Structure Modification of Calanolides

S Synthesis of (+)-Calanolide A From Enzyme-Catalyzed Optical Resolution of Compound (+)-53 

The synthetic ( )-calanolide A was resolved into its enantiomers, (+)-calanolide A (1) and ( )-calanolide A, by using a semipreparative chiral HPLC column packed with amylose carbamate eluting with hexane/ethnol (95 5). The ultraviolet detection was set at a wavelength of 254 nm. (+)-calanolide A and its enantiomer (—)-calanohde A were collected, and their chemical structures were identified based on their optical rotations and spectroscopic data, as compared with the corresponding natural and synthesis compounds. 

Four research groups were engaged in the structural modification of calanolides for the structure activity relationship studies. Gahnis et al. have focused on a catalytic reduction of the A -olefinic bond in (+)-calanohde A (1) and (—)-calanolide B (15), such as chemical modifications of C12 hydroxy group in (—)-calanolide B (15) because 15 was not only active against HIV-1 with a potency similar to that of (-l-)-calanolide A but also produced a selectively high yield ( 15%) isolated 

Some structural modifications of racemic calanolide A have been studied by us. Removal of Cn-methyl or methyl groups at both Cn and Cg positions maintains the basic stereochemistry of (it)-calanolide A as well as evaluates their anti-HIV activity. ( )-Cn-demethyl calanolide A and ( )-calanolide A exhibited similar potencies, whereas the 6,6,11-demethyl calanolide A also had diminished activity. The primary biological indicated that two methyl groups in the Cg position might be necessary for antiviral activity. 

Some structural modihcations of (+)-calanohde A or (-)-calanolide B have been carried out. However, no compounds showed anti-HIV-1 activity superior to the two lead compounds (1 and 15). Hopefully, calanolide A continues to have promise as an anti-HIV drug in the near future. 

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