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 anti-cancer 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 where 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, 8-membered heterocycle formation via carbonylative lactamization, and amination through late-stage C-H insertion via rhodium catalysis all featured prominently in our synthetic studies.

Metal catalyzed allylic alkylation: its development in the Trost laboratories

“…Using phthalimide as nucleophile indeed provided a 72% yield (96% based upon 25% being non-reactive) of the monoalkylated product of 89% ee (see Table 2, entry 10). This intermediate led to the alkaloid australine 108a and the mitomycin analog 7-epi-(+)-FR900482. 108b …”

“…This intermediate led to the alkaloid australine 108a and the mitomycin analog 7-epi-(+)-FR900482. 108b …”

Nickel-catalyzed regiodivergent approach to macrolide motifs

“…4a,9 This limitation was confirmed in a recent attempt to access exo-selective reductive macrocyclizations 10 using existing protocols including those originating from our laboratory. 11 However, a recent disclosure from our laboratory described studies with an expanded set of ligands, wherein a broad range of alkynes participated in intermolecular reductive couplings to provide either regioisomer in a ligand-controlled process.…”

Chemoselective Intramolecular Formal Insertion Reaction of Rh–Nitrenes into an Amide Bond Over C−H Insertion

“…[12a] As ar esult,t he chemoselective formationo fa nN + ÀN À ylide with an electronically deactivated amine such as an amide group over aC ÀHi nsertion reaction remains achallenge. [9,14] Indeed, the formation of N + ÀN À ylides from metal-nitrenes and amides has not yet been reported. [15] These problematic factors have hindered the development of new reactions involving N + ÀN À ylide intermediates, even thoughd ipolar nitrogen ylides are potentiali ntermediates for efficient and unusual transformations.…”

“…The energy barrier for the insertion of metal–nitrenes into C−H bonds is often lower than that for N + −N − ylide formation, especially with a less nucleophilic amino functionality . As a result, the chemoselective formation of an N + −N − ylide with an electronically deactivated amine such as an amide group over a C−H insertion reaction remains a challenge . Indeed, the formation of N + −N − ylides from metal–nitrenes and amides has not yet been reported .…”