We report on our accomplishment of the asymmetric synthesis of hispidanin A and its natural precursor, a labdane diterpenoid. In the first generation of synthesis, a semi-synthesis strategy was employed to construct a labdane-type diterpenoid, a natural precursor of hispidanin A, in which Barton's photolytic remote functionalization was employed as a key transformation. In addition, the totarane-type dienophile counterpart was derived from commercially available (-)-scalareol. In the second generation of synthesis, key elements included an iron-catalyzed radical cascade to access the labdane-type diene on the basis of hydrogen atom transfer, and an enantioselective cationic polyene cyclization furnished the totarane-type dienophile. Reaction optimization and mechanistic analysis of the radical cascade reaction was conducted. Furthermore, the [4+2] cycloaddition reaction was achieved in excellent yield and selectivity under thermal conditions, which has been rationalized by using DFT transition-state analysis and paved the way for final accomplishment of the total synthesis of hispidanin A.
Keywords: Diels-Alder reaction; cyclization; hispidanin A; radical reactions; total synthesis.
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