A Short Synthetic Approach to Chiral Serine Azido Derivatives

Abstract

We report a new synthetic methodology for the synthesis of chiral serine azido derivatives through a conversion of N-protected (Boc, Cbz and Fmoc) serine amino acid into its corresponding Weinreb amide. Thus, acidity of the a-proton of the serine is reduced and it allows nucleophilic addition reaction onto Weinreb amide to furnish chiral serine azido derivatives.Biologically important and synthetically useful nonproteinogenic a-amino acids 2 have been found in natural products. They are important constituents in peptidederived chemotherapeutics. a-Amino acids are versatile synthons and their unique structural motif has been found in several medicinally important entities like proteintyrosine kinase inhibitors, 3 glycoprotein IIb/IIIa RGD receptor antagonists 4 and quisqualic acid analogues. 5 Thus, the development of new synthetic methodologies providing an expedient, general and novel approach for the synthesis of this class of compounds is as an active area of research. 6 A number of elegant approaches are available from the literature for the synthesis of various a-amino acids in their optically pure form. 7 Most of them involve the diastereoselective alkylation reactions of highly effective chiral glycine enolate synthons. 8 Indirect homologation of the serine side chain is also reported. Another common route to prepare a,b-diamino acids involves azide displacement under Mitsunobu conditions of the hydroxy group of serine, followed by reduction of the azide. 9 But these strategies suffer from a lack of flexibility in terms of stereochemical control at the bcarbon of the amino acid. In this preliminary communication, we wish to report a simple and direct approach for the synthesis of novel chiral L-serine Weinreb amide 8 azido derivatives and illustrate the versatility of this amide for the synthesis of various a-amino and a,b-diamino acids and their derivatives.Retrosynthetic analysis suggests that the compounds 2a-c were expected to deliver serine azido ester 1a-c through the displacement of the hydroxyl group in 2a-c under Mitsunobu conditions (Figure 1). Attempted reaction between 2a-c and the freshly prepared HN 3 solution in toluene in the presence of DEAD and PPh 3 furnished only the elimination product 3a-c. There was no trace of the required product 1a-c as indicated by electrospray MS. The hydroxyl group in 2a-c was then converted to its mesylate derivative by reacting with MsCl and Et 3 N. Subsequent reaction with sodium azide at 40 °C in DMF again yielded the elimination product 3a-c, (Scheme 1). Figure 1This is attributed to the fact that the relative acidity of the a proton of the serine methyl ester 2a-c causes its easy removal under Mitsunobu conditions. The alkoxy phosphonium intermediate in Mitsunobu reaction is a good leaving group, which eliminates easily to form the b-elimination product 3a-c. To overcome this problem, we have done a literature search. 9,10 Recently, Lajoie et. al 9 reported that by masking the carboxylic end of the serine to its cyclic base stable ortho ester derivative t...

Huisgen Cycloaddition in Peptidomimetic Chemistry

“…Activation of the serine hydroxyl by conversion to a leaving group, followed by nucleophilic substitution, has been attempted, but this generally results in elimination to give dehydroalanine 17 [70]. Panda and Rao reported the synthesis of azido alanine by nucleophilic displacement of mesylated Weinreb amide derivatives [72]. However, in our hands dehydroalanine is formed almost quantitatively, with similar results using mesylates and tosylates [70].…”

Synthesis of Constrained Peptidomimetics Containing 2‐Oxo‐1,3‐oxazolidine‐4‐carboxylic Acids

“…Only the reaction of dipeptide Ts-Pro-Ser-OMe (1a), containing a serine methyl ester, gave the dehydration product Ts-Pro-DHA-OMe (3a) as the major product (82 %, Table 1). Apparently, in this case, the comparatively high acidity of the α-H atom of the serine methyl ester with respect to that of the serine amides (1b-i) [18] promoted the elimination of the intermediate Ser-O-succinimidyl carbonate.…”

Use of the Mitsunobu reaction in the synthesis of orthogonally protected α,β-diaminopropionic acids

“…protected L-serine-derived Weinreb amides. 4 The reason for the use of the Weinreb amide derivative was to reduce the acidity of the serine -hydrogen and thus stop the formation of a dehydroalanine (Dha) by a dehydration reaction. Pedatella prepared orthogonally protected 2,3-diamino acids by treatment of the enolate of N,Ndibenzylated -amino esters with di-tert-butyl azodicarboxylate (DBAD).…”