Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Studies Targeting Ryanodol Result in an Annulation Reaction for the Synthesis of a Variety of Fused Carbocycles Rajdip Karmakar,† Arnold L. Rheingold,‡ and Glenn C. Micalizio*,† †
Department of Chemistry, Dartmouth College, Burke Laboratory, Hanover, New Hampshire 03755, United States Department of Chemistry, University of CaliforniaSan Diego, La Jolla, California 92093, United States
‡
Downloaded via KEAN UNIV on July 17, 2019 at 09:33:16 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information *
ABSTRACT: An annulation reaction is described to access a range of polycyclic and highly oxygenated carbocycles. First developed in an approach to the synthesis of ryanodol, metallacycle-mediated annulative diketone−alkyne coupling defines a framework for realization of new retrosynthetic relationships for complex molecule synthesis. In addition to demonstrating this reaction in the context of forging distinct carbocyclic systems, including those featuring a sevenmembered ring, the choice of quenching reagent leads to unique reaction outcomes.
N
mediated and hydroxyl-directed alkene epoxidation. While this reaction for forging a stereodefined and densely oxygenated bicyclo[3.3.0]octane plays a central role in ongoing studies aimed at completing a total synthesis of ryanodol, general aspects of this annulation process have become of great current interest due to this reaction’s potential value in addressing a variety of fused polycyclic systems,6 including those possessing medium-sized rings. Here it is revealed that alkyne−diketone annulation reactions are effective at generating a wide variety of fused carbocyclic systems beyond that originally targeted in the context of our program focused on the synthesis of ryanodol (Figure 1C). Notably, cyclization reactions in this class are shown to be capable of delivering a variety of complex carbocyclic systems by way of five-, six-, and even sevenmembered ring-forming processes, where a 1,5-diketone is embraced as a reactive loci in intramolecular reactions with a pendant alkyne.7 These studies also reveal that this class of annulation reaction typically proceeds with exquisite levels of stereoselectivity, and varied quenching techniques provide a means to subtly alter product structure and establish yet additional novel retrosynthetic relationships of value in stereoselective synthesis. Our study began by examining a potential annulation process for the establishment of a seven-membered ring by engaging an alkyne in intramolecular metallacycle-mediated coupling with a 1,5-diketone. As illustrated in eq 1 of Figure 2A, exposure of 5 to the combination of Ti(Oi-Pr)4 and cC5H9MgCl results in ring formation, and termination of the process by the addition of aq NaHCO3 delivers the hydrazulene 6 in 48% yield, as what appears as a single stereoisomer. Moving beyond simple diastereoselection associated with cyclization of an achiral substrate, eqs 2 and
atural product total synthesis is widely appreciated to serve as an enduring platform for the development of organic chemistry. The complex structures associated with scores of molecules from Mother Nature provide stimuli for the invention of synthesis strategies and stereoselective reactions, while the frequently encountered unexpected reactivity of unique synthetic intermediates prepared in such pursuits is a never-ending source of challenges to push invention within the field.1 Highly oxygenated carbocycles are compelling modern targets for natural product total synthesis owing to the combined challenges associated with generating complex polycyclic systems while addressing required sites of heteroatom substitution. Ryanodol (1; Figure 1A) is a particularly compelling target in this regard due not only to its unique polycyclic skeleton and high degree of oxygenation but also because of the great number of fully substituted sp3 carbon atoms resident in its pentacyclic skeleton (i.e., quaternary centers and tertiary alcohols).2 Our recent efforts to accomplish a total synthesis of this natural product3 were driven by a desire to invent an annulation method capable of forging the central bicyclo[3.3.0]octane (the “AB” ring system; Figure 1A),4 the “B”-ring of which does not contain a single hydrogen atom (it has five fully substituted and stereogenic sp3 carbon atoms).5 The reaction technology that has emerged to address this synthetic challenge is summarized in Figure 1A and allows for the conversion of 2 to 3 by way of a metalcentered oxidative alkyne−diketone coupling reaction. An empirical model that is consistent with our experimental observations is depicted in Figure 1B and features initial formation of a metallacyclopropene (A) and intramolecular stereoselective addition to the proximal ketone to generate the oxametallacyclopentene B, followed by a second stereoselective C−C bond-forming process to yield the intermediate C. Oxidative quenching of this reaction with t-BuOOH is then thought to deliver the observed product 3 by titanium© XXXX American Chemical Society
Received: July 2, 2019
A
DOI: 10.1021/acs.orglett.9b02278 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Figure 1. Annulation reaction suitable for a wide variety of fused polyclic carbocycles, including those bearing medium-sized rings.
3 demonstrate that this seven-membered ring-forming reaction can proceed in a highly stereoselective manner with the chiral stereodefined substrate 7. Here, protic quenching of the reaction delivers the ene-1,4-diol 8, while termination of the reaction with t-BuOOH delivers the epoxydiol product 9.8 In both cases, no evidence could be found for the production of stereoisomeric products. Notably, the highly oxygenated sevenmembered ring generated here (9) possesses four contiguous fully substituted sp3 carbon atoms, all bearing oxygenation on a single face of the tricyclic system. As represented in the empirical model depicted in Figure 1B for the preparation of the tricyclic heterocycle 3, it is believed that this stereoselective hydrazulene-forming reaction proceeds by initial C−C bond formation to generate an intermediate cis-fused hydrindane core, with stereoselection for the second C−C bond-forming event being dictated by the stereochemistry of the tertiary metal alkoxide intermediate (e.g., B → C; Figure 1B). A previous study4 provided a glimpse that this class of alkyne−diketone annulation reactions is compatible with 1,4diketone-containing substrates, defining a new approach to the synthesis of oxygenated hydrindanes. For example, as reported previously and illustrated in eq 4 of Figure 2B, oxidative annulation of 10 delivers the cis-fused oxygenated hydrindane 11 in 49% isolated yield.4 Here, we demonstrate that this sixmembered ring-forming process is also highly effective with stereodefined substrates and can be used to generate complex
Figure 2. Alkyne−diketone annulation reactions to forge 5-, 6-, and 7membered rings. Typical annulation reactions are conducted with the combination of Ti(O-i-Pr)4 and c-C5H9MgCl. (a) Quench with NaHCO3 (half satd aq). (b) t-BuOOH is added for the oxidative quench. (c) 5 was used as a 1:1 mixture of diastereomers. (d) Quench with aq HCl (1 N). *Structures of these compounds are supported by X-ray diffraction. B
DOI: 10.1021/acs.orglett.9b02278 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
■
fused tricyclic carbocycles with ease. For example, as depicted in eqs 5 and 6, annulation reactions of the 1,4-diketonecontaining substrate 12 deliver either the ene-1,4-diol system 13 or the highly oxygenated variant 14 when termination of the reaction is conducted with t-BuOOH. Next, the cyclopentanone-containing system 15 was explored as a substrate for this annulation process, with the goal of accessing a distinct fused tricyclic system. Unfortunately, the synthesis employed for this substrate was not stereoselective, and attempts to separate the isomeric substrates were met with failure. Nevertheless, using 15 as a 1:1 mixture of stereoisomers as a substrate for the oxidative annulation reaction resulted in the tricyclic system 16 as a single stereoisomer. The yield for this reaction (38%) appears to reflect engagement of only the 2,5-cis isomer of 15 in the cyclization process. With momentum being gained for the value of metallacyclemediated alkyne−diketone annulation as an entry to a wide range of stereodefined carbocyclic systems, we redirected attention toward the intramolecular reactions of alkynes with 1,3-diketonesthe reaction process that is currently playing a central role in our studies toward a total synthesis of ryanodol. As illustrated in eq 8, this process has previously been shown to be effective with chiral diketone-containing substrates like 17 (eq 8; Figure 2C),4 providing an entry to complex tricyclic systems. It is revealed here that this type of cyclization (alkyne−1,3-diketone) can deliver structurally distinct polycyclic oxygenated products through an acid-mediated quench. As depicted in eq 9, Ti-mediated annulation of 17, followed by quenching with 1 N HCl delivers the rearranged product 19, now possessing a vicinal diol at the union of the fused bicyclo[3.3.0]octene motif of the tricyclic system. Finally, a limitation associated with stereoselectivity in these cyclization reactions has been observed. Attempts to employ alkyne−1,3-diketone coupling with a cycloheptanone-based substrate revealed that stereoselection can be negatively impacted by the nature of the cyclic ketone substrate. As illustrated in eq 10, oxidative annulation of 20 proceeds with 71% yield and delivers a 1:1 mixture of the tricylic products 21 and 22. It appears that the dampened diastereoselectivity of this annulation reaction is due to a lack of stereoselectivity in the initial C−C bond-forming event that establishes the first hydrazulene intermediate (cis- or trans-fused).9 The remaining stereocenters formed from the second C−C bond-forming event, as well as the directed epoxidation, appear to be tightly controlled by the stereochemistry of the initially formed tertiary metal alkoxide. Overall, we report that metallacycle-mediated alkyne− diketone coupling chemistry can be wielded to provide convenient and stereoselective access to a variety of fused tricyclic carbocycles, including those that contain oxygenated seven-membered rings. Valuable features of the annulation processes include (1) very high levels of stereoselectivity, (2) common sets of reaction conditions for annulation processes that forge 5-, 6-, and 7-membered rings, (3) utility of the process to access a wide variety of stereoedefined and highly oxygenated polycyclic systems, and (4) flexibility associated with the quenching of these processes (simple protic, acid, or oxidative). These combined features are rare among methods for the synthesis of stereodefined carbocycles, and efforts are ongoing to explore the value of these processes in target- and function-oriented synthesis.
Letter
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02278. Procedures and spectroscopic data, accompanied by additional examples of the annulation reaction (PDF) Accession Codes
CCDC 1903020−1903021, 1903032−1903034, 1903083, 1903097, and 1905540 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Glenn C. Micalizio: 0000-0002-3408-5570 Notes
The authors declare no competing financial interest.
■ ■
ACKNOWLEDGMENTS The authors acknowledge financial support from the National Institutes of Health (GM124004). REFERENCES
(1) For recent reviews of natural product synthesis, see: (a) Nicolaou, K. C.; Sorensen, E. J.; Winssinger, N. The Art and Science of Organic and Natural Products Synthesis. J. Chem. Educ. 1998, 75, 1225−1258. (b) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century. Angew. Chem., Int. Ed. 2000, 39, 44−122. (c) Nicolaou, K. C.; Hale, C. R. H.; Nilewski, C.; Ioannidou, H. A. Constructing molecular complexity and diversity: total synthesis of natural products of biological and medicinal importance. Chem. Soc. Rev. 2012, 41, 5185−5238. (d) Hoffmann, R. W. Natural Product Synthesis: Changes over Time. Angew. Chem., Int. Ed. 2013, 52, 123−130. (e) Mulzer, J. Trying to rationalize total synthesis. Nat. Prod. Rep. 2014, 31, 595−603. (f) Kuttruff, C. A.; Eastgate, M. D.; Baran, P. S. Natural product synthesis in the age of scalability. Nat. Prod. Rep. 2014, 31, 419−432. (g) Zweig, J. E.; Kim, D. E.; Newhouse, T. R. Methods Utilizing First-Row Transition Metals in Natural Product Total Synthesis. Chem. Rev. 2017, 117, 11680−11752. (h) Hui, C.; Chen, F.; Pu, F.; Xu, J. Innovation in protecting-group-free natural product synthesis. Nat. Rev. Chem. 2019, 3, 85−107. (2) (a) Bidasee, K. R.; Besch, H. R. Structure-Function Relationships among Ryanodine Derivatives. Pyridyl Ryanodine Definitively Separates Activation Potency from High Affinity. J. Biol. Chem. 1998, 273, 12176−12186. (b) McPherson, P. S.; Campbell, K. P. The Ryanodine Receptor/Ca2+ Release Channel. J. Biol. Chem. 1993, 268, 13765−13768. (c) Meissner, G. Ryanodine Receptor/Ca2+ Release Channels and Their Regulation by Endogenous Effectors. Annu. Rev. Physiol. 1994, 56, 485−508. (d) Fill, M.; Copello, J. A. Physiol. Rev. 2002, 82, 893−922. (e) McCauley, M. D.; Wehrens, X. H. T. Targeting Ryanodine Receptors for Anti-Arrhythmic Therapy. Acta Pharmacol. Sin. 2011, 32, 749−757. (f) Jenden, D. J.; Fairhurst, A. S. The Pharmacology of Ryanodine. Pharmacol. Rev. 1969, 21, 1−25. (g) Waterhouse, A. L.; Pessah, I. N.; Francini, A. O.; Casida, J. E. Structural Aspects of Ryanodine Action and Selectivity. J. Med. Chem. C
DOI: 10.1021/acs.orglett.9b02278 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters 1987, 30, 710−716. (h) Wiesner, K. The Structure, Stereochemistry and Absolute Configuration of Anhydroryanodine. Pure Appl. Chem. 1963, 7, 285−296. (i) Wiesner, K.; Valenta, Z.; Findlay, J. A. The Structure of Ryanodine. Tetrahedron Lett. 1967, 8, 221−225. (j) Srivastava, S. N.; Przybylska, M. The Molecular Structure of Ryanodol-p-Bromo Benzyl Ether. Can. J. Chem. 1968, 46, 795−797. (3) Du, K.; Kier, M. J.; Rheingold, A. L.; Micalizio, G. C. Toward the Total Synthesis of Ryanodol via Oxidative Alkyne−1,3-Diketone Annulation: Construction of a Ryanoid Tetracycle. Org. Lett. 2018, 20, 6457−6461. (4) Kier, M. J.; Leon, R. M.; O’Rourke, N. F.; Rheingold, A. L.; Micalizio, G. C. Synthesis of Highly Oxygenated Carbocycles by Stereoselective Coupling of Alkynes to 1,3- and 1,4-Dicarbonyl Systems. J. Am. Chem. Soc. 2017, 139, 12374−12377. (5) For examples of efforts targeting the total synthesis of ryanodol, see: (a) Deslongchamps, P. Synthetic Studies Towards Ryanodine. Pure Appl. Chem. 1977, 49, 1329−1359. (b) Bélanger, A.; Berney, D. J. F.; Borschberg, H. J.; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C.-C.; MacLachlan, F. N.; Maffrand, J. P.; Marazza, F.; Martino, R.; Moreau, C.; Saintlaurent, L.; Saintonge, R.; Soucy, P.; Ruest, L.; Deslongchamps, P. Total Synthesis of Ryanodol. Can. J. Chem. 1979, 57, 3348−3354. (c) Deslongchamps, P.; Bélanger, A.; Berney, D. J. F.; Borschberg, H. J.; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C.-C.; MacLachlan, F. N.; Maffrand, J. P.; Marazza, F.; Martino, R.; Moreau, C.; Ruest, L.; Saintlaurent, L.; Saintonge, R.; Soucy, P. The Total Synthesis of (+)-Ryanodol. Part I. General Strategy and Search for a Convenient Diene for the Construction of a Key Tricyclic Intermediate. Can. J. Chem. 1990, 68, 115−126. (d) Deslongchamps, P.; Bélanger, A.; Berney, D. J. F.; Borschberg, H. J.; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C.-C.; MacLachlan, F. N.; Maffrand, J. P.; Marazza, F.; Martino, R.; Moreau, C.; Ruest, L.; Saintlaurent, L.; Saintonge, R.; Soucy, P. The Total Synthesis of (+)-Ryanodol. Part II. Model Studies for Rings B and C of (+)-Anhydroryanodol. Preparation of a Key Pentacyclic Intermediate. Can. J. Chem. 1990, 68, 127−152. (e) Deslongchamps, P.; Bélanger, A.; Berney, D. J. F.; Borschberg, H. J.; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C.-C.; MacLachlan, F. N.; Maffrand, J. P.; Marazza, F.; Martino, R.; Moreau, C.; Ruest, L.; Saintlaurent, L.; Saintonge, R.; Soucy, P. The Total Synthesis of (+)-Ryanodol. Part III. Preparation of (+)-Anhydroryanodol from a Key Pentacyclic Intermediate. Can. J. Chem. 1990, 68, 153−185. (f) Deslongchamps, P.; Bélanger, A.; Berney, D. J. F.; Borschberg, H. J.; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C.-C.; MacLachlan, F. N.; Maffrand, J. P.; Marazza, F.; Martino, R.; Moreau, C.; Ruest, L.; Saintlaurent, L.; Saintonge, R.; Soucy, P. The Total Synthesis of (+)-Ryanodol. Part IV. Preparation of (+)-Ryanodol from (+)-Anhydroryanodol. Can. J. Chem. 1990, 68, 186−192. (g) Nagatomo, M.; Koshimizu, M.; Masuda, K.; Tabuchi, T.; Urabe, D.; Inoue, M. Total Synthesis of Ryanodol. J. Am. Chem. Soc. 2014, 136, 5916−5919. (h) Masuda, K.; Koshimizu, M.; Nagatomo, M.; Inoue, M. Asymmetric Total Synthesis of (+)-Ryanodol and (+)-Ryanodine. Chem. - Eur. J. 2016, 22, 230−236. (i) Chuang, K. V.; Xu, C.; Reisman, S. E. A 15-Step Synthesis of (+)-Ryanodol. Science 2016, 353, 912−915. (j) Xu, C.; Han, A.; Virgil, S. C.; Reisman, S. E. Chemical Synthesis of (+)-Ryanodine and (+)-20Deoxyspiganthine. ACS Cent. Sci. 2017, 3, 278−282. (6) Millham, A. B.; Kier, M. J.; Leon, R. M.; Karmakar, R.; Stempel, Z. D.; Micalizio, G. C. A Complementary Process to Pauson−KhandType Annulation Reactions for the Construction of Fully Substituted Cyclopentenones. Org. Lett. 2019, 21, 567−570. (7) For manuscripts that discuss strategies and methods for the synthesis of medium-sized rings, see: (a) Molander, G. A. Diverse Methods for Medium Ring Synthesis. Acc. Chem. Res. 1998, 31, 603− 609. (b) Yet, L. Metal-Mediated Synthesis of Medium-Sized Rings. Chem. Rev. 2000, 100, 2963−3007. (c) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073−2077. (d) Watson, I. D. G.; Ritter, S.; Toste,
F. D. Asymmetric Synthesis of Medium-Sized Rings by Intramolecular Au(I)-Catalyzed Cyclopropanation. J. Am. Chem. Soc. 2009, 131, 2056−2057. (e) Illuminati, G.; Mandolini, L. Ring Closure Reactions of Bifunctional Chain Molecules. Acc. Chem. Res. 1981, 14, 95−102. (8) For a review of substrate-directable chemical reactions, including metal-mediated hydroxyl-directed epoxidation, see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Substrate-Directable Chemical Reactions. Chem. Rev. 1993, 93, 1307−1370. (9) Sugimura, T.; Futagawa, T.; Tai, A. Synthetic Approach for (+)-Africanol. Chem. Lett. 1990, 19, 2295−2298.
D
DOI: 10.1021/acs.orglett.9b02278 Org. Lett. XXXX, XXX, XXX−XXX
