4-AMINO-4,5-DIHYDROTHIOPHENE-2-CARBOXYLIC ACID
4-AMINO-4,5-DIHYDROTHIOPHENE-2-CARBOXYLIC ACID
复制标题
DOI：
10.1021/jo00215a027
复制
发表时间：
1985-01-01
影响因子：
3.6
通讯作者：
METCALF, BW
中科院分区：
文献类型：
--
作者：
ADAMS, JL;CHEN, TM;METCALF, BW
描述了4-氨基-4，5-二氢噻吩-2-羧酸（1）的合成，该化合物被设计为用作基于机制的GABA-T抑制剂。合成外消旋体1以及（R，S）-1的C3-取代类似物化合物3的关键中间体通过（R，S）-N-（叔丁氧羰基）-S-（乙氧羰基甲基）半胱氨酸乙酯（2）的Dieckmann环化反应制备。β-还原酮酯3与NaBH 4产生β-羟基酯5，将其用MsCl/Et 3 N脱水，得到4，5-二氢噻吩6。随后除去保护基得到外消旋1。当使用光学活性的2时，该顺序得到不同光学纯度的1。β-酮酯3显示出在构型上极其不稳定，并且不进行外消旋化就不能实现其分离。光学纯的1（> 99%ee）通过对2的N-唾液酸化衍生物化合物20进行Dieckmann环化而获得。20与LDA在THF中在-65 ℃下反应。C通过分子内甲硅烷基转移进行，得到缩醛22，没有任何明显的外消旋化。脱甲硅烷基化和硼氢化物还原条件的明智选择允许22到5的有效转化而没有外消旋化。以这种方式产生的化合物5向对映体纯的1的转化以与合成外消旋体1所述相同的方式完成。
The synthesis of 4-amino-4,5-dihydrothiophene-2-carboxylic acid (1), a compound designed to function as a mechanism-based inhibitor of GABA-T, is described. The key intermediate for the synthesis of racemic 1, as well as the C3-substituted analogues of (R,S)-1, compound 3, is prepared by a Dieckmann cyclization of (R,-S)-N-(tert-butoxycarbonyl)-S-(carbethoxymethyl)cysteine, ethyl ester (2). Reduction of the .beta.-keto ester 3 with NaBH4 produces the .beta.-hydroxy ester, 5, which is dehydrated with MsCl/Et3N to afford the 4,5-dihydrothiophene, 6. Subsequent removal of the protecting groups yields racemic 1. When optically active 2 was employed, this sequence afforded 1 of varying optical purity. The .beta.-keto ester 3 was shown to be extremely configurationally labile, and its isolation without racemization could not be accomplished. Optically pure 1 (> 99% ee) is obtained by performing the Dieckmann cyclization on the N-sialylated derivative of 2, compound 20. The reaction of 20 with LDA in THF at -65.degree. C proceeds via an intramolecular silyl transfer to afford the acetal 22 without any apparent racemization. The judicious choice of desilylation and borohydride reduction conditions allows for the efficient conversion of 22 to 5 without racemization. The conversion of compound 5 generated in this fashion to enantiomerically pure 1 is accomplished in the same manner as that described for the synthesis of racemic 1.