Totally Synthetic by Paul H. Docherty, 5 April 2009

Total Synthesis of 7-Methylomuralide

Corey

R. A. Shenvi, E. J. Corey, J. Am. Chem. Soc. 2009, 131, 5746-5747.

7-Methylomuralide is a derivative of muralide, a target quite popular with Corey (with syntheses back in ’98 and ’03). In this case, a simplification was made to eliminate the stereocenter at C-7 by converting the methyl group into a gem-dimethyl group - and retaining most of the potent proteasome inhibition activity, which may cause apoptosis of cancer cells. Although 7-methylomuralide is not a natural product anymore, the compound is still a neat, compact target!

Key to the synthesis is a very interesting preparation of a β-keto lactam using a protected glycine and dimethylmalonyl dichloride. An aldol reaction with isobutyraldehyde should have basically constructed the carbon skeleton in only a couple of steps, but the reaction couldn’t be driven to completion when using their PMB protected initial substrate.

They then screened some protecting groups. The Boc protected substrate gave them the desired product, but unfortunately as the wrong diastereoisomer. A further attempt using the Troc protecting group (trichloroethoxycarbonyl) gave the right diastereomer in a d.r. of 11:1.

Uing a chiral (naphthylsulfonyl)cyclohexanol as directing group for an asymmetric Diels-Alder reaction generated two new stereocenters at the same time:

It only took a few more steps to finish the total synthesis: a tandem reduction / deprotection was used to prevent retro-aldol reaction, leaving them with only removal of the auxiliary, and β-lactone formation. An interesting work!

If you refer to the correct paper (which is misreferenced in the paper in JACS), you’ll see a rather nice prepration of the auxiliary. Opening of cyclohexene oxide with thionaphthalene, enzymatic resolution and oxidation gives them one enantiomer. A nice synthesis!

I liked this synthesis a lot, and think the auxiliary directed aldol reaction is a good approach.