基于稠环偕二卤代环丙烷不对称开环反应的天然产物全合成研究

Ring-fused gem-dihalocyclopropanes are important substrates with ready availability and great potentials in chemical synthesis. Due to their versatile chemistry, they have wide-spread applications in the development of high efficient, concise and divergent synthetic strategies. In current application, the asymmetric total syntheses of several bioactive Amaryllidaceae alkaloids, morphine, and recently isolated sesquiterpenoid tropolone glycoside liriosmaside A based on the ring-opening reaction of certain ring-fused gem-dihalocyclopropanes are proposed. In broad terms there are three major components to the proposed program of work outlined below, the first being focused on the development of the first asymmetric ring-opening methodologies using chiral amines as nucleophiles to trap the π-allyl cation formed as a result of the ring-opening process of 6,6-dibromobicyclo[3.1.0]hexane. This will allow for the preparation of enantiomer pure ring-opening products that, when in combination of an intramolecular Alder-Ene reaction and functional group interconversions (FGIs), leads to synthesize a variety of Amaryllidaceae alkaloids. The second content will be exploring the asymmetric ring-opening strategy of certain substituted 6,6-dibromobicyclo[3.1.0]hexane to have the morphine skeleton built, during which an intramolecular Heck alkenylation reaction and Eschenmoser–Claisen rearrangement will be employed, and the shortest asymmetric total synthesis of morphine is expected to achieve. In the last program, a highly functionalized ring-fused gem-dihalocyclopropanes will be prepared so as to complete the first total synthesis of sesquiterpenoid tropolone glycoside liriosmaside A by utilizing a ring-expansion reaction.

稠环偕二卤代环丙烷是一类制备简单且潜力巨大的有机结构，深入拓展该类化合物在有机合成中的应用，对提高合成效率，发展简洁、多样化合成策略具有十分重要的意义。本项目拟应用稠环偕二卤代环丙烷不对称开环反应为关键步骤，完成一系列具有显著生物活性的石蒜科生物碱、吗啡及倍半萜类天然产物liriosmaside A的不对称全合成。具体内容为：（1）在代表性稠环偕二卤代环丙烷6,6-二溴双环[3.1.0]己烷的开环反应中，以商品化手性胺进攻其π-烯丙基碳正离子，生成对映体纯开环产物，结合分子内Alder-Ene反应及官能团转化策略，完成超过6个具有优良生物活性的石蒜科生物碱的全合成；（2）深入拓展取代6,6-二溴双环[3.1.0]己烷的开环反应，探索迄今最为简短的吗啡全合成路线；（3）构建高度官能化的稠环偕二卤代环丙烷，并应用其扩环策略从而实现倍半萜类天然产物liriosmaside A的首次全合成。

本项目拟应用稠环偕二卤代环丙烷不对称开环反应为关键步骤，完成一系列具有显著生物活性的石蒜科生物碱、吗啡及倍半萜类天然产物liriosmaside A的不对称全合成。通过开展本项目的研究，目前已完成了拟定的大部分研究目标，取得了丰硕的成果：1. 筛选出带有合适手性辅基的胺与6,6-二溴双环[3.1.0]己烷进行不对称开环反应，寻找合适的反应条件以达到最佳非对映体选择性，在脱去其手性辅基后制备后续全合成所需对映体纯的2-溴-2-环己烯-1-胺。以此为原料，应用不同的构建含芳基取代顺式氢化吲哚环的合成策略完成完成了5种具备优良活性的石蒜科生物碱(+)-bulbispermine (14步)、(+)-11-hydroxyvittatine (13步)、(–)-haemanthidine (15步)、(+)-pretazettine (16步)及(+)-tazettine (17步)的全合成，提供了一套全新的构建石蒜科生物碱骨架的合成方法; 2. 实现了迄今最简洁高效的吗啡类生物碱的全合成，以7步反应，总收率9%，完成了可待因的不对称全合成，开创了该类天然产物全合成的全新方法；3. 首次构建了Liriosmaside A/B的核心骨架，距实现其首次全合成仅一步之遥。总之，本项目已取得一系列成果，包括发表了8篇SCI论文（3篇一区，4篇二区）、其中第二项主要研究工作成果正在撰写，计划近期投稿，第三项研究工作尚未完成。目前基于吗啡类生物碱最简洁全合成工艺正在撰写两项PCT专利，计划后续进一步完善相关研究，并推进产业化应用。