Synthesis of highly epimerizable N-protected -amino aldehydes of high enantiomeric excess

The Dess–Martin periodinane was found to be a superior oxidant for the efficient, epimerization-free synthesis of optically active N-protected -amino aldehydes from the corresponding N-protected -amino alcohols. Highly racemization-prone products, including N-Fmoc phenylglycinal and N-trifluoroacetyl -amino aldehydes, were prepared in 95% yield with 1% epimerization. © 2000 Elsevier Science Ltd. All rights reserved. Optically active N-protected -amino aldehydes are widely used synthetic intermediates of importance in the pharmaceutical and fine chemical industries.1 The facility with which they undergo epimerization has been noted and strategies have been devised to minimize this propensity, such as Rapoport’s 9(9-phenylfluorenyl) substitution of the -amino group2 and Reetz’ N,N-dibenzyl derivatization.3 In the course of studies directed toward the synthesis of saframycin A and related alkaloids with antitumor activity, we were led to prepare a series of chiral -amino aldehydes with simple, base-labile N-protective groups such as fluorenylmethoxycarbonyl (Fmoc) and trifluoroacetyl (TFA). Several of these aldehydes proved to be exceedingly susceptible to base-induced epimerization. In surveying methods for the preparation of these compounds with maximal enantiomeric enrichment we have consistently found that oxidation of the corresponding N-protected -amino alcohols with the Dess–Martin periodinane4 provides exceptional results, furnishing the desired aldehydes with 1% epimerization of the -stereocenter, including highly epimerizable products such as N-Fmoc phenylglycinal. Because of the broad utility of these compounds as intermediates in chemical synthesis, we describe the details of our findings herein. A large number of optically active N-protected -amino aldehydes have been described in the literature.1 These are typically among the less racemization-prone -amino aldehydes, however, with -side-chains such as benzyl, isobutyl, and the like, and can often be prepared in high optical purity by Swern oxidation of the corresponding N-protected -amino alcohols.1 There are far fewer references to -amino aldehydes with epimerization-enhancing features such as an -aryl group or a strongly electronwithdrawing N-protective group. From consideration of literature reports concerning N-protected derivatives of phenylglycinal, it is evident that such compounds can be difficult to prepare and handle. Corresponding author. 0040-4039/00/$ see front matter © 2000 Elsevier Science Ltd. All rights reserved. P I I: S0040-4039(99)02293-5