N O H O H H N N O O O O 2 OMe O O H OH OH H H paspalinine[403] H H MeO OH OMe OH N O O O O H H [Smith, 1990] Ph OH isorobustin[405] OH OH OH chaparrinone[407] [Barton, 1990] HO NH2 Me CON(Me)2 [Grieco, 1990] OH rocaglamide[409] hikizimycin[406] Me [Trost, 1990] N [Schreiber, 1990] indolizomycin[404] CO2Me Me N OMe Me Me Me H H H Me [Danishefsky, 1990] O H Me OH HO H H OH O HO O Et O [408] MeO2C Me HO OH ambruticin O Me Me [410] O [Kende, 1990] isorauniticine Me H O Me H Me OH HO H O [Oppolzer, 1991] O O N H HO HH O Me Me OAc S Me H H H [411] [412] O O kempene-2 myrocin C H O [422] thebainone A[424] [Danishefsky, 1992] O O [Dauben, 1991] breynolide O H [Tius, 1992] O O Br Br [Smith, 1991] HO O O O H H H H H H O Me N OH O R Me [413] H H halichondrin B O O OH HO Me O O Me H [Kishi, 1992] MeO N H O Me O H H NMe OH N O HO H N N 2 H H Me Me Me Me O O O O H H HO H O Me [425] O discorhabdin C Me HO OH OCONH2 HO P Me [Kita, 1992] O Me O O CN Me Me MeHO hemibrevetoxin B[414] O NMe2 OH Me OMeO O [Nicolaou, 1992] HO Me OH Et N [Yamamoto, 1995] Me O Me MeO2C Me Me OH OH OMe [Nakata, 1996] H N [Mori, 1997] OH OH [415] O Me CO Me R = H: calyculin A (ent) O MeO 2 O Me Me O H O [426] [Evans, 1992] [Shioiri, 1996] O Me H isochrysohermidin [Masamune, 1994] [Smith, 1998] HH O H [Wasserman and Boger, 1993] O Me H [415] [416] R = Me: calyculin C (ent) H N H CO H OH O [Schreiber, 1993] O 2 [Armstrong, 1998] H H OMe [Smith, 1995] Me H O Me Me OBz [Myles, 1997] [417] OMe Me O lepicidin A N HO [Marshall, 1998] OMe MeO OCOPh [418] [Evans, 1993] OMe O stenine [430] MeO OCOPh O scopadulcic acid B H [Hart, 1993] Me HO [Overman, 1993] Me O [Wipf, 1995] H N O [Ziegler, 1995] O OMe H Me OH O HO2C O OH O H H [429] HO Me H H H calphostin A HO H OH [Coleman, 1994] O O member of the H [434] OMe Me OH OH HO clavularanes H [423] H H N O chlorothricolide H N N H Me O OMe magellanine[431] [Williams, 1993] [Roush, 1994] H H [Overman, 1993] [421] HN N OMe petrosin H O H H NH H H OH N [Heathcock, 1994] balanol[419] MeO C [420] 2 papuamine [Nicolaou, 1994] O H Me N [Barrett, 1994] [Hu, 1994] N [427] O H duocarmycin A [Weinreb, 1994] [Adams, 1994] O [Terashima, 1994] O [Stadlwieser, 1996] HO [Boger, 1996] HN O nPent [Tanner, 1997] H Cl Me OH [Naito, 1997] HN N N N Me O O O OCONH2 Me H H O OH Me Me H H H O Me H [439] OH H H Me syringolide 1 Me MeO O H O O O HO AcO [Wood, 1995] NHMe O NH O Me [Kuwahara, 1995] OHC N (CH ) H H H2N N 2 14 [435] [Murai, 1996] staurosporine [Sims, 1997] [441] H [445] 7-deacetoxyalcyonin FR-900482 [437] 2N ptilomycalin [438] epoxydictimene [Danishefsky, 1995] acetate [Yoda, 1997] [Fukuyama,1992] [Wong, 1998] [Schreiber, 1994] [Overman, 1995] [Wood, 1997] [Overman, 1995] [Danishefsky, 1995]

Figure 7. Selected natural product syntheses from the twentieth century. ments and power. As a practitioner of the art, one is filled with Abbreviations overwhelming pride to be part of such attractive and vigorous endeavors and apprehensive in being responsible for convey- AA asymmetric aminohydroxylation ing its true meaning and value to society.[284] But, most Ac acetyl importantly, the surveyor must be overly excited and opti- acac acetylacetonyl mistic about the future of the discipline and in transferring AD asymmetric dihydroxylation this enthusiasm to the next generation of chemists. It would, AIBN 2,2'-azobisisobutyronitrile indeed, be of considerable interest to compare the All allyl present state-of-the-art with that at the end of the twenty- Alloc allyloxycarbonyl first century. 9-BBN 9-borabicyclo[3.3.1]nonane

Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 107 REVIEWS K. C. Nicolaou et al.

Me Me OH O O O OH HN O O H OH FR-90848[436] O O O O [Barrett, 1996] N Me CH2OH [Falck, 1996] H N O O Me H H NC N H OH O [428] trichoviridin Me [433] O O OH croomine [Baldwin, 1996] lubiminol[442] OH [Martin, 1996] O OH H O O [Crimmins, 1996] Me O Me Me HN Me MeO OH Me HO O Me N NMe2 Me HN Me O H O Me hispidospermidin[443] H Me Me O O Me O [Danishefsky, 1997] Me Me [Overman, 1998] H CO2 Me Me Me O Me [447] N chromophore HO O H OH OH H O H HO [Myers, 1998] O Me O Me HO Me O O [456] [458] rubifolide Me pinnatoxin A (ent) [Marshall, 1997] [Kishi,1998] O [451] Me dysidiolide [432] HO Me salsolene oxide H [Corey, 1997] [Paquette, 1997] O Me Me Me batrachotoxinin A[439] H [Robichaud, 1998] O Me N [Danishefsky, 1998] AcO HO OH nBu Me S [Kishi, 1998] O [Yamada, 1999] O NMe2 H Me H O OH N Me N O Me HO O OH H H H pateamine[444] H2N Me N [Romo, 1998] Me H O Me HO OH HO O O O Me Me [455] N O H OH H H O OAc cephalostatin 7 OH O OH O Me Me [Fuchs,1999] O O H OMe NH HO Me O HO O O Me OMe O X OH O O H [448] O [453] H O manumycin B OMe N X = Cl: spongistatin 1 Me Me Me [Taylor, 1999] Br [Kishi, 1998] O H O O O O [454] Me H OH X = H: spongistatin 2 AcO Me OH [449] OAc MeO phorboxazole A [Evans, 1998] Me [Forsyth, 1998] O OH O Me OH HO AcO Me OMe OH O O Me O H O O Me O H OH MeO OH N N O O N H O O O OH O O H H O N OH Me O MeO N N O O O O OH OH O O O N N O Me Me O O O [452] O N N O OH HO HO luzopeptin B O Me AcO N O O H H Me O [Boger, 1999] H Me [450] [446] N O σ[457] O olivomycin A preussomerin I N N O HO OMe diepoxin iPrO2C HO H HO [Roush, 1999] [Heathcock, 1999] Me O [Wipf, 1999]

Figure 8. Selected natural product syntheses from the twentieth century.

X1 1 BOP benzotriazol-1-yloxy-tris(dimethylamino)phos- 2 X R1 X NH 2 phonium hexafluoride N 5 X H R N O 1 4 5 Bz benzoyl N R R R H 3 2 R2 4 1 R2 O O H R O R R R CA chloroacetyl N R3 R3 O 1 2 CAN cerium ammonium O X = O, S; X = CR2, O, NR O Cbz benzyloxycarbonyl 7-8 steps 2 steps Cod cyclooctadiene Schreiber (1998) Nicolaou (1999) Cp cyclopentadienyl O R2 CSA 10-camphorsulfonic acid 3 3 R R 3 N O R Ar2 R3 Cy cyclohexyl R2 R2 R1 N N NH N N DABCO 1,4-diazabicyclo[2.2.2]octane 2 1 N R 1 Ar O DAST (diethylamino)sulfur trifluoride R5 X R4 Ar O N N 1 1 1 dba trans,trans- X = SO2, CO, CH2 R R1 R R 4-6 steps 4 steps 4 steps DBN 1,5-diazabicyclo[5.4.0]non-5-ene Sharpless (1999) DBU 1,8-diazabicyclo[5.4.0]undec-7-ene Figure 9. Novel, natural productlike, molecular architectures recently DCB 3,4-dichlorobenzyl synthesized for biological screening purposes (number of steps from DCC N,N'-dicyclohexylcarbodiimide commercially available materials).[283] Ddm 4,4'-dimethoxydiphenylmethyl DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone BINAP 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl DEAD diethyl azodicarboxylate Bn benzyl DEIPS diethylisopropylsilyl Boc tert-butyloxycarbonyl DET diethyl trtrate

108 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS

DHP 3,4-dihydro-2H-pyran TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy DIAD diisopropylazodicarboxylate TEOC trimethylsilylethylcarbonyl DIBAL-H diisobutylaluminum TES triethylsilyl DIC 5-(3,3-dimethyl-1-triazenyl)-1H--4- Tfa trifluoroacetyl carboximide TFA trifluoroacetic acid DIPT diisopropyl tartrate TFAA trifluoroacetic anhydride DMA N,N-dimethylacetamide THF tetrahydrofuran 4-DMAP 4-dimethylaminopyridine THP tetrahydropyranyl DMF N,N- TIPS triisopropylsilyl DMP Dess-Martin-periodinane TMGA tetramethylguanidinium azide DMPU N,N-dimethylpropyleneurea TMS DMSO dimethylsulfoxide TPAP tetra-n-propylammonium perruthenate Dopa 3-(3,4-dihydroxyphenyl) TPS triphenylsilyl DPPA diphenyl phosphoryl azide Tr trityl dppb 1,4-bis(diphenylphosphinyl)butane dppf 1,1'-bis(diphenylphosphanyl)ferrocene It is with enormous pride and pleasure that we wish to thank DTBMS di-tert-butylmethylsilyl our collaborators whose names appear in the references and EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide whose contributions made the described work possible and FDPP pentafluorophenyl diphenylphosphinate enjoyable. We gratefully acknowledge the National Institutes of Fmoc 9-fluorenylmethoxycarbonyl Health (USA), Merck & Co., DuPont, Schering Plough, HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl- Pfizer, Hoffmann-La Roche, Glaxo Wellcome, Rhone-Poulenc uronium hexafluorophosphate Rorer, Amgen, Novartis, Abbott Laboratories, Bristol Myers HBTU O-benzotriazol-1-yl-N,N,N',N'-tetramethyluroni- Squibb, Boehringer Ingelheim, Astra-Zeneca, CaPCURE, the um hexafluorophosphate George E. Hewitt Foundation, and the Skaggs Institute for HMDS bis(trimethylsilyl)amide Chemical Biology for supporting our research programs. HMPA HOAt 1-hydroxy-7-azabenzotriazole Received: June 10, 1999 [A349] HOBt 1-hydroxybenzotriazole IBX o-iodoxybenzoic acid imid. imidazole [1] Nobel Lectures: Chemistry 1963 ± 1970, Elsevier, New York, 1972, pp. 96 ± 123. Ipc isopinocamphenyl [2] Nobel Lectures: Chemistry 1981 ± 1990, World Scientific, New Jersey, KSAE Katsuki ± Sharpless asymmetric epoxidation 1992, pp. 677 ± 708. LDA [3] K. C. Nicolaou, E. J. Sorensen, Classics in Total Synthesis, VCH, lut. 2,6-lutidine Weinheim, 1996. [4] E. J. Corey, X.-M. Cheng, The Logic of Chemical Synthesis, Wiley, mCPBA 3-chloroperoxybenzoic acid New York, 1989. MOM methoxymethyl [5] I. Fleming, Selected Organic Syntheses, Wiley, New York, 1973. Ms methanesulfonyl [6] K. C. Nicolaou, E. J. Sorensen, N. Winssinger, J. Chem. Educ. 1998, MSTFA N-methyl-N-(trimethylsilyl) trifluoroacetamide 75, 1225 ± 1258. [7] R. Breslow, Chemistry: Today and Tomorrow, American Chemical nbd norbaranadine (bicyclo[2.2.1]hepta-2,5-diene) Society, Washington, D.C. 1996. NBS N-bromosuccinimide [8] F. Wöhler, Ann. Phys. Chem. 1828, 12, 253. NIS N-iodosuccinimide [9] H. Kolbe, Ann. Chem. Pharm. 1845, 54, 145. NMO 4-methylmorpholine-N-oxide [10] a) C. Graebe, C. Liebermann, Ber. Dtsch. Chem. Ges. 1869, 2, 332; Nos 4-nitrobenzolsulfonyl b) first commercial synthesis: C. Graebe, C. Liebermann, H. Caro, Ber. Dtsch. Chem. Ges. 1870, 3, 359; W. H. Perkin, J. Chem. Soc. 1970, OTf trifluoromethanesulfonate 133 ± 134. PCC chlorochromate [11] A. Baeyer, Ber. Dtsch. Chem. Ges. 1878, 11, 1296 ± 1297; first PDC pyridinium dichromate commercial production: K. Heumann, Ber. Dtsch. Chem. Ges. 1890, PG protecting group 23, 3431. [12] E. Fischer, Ber. Dtsch. Chem. Ges. 1890, 23, 799 ± 805. Pht phthalimidyl [13] See brochure of Nobel Committees for Physics and Chemistry, The Piv pivaloyl Royal Swedish Academy of Sciences, List of Nobel Prize Laureates PMB p-methoxybenzyl 1901 ± 1994, Almquist & Wiksell Tryckeri, Uppsala, Sweden, 1995. PPTS pyridinium 4-toluenesulfonate [14] W. H. Perkin, J. Chem. Soc. 1904, 85, 654 ± 671. pTs 4-toluenesulfonyl [15] See S. F. Thomas in The Total Synthesis of Natural Products, Vol. 2 (Ed.: J. Apsimon), Wiley, New York, 1973, pp. 149 ± 154. py [16] R. Robinson, J. Chem. Soc. 1917, 111, 762 ± 768. Red-Al sodium bis(2-methoxyethoxy)aluminum hydride [17] R. Willstätter, Ber. Dtsch. Chem. Ges. 1901, 34, 129 ± 130; R. SEM 2-(trimethylsilyl)ethoxymethyl Willstätter, Ber. Dtsch. Chem. Ges. 1901, 34, and 3163 ± 3165; R. TBAF tetra-n-butylammonium fluoride Willstätter, Ber. Dtsch. Chem. Ges. 1986, 29, 936 ± 947. For an account in English, see H. L. Holmes in The Alkaloids, Vol. 1 (Eds.: R. H. F. TBAI tetra-n-butylammonium iodide Manske, H. L. Holmes), Academic Press, New York, 1950, pp. 288 ± TBDPS tert-butyldiphenylsilyl 292. TBS tert-butyldimethylsilyl [18] H. Fischer, K. Zeile, Justus Liebigs Ann. Chem. 1929, 468, 98.

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