The pimarane diterpene (+)-myrocin C (1) is an antitumor antibiotic isolated from the soil fungus Myrothecium verrucaria. 1 was found to exhibit a therapeutic effect in mice infected with Ehrlisch ascites carcinoma and was also shown to possess antibiotic activity against certain Gram-positive bacteria. Several structural features of 1, such as its highly oxidized central ring, three all-carbon quaternary strereocenters, and masked electrophilic cyclopropane render it a challenging target for chemical synthesis. In 1992, Danishefsky and coworkers reported the sole synthesis of (±)-1 and hypothesized its biological mode of action involves DNA interstrand crosslinking. Given our interest in DNA-damaging natural products with unique structural complexity, we decided to pursue the enantioselective synthesis of 1. Our synthetic strategy relies on a powerful fragment coupling between two complex cyclohexyl fragments 2 and 3. This highly diastereoselective transformation sets in place the C-9 quaternary strereocenter and provides acyclic precursor 4 in excellent yield. Advancement of 4 to 5 was accomplished via Stille coupling-Rubottom oxidation sequence. Ring-closing aldol cyclization provides a complete carbon skeleton of 1. Following selective dehydration of the tertiary alcohol at C-5 and global deprotection, the final task of our synthesis is to install the remaining gamma-hydroxy lactone. Our short and scalable synthesis of (+)-myrocin C will enable access to the natural product and facilitate extensive mechanism of action studies, helping to validate 1 as a small-molecule antitumor antibiotic.

Synthetic studies toward the antitumor antibiotic (+)-myrocin C

256th National Meeting (2018)

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