(+)-Calanolide A (1) and (+)-inophyllum B (2) were isolated as strong anti HIV-1 active coumarins from Calophyllum genus (Guttiferae), which are composed of 4-substituted coumarin (A-B), 2,2-dimethylchromene (A-C), and 2,3-dimethyl-4-chromanol (A-D) skeletons. The stereochemistry of (10R,11S,12S) in the ring D is suggested to be the most responsible function for anti HIV-1 activity. We have approached the enantioselective construction of chromanone ring, leading to chromanol function by reduction, by intramolecular Michael addition (IMA) of an o-tigloylphenol in THF containing a chincona alkaloid such as (-)-quinine, and effective asymmetric induction (up to 87% ee) had been achieved in cis-chromanone cyclization in model studies using a coumarin 5 lacking a 4-propyl group. However, no diastereoselectivity between cis- and trans-products 6 had been observed. Precise examination of the quinine-catalyzed IMA using 4-propyl-8-tigloylcoumarin 12 in various solvents toward (+)-calanolide A (1) synthesis led to the formation of (+)-enantiomer-riched cis-chromanone (+)-cis-1 3 with 60% de and 98% ee when chlorobenzene was used as a solvent. Application of this condition to a 4-phenyl-8-tigloylcoumarin 14 belong to inophyllum series expectedly afforded cis-chromanone 15 with satisfactory stereoselectivity (69% de and 97% ee). Trials for demethylation of the 5-methoxy group in cis-13 failed. Therefore, we newly prepared a 10-tigloylpyranocoumarin 22 from 2-hydroxy-4-methoxy-6-triisopropylsilylbutyrophenone (19) as a substrate for IMA. Subjection of 22 to the established IMA smoothly gave (+)-cis-chromanone (+)-cis-17 with 60% de and 94% ee. Isomerization of (+)-cis-17 followed by hydride reduction successfully afforded (+)-calanolide A (1).
