A bridged backbone strategy enables collective synthesis of strychnan alkaloids

Published in Chemistry
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Bridged frameworks are central motifs found in the scaffolds of numerous clinical drugs and bioactive natural products. Largely due to the ring strain, it is usually difficult to construct the bridged frameworks efficiently, and specific structures are usually pre-set to facilitate construction of these motifs, resulting in multiple pre- and re-functionlization steps and target-specific syntheses.

Figure 1. a, Monomeric and dimeric strychnan alkaloids targeted in this study. b, Enantioselective α-allenylation of the ketone via SN2′ reaction of the propargylic alcohol ester using synergistic organocatalysis and metal catalysis.

The strychnan alkaloids represent one of the most populous classes of natural products identified to date. Structurally, the bridged morphan core is the central motif, which is surrounded by up to five fusing rings to constitute the cage-shaped scaffold for both monomeric and dimeric strychnan alkaloids (Figure 1a). The scaffold rigidity coupled with the broad array of functionalities on C16 and C20 of the morphan core (2-azabicyclo[3.3.1]nonane) set the structural basis for a wide range of bioactivities, but present daunting challenges for chemical synthesis. The bridged morphan core is typically central to retrosynthetic planning for strychnan alkaloids. Complex and peculiar ring systems are often created first, then the morphan core is formed at the middle or late stage of synthesis.

Driven by our continuous interest in application of strained rings in total synthesis of polycyclic alkaloids,1−4 we proposed an alternative synthesis design in which an allene/ketone-equipped morphan core was constructed at the outset and then employed as a structural platform to guide and facilitate assembly of the surrounding rings and installment of functionalities at C16 and C20. To realize this strategy, we have developed a method of catalytic enantioselective α-allenylation of ketone by means of synergistic organocatalysis and metal catalysis, which assembles the morphan skeleton and installs an exocyclic allene group simultaneously (Figure 1b). Experimental and theoretical results indicated that the high reaction barrier to form a bridged framework bearing two sp2-hybridized endocyclic carbon atoms is overcome by the cooperative effects of the organocatalyst and metal catalyst. During this catalytic process, the bifunctional organocatalyst allows concurrent activation and fine spatial orientation of the substrates by forming an enamine and hydrogen bonds, while the Lewis acidic metal catalyst promotes the reaction to take place through triple-bond activation. Using this functionalized morphan as the structural platform, total synthesis of seven monomeric strychnan alkaloids including strychnine has been accomplished in short steps (Figure 2).

Figure 2. The collective access to strychnan alkaloids.

Besides the homodimeric alkaloid leucoridine A, the heterodimeric alkaloid geissolosimine has been synthesized though a biomimetic condensation of strychnan alkaloid geissoschizoline and sarpagine alkaloid vellosimine, which was synthesized recently in our group with homo-Mannich reaction of cyclopropanol as the key step (Figure 3).1,2

Figure 3. Bomimetic total synthesis of geissolosimine.

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References

  1. Tan, Q., Yang, Z., Jiang, D., Cheng, Y., Yang, J., Xi, S. & Zhang, M. Copper-Catalyzed Aerobic Oxidative Cyclization Cascade to Construct Bridged Skeletons: Total Synthesis of (-)-Suaveoline. Angew. Chem. Int. Ed. 58, 6420–6424 (2019).
  2. Yang, Z., Tan, Q., Jiang, Y., Yang, J., Su, X., Qiao, Z., Zhou, W., He, L., Qiu, H. & Zhang, M. Asymmetric Total Synthesis of Sarpagine and Koumine Alkaloids. Angew. Chem. Int. Ed. 60, 13105−13111 (2021).
  3. Zhou, W., Zhou, T., Tian, M., Jiang, Y., Yang, J., Lei, S., Wang, Q., Zhang, C., Qiu, H., He, L., Wang, Z.; Deng, J. & Zhang, M. Asymmetric Total Syntheses of Schizozygane Alkaloids. J. Am. Chem. Soc. 143, 19975–19982 (2021).
  4. Zhang, Q., Yang, Z., Wang, Q., Liu, S., Zhou, T., Zhao, Y. & Zhang, M. Asymmetric Total Synthesis of Hetidine-Type C20-Diterpenoid Alkaloids: (+)-Talassimidine and (+)-Talassamine. J.  Am. Chem. Soc. 143, 7088–7095 (2021).

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