Synthesis of 7-Epi (+)-FR900482:  An Epimer of Comparable Anti-Cancer Activity

Abstract

FR900482 is a potent anti-tumor therapeutic that has been investigated as a replacement candidate for the clinically useful Mitomycin C. Herein, we report synthesis and biological testing of 7-Epi (+)-FR900482, which demonstrates equal potency relative to the natural product against several cancer cell lines. Highlights of this work include utilization of our palladium-catalyzed DYKAT methodology and development of a Polonovski oxidative ring expansion strategy to yield this equipotent epimer in 23 linear steps.

Biomimetic Thioesters as Probes for Enzymatic Assembly Lines: Synthesis, Applications, and Challenges

“…tert-butyl, and phenyl thioesters (Michalak and Wicha, 2011;Sewing and Hilvert, 2001;Trost and O'Boyle, 2008;Zhou et al, 2008). However, at least one example is known for the use of NAC combined with AlMe 3 (Tsantrizos et al, 1995), which might inspire future developments in this direction.…”

Mitomycinoid Alkaloids: Mechanism of Action, Biosynthesis, Total Syntheses, and Synthetic Approaches

“…[332] While technically not a natural product total synthesis, since 7- epi -FR900482 has not yet been discovered, it is included here as this molecule is functionally active as cytotoxic agent and DNA cross-linking agent and intercepts the same mitosene species produced by the reductive activation of the natural product. Although an earlier report detailed the construction of the benzazocine core of FR900482 via palladium-catalyzed carbonylative lactamization, [333] the latter paper described a different approach.…”

Investigation of a Domino Heck Reaction for the Rapid Synthesis of Bicyclic Natural Products

“…During efforts toward the synthesis of FR900482,4 we intended to utilize an 8‐ exo ‐ trig Heck reaction to forge the benzazacine core of the molecule (Scheme ). Instead when 3 was exposed to Heck reaction conditions5 a remarkable result was obtained.…”

“…A number of clever domino reactions [1] have been implemented using either sequential Heck reactions [2] or an initial Heck reaction in tandem with another palladium catalyzed process. [3] During efforts toward the synthesis of FR900482, [4] we intended to utilize an 8-exo-trig Heck reaction to forge the benzazacine core of the molecule (Scheme 1). Instead when 3 was exposed to Heck reaction conditions [5] a remarkable result was obtained.…”