Practical enantioselective synthesis of beta-substituted-beta-amino esters.
[reaction: see text] A practical, large-scale synthesis of a beta-amino ester 1 was developed. A chiral imine derived from (S)-phenylglycinol and 3-trimethylsilylpropanal was coupled with the Reformatsky reagent 3 with high diastereoselectivity (de > 98%) to give (SS)-4a as the major isomer. The amino alcohol residue of the coupling product 4 was oxidatively cleaved with sodium periodate in the presence of methylamine. An unusual selective oxidative cleavage of the (SS)-isomer was observed and the imine 6 was obtained with ee > 99% while the (RS)-4b isomer was not cleaved. Reaction with p-toluenesulfonic acid monohydrate allowed for the hydrolysis of the imine and the isolation of the amine as its salt. The title compound 1 was then obtained by transesterification, desilylation, and hydrochloride salt formation in a one-pot process. The method was successfully applied toward the synthesis of a wide variety of beta-amino esters.
Pfizer Global Research & Development, Pfizer Inc., Ann Arbor, Michigan 48105, USA. alok.k.awasthi@pfizer.com
Alok K
AK
Awasthi
Mark L
ML
Boys
Kimberly J
KJ
Cain-Janicki
Pierre-Jean
PJ
Colson
Wendel W
WW
Doubleday
Joseph E
JE
Duran
Payman N
PN
Farid
D000447:Aldehydes / Q000737:chemistry; D000596:Amino Acids / Q000138:chemical synthesis*; D000605:Amino Alcohols / Q000737:chemistry; D001557:Benzenesulfonates / Q000737:chemistry; D004952:Esters / Q000138:chemical synthesis*; D004983:Ethanolamines; D005998:Glycine / Q000031:analogs & derivatives; D006868:Hydrolysis; D007097:Imines / Q000737:chemistry; D008744:Methylamines / Q000737:chemistry; D008956:Models, Chemical; D010504:Periodic Acid / Q000737:chemistry; D013237:Stereoisomerism; D014297:Trimethylsilyl Compounds / Q000737:chemistry
D000447:Aldehydes; D000596:Amino Acids; D000605:Amino Alcohols; D001557:Benzenesulfonates; D004952:Esters; D004983:Ethanolamines; D007097:Imines; D008744:Methylamines; D014297:Trimethylsilyl Compounds; D010504:Periodic Acid; C005332:N-phenylethanolamine; C005556:propionaldehyde; C009288:metaperiodate; C027451:methylamine; C029501:4-toluenesulfonic acid; D005998:Glycine