Synthetic Strategies for the Total Synthesis of the Ryanoid and Isoryanoid Diterpenes

Citation

Han, Arthur (2019) Synthetic Strategies for the Total Synthesis of the Ryanoid and Isoryanoid Diterpenes. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/JDZV-P010. https://resolver.caltech.edu/CaltechTHESIS:09292018-211645714

Abstract

Highly oxygenated, polycyclic terpenoids provide a rich source of biologically active natural products, yet the translation of their activity to lead candidate analogs and useful biological probes requires concise solutions to address, at once, accessibility and diversification. This dissertation will disclose our efforts to bridge that gap through the development of synthetic strategies for the total synthesis of the ryanoid and isoryanoid diterpenes. The studies herein will address the strategy and logic that rendered the success of a challenging C3 acylation to directly incorporate a pyrrole-2-carboxylate ester, ultimately resulting in an 18-step total synthesis of (+)-ryanodine. The versatility of the route was demonstrated by the preparation of the related ryanoid diterpene (+)-20-deoxyspiganthine. Enabling the success of both syntheses was the development of robust conditions to induce late-stage reductive ring closure and forge the C1–C15 bond.

The lessons learned from these synthetic efforts drew us thereafter to the complex, polycyclic structure of the isoryanoid diterpene (+)-perseanol. The evaluation of several different approaches culminated in the discovery of a successful fragment coupling approach, hinging on a 2-step sequence involving (1) 1,2-addition to induce convergent union of two fragments of equal complexity and (2) Heck-Stille cyclization/cross-coupling cascade to complete the preparation of the ABC tricyclic core. Emphasis will be placed on the strategic use of our fragment coupling approach to overcome the inherent stereochemical bias presented by late-stage intermediates, thereby enabling an 18-step total synthesis. The oxidation tactics developed herein should find broad utility in the preparation of other ryanoid, isoryanoid, and highly oxidized diterpenoids.

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