Abstract
C19-diterpene alkaloids are a class of alkaloids with pharmacologically important activities having an intricately fused hexacyclic ABCDEF-ring system. Here we report expeditious assembly of the ACE-ring substructure 4a by applying a three-component coupling strategy. A radical–polar crossover reaction between an AE-ring radical precursor, a C-ring radical acceptor and an aldehyde was realized by the actions of Et3B and O2, resulting in the installation of three new stereocenters and extension of the carbon chain corresponding to the B-ring. As the ACE-ring 4a possesses the correct C4,11-quaternary and C10-tertiary carbons, 4a would serve as an advanced intermediate for constructing the entire C19-diterpene alkaloid structures.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Wang, F. P. & Chen, Q.-H. in The Alkaloids: Chemistry and Biology Vol. 69: (ed. Cordell, G. A. 1–577 Elsevier, New York, (2010).
Goodall, K. J., Barker, D. & Brimble, M. A. A review of advances in the synthesis of analogues of the Delphinium alkaloid methyllycaconitine. Synlett 2005, 1809–1827 (2005).
Cherney, E. C. & Baran, P. S. Terpenoid-alkaloids: their biosynthetic twist of fate and total synthesis. Isr. J. Chem. 51, 391–405 (2011).
Hamlin, A. M., Kisunzu, J. K. & Sarpong, R. Synthetic strategies toward hetidine and hetisine-type diterpenoid alkaloids. Org. Biomol. Chem. 12, 1846–1860 (2014).
Liu, X.-Y. & Qin, Y. Ongoing pursuit of diterpenoid alkaloids: a synthetic view. Asian J. Org. Chem. 4, 1010–1019 (2015).
Zhu, G., Liu, R. & Liu, B. Total synthesis of atisane-type diterpenoids and related diterpenoid alkaloids. Synthesis 47, 2691–2708 (2015).
Wiesner, K. The total synthesis of racemic talatisamine. Pure Appl. Chem. 41, 93–112 (1975).
Wiesner, K. Total synthesis of delphinine-type alkaloids by simple, fourth generation methods. Pure Appl. Chem. 51, 689–703 (1979).
Shi, Y., Wilmot, J. T., Nordstrøm, L. U., Tan, D. S. & Gin, D. Y. Total synthesis, relay synthesis, and structural confirmation of the C18-norditerpenoid alkaloid neofinaconitine. J. Am. Chem. Soc. 135, 14313–14320 (2013).
Marth, C. J. et al. Network-analysis-guided synthesis of weisaconitine D and liljestrandinine. Nature 528, 493–498 (2015).
Nishiyama, Y., Yokoshima, S. & Fukuyama, T. Total synthesis of (-)-cardiopetaline. Org. Lett. 18, 2359–2362 (2016).
Tabuchi, T., Urabe, D. & Inoue, M. Construction of the fused pentacycle of talatisamine via a combination of radical and cationic cyclizations. J. Org. Chem. 81, 10204–10213 (2016).
Hagiwara, K., Tabuchi, T., Urabe, D. & Inoue, M. Expeditious synthesis of the fused hexacycle of puberuline C via a radical-based cyclization/translocation/cyclization process. Chem. Sci. 7, 4372–4378 (2016).
Tojino, M. & Ryu, I. in Multicomponent Reactions (eds Zhu, J. & Bienaymé, H. 169–198 Wiley-VCH, Weinheim, (2005).
Nicolaou, K. C., Edmonds, D. J. & Bulger, P. G. Cascade reactions in total synthesis. Angew. Chem. Int. Ed. 45, 7134–7186 (2006).
Godineau, E. & Landais, Y. Radical and radical-ionic multicomponent processes. Chem. Eur. J. 15, 3044–3055 (2009).
Pellissier, H. Stereocontrolled domino reactions. Chem. Rev. 113, 442–524 (2013).
Urabe, D., Asaba, T. & Inoue, M. Convergent strategies in total synthesis of complex terpenoids. Chem. Rev. 115, 9207–9231 (2015).
Inoue, M. Evolution of radical-based convergent strategies for total syntheses of densely oxygenated natural products. Acc. Chem. Res. 50, 460–464 (2017).
Kamimura, D., Urabe, D., Nagatomo, M. & Inoue, M. Et3B-mediated radical-polar crossover reaction for single-step coupling of O,Te-acetal, α,β-unsaturated ketones, and aldehydes/ketones. Org. Lett. 15, 5122–5125 (2013).
Kamimura, D., Nagatomo, M., Urabe, D. & Inoue, M. Expanding the scope of Et3B/O2-mediated coupling reactions of O,Te-acetal. Tetrahedron 72, 7839–7848 (2016).
Walton, J. C. Bridgehead radicals. Chem. Soc. Rev. 21, 105–112 (1992).
Kraus, G. A., Andersh, B., Su, Q. & Shi, J. Bridgehead radicals in organic chemistry. An efficient construction of the ABDE ring system of the lycoctonine alkaloids. Tetrahedron Lett. 34, 1741–1744 (1993).
Urabe, D., Yamaguchi, H. & Inoue, M. Application of α-alkoxy bridgehead radical for coupling of oxygenated carbocycles. Org. Lett. 13, 4778–4781 (2011).
Schnermann, M. J. & Overman, L. E. A concise synthesis of (-)-aplyviolene facilitated by a strategic tertiary radical conjugate addition. Angew. Chem. Int. Ed. 51, 9576–9580 (2012).
Lackner, G. L., Quasdorf, K. W. & Overman, L. E. Direct construction of quaternary carbons from tertiary alcohols via photoredox-catalyzed fragmentation of tert-alkyl N-phthalimidoyl oxalates. J. Am. Chem. Soc. 135, 15342–15345 (2013).
Rowlands, G. J. Radicals in organic synthesis. Part 1. Tetrahedron 65, 8603–8655 (2009).
Rowlands, G. J. Radicals in organic synthesis. Part 2. Tetrahedron 66, 1593–1636 (2010).
Beraud, V., Gnanou, Y., Walton, J. C. & Maillard, B. New insight into the mechanism of the reaction between α,β-unsaturated carbonyl compounds and triethylborane (Brown's reaction). Tetrahedron Lett. 41, 1195–1198 (2000).
Nozaki, K., Oshima, K. & Utimoto, K. Trialkylborane as an initiator and terminator of free radical reactions. Facile routes to boron enolates via α-carbonyl radicals and aldol reaction of boron enolates. Bull. Chem. Soc. Jpn 64, 403–409 (1991).
Ollivier, C. & Renaud, P. Organoboranes as a source of radicals. Chem. Rev. 101, 3415–3434 (2001).
Godineau, E. & Landais, Y. Multicomponent radical processes: synthesis of substituted piperidinones. J. Am. Chem. Soc. 129, 12662–12663 (2007).
Kraus, G. A. & Shi, J. Reactions of bridgehead halides. A synthesis of modhephene, isomodhephene, and epi-modhephene. J. Org. Chem. 56, 4147–4151 (1991).
Ihara, M., Suzuki, M., Fukumoto, K. & Kabuto, C. Asymmetric total synthesis of atisine via intramolecular double Michael reaction. J. Am. Chem. Soc. 112, 1164–1171 (1990).
Hudlicky, T. & Reed, J. W. Applications of biotransformations and biocatalysis to complexity generation in organic syntheses. Chem. Soc. Rev. 38, 3117–3132 (2009).
Akita, H. Recent advances in the synthesis of biologically active natural products using biocatalyst. Heterocycles 78, 1667–1713 (2009).
Sasano, Y. et al. Highly chemoselective aerobic oxidation of amino alcohols into amino carbonyl compounds. Angew. Chem., Int. Ed. 53, 3236–3240 (2014).
Bickley, J. F., Roberts, S. M., Santoro, M. G. & Snape, T. J. Synthesis and revision of the stereochemistry of a cyclopentenone natural product isolated from ascomycete strain A23-98. Tetrahedron 60, 2569–2576 (2004).
Inoue, T. & Mukaiyama, T. Regio- and stereoselective cross-aldol reactions via dialkylboryl triflates. Bull. Chem. Soc. Jpn 53, 174–178 (1980).
Evans, D. A., Nelson, J. V., Vogel, E. & Taber, T. R. Stereoselective aldol condensations via boron enolates. J. Am. Chem. Soc. 103, 3099–3111 (1981).
Acknowledgements
This research was financially supported by the Funding Program for a Grant-in-Aid for Scientific Research (A) (JSPS Grant Number 26253003) to MI and a Grant-in-Aid for Young Scientists (A) (JSPS Grant Number 16H06213) to DU.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Dedicated with respect and admiration to Professor KC Nicolaou for his many outstanding contributions to natural product synthesis.
Supplementary Information accompanies the paper on The Journal of Antibiotics website
Supplementary information
Rights and permissions
About this article
Cite this article
Minagawa, K., Urabe, D. & Inoue, M. A three-component coupling approach to the ACE-ring substructure of C19-diterpene alkaloids. J Antibiot 71, 326–332 (2018). https://doi.org/10.1038/ja.2017.69
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/ja.2017.69
