An efficient route to either enantiomer of orthogonally protected trans-3-aminopyrrolidine-4-carboxylic acid.
An efficient route to either enantiomer of orthogonally protected trans-3-aminopyrrolidine-4-carboxylic acid.
复制标题
获得正交保护的反式-3-氨基吡咯烷-4-羧酸任一对映体的有效途径。
DOI：
10.1021/jo001534l
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Gellman,SH
中科院分区：
文献类型：
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作者：
Lee,HS;LePlae,PR;Porter,EA;Gellman,SH
寡-β-氨基酸（“β-肽”）和具有离散和可预测的折叠倾向的其他寡聚物（“折叠体”）是日益受到关注的主题。1最近的工作已经确定，含有构象受限残基的短β-肽（esix残基）在水溶液中显示出明确的构象。2此外，β-肽已显示出有趣的生物活性。3探索β-肽的结构和功能特性需要获得广泛的对映体纯的β-氨基酸。尽管已经对β-氨基酸合成进行了广泛的努力，但是，许多取代模式，特别是提供构象限制的那些，并不容易获得。我们已经表明，对映体纯的反式-2-氨基环戊烷羧酸（ACPC）的均聚物形成由骨架酰胺基团之间的12元环氢键定义的螺旋（“12-螺旋”）。这一发现促使我们寻找在五元环上具有额外官能化点的ACPC类似物。反式-3-氨基吡咯烷-4-羧酸（APC）满足了这一需要。我们最近发现，由APC和ACPC构建的短β-肽在水溶液中采用12-螺旋构象2b，并且由这两个残基组成的17-残基β-肽显示抗微生物活性。在此，我们报道了一种改进的APC合成方法，该方法适合于大规模制备。我们最初的路线，2b像新路线一样，从已知的β-酮酯1开始。6在最初的路线中，还原然后消除产生R，β-不饱和酯，对映体纯的R-甲基苄胺的迈克尔加成然后产生四种非对映体β-氨基酯的混合物。在冗长的柱色谱法后，以13%的产率分离出所需的异构体。2b该原始路线可用于APC作为β-肽结构单元的初始评估，但该路线对于彻底探索含APC的β-肽的结构和性质不够有效。新路线（方案1）通过减少化学操作的数量和消除对色谱分离的需要而得到简化。该路线的开发受到Xu等人报道的顺式-2-氨基环己烷羧酸的不对称合成的启发。使7 β-酮酯1与（R）-R-甲基苄胺在乙酸存在下反应，并且所得烯胺用NaBH 3-CN原位还原。8该还原产生四种非对映异构体β-氨基酯的混合物，其中3是主要产物，并且我们已经发现两步结晶方案，其允许分离非对映异构体纯形式的盐酸盐2。将粗β-氨基酯混合物溶于乙酸乙酯中，用4 N HCl的二氧六环溶液处理，转化为盐酸盐的混合物。一个单一的反式异构体结晶后，这种处理（g98%de）相对纯净的形式，虽然有其他反式异构体的污染。从乙腈中重结晶，以38%的总收率从1得到非常纯的2形式（g99%de）。当使用（R）-R-甲基苄胺时，纯化的β-氨基酯盐酸盐在光谱学上与先前通过晶体结构测定鉴别为方案1中所示非对映异构体的物质相同。因此，使用（R）-R-甲基苄胺最终导致（3S，4 R）-反式-3-氨基吡咯烷-4-羧酸的保护形式。9新的路线是通过碱性酯水解，氢解除去R-甲基苄基，和...
Oligo-β-amino acids (“β-peptides”) and other oligomers with discrete and predictable folding propensities (“foldamers”) are subjects of increasing attention. 1 Recent work has established that short β-peptides (esix residues) containing conformationally restrained residues display well-defined conformations in aqueous solution. 2 In addition, β-peptides have been shown to display interesting biological activities. 3 Exploration of the structural and functional properties of β-peptides requires the availability of a wide range of enantiomerically pure β-amino acids. Despite the extensive effort that has been devoted to β-amino acid synthesis, 4 however, many substitution patterns, particularly those that provide conformational constraint, are not readily accessible. We have shown that homooligomers of enantiomerically pure trans-2-aminocyclopentanecarboxylic acid (ACPC) form a helix defined by 12-membered ring hydrogen bonds between backbone amide groups (“12-helix”). 5 This finding prompted us to seek ACPC analogues that bear an additional point of functionalization on the five-membered ring. trans-3-Aminopyrrolidine-4-carboxylic acid (APC) fulfills this need. We have recently shown that short β-peptides constructed from APC and ACPC adopt the 12-helical conformation in aqueous solution2b and that a 17-residue β-peptide composed of these two residues displays antimicrobial activity. 3c Here we report an improved synthesis of APC that is amenable to large-scale preparation.The new route is summarized in Scheme 1. Our original route, 2b like the new one, started from the known β-ketoester 1. 6 In the original route, reduction followed by elimination produced the R, β-unsaturated ester, and Michael addition of enantiomerically pure R-methylbenzylamine then yielded a mixture of the four diastereomeric β-aminoesters. The desired isomer was isolated in 13% yield after tedious column chromatography. 2b This original route was serviceable for initial evaluation of APC as a β-peptide building block, but this route was not efficient enough for thorough exploration of the structures and properties of APC-containing β-peptides. The new route (Scheme 1) has been streamlined by reducing the number of chemical operations and by eliminating the need for chromatographic separations. Development of this route was inspired by an asymmetric synthesis of cis-2-aminocyclohexanecarboxylic acid reported by Xu et al. 7 β-Ketoester 1 is allowed to react with (R)-R-methylbenzylamine in the presence of acetic acid, and the resulting enamine is reduced in situ with NaBH3-CN. 8 This reduction produces a mixture of four diastereomeric β-aminoesters in which 3 is the major product, and we have found a two-step crystallization protocol that allows isolation of hydrochloride salt 2 in diastereomerically pure form. The crude β-aminoester mixture is dissolved in ethyl acetate and converted to a mixture of hydrochloride salts by treatment with 4 N HCl in dioxane. A single trans isomer crystallizes in relatively pure form after this treatment (g98% de), although there is contamination from the other trans isomer. Recrystallization from acetonitrile yields a very pure form of 2 (g99% de) in 38% overall yield from 1. When (R)-R-methylbenzylamine is used, the purified β-aminoester hydrochloride is spectroscopically identical to material previously identified by crystal structure determination as the diastereomer shown in Scheme 1. Thus, use of (R)-R-methylbenzylamine leads ultimately to a protected form of (3S, 4R)-trans-3-aminopyrrolidine-4-carboxylic acid. 9 The new route is completed by alkaline ester hydrolysis, hydrogenolytic removal of the R-methylbenzyl group, and …