Asymmetric Total Synthesis of Naturally Occurring Indoloditerpene Alkaloid: (+)-Shearilicine

Roy, Nanda Kishore (2026) Asymmetric Total Synthesis of Naturally Occurring Indoloditerpene Alkaloid: (+)-Shearilicine. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (Phd thesis of Nanda Kishore Roy (21RS070)) 21RS070.pdf - Submitted Version Restricted to Repository staff only Download (27MB)

Abstract

Carbazole-containing diterpenoid alkaloids constitute a class of natural products exhibiting diverse biological activities. Shearilicine features a unique indole diterpenoid framework comprising a rare 6/5/6/6/6/6/5 fused ring system in which an aromatic ring is joined to a decalin core. Notably, shearilicine (1) bears a highly oxidized terminal ring, a structural motif often correlated with potent bioactivity. In their total synthesis of shearilicine, Timothy R. Newhouse and co-workers employed a biomimetic strategy featuring a mild Heck-type cyclization as the key step to construct the natural product’s core framework. Xiamycins, another family of indolosesquiterpene alkaloids, possess a carbazole moiety fused to a trans-decalin scaffold. Several groups, including Baran, Li, and Sarpong, have reported distinct synthetic approaches toward these targets. Oridamycin A, a close structural relative of the xiamycins, was first synthesized by Meng, Li, and co-workers. Our group is currently developing a concise and enantioselective synthetic route to carbazole-fused indolosesquiterpenoid and diterpenoid alkaloids. We have successfully achieved the first catalytic asymmetric total synthesis of indolo diterpenoid alkaloid shearilicine [(+)-1] in 24 steps in longest linear sequence (LLS). A key transformation in the route is the Ag(I)-catalyzed ene-yne cyclization of enantioenriched TBS-protected alcohol. The highly diastereoselective construction of the trans-decalin core in not only enabled access to shearilicine [(+)-1] but also provides valuable insights for the synthesis of other bioactive natural products featuring the trans-decalin scaffold.

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