Virta Pasi, Karskela Marika, Lönnberg Harri
Department of Chemistry, University of Turku, FIN-20014 Turku, Finland.
J Org Chem. 2006 Mar 3;71(5):1989-99. doi: 10.1021/jo052348o.
Two novel peptide scaffolds, viz. cyclo[(N(alpha)-Alloc)Dpr-beta-Ala-(N(alpha)-Fmoc)Dpr-beta-Ala] (1) and cyclo[(N(alpha)-Alloc)Dpr-alpha-azido-beta-aminopropanoyl-(N(alpha)-Fmoc)Dpr-beta-Ala] (2), composed of orthogonally protected 2,3-diaminopropanoyl (Dpr) and beta-alanyl residues, have been described. Fmoc chemistry on a backbone amide linker derivatized resin has been used for the chain assembly. Selective removal of the 4-methyltrityl (Mtt) and 1-methyl-1-phenylethyl protections (PhiPr) exposes the beta-amino and carboxyl terminus, respectively, and on-resin cyclization then gives the desired orthogonally protected cyclo-beta-tetrapeptides (1 and 2). The alpha-amino groups, bearing the Fmoc and Alloc protections and the azide mask, allow stepwise orthogonal derivatization of these solid-supported cyclo-beta-tetrapeptide cores (1 and 2). This has been demonstrated by attachments of various sugar units [viz., acetyl- or toluoyl-protected carboxymethyl alpha-d-glycopyranosides (13-15) and methyl 6-O-(4-nitrophenoxycarbonyl)-alpha-d-glycopyranosides (22-24)] to obtain diverse di- and trivalent glycoclusters (33-42). Acidolytic release (TFA) from the support, followed by conventional NaOMe-catalyzed transesterification (33-40) or hydrazine-induced acyl substitution in DMF (41 and 42), gives the fully deprotected clusters (43-52) as final products.
已描述了两种新型肽支架，即环[（Nα-烯丙氧羰基）Dpr-β-丙氨酸-（Nα-芴甲氧羰基）Dpr-β-丙氨酸]（1）和环[（Nα-烯丙氧羰基）Dpr-α-叠氮基-β-氨基丙酰基-（Nα-芴甲氧羰基）Dpr-β-丙氨酸]（2），它们由正交保护的2,3-二氨基丙酰基（Dpr）和β-丙氨酰基残基组成。在主链酰胺连接基衍生化树脂上使用芴甲氧羰基化学进行链组装。选择性去除4-甲基三苯甲基（Mtt）和1-甲基-1-苯乙基保护基（PhiPr）分别暴露出β-氨基和羧基末端，然后在树脂上进行环化反应，得到所需的正交保护的环-β-四肽（1和2）。带有芴甲氧羰基和烯丙氧羰基保护基以及叠氮基保护基的α-氨基允许对这些固相支持的环-β-四肽核心（1和2）进行逐步正交衍生化。通过连接各种糖单元[即乙酰基或甲苯甲酰基保护的羧甲基α-D-吡喃葡萄糖苷（13 - 15）和甲基6 - O -（4 - 硝基苯氧基羰基）-α-D-吡喃葡萄糖苷（22 - 24）]来获得各种二价和三价糖簇（33 - 42），已证明了这一点。从载体上酸解释放（三氟乙酸），然后进行常规的甲醇钠催化的酯交换反应（33 - 40）或在N,N-二甲基甲酰胺中肼诱导的酰基取代反应（41和42），得到完全脱保护的簇（43 - 52）作为最终产物。
