A new method for the synthesis of enantiopure a-substituted piperazines via direct functionalization of the intact piperazine ring is described. The approach utilizes the asymmetric lithiation-substitution of an alpha-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.