Synthesis of Enantiomerically Pure <i>cis</i>‐ and <i>trans</i>‐4‐Amino‐1‐oxyl‐2,2,6,6‐tetramethylpiperidine‐3‐carboxylic Acid: A Spin‐Labelled, Cyclic, Chiral β‐Amino Acid, and 3D‐Structural Analysis of a Doubly Spin‐Labelled β‐Hexapeptide

Abstract

Abstract Amination of 3‐carboxymethyl‐1‐oxyl‐2,2,6,6‐tetramethyl‐4‐piperidone ( 1 ) with either ( R )‐ or ( S )‐α‐methylbenzylamine gave corresponding enamines 2 . Whereas the reduction with NaBH 3 CN/CH 3 COOH afforded predominantly a mixture of two possible cis diastereomers of 3 , (1′ R ,3 S ,4 S )/(1′ R ,3 R ,4 R ) or (1′ S ,3 R ,4 R )/(1′ S ,3 S ,4 S ), which could be separated by crystallisation of their HCl salts, the use of NaBH 4 /(CH 3 ) 2 CHCOOH as the reducing agent resulted in a mixture of one trans ‐ and one cis diastereomer of 3 (1′ R ,3 S ,4 R )/(1′ R ,3 R ,4 R ) or (1′ S ,3 R ,4 S )/(1′ S ,3 S ,4 S ) in varying proportions depending upon the conditions used. The stereochemistry of the four diastereomers of 3 was clearly established by X‐ray diffraction analysis of one of them, combined with 1 H NMR spectroscopic studies after nitroxide reduction. Removal of the chiral auxiliary from the separated diastereomers of 3 by hydrogenation and regeneration of the nitroxide radical gave expected amino esters 4 . A model β‐hexapeptide containing (3 R ,4 S )‐β‐TOAC combined with (1 S ,2 S )‐2‐aminocyclohexane carboxylic acid was synthesised by solution methods and its preferred conformation (3 14 ‐helix) was assessed by FTIR absorption, CD, and EPR spectroscopy.(© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2007)