One-carbon chain extension of esters to alpha-chloroketones: a safer route without diazomethane.
The reaction of a variety of methyl esters with dimethylsulfoxonium methylide at 0-25 degrees C affords the chain-extended beta-keto dimethylsulfoxonium ylides. Subsequent treatment with hydrogen chloride in THF proceeds with loss of DMSO to afford the corresponding alpha-chloroketones. This sequence has been utilized to convert the methyl esters of CBZ-protected alanine and valine to the anti N-protected alpha-amino epoxides, which are important pharmaceutical intermediates. When the same protocol is applied to BOC-protected phenylalanine methyl ester, epimerization occurs so that the use of a more reactive aryl ester is required. This chemistry provides a practical route to alpha-chloroketones that avoids the use of toxic and explosive diazomethane.
Wang
Dengjin
D
Process Research and Development Department, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA.
Schwinden
Mark D
MD
Radesca
Lilian
L
Patel
Bharat
B
Kronenthal
David
D
Huang
Ming-Hsing
MH
Nugent
William A
WA
D000590:Amino Acid Chloromethyl Ketones / Q000138:chemical synthesis* / Q000737:chemistry; D003978:Diazomethane / Q000737:chemistry*; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure
D000590:Amino Acid Chloromethyl Ketones; D004952:Esters; D003978:Diazomethane