Enantioselective Total Synthesis of Bioactive Polysubstituted Terpenoid Chromans

本项目的目的是建立多取代萜类色曼的区域和对映体选择性合成方法，并将该方法应用于生物活性天然和非天然产物的合成。通过苯酚与无环单萜醇的邻位烷基化反应，通过[2，3]S型重排反应合成了色满前体2-取代苯酚。通过对取代苯酚的脱硫、脱保护和保护，再转化为环氧化物和酸催化剂的作用，成功地以区域和对映体选择性的方式合成了3-羟基色满。建立了4，6-二羟基苯酞的有效合成方法，其中6-位被选择性保护，但该化合物不适合通过S型重排进行烷基化反应。将合成计划修改为第一步苯酞前体的烷基化，然后生成色满，最后一步合成苯酞。3，5-二羟基苯甲酸酯或相应的酰胺被发现是修订计划的起始酚选择。3，5-二羟基苯甲酸乙酯和3，3-二甲基丙烯醛缩醛的偶联反应得到苯环上有两个取代基的3-羟基色满，然后区域选择性甲酰化得到所需的产物。通过还原和酸处理，将其转化为多取代色满。以N，N-二乙基-3-羟基-5-甲氧基苯甲酰胺和2，3-二羟基异戊硫醚为原料，在3-羟基铬-7-甲酰胺上构筑了5元内酯骨架。由于3-羟基色满的区域选择性合成已经建立，本结果意味着生物活性多取代萜类色曼的非对映选择性合成的建立。

This Project was undertaken to establish a regio- and enantio-selective synthesis of polysubstituted terpenoid chromans and to apply the method to a synthesis of bioactive natural and unnatural products.1. A synthesis of 2-substituted phenols, precursors of chromans, was established by ortho-alkylation of phenols with acyclic monoterpene alcohols via [2,3] sigmatropic rearrangement. We succeeded in obtaining 3-hydroxychromans in regio- and enantio-selective manner by desulfurization, deprotection, and protection of the substituted phenols, followed by conversion to epoxides and action of acid catalyst.2. effective method was established for a synthesis of 4,6-dihydroxyphthalide in which the 6-position was selectively protected, but this compound was proved to be unsuitable for the alkylation via sigmatropic rearrangement.3. The synthetic plan was revised into the first alkylation of a phthalide precursor followed by chroman formation, and construction of the phthalide at the final step. 3,5-Dihydroxybenzoate ester or the corresponding amide were found to be the starting phenols of choice for the revised plan.4. The coupling of ethyl 3,5-dihydroxybenzoate and 3,3-dimethylacrolein acetal afforded a 3-hydroxychroman which had two substituents on the benzene ring, which was formylated regioselectively to give a desired product. This was converted to a polysubstituted chroman via reduction and acidic treatment.5. Five-membered lactone skeleton was built up on 3-hydroxychroman- 7-carboxamide which was in turn prepared from N,N-diethyl-3-hydroxy-5-methoxy-benzamide and 2,3-dihydroxy-isopentyl sulfide derivative. As the regioselective synthesis of 3-hydroxychroman had been established, the present result means the establishment of diastereoselective synthesis of bioactive polysubstituted terpenoid chromans.