Simpotentin (1), isolated from the culture broth of Simplicillum sp. by our group, is a new potentiator of amphotericin B activity against C. albicans, and is a unique β-mannoside. The aglycone has a hydroxylated lipophilic carboxylic acid moiety with three unknown chiral centers. Herein, we report a concise total synthesis and structural determination of 1 through the synthesis of all stereoisomers. At first, we set the all R isomer (3R, 5R, 13R)-1 as a primary target molecule. The aglycone unit of (3R, 5R, 13R)-1 was derived from n-hexanal via sequential SmI2-mediated sterereoselective Reformatsky reactions and functional group interconversions. β-Glycosylation of the aglycone with ulosyl bromide in the presence of AgOTf followed by the reduction of ketone furnished the desired β-mannnoside. Finally, deprotection of all Bn groups gave the (3R, 5R, 13R)-1. Extension of this chemistry enabled the synthesis of all stereoisomers of 1, and (3R, 5R, 13R)-1 was completely identical to natural natural 1. Furthermore, we have discovered the new stereoisomer (3R,5S,13S)-1 which has a more potent activity as an AMPB potentiator than 1. It indicates that application of our total synthesis would allow the synthesis of a variety of simpotentin analogs. Further structure-activity relationship study of simpotentin (1) is currently under way.

Total synthesis and absolute configuration of simpotentin, a potentiator of amphotericin B activity

2019 Fall National Meeting

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