Gustafsson Tomas, Hedenström Mattias, Kihlberg Jan
Organic Chemistry, Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
J Org Chem. 2006 Mar 3;71(5):1911-9. doi: 10.1021/jo052256z.
A stereoselective synthesis of the C-glycoside analogue of beta-D-galactosyl-(5R,2S)-hydroxylysine (1) has been achieved starting from tetra-O-benzyl-D-galactopyranosyl lactone. The synthesis involved establishment of three stereogenic centers in an unambiguous manner. A facially selective Grignard reaction followed by a silane reduction was used for the anomeric position of the C-galactose residue. An Evans allylation established the configuration of the delta-aminomethylene group of the hydroxylysine moiety, whereas an asymmetric hydrogenation utilizing Burk's catalyst was used for the alpha-amino acid moiety itself. The synthesis was completed in 17 steps with an overall yield of 18%, resulting in the most complex and functionalized C-glycoside analogue of a naturally occurring glycosylated amino acid prepared to date. In addition, amino acid 1 was incorporated in a glycopeptide from type II collagen known to be crucial for the response of autoimmune T cells obtained in models of rheumatoid arthritis. A preliminary immunological study revealed that four out of five members in a panel of T cell hybridomas were able to recognize this C-linked glycopeptide when presented by A(q) class II MHC molecules.
以四 - O - 苄基 - D - 吡喃半乳糖内酯为起始原料，实现了β - D - 半乳糖基 - (5R,2S) - 羟基赖氨酸（1）的C - 糖苷类似物的立体选择性合成。该合成以明确的方式构建了三个立体中心。对C - 半乳糖残基的异头位置采用了面选择性格氏反应，随后进行硅烷还原。通过埃文斯烯丙基化反应确定了羟基赖氨酸部分δ - 氨基亚甲基的构型，而利用伯克催化剂进行的不对称氢化反应则用于α - 氨基酸部分本身。该合成反应共17步，总产率为18%，得到了迄今为止制备的最复杂且功能化的天然存在的糖基化氨基酸的C - 糖苷类似物。此外，氨基酸1被掺入到来自II型胶原蛋白的糖肽中，已知该糖肽对于类风湿性关节炎模型中获得的自身免疫性T细胞的反应至关重要。一项初步的免疫学研究表明，当由A(q) II类MHC分子呈递时，一组T细胞杂交瘤中的五分之四能够识别这种C - 连接的糖肽。
