A Rapid Approach to Amino-Acid Derivatives by [2,3]-Stevens Rearrangement

Abstract

Allylation of amino-acid esters gives rise to intermediate quaternary ammonium salts, which undergo proton abstraction to give ylides and [2,3]-sigmatropic rearrangement. The resulting aamino-acid derivatives can be subjected to N-deallylation to provide a rapid access to a-allyl-a-amino-esters. Using N-benzyl proline methyl ester, chirality transfer from carbon to nitrogen then back to carbon takes place.The preparation of unnatural amino-acids and their derivatives continues to attract considerable research interest. 1 This is due in part to their use as sources of ligands for catalytic reactions or their incorporation within peptides or analogues in order to confer desirable properties such as conformational restriction. We have reported recently a new approach to amino-acids by N-alkylation of N-allyl a-amino-esters. 2,3 The resulting quaternary ammonium salts rearrange, after ammonium ylide formation, by a [2,3]-Stevens rearrangement. For example, the allyl glycine derivative 2 can be formed using a one pot N-alkylation-ylide formation-rearrangement protocol from the amine 1.The [2,3]-Stevens rearrangement of ammonium ylides is known using a variety of N-allyl quaternary ammonium salts and basic conditions, although the use of simple Nallyl a-amino-esters is rare. 4 The combined N-alkylation, ylide formation and rearrangement strategy (e.g. 1 to 2, Scheme 1) occurs under mild conditions and avoids the need to isolate the ammonium salt, providing N,N-dialkylated a-amino-acid derivatives from N-allyl a-amino-esters in one pot. A drawback of this method, however, is the necessity to prepare the starting materials from the Nunsubstituted a-amino-esters and the inability to convert the product to the a-amino-acid derivatives which are unsubstituted on the nitrogen atom. In this paper we report a more convenient approach to a-amino-acid derivatives using this type of chemistry, starting from simple esters of natural amino acids and leading, after N-deallylation, to N-unsubstituted a-amino-esters.Taking the simple glycine methyl ester as the starting material, allylation with excess allyl bromide under the conditions described above, resulted in the formation of the [2,3]-Stevens product 4 (Scheme 2). Tri-allylation on the nitrogen atom generates the intermediate quaternary ammonium salt, which undergoes proton abstraction to the ylide 3 and rearrangement to give the a-amino-acid derivative 4. We were pleased to find that the N-allyl groups could be cleaved selectively using palladium(0) 5 to give the primary amine 5 (Scheme 3). This method therefore allows a rapid (two step) preparation of allyl glycine methyl ester from the simple glycine methyl ester. 6 Scheme 2 Scheme 3The allylation and in situ rearrangement of various simple a-amino-esters was investigated as outlined in Table 1. Allyl iodides, bromides or chlorides could be used successfully. Slight improvements to the yields were obtained by adding Bu 4 NI to the reactions with allyl bromide. The use of crotyl chloride gave the allyl-transposed product 7c (...

Stereoselective Synthesis of Quaternary Proline Analogues

“…Exclusive [2,3]-shifts of an allyl and a prenyl group for substrate 76 had previously been reported by West [57] and by Coldham, [58] respectively (Scheme 19). In this case, the rearrangements are stereospecific because the [2,3]-migrations are restricted to the same face, and the stereoselectivity arises from the previous N-alkylation step.…”

Studies towards the construction of quaternary indolizidines by [2,3]-sigmatropic rearrangement cocatalyzed by ionic liquid

“…Product (S)-9 was obtained as the major enantiomer in all the studied cases (Table 1), consistent with the notion that when an prenyl group is added to 7 a [2,3]-shift mechanism is ongoing and would be restricted to the same face of proline derivative, due to the trans arrangement of the benzyl and ester groups. Stereospecificity for exclusive [2,3]-shifts of a prenyl group derivative had previously been reported by West and Glaeske 12 and by Coldham and co-workers, 11 respectively. Then, benzyl group deprotection of 9 using Et 3 SiH/PdCl 2 in CH 2 Cl 2 13 afforded 5 in quantitative yield.…”

“…10 It was previously reported that allyl-migration using K 2 CO 3 afforded 9 in low yield (40%) and good enantioselectivities (entry 1, Table 1). 11 Then, using [BMIm] . PF 6 as co-catalyst it was observed the same selectivity, but in a better yield of 50% (Table 1, entry 2).…”

“…11 The cocatalyzed reactions were performed as the procedure described above with addition of [BMIm] . PF 6 (0.5% mol).…”

Asymmetric Synthesis of Cα‐Substituted Prolines through Curtin–Hammett‐Controlled Diastereoselective N‐Alkylation

“…The diastereoselectivity during the quaternization was approximately 4:1, and thus, the diastereomerically pure ammonium salt E was obtained by several recrystallizations. This low diastereoselectivity was also observed by Coldham and co‐workers in the N‐quaternization of the same proline substrate with allyl bromide.…”