Design and Application of Complexity Generating Strategies and Transformations in Natural Product Synthesis

Author: Stegner, Andrea Anna Therese

Year: 2025

Degree: Dissertation (Ph.D.)

Advisor: Reisman, Sarah E.

Committee Members: Robb, Maxwell J.; Stoltz, Brian M.; Wilson, Linda C.; Reisman, Sarah E.

Option: Chemistry

DOI: 10.7907/w4xa-hy67

Abstract

Rapid and efficient chemical synthesis of complex molecules is critical for enabling studies of their biological function and therapeutic potential. Complexity generation can be achieved by: (1) the development of selective transformations that rapidly construct complex scaffolds from simple precursors, and (2) the application of strategic retrosynthetic disconnections that maximize the efficiency of a synthesis i.e., via convergent fragment coupling strategies. We disclose efforts to address these aims by combining reaction design with the identification of strategic disconnections.

Toward the first aim, a diastereoselective dearomative pyridine cyclization that forges the tetracyclic core of the matrine-type lupin alkaloids in a single step from commodity feedstocks was developed. This reaction, paired with a C15-selective oxidation cascade and late-stage isomerization, enabled the first total synthesis of (–)-sophoridine and the shortest syntheses to date of (+)-matrine, (+)-isomatrine, (+)-allomatrine, and (+)- isosophoridine.

To address the second aim, a convergent strategy for the synthesis of 6,7-seco-ent- kauranoids via strategic, transition metal-catalyzed C-C bond formation was developed. Both a Ni-catalyzed sp²–sp³ and a dual Ni/Pd-catalyzed sp²–sp² coupling were developed and enabled efficient union of complex fragments, the latter yielding 1,3 dienes that underwent divergent annulation reactions to form various complex ring systems. These transformations provided the complete skeleton of isorosthin A and advanced intermediates en route to isodocarpin and secoexertifolin A.

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