ENANTIOSELECTIVE SYNTHESIS OF (3R)-PIPERAZIC AND (3S)-PIPERAZIC ACIDS- THE COMPARATIVE UNIMPORTANCE OF DMPU MEDIATED RETRO-HYDRAZINATION

In response to a recent literature report by Decicco and Leathers (Ref . 13), the work of Hale, Delisser, and Manaviazar (1992) on the asymme tric synthesis of (3R)- and (3S)-piperazic acids has been reinvestigat ed, and the originally claimed product yields fully substantiated. The claims made in reference 13 about the proportions of cyclised product 6 and starting bromide 20 isolated from the low temperature electroph ilic hydrazination-nucleophilic cyclisation of 20 with di-t-butylazodi carboxylate (DEAD) and DMPU as an additive are inaccurate. The retro-h ydrazination reaction that they claim is problematic when DMPU is adde d to the hydrazinated reaction mixture has been demonstrated not to ha ve a seriously detrimental effect on cyclisation product yield and to be unimportant. The other main assertion of reference 13, that the ele ctrophilic hydrazination and nucleophilic cyclisation of 20 gives 6 in 91% isolated yield when, n-Bu(4)NI is employed as an additive (instea d of DMPU) has also been shown to be in error. We have carefully repea ted a scaled-down version of the n-Bu(4)NI catalysed procedure (Ref. 1 3) and have found that 6 is generally isolated in yields of 50-56% aft er flash chromatography. We have concluded that n-Bu(4)NI does not sig nificantly increase the yields of cyclisation products 6 or 17 when it is employed as a cyclisation additive. Herein, we report details of o ur two preferred ''crude'' experimental procedures for preparing the e nantiomers of piperazic acid in high optical purity, neither of which requires chromatographic purification of the reaction intermediates en route. Both these preferred ''crude'' methods for preparing 11 and 19 have been consistently reproduced many times in these laboratories ov er the past few years. In our view, they remain the most expedient and highest yielding methods currently available for obtaining 11 and 19 in high optical purity.