On the halogenation of <i>N</i>(1)<i>,N</i>(2)-di-<i>t</i>-Boc-5-hydroxy-piperazic acid esters and the conformational preferences of their 5-halo-piperazic acid products. The importance of A^1,3 rotameric-strain in determining <i>N</i>(2)-acyl piperazic acid ring conformation

In this Letter, an unambiguous synthetic strategy is reported for the preparation of enantiomerically pure<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">cis</em>-5-halo-piperazic acid derivatives in single diastereoisomer form. Contrary to the recent report by Shin and co-workers (<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">Chem. Lett</em>. 2001, 1172), in which it is claimed that the Ph<sub style="border: 0px; font-size: 0.75em; margin: 0px; padding: 0px; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; line-height: 0; color: rgb(46, 46, 46); text-align: justify; word-spacing: -1.03598487377167px;">3</sub>P and <em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">N</em>-chlorosuccinimide (NCS)-mediated chlorination of (3<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">R</em>,5<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">S</em>)-<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">trans</em>-<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">N</em>(1),<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">N</em>(2)-di-<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">t</em>-Boc-5-hydroxy-piperazic acid derivative 1proceeds with retention of configuration at C(5) to give 2, we now show that this and related Ph<sub style="border: 0px; font-size: 0.75em; margin: 0px; padding: 0px; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; line-height: 0; color: rgb(46, 46, 46); text-align: justify; word-spacing: -1.03598487377167px;">3</sub>P-mediated halogenations all occur with S<sub style="border: 0px; font-size: 0.75em; margin: 0px; padding: 0px; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; line-height: 0; color: rgb(46, 46, 46); text-align: justify; word-spacing: -1.03598487377167px;">N</sub>2 inversion at the alcohol center, as is customary for such reactions. Specifically, we demonstrate that the (3<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">R</em>,5<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">S</em>)-<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">trans</em>-5-Cl-piperazic acid derivative 2 claimed by Shin and co-workers (<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">Chem. Lett</em>. 2001, 1172) is in actual fact the chlorinated (3<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">S</em>,5<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">R</em>)-enantiomer 6, which must have been prepared from the <em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">cis</em>-(3<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">S</em>,5<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">S</em>)-alcohol 3, a molecule whose synthesis is not formally described in the Shin paper. We further show here that the <em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">cis</em>-(3<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">R</em>,5<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">R</em>)-5-Cl-Piz 13 claimed by Shin and co-workers in<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">Chem. Lett</em>. 2001, 1172, is also (3<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">S</em>,5<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">R</em>)-<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">trans</em>-5-Cl-Piz 6. Authentic 13 has now been synthesized by us, for the very first time, here. Since Lindsley and Kennedy have recently utilized the now invalid Shin and co-workers’ retentive Ph<sub style="border: 0px; font-size: 0.75em; margin: 0px; padding: 0px; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; line-height: 0; color: rgb(46, 46, 46); text-align: justify; word-spacing: -1.03598487377167px;">3</sub>P/NCS chlorination procedure on 1 in their synthetic approach to piperazimycin A (<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">Tetrahedron Lett</em>. 2010, <em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">51</em>, 2493), it follows that their claimed 5-Cl-Piz-containing dipeptide 25 probably has the alternate structure 26, where the 5-Cl-Piz residue has a 3,5-<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">cis</em>-configuration. The aforementioned stereochemical misassignments appear to have come from a mix-up of starting materials by Shin and co-workers (<em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">Chem. Lett</em>. 2001, 1172), and an under-appreciation of the various steric and conformational effects that operate in <em style="border: 0px; font-size: 13.3333330154419px; margin: 0px; padding: 0px; vertical-align: baseline; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; color: rgb(46, 46, 46); line-height: 20px; text-align: justify; word-spacing: -1.03598487377167px;">N</em>(2)-acylated piperazic acid systems, most especially rotameric A<sup style="border: 0px; font-size: 0.75em; margin: 0px; padding: 0px; font-family: 'Arial Unicode MS', 'Arial Unicode', Arial, 'URW Gothic L', Helvetica, Tahoma, 'Cambria Math', sans-serif; line-height: 0; color: rgb(46, 46, 46); text-align: justify; word-spacing: -1.03598487377167px;">1,3</sup>-strain. The latter has now been unambiguously delineated and defined here under the banner of the A<sup style="border: 0px; font-size: 0.75em; font-weight: 100; margin: 0px; padding: 0px; line-height: 0;">1,3</sup>-rotamer effect.