| Research Abstract |
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.
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