Total Synthesis of (+)-Granatumine A and Progress Toward the Total Synthesis of Xylogranin B

Date of Award

Fall 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Newhouse, Timothy

Abstract

Limonoids are tetranotriterpenoid natural products that include more than athousand members with remarkable structural diversity and biological activities. Over the past several decades, there have been numerous literatures on their biology and chemical synthesis. This thesis delineates synthetic efforts to access two subclasses of limonoid natural products, bislactone limonoid alkaloids and phragmalin-type limonoids, which have interesting bioactivities and structural features and yet received little attention from the synthetic community. Chapter one of this thesis describes the background, biosynthesis, and previous classic total synthesis of limonoid natural products. To tackle these complicated natural products, two main synthetic strategies, polyolefin cyclization and fragment-coupling, have been developed to boost the synthetic efficiency. Chapter two discusses the convergent synthesis of (+)-granatumine A and related limonoid alkaloid natural products. A fragment-coupling strategy was devised to access (+)-granatumine A and its congeners through central pyridine ring construction. The previous late-stage benzylic oxidation approach employed in the xylogratopyridine B synthesis was unsuccessful in accessing (+)-granatumine A due to increased steric hindrance and unfavorable electronic properties. To circumvent this issue, a pre-installed C3 oxidation state was introduced before the pyridine formation step. DFT and NMR ii computations were employed to obtain mechanistic insights, and guide the structural reassignment of several natural products including granatoine and xylogranatin F respectively. PTP1B inhibitory activities of several limonoid alkaloids as well as their analogs were evaluated. Chapter three documents the current progress in the total synthesis of xylogranin B and related phragmalin natural products. A B-ring endocyclic functionalization strategy was first designed in accessing the bridgehead C2-OH of the C2-hydroxy bicyclo[3.3.1]nonane scaffold, albeit unsuccessful due to unintended B-ring aromatization and undesired regioselectivity. These problems were solved by lowering the B-ring oxidation state and utilizing an alternative B-ring exocyclic functionalization strategy. To complete the bicyclo[3.3.1]nonane motif in the tricyclo[3.3.12,10.11,4]decane skeleton, an allylation approach and an HWE-olefination approach were first proposed and implemented, which proved to be challenging and unfruitful. Finally, the C2-hydroxy bicyclo[3.3.1]nonane motif was constructed through a Still-Gennari olefination approach.

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