Stereoselective synthesis of threo and erythroβ-hydroxy and β-disubstituted-β-hydroxy α-amino acids
Stereoselective synthesis of threo and erythroβ-hydroxy and β-disubstituted-β-hydroxy α-amino acids
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DOI：
10.1021/jo972294l
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发表时间：
1998-05-29
影响因子：
3.6
通讯作者：
Lajoie, GA
中科院分区：
文献类型：
--
作者：
Blaskovich, MA;Evindar, G;Lajoie, GA
光学纯的N-保护的丝氨酸醛等价物可以通过用环状原酸酯保护丝氨酸的羧基来制备。N-Cbz-、N-Fmoc-或N-Boc-保护的丝氨酸与氧杂环丁烷甲苯磺酸酯1或溴化物2的烷基化得到相应的氧杂环丁烷酯4a-c，其可以容易地转化为环状原酸酯5a-c。各种不寻常的苏型β-羟基氨基酸已被合成的格氏除了这些光学纯的丝氨酸醛等价物。邻位非对映异构体可以通过氧化最初的三种加合物，然后用LiBH 4还原来获得。还描述了非对映选择性合成光学纯β，β-二烷基-β-羟基α-氨基酸的一般方法。这些高度取代的氨基酸是通过一系列的格氏加成反应制备的光学活性的丝氨酸醛等价物，然后通过氧化的初始加合物，和第二格氏加成得到的酮。以非常高的非对映选择性（84- 96%de）获得羟基加合物。所有四种非对映异构体都可以通过改变格氏加成的顺序和初始合成子的手性来选择性地合成。保护基的去除可以在非常温和的条件下进行，以高非对映异构体纯度得到优异的高度取代的氨基酸产率。
Optically pure N-protected serine aldehyde equivalents can be prepared by the protection of the carboxylic group of serine by a cyclic ortho ester. Alkylation of N-Cbz-, N-Fmoc- or N-Boc-protected serine with oxetane tosylate 1 or bromide 2 gives the corresponding oxetane esters 4a-c which can easily be converted to the cyclic ortho esters 5a-c. A variety of unusual threo beta-hydroxy amino acids have been synthesized by Grignard addition to these optically pure serine aldehyde equivalents. The erythro diastereomers can be obtained by oxidation of the initial three adduct followed by reduction with LiBH4. Also described is a general approach for the diastereoselective synthesis of optically pure beta,beta-dialkyl-beta-hydroxy alpha-amino acids. These highly substituted amino acids are prepared by a sequence of Grignard addition to the optically active serine aldehyde equivalent, followed by oxidation of the initial adduct, and a second Grignard addition to the resulting ketone. The hydroxy adduct is obtained with very high diastereoselectivity (84-96% de). All four diastereomers can be selectively synthesized by varying the order of the Grignard additions and the chirality of the initial synthon. Removal of the protecting groups can be effected in very mild conditions, giving excellent yields of highly substituted amino acids in high diastereomeric purity.