Enantioselective synthesis of beta-Amino acids. 12. experimental and theoretical study of the diastereoselectivity of alkylation of the dianion of N',N'-Bis(alpha-phenylethyl)-N -carbobenzyloxypropionamide

Abstract

b-Alanina, matéria-prima aquiral e de baixo custo, foi convertida na amida quiral 1 em 53% de rendimento global. A alquilação de (R,R)-1 requereu a formação de seu diânion, (R,R)-1-Li 2 que foi alcançada de maneira mais eficiente pela metação direta com dois equivalentes de n-BuLi em solução de THF a -78 o C. O tratamento de (R,R)-1-Li 2 com vários haletos de alquila forneceu os produtos monoalquilados 3-6 em 24-85% de rendimento e 65-86% de diastereosseletividade. O efeito do aditivo LiCl ou de HMPA como co-solvente na diastereosseletividade da reação de alquilação foi essencialmente desprezível, embora os reandimentos tenham geralmente aumentado. A correlação química do diastereoisômero majoritário da reação de metilação com (S)-a-metil-balanina mostra que a adição do eletrófilo ocorre preferencialmente na face Si do enolato. Esta conclusão é também apoiada por estudos de modelagem molecular (ab initio HF/3-21G) que indicam que a conformação de menor energia para (R,R)-1-Li 2 apresenta a face Re do enolato mais impedida estericamente. Os estudos teóricos também ofereceram indicações úteis sobre a importância da ligação de hidrogênio e de interações atrativas p-p em (R,R)-1. Adicionalmente, os cálculos prevêem um papel determinante para a quelação N-Li-O em (R,R)-1-Li assim como um interessante configuração de tripleto iônico para o diânion de lítio (R,R)-1-Li 2 . Achiral, inexpensive b-alanine was converted into the title chiral amide 1 in 53% overall yield. C-Alkylation of (R,R)-1 required formation of its dianion derivative, (R,R)-1-Li 2 , which was best achieved by direct metallation with two equivalents of n-BuLi in THF solution and at -78°C. Treatment of (R,R)-1-Li 2 with various alkyl halides afforded the monoalkylated products 3-6 in 24-85% yield and 65-86% diastereoselectivity. The effect of LiCl additive or HMPA cosolvent on the diastereoselectivity of the alkylation reaction was essentially negligible, although reaction yields generally improved. Chemical correlation of the major diastereomer from the methylation reaction with (S)-a-methyl-b-alanine shows that addition of the electrophile takes place preferentially on the enolate's Si face. This conclusion is also supported by molecular modelling studies (ab initio HF/3-21G), which indicate that the conformation of lowest energy for (R,R)-1-Li 2 presents a more sterically hindered Re face of the enolate. The theoretical studies also provided useful insight into the importance of hydrogen bonding and attractive p-p interactions in (R,R)-1. Furthermore, the calculations predict a determining role for N-Li-O chelation in (R,R)-1-Li, as well as an interesting ion triplet configuration for dilithium dianion (R,R)-1-Li 2 .

β2‐amino acids—syntheses, occurrence in natural products, and components of β‐peptides1,2

“…In contrast, precursor (R)-V affords low selectivity in the absence of additives and complete inversion of selectivity in the presence of 3 equivalents of HMPA (Scheme 16). As a further extension toward the preparation of enantiopure ␤ 2 -amino acids, the stereoselective alkylation of ␤-homoglycine dianion derivatives I-2Li 139 and IV-2Li 140 has also been tested (Scheme 17). Previous work of several groups has, indeed, demonstrated that alkylation of chiral dianion derivatives proceeds with high stereoselectivity.…”

Fundamental Developments of Chiral Phase Chromatography in Connection with Enantioselective Synthesis of β‐Amino Acids

“…Consequently, given the crucial importance of b-amino acids, 181] their enantioselective synthesis became a central aim in our research group. [182][183][184][185][186][187][188] In this regard, in view of the fact that (R)-or (S)-a-amino acids can be synthesised by means of the derivatisation of glycine derivatives such as imidazolidinone 13 (Figure 10a), [189,190] a similar strategy to obtain the b-analogues starting from achiral b-alanine (Figure 10b) was developed. [191] Variations of the proposed methodology allowed the development of the enantioselective synthesis of a-substituted b-amino acids by using the (2S)tert-butyl-3-methyl-perhydropyrimidin-4-one (2S)-14 formed via (S)-asparagine.…”