Masters Thesis

Enantioselective synthesis of Hydnocarpin D

Hydnocarpin D was isolated from the flowering plant Hydnocarpus anthelminthic in family Flacourtiaceae, as a racemic mixture devoid of optical activities, in an extremely limited amount. Racemic Hydnocarpin D has been reported to have promising anti-proliferative potency towards a human DU145 prostate cancer cell line. There are no reports, however, on the anti-proliferative potency of its optically pure enantiomers. Also, no other anticancer activity has been reported for hydnocarpin D due to the supply issue compared to its extensively explored cousin silybin. This study aims to synthesize the (10S,11S)- and (10R, 11R)-hydnocrapin D, to be tested against prostate cancer cell lines for its anti-proliferative activity and to find if a correlation exists for different enantiomers. The synthesis was simplified by combining a flavone fragment and lignan fragment through convergent synthetic scheme. The flavone intermediate had to go through two phases for the final flavone fragment 4',7-O-di(benzyl)luteolin (37) which was synthesized from naturally abundant hesperidin through a four-step transformation. During this exploration a reaction condition for regioselective C-3’ dealkylation of flavonoids was identified. The lignan intermediates 47 & 48 containing the phenylpropanoid moiety with R,R and S,S-configuration at C-1 and C-2 has was synthesized through a six-step transformation. The combination of 4',5,7-O-tri(p- methoxybenzyl)luteolin and intermediate two with S,S through a three step reaction involving mitsunobu coupling , debenzylation and ring closing reaction has so far yielded (10R, 11R)-hydnocrapin D (19)at an 6% yield.

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