Wang Bo, Liu Yunpeng, Jiao Rui, Feng Yiqing, Li Qiong, Chen Chen, Liu Long, He Gang, Chen Gong
Department of Chemistry, The Pennsylvania State University , University Park, Pennsylvania 16802, United States.
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University , Tianjin 300071, China.
J Am Chem Soc. 2016 Mar 23;138(11):3926-32. doi: 10.1021/jacs.6b01384. Epub 2016 Mar 10.
The mannopeptimycins are a class of glycopeptide natural products with unusual structures and potent antibiotic activity against a range of Gram-positive multidrug-resistant bacteria. Their cyclic hexapeptide core features a pair of unprecedented β-hydroxyenduracididines (L- and D-βhEnd), an O-glycosylated D-Tyr carrying an α-linked dimannose, and a β-methylated Phe residue. The D-βhEnd unit also carries an α-linked mannopyranose at the most hindered N of its cyclic guanidine ring. Herein, we report the first total synthesis of mannopeptimycin α and β with fully elaborated N- and O-linked sugars. Critically, a gold-catalyzed N-glycosylation of a D-βhEnd substrate with a mannosyl ortho-alkynylbenzoate donor enabled the synthesis of the most challenging N-Man-D-βhEnd unit with excellent efficiency and stereoselectivity. The L-βMePhe unit was prepared using a Pd-catalyzed C-H arylation method. The L-βhEnd, D-Tyr(di-Man), and L-βMePhe units were prepared in gram quantities. A convergent assembly of the cyclic peptide scaffold and a single global hydrogenolysis deprotection operation provided mannopeptimycin α and β.
甘露肽霉素是一类具有独特结构的糖肽类天然产物，对多种革兰氏阳性多重耐药菌具有强大的抗生素活性。它们的环状六肽核心具有一对前所未有的β-羟基持久霉素（L-和D-βhEnd）、一个携带α-连接的二甘露糖的O-糖基化D-酪氨酸，以及一个β-甲基化的苯丙氨酸残基。D-βhEnd单元在其环状胍环最受阻的氮原子上还携带一个α-连接的甘露吡喃糖。在此，我们报道了甘露肽霉素α和β的首次全合成，其中N-和O-连接的糖均已完全构建。至关重要的是，用邻炔基苯甲酸甘露糖供体对D-βhEnd底物进行金催化的N-糖基化反应，能够以优异的效率和立体选择性合成最具挑战性的N-Man-D-βhEnd单元。L-βMePhe单元是使用钯催化的C-H芳基化方法制备的。L-βhEnd、D-Tyr（二甘露糖）和L-βMePhe单元的制备量为克级。通过环状肽支架的汇聚组装和单一的全局氢解去保护操作得到了甘露肽霉素α和β。
