Evolution of Radical-Based Convergent Strategies for Total Syntheses

Mar 21, 2017 - Densely oxygenated natural products often exhibit potent bioactivities and are expected to function as selective cellular probes and no...
0 downloads 3 Views 1MB Size
Download PDF
Commentary pubs.acs.org/accounts

Evolution of Radical-Based Convergent Strategies for Total Syntheses of Densely Oxygenated Natural Products Published as part of the Accounts of Chemical Research special issue “Holy Grails in Chemistry”. Masayuki Inoue* Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

ABSTRACT: Densely oxygenated natural products often exhibit potent bioactivities and are expected to function as selective cellular probes and novel drug leads. Here we describe our efforts to perfect radical-based convergent strategies for generic total syntheses of these exceedingly challenging structures.

■

INTRODUCTION Natural products are a valuable source of tools for chemical biology and provide a crucial foundation for novel drug discovery. The evolutionary optimization of natural products for a specific function during 3.8 billion years confers their intrinsic superiority to bind with biological macromolecules, making them excellent drug candidates. In fact, over 30% of modern drugs are natural products or their derivatives.1 Advances in NMR, mass, and X-ray spectroscopic techniques and biological screening protocols allow for the identification of new bioactive natural products from only small amounts of material, which has accelerated the structure determination process. To date, ∼170 000 unique structures are recorded in The Dictionary of Natural Products.2 Compared with the abundant structural information, the biological profiles of most of natural products are not well elucidated. This is likely due to the fact that early findings regarding the biological activity of trace amounts of natural products are often the end-point of many isolation programs. In this situation, total synthesis may be the only practical option for revitalizing such projects and for obtaining sufficient amounts of the agents for more complete evaluation of their biological profiles and mechanisms of action. The C(sp3)-rich structures of natural products in general possess well-defined three-dimensional structures and incorporate more oxygen atoms and fewer nitrogen atoms per molecule than synthetic compounds or drugs. As the oxygen-based functional groups potentially form hydrogen bonds with biological polymers such as proteins, natural products with multiple oxygen atoms often exhibit more potent bioactivities © 2017 American Chemical Society

than their counterparts with fewer oxygen atoms and represent privileged structures for the development of pharmaceuticals. From a synthetic point of view, bioactive natural products with multiple oxygen functionalities are an ideal platform for devising new strategies and tactics in chemical science. Historically, both linear and convergent strategies have been applied for constructing these molecules. The linear strategy includes the one-by-one transformations from the substructure of a target compound, whereas the convergent strategy involves coupling of the fragments of the target compound. Since the stepwise nature of linear strategies results in a large number of steps, convergent strategies are more advantageous for designing shorter synthetic routes to these compounds. To take maximum advantage of convergent strategies, coupling partners with multiple polar functional groups need to be readily synthesized, and subsequent functional group manipulations after the coupling must be minimized. Such ideal convergent strategies not only make sufficient natural products available for investigation of their unknown biological functions in cases where the natural supply is inadequate, but they also allow for the preparation of structurally related compounds in a unified fashion simply by switching the structures of the fragments. Furthermore, structure−activity relationship (SAR) studies of synthetic analogues would enable one to pinpoint essential functionalities within a molecule for a specific activity, enhance their drug-like properties, and offer new lead compounds for drug discovery.3 Received: September 20, 2016 Published: March 21, 2017 460

DOI: 10.1021/acs.accounts.6b00475 Acc. Chem. Res. 2017, 50, 460−464

Commentary

Accounts of Chemical Research

Scheme 1. Development of the α-Alkoxy Bridgehead Radical Reaction for Unified Total Synthesis of Ryanodane Diterpenoids

Scheme 2. Application of the α-Alkoxy Bridgehead Radical to the Three-Component Coupling Strategy and Synthesis of the Resiniferatoxin Structure

both chemists and biologists because of their diverse biological activities, such as channel-modulatory (4), insecticidal (6, 7), and anti-complement (7, 8) functions. The ABDE-ring system of 3 possesses six tetrasubstituted carbons within its compact skeleton. Accommodation of the C11-tetrasubstituted carbon is the most difficult issue to overcome due to the fused rings and the bulky functional groups that surround the C11-position. To address this particular problem, we employed the α-alkoxy bridgehead radical reaction of thiocarbonate 1.7,8 Homolytic cleavage of the C11−O bond of thiocarbonate 1 was induced with allyltributyltin and AIBN [2,2′-azobis(isobutyronitrile)] to give α-alkoxy bridgehead radical 2. Subsequently, 2 was added to allyltributyltin, delivering 3 with stereochemical retention at C11. Therefore, the powerful bridgehead radical reaction accomplished the stereospecific C(sp3)−C(sp3) bond formation via C−O bond cleavage in this sterically demanding environment. The thus obtained 3 was then utilized as the common intermediate for the total syntheses of five structurally distinct diterpenoids, ryanodine (4),9 ryanodol (5),7,9 3-epiryanodol (6), cinnzeylanol (7), and cinncassiol B (8).10 The

This paper focuses on our synthetic efforts toward a longterm goal of developing ideal convergent strategies for assembling and diversifying densely oxygenated natural products. Interested readers can consult several comprehensive reviews4−6 and references of the cited original papers for related or alternative approaches by other research groups. We hope that this manuscript exemplifies the present status of the challenges in the total synthesis of complex natural products and fosters future trajectories in the field.

■

DEVELOPMENT OF AN α-ALKOXY BRIDGEHEAD RADICAL REACTION Ryanodane diterpenoids, named after ryanodine (4, Scheme 1), possess one of the most densely oxygenated molecular frameworks among the numerous known terpenoids. Compound 4 comprises 1H-pyrrole-2-carboxylic acid ester and a polyoxygenated terpene portion, ryanodol (5), which comprises five fused ABCDE-rings, and 11 contiguous stereocenters. A number of analogous structures (e.g., 6−8) that share the same molecular framework have been disclosed. These structures together have attracted intense interest from 461

DOI: 10.1021/acs.accounts.6b00475 Acc. Chem. Res. 2017, 50, 460−464

Commentary

Accounts of Chemical Research Scheme 3. Development of a Et3B/O2-Mediated Three-Component Coupling Strategy

hydroxy group of 19 was first transformed into the corresponding xanthate 20. Then, exposure of 20 to nBu3SnH and V-40 successfully triggered the formation of the C8-radical 21, which cyclized onto the C6−7 olefin in a 7-endo manner, leading to 22 with introduction of the correct C8stereochemistry. Overall, integration of the inter- and intramolecular radical reactions significantly simplified the synthetic route to the fused tricycle 22.

developed unified synthetic route to ryanodanes will accelerate detailed investigation of their various biological functions.

■

APPLICATION OF THE α-ALKOXY BRIDGEHEAD RADICAL TO A THREE-COMPONENT COUPLING STRATEGY The high versatility of the α-alkoxy bridgehead radical reaction was further explored using oxaadamantane structure 9 as the model substrate (Scheme 2).8 The two components, 9 and allyltributyltin, were stereospecifically coupled in the presence of AIBN to generate 11 via radical 10. More importantly, the same starting material 9, cyclopentenone, and allyltributyltin were found to participate in a three-component coupling reaction. Upon heating with V-40 [1,1′-azobis(cyclohexane-1carbonitrile)], the generated electron-rich radical 10 preferred addition to the electron-deficient olefin of cyclopentenone. The electron-rich allyltin then reacted with the resultant electrondeficient radical 12 from the face opposite to the bulky oxaadamantane structure, producing 2,3-trans-disubstituted cyclopentanone 13 as a single diastereoisomer. These model experiments demonstrated the high efficiency of the threecomponent coupling reaction for increasing the complexity of molecules in a single step. The powerful coupling reaction was then applied to synthetic studies of the diterpenoid resiniferatoxin (23).11 Compound 23 is a potent activator of transient receptor potential vanilloid 1, an ion channel protein, and exhibits strong analgesic properties. Retrosynthetic disconnection of the fused 5/7/6-membered carbocyclic framework (ABC-ring) of 23 revealed three components: C-ring 14, A-ring 15, and branched allyl stannane 16. The most structurally complex component, 14, was designed to possess the α-alkoxy selenide at the bridgehead position. In refluxing chlorobenzene in the presence of V-40, the bridgehead radical 17 generated from 14 reacted with the double bond of 15 from the opposite side of the TBS-oxy group, and then the resultant α-carbonyl radical was added to tin reagent 16 in a trans manner to the cyclohexane to furnish the adduct 18, which was in turn converted to 19. Remarkably, the three-component coupling reaction realized stereospecific introduction of the C9-tetrasubstituted carbon and stereoselective formation of the two sterically congested C4- and C10-stereocenters without touching any of the acid- and basesensitive functional groups. Next, cyclization of the remaining B-ring was accomplished by another radical reaction. The C8-

■

DEVELOPMENT OF A Et3B/O2-MEDIATED THREE-COMPONENT COUPLING STRATEGY We then envisioned to develop alternative three-component coupling reactions based on a radical-polar crossover mechanism. Since the reactivities of the radical and ionic intermediates are orthogonal, one-pot application of these two mechanisms offers great advantages in assembly of complex molecular architectures. To realize the radical-polar reaction, a reagent combination of Et3B and O2 was selected as the radical initiator, and αalkoxy telluride 24 was utilized as the radical precursor in place of less reactive α-alkoxy selenide (Scheme 3).12 When a mixture of α-alkoxy telluride 24, 2-acetoxycyclopentenone (25), and 26 was treated with Et3B/O2 in CH2Cl2 at 0 °C, the coupling adduct 29 was produced through stereoselective installation of the three new stereocenters. In this reaction, the ethyl radical generated by the reaction of Et3B and O2 induced homolytic cleavage of the highly activated C−Te bond of 24 to produce the α-alkoxy bridgehead radical 27. Intermolecular addition of 27 to 25 formed the α-carbonyl radical that was then converted to boron enolate 28 via reaction with Et3B. Finally, aldol reaction of 28 with the carbonyl group of 26 controlled the stereocenters at the α-position and the two β-positions of the ketone to deliver 29. The four contiguous stereocenters in 29 directly matched those of trigohownin A (30, highlighted as gray circles), a cytotoxic daphnane diterpenoid. Although the coupling reaction of α-alkoxy telluride 24 was corroborated to be highly efficient, expansion of the substrate scope from the trioxaadamantane skeleton was problematic due to the chemical instability of the α-alkoxy telluride moieties without the caged ring systems. Thus, we alternatively designed α-alkoxyacyl tellurides as more stable nonacetal precursors and expected their decarbonylative formation of α-alkoxy radicals.13 The decarbonylative three-component coupling reaction of readily available 2-keto-L-gulonic acid derivative 31 is shown in 462

DOI: 10.1021/acs.accounts.6b00475 Acc. Chem. Res. 2017, 50, 460−464

Commentary

Accounts of Chemical Research

Scheme 4. Development of a Radical−Radical Cross-Coupling Strategy for Synthesis of the Hikizimycin Structure

Scheme 3. Despite being stable to air, light, and silica gel, αalkoxyacyl telluride 31 was readily converted to the adduct 35 with complete control of the four new stereocenters when treated with 15, α,β-unsaturated aldehyde 32, and Et3B/O2 at room temperature. In this reaction, Et3B/O2-promoted C−Te homolysis of 31 leads to acyl radical 33. The favorable orbital interaction between the σ*-bond of 33 and the adjacent oxygen lone pair facilitates C−CO scission to form α-alkoxy radical 34 via decarbonylation. Radical addition of 34 to 15, followed by the stereoselective aldol reaction with 32, gave rise to the adduct 35. It is noteworthy that the reaction realized one-step construction of the complex product 35 with the eight contiguous stereocenters, five of which correspond to those of sororianolide B (36, highlighted as gray circles). These advantageous features of the radical-polar crossover reaction, such as the tin-free procedure and milder conditions, make it a novel and valuable convergent strategy for streamlined synthesis of densely oxidized carboskeletons.

possible six homo- and four hetero-coupling adducts, showing the exceptional efficacy of the present method for synthesizing densely functionalized structures. The thus obtained 41-SS was derivatized into the known methyl peracetyl hikosaminide (44) via the subsequent four steps to confirm the integrity of its structure.

■

CONCLUSIONS AND FUTURE PROSPECTS As its history proves, total synthesis has served as the driving force for discovering new reactions and strategies. This paper described exploration and optimization of various radical-based strategies for the total synthesis of densely oxygenated natural products in our laboratory. The α-alkoxy bridgehead radical strategy was first implemented in the unified construction of five ryanodane diterpenoids (4−8) for stereospecific threecarbon extension at the unusually hindered position. Then, the α-alkoxy bridgehead radicals were applied to a convergent assembly of the three components to build the skeleton of resiniferatoxin (22). The scope of the convergent strategy was further expanded by employing Et3B/O2-mediated radical-polar crossover reactions. A one-pot reaction enabled the intermolecular radical and aldol reactions of α-alkoxy telluride 24 to afford the substructure of trigohownin A (29), while the substructure of sororianolide B (35) was produced via facile decarbonylative formation of α-alkoxy radical 34 from the chemically stable α-alkoxyacyl telluride 31. Finally, α-alkoxyacyl tellurides 37 and 38 were utilized in the radical−radical crosscoupling reaction for construction of the hikizimycin structure (41-SS). The developed convergent strategies in Schemes 2−4 are particularly useful for increasing the molecular complexity from readily available fragments in a single step without affecting the pre-existing oxygen functional groups. Because of the broadness of the reaction scope, the simplicity of the reagent system, and the mildness of the conditions, these powerful convergent radical strategies provide new principles for retrosynthetic analyses and introduce novel technologies for expedited total synthesis of densely polyoxygenated natural products. Even these efficient convergent strategies, however, are potentially inapplicable to specific functional group patterns present in some members of structurally diverse complex natural products. Therefore, it is essential that even milder, more robust, and more powerful reactions and methodologies continue to be developed to maximize convergency and minimize the need for postcoupling manipulations of the

■

DEVELOPMENT OF A RADICAL−RADICAL CROSS-COUPLING STRATEGY Contiguously hydroxylated unbranched carbon chains are embedded in a number of naturally occurring secondary metabolites with pharmacologically important bioactivities. Radical−radical coupling reactions of α-alkoxy carbon radicals are a potentially ideal convergent strategy for efficiently constructing highly oxygenated carbon chains. In 2016, we developed efficient Et3B/O2-promoted radical−radical homoand cross-coupling reactions of α-alkoxyacyl tellurides.14 Scheme 4 depicts the cross-coupling reaction of sugarderived α-alkoxyacyl telluride 37 and 38 for direct construction of the structure of the anthelmintic hikizimycin (45). The cross-coupling reaction of the two components significantly increased the synthetic complexity due to the competing homocoupling of each component. We decided to address this unconventional and formidable problem because a single-step construction of 41-SS would ensure optimal synthetic convergence. Et3B was utilized under air at room temperature to promote the decarbonylative radical formation from 37 and 38 to 39 and 40, respectively. Radical−radical coupling between 39 and 40 gave rise to 41-SS as the major compound, and the cross-coupled stereoisomers 41-RS/SR/RR and dimers 42 and 43 were isolated as minor components. Hence, the hikizimycin structure 41-SS with nine correct contiguous stereocenters was selectively built in a single-step among the 463

DOI: 10.1021/acs.accounts.6b00475 Acc. Chem. Res. 2017, 50, 460−464

Commentary

Accounts of Chemical Research

(13) Nagatomo, M.; Kamimura, D.; Matsui, Y.; Masuda, K.; Inoue, M. Et3B-mediated Two- and Three-component Coupling Reactions via Radical Decarbonylation of α-Alkoxyacyl Tellurides: Single-step Construction of Densely Oxygenated Carboskeletons. Chem. Sci. 2015, 6, 2765−2769. (14) Masuda, K.; Nagatomo, M.; Inoue, M. Direct Assembly of Multiply Oxygenated Carbon Chains by Decarbonylative Radical− Radical Coupling Reactions. Nat. Chem. 2016, DOI: 10.1038/ nchem.2639.

functional groups. Such convergent strategies make sufficient amounts of synthetic material, which will contribute to revealing the unknown biological functions of these molecules and allow for the unified synthesis of modified variants for detailed SAR studies. These studies will expand biologically relevant regions of chemical space and lead to the discovery and development of novel therapeutic agents based on these highly oxygenated natural products. In this regard, continuing evolution of convergent strategies is required for a myriad of applications in future pharmaceutical and biological sciences.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Masayuki Inoue: 0000-0003-3274-551X Notes

The author declares no competing financial interest.

■

ACKNOWLEDGMENTS I am especially pleased to acknowledge an inspiring and dedicated group of past and present co-workers whose names and contributions are referenced. I also thank Drs. Daisuke Urabe and Masanori Nagatomo for their help in manuscript preparation.

■

REFERENCES

(1) Newman, D. J.; Cragg, G. M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 2016, 79, 629−661. (2) Harvey, A. L.; Edrada-Ebel, R.; Quinn, R. J. The Re-emergence of Natural Products for Drug Discovery in the Genomics Era. Nat. Rev. Drug Discovery 2015, 14, 111−129. (3) Lachance, H.; Wetzel, S.; Kumar, K.; Waldmann, H. Charting, Navigating, and Populating Natural Product Chemical Space for Drug Discovery. J. Med. Chem. 2012, 55, 5989−6001. (4) Maimone, T. J.; Baran, P. S. Modern Synthetic Efforts toward Biologically Active Terpenes. Nat. Chem. Biol. 2007, 3, 396−407. (5) Urabe, D.; Asaba, T.; Inoue, M. Convergent Strategies in Total Syntheses of Complex Terpenoids. Chem. Rev. 2015, 115, 9207−9231. (6) Liu, F.; Myers, A. G. Development of a Platform for the Discovery and Practical Synthesis of New Tetracycline Antibiotics. Curr. Opin. Chem. Biol. 2016, 32, 48−57. (7) Nagatomo, M.; Koshimizu, M.; Masuda, K.; Tabuchi, T.; Urabe, D.; Inoue, M. Total Synthesis of Ryanodol. J. Am. Chem. Soc. 2014, 136, 5916−5919. (8) Nagatomo, M.; Hagiwara, K.; Masuda, K.; Koshimizu, M.; Kawamata, T.; Matsui, Y.; Urabe, D.; Inoue, M. Symmetry-Driven Strategy for the Assembly of the Core Tetracycle of (+)-Ryanodine: Synthetic Utility of a Cobalt-Catalyzed Olefin Oxidation and α-Alkoxy Bridgehead Radical Reaction. Chem. - Eur. J. 2016, 22, 222−229. (9) Masuda, K.; Koshimizu, M.; Nagatomo, M.; Inoue, M. Asymmetric Total Synthesis of (+)-Ryanodol and (+)-Ryanodine. Chem. - Eur. J. 2016, 22, 230−236. (10) Koshimizu, M.; Nagatomo, M.; Inoue, M. Unified Total Synthesis of 3-epi-Ryanodol, Cinnzeylanol, Cinncassiols A and B, and Structural Revision of Natural Ryanodol and Cinnacasol. Angew. Chem., Int. Ed. 2016, 55, 2493−2497. (11) Murai, K.; Katoh, S.; Urabe, D.; Inoue, M. A Radical-Based Approach for the Construction of the Tetracyclic Structure of Resiniferatoxin. Chem. Sci. 2013, 4, 2364−2368. (12) Kamimura, D.; Urabe, D.; Nagatomo, M.; Inoue, M. Et3BMediated Radical-Polar Crossover Reaction for Single-Step Coupling of O,Te-Acetal, α,β-Unsaturated Ketones, and Aldehydes/Ketones. Org. Lett. 2013, 15, 5122−5125. 464

DOI: 10.1021/acs.accounts.6b00475 Acc. Chem. Res. 2017, 50, 460−464