Tetrahedron Letters 55 (2014) 6156–6162

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Tetrahedron Letters

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Digest Paper Divergent strategy in natural product ⇑ Jun Shimokawa

Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan article info abstract

Article history: Divergent strategy in natural product synthesis allows the comprehensive synthesis of family natural Received 24 July 2014 products. Efficient formulation of this idea requires the biosynthetic/-inspired insight toward Revised 13 September 2014 the well-orchestrated design of a pluripotent late-stage intermediate, in concomitant with the applicabil- Accepted 15 September 2014 ity of the intermediates for versatile transformations. This digest focuses on the actual applications of Available online 22 September 2014 those strategies in natural product synthesis with an emphasis on the recipes for the choice of the com- mon intermediates. Keywords: Ó 2014 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY license Diversity-oriented synthesis (http://creativecommons.org/licenses/by/3.0/). Diverted total synthesis Collective total synthesis Divergent total synthesis

Contents

Introduction...... 6156 Divergent approach allows the streamlined syntheses of biosynthetically similar natural products ...... 6157 Baran’s syntheses of eudesmane terpenes8 ...... 6157 Fukuyama’s syntheses of all the amathaspiramides9 ...... 6158 Movassaghi’s syntheses of all agelastatins10 ...... 6159 Li’s syntheses of Taiwaniaquinols and Taiwaniaquinones11 ...... 6159 Baran’s syntheses of meroterpenoids12 ...... 6160 Boger’s divergent syntheses of Kopsia alkaloids13 ...... 6160 MacMillan’s syntheses of several families of indole alkaloids6 ...... 6160 Oguri’s syntheses of biogenetically related indole alkaloids14 ...... 6161 Conclusion ...... 6162 References and notes ...... 6162

Introduction has to deal with structurally complex molecules, serendipitous discoveries emerge. It is also important to note that reaching to Chemists have often made an analogy of natural product total the single summit of the highest peak is not always the purpose synthesis with climbing the mountain. During the climbing, one of climbing the mountain. Walking along the ridge line of the has to find out a mountain path that you believe would go to the adjoining peaks of the mountain range has its own allure. Likewise, summit of the heap. By trying for those shorter and more efficient the synthesis of an array of compounds with small structural routes, there would be more chances for gaining unfamiliar and differences has its rich potential information. When combined, unexpected precious experiences. This shows similarity to the pro- information on those compounds is able to provide a detailed cess toward the evolution of the artificial synthetic route of the tar- structure–activity relationship, which would not be available from get natural product. By keeping this endeavor, one may notice a a single-shot scrutiny of a certain molecule.1 The aim of those novel synthetic method that would be hard to get across without divergent syntheses is the streamlined construction of a set of trying to manage such synthetic challenges. Therefore, when one invaluable compounds, which contrasts to the traditional target- oriented linear or (Fig. 1). One of the most popular ideas of those kinds is called ‘Diversity-oriented synthe- ⇑ Tel.: +81 (0) 52 788 6105; fax: +81 (0) 52 789 2959. sis’.2 This idea was originally proposed by Schreiber and has E-mail address: [email protected] http://dx.doi.org/10.1016/j.tetlet.2014.09.078 0040-4039/Ó 2014 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). J. Shimokawa / Tetrahedron Letters 55 (2014) 6156–6162 6157

naturally occurring molecules as a synthetic intermediate. This is because of the high polarity or instability that would not be com- patible with most of the laboratory techniques. Thus the selection of the one or several target molecules and designing of the artificial common synthetic intermediate would be the most significant and difficult points of the divergent way of total synthesis. This digest thus deals with the recent inspiring examples of nat- ural product synthesis that deals with an appreciable collection of biosynthetic relatives. With an emphasis on the strategy for choos- ing the common intermediate, the potential of this productive strategy will be discussed.

Divergent approach allows the streamlined syntheses of biosynthetically similar natural products

Baran’s syntheses of eudesmane terpenes8 Figure 1. Schematic explanation of linear, convergent, and divergent synthesis.

The construction of the core structure of certain family of influenced much to the drug discovery. Another important concep- natural products, especially terpenes, could be made possible by tual approach proposed by Danishefsky is named ‘Diverted total two-phase synthesis. The common carbon skeleton of the family synthesis’.3 This is an approach toward the preparation of a natural is synthesized first by reducing the use of protective groups and product-like compound library by the derivatization of a versatile functionality-manipulating steps. This is followed by the introduc- synthetic intermediate. These concepts led to the successful find- tion of hetero- or carbon-functionalities. Their approach was most ing of various bioactive compounds, which showcased its poten- impressively presented in their syntheses of various eudesmane tials to reach the real drug candidate.4 terpenes by the diverse way of introducing oxygen functionality It is natural to infer that these ramifying approaches have an to the common precursor dihydrojunenol (1)(Scheme 1). Diphe- effect on the natural product synthesis. The original definition of nylprolinol methyl ether-mediated enantioselective Michael–aldol this ‘Divergent total synthesis’ approach was given by Boger to combination between 2 and 3 gives enone 4, followed by a side be ‘the synthesis of at least two members of the class of com- chain introduction and Heck reaction to give 5. This was pounds’ from the common, advanced synthetic intermediate.5 transformed to dihydrojunenol (1) in a very efficient manner via Application of divergent synthesis could be encompassed even to 1,4-addition and reduction on a gram scale. These eudesmane ter- the groups of molecules with different family names. The method pene members with various oxidation states were biosynthesized with this widened applicability to several skeletons is what Mac- following these transformations via P450 oxidation. The regiose- Millan defines as ‘Collective total synthesis’.6 The syntheses that lectivity observed in Nature is usually difficult to reproduce in lab- could fall into this type seem to be gathering more and more atten- oratory synthesis. The evolution of C–H oxidation procedure with tion.7 Upon planning the synthetic route to these projects, it is nec- predictable regio- and chemoselectivity is thus necessary for exe- essary to set the pluripotent late-stage synthetic intermediate that cuting the diversified syntheses of this natural products family. could transform into the array of the desired target families. In The oxidation of unactivated terpene C–H bond is made possible most cases, those targets are in one or several biosynthetic families by the functional group-tethered method. One is the TFDO that share the same biosynthetic intermediate. The mutual rela- (methyl(trifluoromethyl)dioxirane)-mediated C–H oxidation that tionship among those target compounds, about appendage, stereo- regioselectively oxidizes the C–H bond within the bicyclic core chemical or skeletal diversity, has a great influence on the strategy structure. Interestingly, C–H bromination by Hofmann–Löffler– chosen. The biosynthetic intermediates could be a candidate for Freytag (HLF) reaction, the other C–H functionalization process the common intermediate, but it is often difficult to use those they employed, mediated the functionalization of the other C–H

Scheme 1. Baran’s syntheses of eudesmane alkaloids. 6158 J. Shimokawa / Tetrahedron Letters 55 (2014) 6156–6162

Scheme 2. Fukuyama’s syntheses of all the amathaspiramides. position of side chain isopropyl group. With this orthogonal oxida- to find out the pluripotent late-stage intermediate for the compre- tion procedures and 1,2-directed oxidation methodology, various hensive syntheses of all the members of this family. To this end, an eudesmane terpenoids were synthesized one after the other. From appropriate methodology was required to make this idea possible. the trifluoroethyl carbamate 6, the intrinsic difference in the selec- In this case, the envisioned transformation does not mimic the Nat- tivity of transformations emerges. The reaction with TFDO pro- ure’s transformation order that gradually increases the oxidation motes the inward oxygenation to afford 7, providing 4-epiajanol state. It is characteristic to employ the gradual reductions from (8) in a single step. HLF reaction oxidizes outwards instead. Bro- the most oxidized amathaspiramide D (17) as the common precur- mine atom on 9 was substituted intramolecularly and gave dihydr- sor to all the other members of this family. Cyclic imide intermedi- oxyeudesmane (10) shortly. The combination of these two recipes ate 20 was synthesized in 8 steps from butenolide 21 via was also possible in regioselective manner. Through the doubly asymmetric hydrogenation followed by alpha-functionalization, oxidized intermediate 11, pygmol (12) and eudesmanetetraol formation of imide and bromination. Interestingly, reduction with (13) were synthesized. The indispensable point of the success of DIBAL mediated the regio- and diastereoselective transformation this divergent synthesis is the finding of predictable, regioselective, to give Amathaspiramide D (17). The key point was the reduction and orthogonal methodology for introduction of oxygen function- of lactam in 17 to cyclic imine, E (18), mediated by Schwartz ality on this skeleton. This synthesis underscores the importance reagent (Cp2ZrHCl). This relatively rare and chemoselective trans- and necessity of the development of selective and predictive meth- formation was the key to the success of the diversification in this odology of C–H activation transformation. project. Cyclic imine was converted to the corresponding second- ary and tertiary amines C (16) and A (14). An interesting point is Fukuyama’s syntheses of all the amathaspiramides9 the exceptional stability of the stereochemistry of the hemiaminal to various reaction conditions. Cyclic hemiaminal moiety was then Targets of these divergent strategies include the syntheses of successfully epimerized under the basic reaction conditions to give co-isolated natural products bearing partial variation. amathaspi- F(19). With B (15) synthesized from D (17), all the known mem- ramide alkaloids A–F (14–19) differ in the oxidation state of the left bers of amathaspiramides were efficiently obtained. This example side pyrrolidine ring, while F (19) is also typical for an epimeriza- indicates the importance of getting insight into the chemical rela- tion at the cyclic hemiaminal moiety (Scheme 2). Each of these tionship between the selected target compounds and finding their compounds shares the same skeleton. Thus, it would be necessary intrinsic reactivities from it.

Scheme 3. Movassaghi’s syntheses of all agelastatins. J. Shimokawa / Tetrahedron Letters 55 (2014) 6156–6162 6159

Scheme 4. Li’s syntheses of Taiwaniaquinols and Taiwaniaquinones.

Movassaghi’s syntheses of all agelastatins10 Li’s syntheses of Taiwaniaquinols and Taiwaniaquinones11

Sometimes the synthesis of natural product is much simpler Meroterpenoids are natural products containing both of the than it looks to be. This is because certain stereocenters in natural units of terpene and polyketide. They are known to possess various products are controlled by following the simplest and most effi- similar families with variable oxidation states. These molecules are cient route that favors a naturally occurring stereochemistry. Con- attractive targets for divergent synthetic approach (Scheme 4). The trol of the diastereochemistry in natural product synthesis could construction of core structure was realized by Bi(OTf)3-catalyzed thus be envisioned by mimicking the biosynthetic route. This ret- cyclization of chain intermediate 32 that effected the diastereose- robiosynthetic approach was successfully applied to the Mov- lective construction of bicyclo[4.4.2]decane unit 33. Subsequent assaghi’s syntheses of all agelastatins (Scheme 3). The synthesis ring contraction strategy employing Wolff rearrangement effi- started with D-aspartic acid-derived pyrrole 22. The cyclopentane ciently gave the 6-5-6 ring system of 34 that is common to these moiety was constructed from intermediate 23, through stereose- natural products. Transformation of the versatile formyl moiety lective cyclization from the imidazolone moiety to acyl iminium was the key to the diversification of the fate of the route. Epimer- intermediate, which gave agelastatin A (24) in short steps. Bromin- ization of the stereochemistry of aldehyde in 34 gave 35. From this ation and aminal exchange of A (24) give B (25) and E (26) respec- intermediate, oxidation of phenol moiety furnished Taiwaniaqui- tively. Similarly, more oxidized member agelastatin C (27)is none F (36) and A (37). Conversion to the unsaturated aldehyde synthesized from the same intermediate 23 via dihydroxylation by Ito–Saegusa oxidation afforded Taiwaniaquinol D (38). Also, oxi- of dehydrated imidazolone 28. N-Demethylated members, agelast- dative removal of C-1 formyl unit and demethylation of phenol atin D (29) and F (30) was also synthesized from the corresponding moiety furnished Taiwaniaquinol B (39). The choice of the struc- demethylated imidazolone via 31. As such, all agelastatin members ture of the common intermediate 34 is understandable from the with the same core skeleton, on various brominated or oxygenated viewpoint of utilizing the facile construction of six-membered ring states were synthesized. The key to this synthesis was the employ- and possible transformation to the necessary five-membered moi- ment of artificial imidazolone moiety as the alternative potent and ety with versatile formyl group. This collective synthesis under- manipulable nucleophile, which corresponds to imidazole unit in scores the importance of the selection of the versatile common natural biosynthesis. The stereochemistry of the cyclization from intermediate and rapid construction of it, which does not necessar- imidazolone was accordingly controlled by the inherent tendency ily imitate the biosynthetic pathway. For those syntheses, discov- of the molecule to choose the natural stereochemistry. This simple ery of connection between molecules that could be tied with and brilliant solution of the stereochemical induction made it pos- truly artificial transformations is the key to the breakthrough to sible to synthesize family natural products in a unified approach. the fruitful synthetic scheme.

Scheme 5. Baran’s syntheses of meroterpenoids. 6160 J. Shimokawa / Tetrahedron Letters 55 (2014) 6156–6162

Baran’s syntheses of meroterpenoids12 the class of compounds from the common, advanced synthetic intermediate. Thus it was most effectively applied to the natural As already seen above, introduction of various functional groups product group with many family members. As their group have on the common skeleton of a natural product group affords a already devised many synthetic application of their [4+2]/[3+2] focused library of a certain structure motif. Likewise, assemblage cycloaddition cascade of 1,3,4-oxadiazole for the construction of of the core skeletons of several resembling natural product families the late stage core structure of Aspidosperma alkaloids, they from a single common intermediate offers even more considerable accordingly applied this cascade strategy to the more bridged fam- opportunities for the preparation of a broad range of drug leads. ily, Kopsia alkaloids (Scheme 6). The common intermediate 47 was Examples of this potential strategy would show how the transfor- designed to maximize the number of biogenetically close synthetic mations should be planned for diversification purpose. The core targets. The key cascade substrate 48 was equipped with the structures of certain meroterpenoid families resemble each other. terminal C21 silyloxy group for transannular bond-forming. It Those skeletons could be considered as the combination of the was applied to the [4+2]/[3+2] cycloaddition cascade at 180 °Cin unchanged core and the flanking carbon scaffolds as the substitu- o-dichlorobenzene and furnished the pentacyclic intermediate as tion. Baran group succeeded in setting a new potential intermedi- a common intermediate. To assemble the structure of the Kopsia ate borono-sclareolide 40 and applied to the divergent total alkaloids, oxa-bridge was removed to give conjugated ester 49. synthesis of various meroterpenoid natural products (Scheme 5). After the conversion of terminal silyloxy group to xanthate, it The idea stems from the fact that these natural products have dif- was subjected to intramolecular radical conjugate addition to ferences mostly on aromatic moiety and have much in common on unsaturated ester. This promptly furnished the desired structure terpene part. Their synthesis started from the preparation of of (À)-kopsinine (50). From the substrate with Cbz (51) in place borono-sclareolide 40 that bears boronic acid moiety in place of of Bn group, cyclization was performed with silyloxy unit as the the lactone unit of commercially available and inexpensive sclareo- latent leaving group for transannular enamide alkylation. This lide (41) (ca. $5/gram). This compound was thus subjected to the afforded indolenine intermediate that was reduced to give kopsif- removal of one carbon unit to give the versatile boronic lactone oline H (52). Similar transformation from the unsaturated sub- intermediate 40. This intermediate was subjected to Suzuki– strate 53 gave (À)-kopsifoline D (54). Compound 53 could also Miyaura coupling reaction and afforded dictyvaric acid (42) after be applied to the oxa-Michael reaction to eventually furnish the deprotection. The reactivity of 40 was also found in radical (À)-deoxoapodine (55). Kopsia alkaloids thus obtained along these coupling reaction with quinone under the K2S2O8–silver nitrate courses would constitute the results of various cyclization modes reagent combination, which gave the cyclized product chromazo- from the C21-functionalized Aspidosperma alkaloid core structure, narol (43). More oxidized relatives were synthesized by employing which should also be along the biogenetic scheme for those various oxidative transformations known for hydroquinone-type compounds. intermediate. Thus, para-alkyl hydroquinone was oxidized with 6 NaIO4 to give the para-quinone, yahazunone (44) that could then MacMillan’s syntheses of several families of indole alkaloids be reduced to give the hydroquinone, yahazunol (45). Different oxidative transformations of 43 afforded the ortho-quinone that Application of divergent synthesis could be encompassed even constitutes the synthesis of (+)-8-epi-puupehedione (46). As such, to the groups of molecules with different family names. This unified synthetic route was developed to several meroterpenoids widened applicability of the method to several skeletons is what with the same substructure from the new versatile precursor 40. MacMillan defines as ‘Collective Total Synthesis’.6 Their approach The reason for the success of this strategy lies in focusing on the is the combination of organocascade catalysis to the versatile easily available terpenoid unit feedstock and application of the intermediate and application of them to various carbon-unit intro- one-carbon lacking boronic lactone intermediate. This versatile ducing transformations (Scheme 7). By the employment of the reactivity in various coupling reactions to aromatic moiety would organocatalyst 56 that enables the construction of the quaternary have been a difficult transformation from natural sclareolide itself. stereogenic center from propynal 57 and indole 58, subsequent intramolecular aza-Michael reaction afforded the key intermediate Boger’s divergent syntheses of Kopsia alkaloids13 59 or 60. These molecules equip with the common structural motif of many families of indole alkaloids. Thus flexible attaching strat- The idea ‘Divergent Total Synthesis’ was first introduced by egy of various subunits enables an easy access to various natural Boger in their synthesis of azafluoranthene alkaloids.5 This product relatives. As shown in the scheme, route to Aspidosperma approach is defined as the synthesis of at least two members of alkaloids is forged by the allylation of the secondary amine to give

Scheme 6. Boger’s syntheses of Kopsia alkaloids. J. Shimokawa / Tetrahedron Letters 55 (2014) 6156–6162 6161

Scheme 7. MacMillan’s syntheses of several families of indole alkaloids.

Scheme 8. Oguri’s syntheses of biologically related indole alkaloids.

61 and intramolecular Heck reaction followed by the reduction of similar manifold from the common precursors, tryptamine and carbon–carbon double bonds. This transformation gives aspidospe- secologanin. It is thus reasonable to say that a unified synthetic rmidine (62) that was further transformed to vincadifformine (63) proposal to access all of these molecules should exist. Oguri et al. in two steps. Similarly, allylation to 64 and Heck cyclization reac- successfully illustrated the possibility of this divergent proposal tion from the substrate 65 afforded the strychnine (66) with very in a laboratory synthesis (Scheme 8). The biggest obstacle for real- short synthetic route. Kopsia alkaloids differ from the above com- izing this divergent synthetic proposal is supposed to be the design pounds in bearing the bicyclo[2.2.2]octane unit. For the construc- and the construction of the key intermediate by taming a highly tion of the core skeleton, they employed a Diels–Alder strategy. reactive cyclic amino diene structure found in the natural interme- Thus, for the Diels–Alder cyclization strategy for the 6-membered diate 70. They newly designed the stabilized intermediate 71 and ring, diene unit in 67 was constructed via Wittig reaction. This pro- employed the cyclization reaction from amide/ 72 for the cedure enabled the synthesis of kopsinine (68) that was further temporary preparation of the reactive and yet sufficiently stable transformed to kopsanone (69) via the known sequence. As seen intermediate equipped with electron-withdrawing substituent on from these fruitful results, collective approaches to the family com- the diene moiety. They developed the copper-catalyzed cyclization pounds allowed the efficient syntheses. conditions utilizing [Cu(dppf)(MeCN)]PF6 as the very mild and effective catalyst for the construction of this motif. The reaction Oguri’s syntheses of biogenetically related indole alkaloids14 was fast and the product intermediate was found applicable to the next reaction without isolation. Owing to the presence of the Monoterpenoid indole alkaloids have often been chosen as the electron-withdrawing group on the diene in 71, hydrogenation of synthetic targets of natural product synthesis. These alkaloids con- one of the dienes was realized. This was then subjected to the stitute a very big family because they are biosynthesized by a very intramolecular Diels–Alder reaction for the construction of the 6162 J. Shimokawa / Tetrahedron Letters 55 (2014) 6156–6162 main structure of the Aspidosperma alkaloid 73, and this helped approaches to compound libraries with diversity-oriented method- the accomplishment of the total synthesis of aspidospermidine ology are more and more anticipated. Findings from these diversi- (74). Deprotection and the silyl enolate formation set the stage fication strategies are expected to give more and more contribution for Diels–Alder reaction with a different connection mode that to the diverse drug development to which more and more new facilitates the diastereoselective formation of the andranginine ideas can contribute. These progresses would also be expected to (75). Simple heating of the key intermediate 71 mediated the yet pave the road for new findings on biological activity, chemical different mode of Diels–Alder reaction, that realized the construc- transformation methodologies, and new drugs. tion of catharanthine derivative 76, that is easily transformed to catharanthine (77). They also succeeded in the formation of other References and notes families of these indole alkaloids, including andrangine-type, ngouniensine-type and even to the unnatural-type, under various 1. (a) Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science 2003, 302, 613; (b) Oguri, H.; Hiruma, T.; Yamagishi, Y.; Oikawa, H.; Ishiyama, A.; Otoguro, K.; Yamada, reaction conditions. This variety-promoting synthesis strongly H.; Omura, S. J. Am. Chem. Soc. 2011, 133, 7096; (c) Balthaser, B. R.; Maloney, M. indicates the power of biosynthetically inspired synthesis for the C.; Beeler, A. B.; Porco, J. A., Jr.; Snyder, J. K. Nat. 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