Development of a flexible strategy towards FR900482 and the mitomycins.

Abstract

FR900482 and the mitomycins are two intriguing classes of alkaloid natural products that have analogous biological mechanisms and obvious structural similarity. Both classes possess potent anticancer activity, a feature that has led to their investigation and implementation for the clinical treatment of human cancer. Given the structural similarity between these natural products, we envisioned a common synthetic strategy by which both classes could be targeted through assembling the mitomycin skeleton prior to further oxidative functionalization. Realization of this strategy with respect to FR900482 was accomplished through the synthesis of 7-epi-FR900482, which displayed equal potency relative to the natural product against two human cancer cell lines. With the challenging goal of a synthesis of either mitomycin or FR900482 in mind, several methodologies were explored. While not all of these methods ultimately proved useful for our synthetic goal, a number of them led to intriguing findings that provide a more complete understanding of several methodologies. In particular, amination via π-allyl palladium complexes for the synthesis of tetrahydroquinolines, eight-membered heterocycle formation via carbonylative lactamization, and amination through late-stage C-H insertion via rhodium catalysis all featured prominently in our synthetic studies.

• Authors: Barry M Trost, Brendan M O'Boyle, Wildeliz Torres, Michael K Ameriks
• Journal: Chemistry (Weinheim an der Bergstrasse, Germany) (Chemistry) Vol. 17 Issue 28 Pg. 7890-903 (Jul 04 2011) ISSN: 1521-3765 [Electronic] Germany
• PMID: 21618622 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• 7-epi-FR900482
• Antineoplastic Agents
• Biological Products
• Mitomycins
• Oxazines
• FR 900482

Topics

• Antineoplastic Agents (chemical synthesis, chemistry)
• Biological Products (chemistry)
• Drug Design
• Humans
• Mitomycins (chemical synthesis, chemistry)
• Molecular Structure
• Oxazines (chemical synthesis, chemistry)
• Stereoisomerism