Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 27 March 2008

Total Synthesis of Minfiensine


L. Shen, M. Zhang, Y. Wu, Y Qin, Angew. Chem. Int. Ed. 2008, 47, 3618-3621.

DOI: 10.1002/anie.200800566

This total synthesis of Minfiensine by Yong Qin at the “Department of Chemistry of Medicinal Natural Products and, Key Laboratory of Drug Targeting, West China School of Pharmacy” shows a few similarities to the recently covered route by Larry Overman, along with some interesting alternatives. Avoiding Overman’s ambitious palladium cascade designs, they planned a carbene insertion into an indole. However, like Overman, they hoped that the imine formed in this reaction would be attacked by a pendant amine to form the desired aminal center. Then, a rather familiar series of reactions would lead to product.

Let’s start by looking at the carbene insertion chemistry. They constructed a variety of substituted and protected indoles using chemistry developed by Pat Bailey, to run trials with a few copper salts and one rhodium catalyst. Copper (I) triflate did the trick, and led them to product in high yield. Interestingly, with some substrates they obtained the product as a mixture of ketone and enol ether isomers depending on the protecting group of the indole nitrogen. Decarboxylating under Krapcho conditions gave ketone from both isomers.

The removal of a tosyl group in the presence of a ketone is tricky. Reduction of the carbonyl, removal of the Ts group and reoxidation was required. They now had a substrate with a remarkable similarity to that of Overman’s synthesis. The same palladium chemistry (initially developed by Cook) with a slightly different catalyst lead to the same result - formation of the five-membered ring. Use of Commins’ reagent gave them the corresponding enol triflate, which reacted in a Stille coupling with tri-n-butylstannylmethanol to the hydroxymethyl derivative.

Deprotection of the Boc group and we are done!