Gustafsson Tomas, Schou Magnus, Almqvist Fredrik, Kihlberg Jan
Organic Chemistry, Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
J Org Chem. 2004 Dec 10;69(25):8694-701. doi: 10.1021/jo049136w.
A synthesis of (2S,5R)-5-hydoxylysine, based on (R)-malic acid and Williams glycine template as chiral precursors, has been developed. This afforded hydroxylysine, suitably protected for direct use in peptide synthesis, in 32% yield over the 13-step sequence. Regioselective reductive opening of a p-methoxybenzylidene acetal and alkylation of the Williams glycine template were key steps in the synthetic sequence. Surprisingly, the regioselectivity in opening of the p-methoxybenzylidene acetal was reversed as compared to what was expected. It was found that this was due to chelation of the trialkylsilyl choride, used as an electrophile in the reductive opening, to an adjacent azide functionality. It was also discovered that an equivalent amount of trialkylsilyl hydride was formed in the reaction, a finding that led to additional mechanistic insight into reductive openings of p-methoxybenzylidene acetals with sodium cyanoborohydride as reducing agent.
基于（R）-苹果酸和威廉姆斯甘氨酸模板作为手性前体，已开发出（2S，5R）-5-羟基赖氨酸的合成方法。通过13步反应序列，以32%的产率得到了适合直接用于肽合成的羟基赖氨酸，且已进行了适当保护。对甲氧基苄叉缩醛的区域选择性还原开环和威廉姆斯甘氨酸模板的烷基化是合成序列中的关键步骤。令人惊讶的是，与预期相比，对甲氧基苄叉缩醛开环的区域选择性发生了反转。结果发现，这是由于在还原开环中用作亲电试剂的三烷基硅基氯与相邻的叠氮官能团发生了螯合作用。还发现反应中生成了等量的三烷基硅基氢化物，这一发现为以氰基硼氢化钠为还原剂的对甲氧基苄叉缩醛的还原开环反应提供了更多的机理见解。
