College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
College of Pharmacy, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon, Gangwon-do, 24341, Republic of Korea.
Angew Chem Int Ed Engl. 2021 May 17;60(21):12060-12065. doi: 10.1002/anie.202101766. Epub 2021 Apr 16.
While numerous studies pertaining to the total synthesis of Cephalotaxus alkaloids have been reported, only two strategies have been reported to date for the successful synthesis of the C-11 oxygenated subset, due to the additional synthetic challenge posed by the remote C-11 stereocenter. Herein, we report the collective asymmetric total synthesis of C-11 oxygenated Cephalotaxus alkaloids using a chiral proline both as a starting material and as the only chirality source. A tetracyclic advanced intermediate was synthesized in a highly stereoselective manner from l-proline in 8 steps involving sequential chirality transfer steps such as a diastereoselective N-alkylation, stereospecific Stevens rearrangement and intramolecular Friedel-Crafts reaction via an unusual O-acyloxocarbenium intermediate. From a common intermediate, the asymmetric total synthesis of six C-11 oxygenated Cephalotaxus alkaloids was completed by a series of oxidation state adjustments.
虽然已经有许多关于 Cephalotaxus 生物碱全合成的研究报告，但由于远程 C-11 立体中心带来的额外合成挑战，迄今为止仅报道了两种成功合成 C-11 含氧亚组的策略。在此，我们报告了使用手性脯氨酸作为起始原料和唯一手性源，通过集体不对称全合成 C-11 含氧 Cephalotaxus 生物碱。通过连续的手性转移步骤，如非对映选择性 N-烷基化、立体特异性史蒂文斯重排和通过不寻常的 O-酰氧基碳正离子中间体的分子内傅克反应，从 l-脯氨酸以 8 步高立体选择性合成了四环高级中间体。从一个共同的中间体，通过一系列氧化态调整完成了六种 C-11 含氧 Cephalotaxus 生物碱的不对称全合成。
