Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique (INRS), 531, boul. des Prairies, Laval, Québec, Canada H7V 1B7.
National Research Council Canada (NRC), 100 Sussex Drive, Ottawa, Ontario, Canada K1A 0R6.
Org Lett. 2020 Aug 7;22(15):5783-5788. doi: 10.1021/acs.orglett.0c01847. Epub 2020 Jul 14.
3-Deoxy-d--oct-2-ulosonic acid (Kdo) biosynthetic pathway is a promising target in antibacterial drug discovery. Herein, we report the total synthesis of 6-amino-2,6-dideoxy-α-Kdo in 15 steps from d-mannose as a potential inhibitor of Kdo-processing enzymes. Key steps of the synthetic sequence involve a Horner-Wadsworth-Emmons reaction for the two-carbon chain homologation followed by either a 6- Pd-catalyzed reductive cyclization or a tandem Staudinger/aza-Wittig reaction with concomitant α-iminoester reduction, enabling the α-stereoselective formation of the Kdo-like six-membered azacyclic ring.
3-去氧-D--辛-2-酮酸（Kdo）生物合成途径是抗菌药物发现的一个有前途的靶点。在此，我们报告了 6-氨基-2,6-二脱氧-α-Kdo 的全合成，该化合物以 D-甘露糖为起始原料，经 15 步反应得到，可作为 Kdo 加工酶的潜在抑制剂。合成序列的关键步骤包括 Horner-Wadsworth-Emmons 反应进行二碳链同系化，随后进行 6-Pd 催化的还原环化或串联 Staudinger/aza-Wittig 反应以及伴随的α-亚氨基酯还原，从而实现了 Kdo 类似的六元氮杂环的 α-立体选择性形成。
