Synthesis of the antifungal beta-1,3-glucan synthase inhibitor CANCIDAS (caspofungin acetate) from pneumocandin B0.
A novel three-step synthesis of the highly functionalized antifungal agent CANCIDAS (caspofungin acetate, 2) is described, starting from the natural product pneumocandin B0 (1). The highlights of the synthesis include a stereoselective formation of a phenylthioaminal, a remarkable chemoselective, high-yielding, one-step borane reduction of a primary amide, and a stereoselective substitution of the phenylthioaminal with ethylenediamine producing 2 in a 45% overall yield.
Leonard
William R
WR
Process Research Department, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900, USA. bill_leonard@merck.com
Belyk
Kevin M
KM
Conlon
David A
DA
Bender
Dean R
DR
DiMichele
Lisa M
LM
Liu
Ji
J
Hughes
David L
DL
D000577:Amides / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D000077336:Caspofungin; D002851:Chromatography, High Pressure Liquid; D054714:Echinocandins; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D055666:Lipopeptides; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry* / Q000302:isolation & purification; D013438:Sulfhydryl Compounds / Q000737:chemistry
D000577:Amides; D000588:Amines; D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D010456:Peptides, Cyclic; D013438:Sulfhydryl Compounds; C079465:pneumocandin B(0); D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase; D000077336:Caspofungin