The complex molecular structure of medicinally important natural products has stimulated the development of new chemical reactions that quickly generate structural complexity from simple starting materials. Transition metal-catalyzed reactions are uniquely suited for this purpose because the chemoselectivity and stereoselectivity of a given process is quite often predictable and reliable. Vanadium catalysts have found widespread application in synthesis, most notably as catalysts for isomerization and asymmetric oxidation reactions. This research plan will focus on the development of a novel vanadium-catalyzed cascade reaction between propargylic alcohols and cyclopropyl aldehydes that generates highly functionalized 1,3-dienes. This tandem process represents a single pot, atom economic construction of highly functionalized dienes that are powerful, flexible intermediates towards more complex targets. After exploring the substrate scope of this cascade reaction, the utility of the 1,3-diene as an intermediate in synthesis will be demonstrated by performing selective inter- and intramolecular transformations to generate important natural product scaffolds. The vanadium-catalyzed cascade will then be used to carry out a concise total synthesis of nodosin and sculponin B of the ent-kauranoid family of natural products. Nodosin and other ent-kauranoids have recently received significant attention due to their potent anticancer activity. Nodosin in particular has shown potent inhibitory activity against K562 human chronic myelogenous leukemia cells. The synthesis of nodosin will represent a general strategy for accessing many of the ent-kauranoids, facilitating further development of this important class of compounds as cancer chemotherapeutic agents.

Public Health Relevance

Natural products have historically been an important source of new chemotherapeutic agents for the treatment of cancer. The ent-kauranoid family of natural products has recently shown large potential for use as anticancer drugs due to their cytotoxic and antitumor properties. This proposal provides a general strategy for rapidly synthesizing the ent-kauranoids and their derivatives, making possible further development of this important class of natural products as anticancer agents

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM093467-03
Application #
8245070
Study Section
Special Emphasis Panel (ZRG1-F04A-B (20))
Program Officer
Lees, Robert G
Project Start
2010-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$52,190
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Trost, Barry M; Michaelis, David J; Truica, Mihai I (2013) Dinuclear zinc-ProPhenol-catalyzed enantioselective *-hydroxyacetate aldol reaction with activated ester equivalents. Org Lett 15:4516-9
Trost, Barry M; Michaelis, David J; Charpentier, Julie et al. (2012) Palladium-catalyzed allylic alkylation of carboxylic acid derivatives: N-acyloxazolinones as ester enolate equivalents. Angew Chem Int Ed Engl 51:204-8
Trost, Barry M; Lehr, Konrad; Michaelis, David J et al. (2010) Palladium-catalyzed asymmetric allylic alkylation of 2-acylimidazoles as ester enolate equivalents. J Am Chem Soc 132:8915-7