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...
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