Virta Pasi, Lönnberg Harri
Department of Chemistry, University of Turku, FIN-20014 Turku, Finland.
J Org Chem. 2003 Oct 31;68(22):8534-8. doi: 10.1021/jo0344945.
A straightforward method for the solid-supported synthesis of cryptand-like bicyclic peptides (1-5) on a backbone amide linker has been described. For the branching, two novel easily available building blocks, viz. N-(4-methoxytrityl)-N-(2-nitrobenzenesulfonyl)-protected N,N-bis(2-aminoethyl)-beta-alanine (6) and N-(9-fluorenylmethoxycarbonyl) protected iminodiacetic acid monoallyl ester (7), have been employed. The key steps of the synthesis are as follows: (i) stepwise coupling of one amino acid and 6 to the secondary amino group of the linker; (ii) removal of the 2-nitrobenzenesulfonyl group and SPPS by the Fmoc chemistry, using 7 as the penultimate and tert-butoxycarbonyl (Boc) protected glycine as the last amino acid; (iii) removal of the 4-methoxytrityl protection and subsequent SPPS by the Fmoc chemistry; (iv) removal of the allyl and Fmoc groups, followed by cyclization; and (v) removal of the Boc and tert-butyl groups, followed by cyclization. Final cleavage from the support and removal of benzyl-derived protecting groups gives the desired bicyclic products.
已描述了一种在主链酰胺连接基上固相合成类穴状双环肽（1-5）的直接方法。对于分支，使用了两种新型且易于获得的构建块，即N-（4-甲氧基三苯甲基）-N-（2-硝基苯磺酰基）保护的N，N-双（2-氨基乙基）-β-丙氨酸（6）和N-（9-芴甲氧羰基）保护的亚氨基二乙酸单烯丙酯（7）。合成的关键步骤如下：（i）将一种氨基酸和6逐步偶联至连接基的仲氨基上；（ii）通过Fmoc化学方法去除2-硝基苯磺酰基并进行固相肽合成，使用7作为倒数第二个氨基酸，叔丁氧羰基（Boc）保护的甘氨酸作为最后一个氨基酸；（iii）去除4-甲氧基三苯甲基保护基，随后通过Fmoc化学方法进行固相肽合成；（iv）去除烯丙基和Fmoc基团，然后进行环化；（v）去除Boc和叔丁基基团，然后进行环化。从载体上最终裂解并去除苄基衍生的保护基，得到所需的双环产物。
