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Organic Chemistry Highlights

Total Synthesis

Monday, March 7, 2016
Douglass F. Taber
University of Delaware

The Menche Synthesis of Leupyrrin A1

Leupyrrin A1 (4), a non-symmetrical macrodiolide isolated from the myxobacterium Sorangium cellulosum, was shown to be antifungal at nanomolar concentrations. After extensive spectroscopic analysis to assign the relative and absolute configuration of 4, Dirk Menche of the Universitšt Bonn envisioned (J. Am. Chem. Soc. 2015, 137, 4086. DOI: 10.1021/jacs.5b01894) the assembly of 3, the open form of 4, by condensation of the amino alcohol 2 with the acid 1.

The preparation of 1 began with the known baker's yeast reduction of the racemic lactone 5 to the 82% ee alcohol 6. Protection followed by recrystallization improved the ee. Dibal reduction followed by the addition of isopropenyl magnesium bromide delivered the lactone 7. Protecting group interchange led to 8, that was cross-coupled with the alkenyl boronate 9 to give 10. The acid 1 was assembled by coupling 10 with the bromide 11, followed by deprotection.

The preparation of the diacid portion of component 2 had already been described. Alkylation of the norephedrine-derived oxazolidinone 12 with t-butyl bromoacetate gave 13, that was hydrolyzed to 14.

The coupling of the alcohol 15 with the tosylate 16 followed by deprotection and oxidation led to the aldehyde 17, that was carried on to the epoxide 18. Selective opening of the epoxide at the propargylic site followed by protection gave 19, that was cyclized with the Negishi reagent to give an intermediate zirconacycle that was selectively brominated, leading to 20. Methylation followed by deprotection then completed the assembly of 21.

The alcohol 21 was acylated with the acid 14 to give 2. As expected, condensation with 1 to form the oxazoline proceeded with inversion of the alcohol stereogenic center. Deprotection followed by macrolactone formation then completed the synthesis of Leupyrrin A1 (4). This highly convergent synthesis is robust enough to enable the preparation of practical quantities of 4 and its derivatives.

D. F. Taber, Org. Chem. Highlights 2016, March 7.