Synthetic organic chemistry is one of the pillars of the drug discovery and development process as it is necessary to prepare medicinally important natural products and related analogs through chemical synthesis. Efficient access to these natural products through development of new, complexity building reactions is of the utmost importance. The recently isolated natural product hopeanol, possessing a unique and complex carbon skeleton, exhibits potent cytotoxic activity against a number of cancer cell lines. This proposal outlines a novel synthetic strategy to efficiently access enantiomerically pure hopeanol. The total synthesis will be highlighted through the development and use of an innovative 1,2-aryl migration to afford highly substituted enantiomerically pure benzofuran scaffolds. In addition, this total synthesis will provide a testing ground for previously developed methods in new and complex settings. More specifically, sequential Pd-catalyzed arylation of 1,1-dichlorostyrene derivatives will stereoselectively afford complex trisubstituted olefins. Additionally, catalytic enantioselective epoxidation of highly functionalized triarylsubstituted olefins with chiral ketone-based catalysts will be demonstrated. Development and utilization of these complexity building reactions will allow enantiomerically pure hopeanol to be prepared in an efficient manner. Initial interest in the target was garnered for its biological activity and overlying reasons for its chemical synthesis are rooted in evaluation of hopeanol as well as structural analogs against cancer cell lines. The total synthesis of hopeanol will provide a foundation on which further studies regarding analogue synthesis will be based. This proposal will broaden our understanding of reaction mechanism and synthetic design and ultimately contribute to human health.

Public Health Relevance

In many cases, isolation of sufficient quantities of molecules from natural sources to be used for the treatment of important diseases is an impossible task. Therefore, synthetic preparation of natural products in a cost effective and time efficient manner from inexpensive starting materials is of the utmost importance. It is the goal of this proposal to efficiently prepare potent anti-tumor natural product hopeanol.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM084571-03
Application #
7923311
Study Section
Special Emphasis Panel (ZRG1-F04A-T (20))
Program Officer
Marino, Pamela
Project Start
2008-09-01
Project End
2011-06-30
Budget Start
2010-09-01
Budget End
2011-06-30
Support Year
3
Fiscal Year
2010
Total Cost
$43,370
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138