Asymmetric synthesis of trans-2,3-piperidinedicarboxylic acid and trans-3,4-piperidinedicarboxylic acid derivatives.
Asymmetric syntheses of (2S,3S)-3-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (1b), (3R,4S)-4-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (2b), and their corresponding N-Boc and N-Cbz protected analogues 8a,b and 17a,b are described. Enantiomerically pure 1b has been synthesized in five steps starting from L-aspartic acid beta-tert-butyl ester. Tribenzylation of the starting material followed by alkylation with allyl iodide using KHMDS produces the key intermediate 5a in a 6:1 diastereomeric excess. Upon hydroboration, the alcohol 6a is oxidized, and the resulting aldehyde 7 is subjected to a ring closure via reductive amination, providing 1b in an overall yield of 38%. Optically pure 2b has been synthesized beginning with N-Cbz-beta-alanine. The synthesis involves the induction of the first stereogenic center using Evans's chemistry and sequential LDA-promoted alkylations with tert-butyl bromoacetate and allyl iodide. Further elaboration by ozonolysis and reductive amination affords 2b in an overall yield of 28%.
Xue
Chu-Biao
CB
Chemical and Physical Sciences, DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880, USA. chu-biao.xue@dupontpharma.com
He
Xiaohua
X
Roderick
John
J
Corbett
Ronald L
RL
Decicco
Carl P
CP