11-Step Enantioselective Synthesis of (−)-Lomaiviticin Aglycon

Abstract

Lomaiviticins A and B are complex antitumor antibiotics that were isolated from a strain of Micromonospora. A confluence of several unusual structural features renders the lomaiviticins exceedingly challenging targets for chemical synthesis. We report an 11-step, enantioselective synthetic route to lomaiviticin aglycon. Our route proceeds by late-stage, stereoselective dimerization of two equivalent monomeric intermediates, a transformation that may share parallels with the natural products’ biosyntheses. The route we describe is scalable and convergent, and it lays the foundation for determination of the mode of action of these natural products.

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

“…To date, no total synthesis of any lomaiviticin has been achieved, although the aglycone can be accessed in just eleven steps and 4 can be generated semi-synthetically from the more abundant metabolite 185 . 449,453,465,468,469 In these total synthesis and semi-synthesis efforts, the diazo groups are installed via Regitz diazo transfer onto an activated methine intermediate.…”

Diazo Compounds: Versatile Tools for Chemical Biology

“…25 Although synthetic routes to the lomaiviticins are unrealized to date, progress has been made towards intermediates and analogues. 26–30 …”

The marine actinomycete genus Salinispora: a model organism for secondary metabolite discovery

“…It was independently characterized in S. pacifica by the Balskus group 39 who established that the associated type II polyketide synthase (PKS) supports a new strategy for propionyl starter unit generation previously observed in type I PKS pathways 45 . Numerous groups have also established synthetic routes to different portions of the lomaiviticin aglycone with Herzon and coworkers completing the first enantioselective synthesis of the aglycone 46 . To date, the total synthesis of lomaiviticin has not been reported.…”