Enantioselective synthesis of largazole, development of multicomponent reactions, and design and synthesis of novel HIV -1 protease inhibitors
Abstract
The dissertation describes the total synthesis of (+)-largazole, the development of multicomponent reactions, and the design and synthesis of novel HIV-1 protease inhibitors incorporating macrocyclic P1'-P 2' ligands. Chapter 1 of the dissertation details the total synthesis of (+)-largazole. Largazole is a highly potent and selective antiproliferative agent. The synthesis involves a lipase catalyzed resolution of β-hydroxy ester, a biomimetic formation of thiazoline-thiazole fragment, a cross metathesis reaction. Two equally dense fragments were assembled by a HATU/HOAt coupling. The final macrolactamization was achieved by a HATU/HOAt macrocyclization. The synthesis also features chemical modifications in presence of sensitive thioester functionality. Chapter 2 of the dissertation describes the development of asymmetric multicomponent reactions. A novel asymmetric three component reaction using optically active phenyldihydrofuran, α-imino ester or β-keto ester and a suitable nucleophile is described. The reaction is highly efficient and leads to formation of a densely functionalized tetrahydrofuran with formation of two new C-C bonds and establishes three new chiral centers in a stereoselective fashion in a single step. An unexpected temperature dependent rearrangement of the furans to pyrrolidines has been discussed. An application of this methodology in synthesis of functionalized cyclopentenes is described. Chapter 3 of the dissertation describes the design and synthesis of HIV-1 protease inhibitors containing a macrocycle as a P1'-P2' ligand. The macrocyclic inhibitors were synthesized from dienes by ring closing metathesis. A number of ring sizes (9- to 15-membered) were synthesized. The effect of the ring size and unsaturation within the macrocyclic ring on the biological activity was studied. The enzyme inhibitory and cellular potency of the acyclic and cyclic unsaturated and saturated macrocycles were compared.
Degree
Ph.D.
Advisors
Ghosh, Purdue University.
Subject Area
Organic chemistry
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.