TY - JOUR
T1 - Synthesis of Enantiopure Piperazines via Asymmetric Lithiation-Trapping of N-Boc Piperazines
T2 - Unexpected Role of the Electrophile and Distal N-Substituent
AU - Firth, James D.
AU - O'Brien, Peter
AU - Ferris, Leigh
PY - 2016/1/20
Y1 - 2016/1/20
N2 - A new method for the synthesis of enantiopure α-substituted piperazines via direct functionalization of the intact piperazine ring is described. The approach utilizes the asymmetric lithiation-substitution of an α-methylbenzyl-functionalized N-Boc piperazine using s-BuLi/(-)-sparteine or (+)-sparteine surrogate and provides access to a range of piperazines (as single stereoisomers). Optimization of the new methodology required a detailed mechanistic study. Surprisingly, it was found that the main culprits affecting the yield and enantioselectivity were the electrophile (the last reagent to be added to the reaction flask) and the distal N-substituent. The mechanistic studies included optimization of lithiation times using in situ IR spectroscopy, identification of a ring-fragmentation of the lithiated piperazines (that could be minimized with sterically hindered N-alkyl groups), and use of a novel "diamine switch" strategy to improve enantioselectivity with certain electrophiles. The methodology was showcased with the preparation of an intermediate for Indinavir synthesis and the stereoselective synthesis of 2,5-trans- and 2,6-trans-piperazines.
AB - A new method for the synthesis of enantiopure α-substituted piperazines via direct functionalization of the intact piperazine ring is described. The approach utilizes the asymmetric lithiation-substitution of an α-methylbenzyl-functionalized N-Boc piperazine using s-BuLi/(-)-sparteine or (+)-sparteine surrogate and provides access to a range of piperazines (as single stereoisomers). Optimization of the new methodology required a detailed mechanistic study. Surprisingly, it was found that the main culprits affecting the yield and enantioselectivity were the electrophile (the last reagent to be added to the reaction flask) and the distal N-substituent. The mechanistic studies included optimization of lithiation times using in situ IR spectroscopy, identification of a ring-fragmentation of the lithiated piperazines (that could be minimized with sterically hindered N-alkyl groups), and use of a novel "diamine switch" strategy to improve enantioselectivity with certain electrophiles. The methodology was showcased with the preparation of an intermediate for Indinavir synthesis and the stereoselective synthesis of 2,5-trans- and 2,6-trans-piperazines.
KW - Lithium/chemistry
KW - Piperazines/chemistry
KW - Spectrophotometry, Infrared
KW - Stereoisomerism
UR - http://www.scopus.com/inward/record.url?scp=84955290985&partnerID=8YFLogxK
U2 - 10.1021/jacs.5b11288
DO - 10.1021/jacs.5b11288
M3 - Article
C2 - 26683825
SN - 0002-7863
VL - 138
SP - 651
EP - 659
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 2
ER -