Enantioselective Total Synthesis of Bioactive Polysubstituted Terpenoid Chromans

本项目旨在建立多取代萜类化合物色满的区域选择性和对映选择性合成方法，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[2，3] σ-转移重排反应，酚与无环单萜醇发生邻位烷基化反应，合成了苯并二氢吡喃的前体2-取代酚。通过对取代酚进行脱硫、脱保护、保护，然后转化为环氧化物，在酸催化剂作用下，成功地实现了对映体和区域选择性合成3-羟基苯并二氢吡喃.对4，6-二羟基苯酞的6-位进行了选择性保护，建立了一种有效的合成方法，但通过σ-迁移反应证明该化合物不适合烷基化反应.将合成计划修改为首先对苯酞前体进行烷基化，然后形成色满，并在最后一步构建苯酞。发现3，5-二羟基苯甲酸酯或相应的酰胺是修订计划选择的起始酚。由3，5-二羟基苯甲酸乙酯与3，3-二甲基丙烯醛缩醛偶合得到苯环上有两个取代基的3-羟基苯并二氢吡喃，再经区域选择性甲酰化得到目标产物。通过还原和酸处理将其转化为多取代的色满。以N，N-二乙基-3-羟基-5-甲氧基苯甲酰胺和2，3-二羟基异戊基硫醚衍生物为原料合成了3-羟基苯并二氢吡喃-7-甲酰胺，并在其上构筑了五元内酯骨架。由于3-羟基苯并二氢吡喃的区域选择性合成已经建立，本研究结果意味着生物活性多取代萜类苯并二氢吡喃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.