TOTAL SYNTHESIS OF (-)-TETRAHYDROLIPSTATIN

The total synthesis of (-)-tetrahydrolipstatin utilizing two approache s is described. In the first, L-malic acid was used as a chiral templa te to obtain enantiomerically pure (R)-3-(benzyloxy)-tetradecanal (11) which was chain-extended using 1-(trimethylsilyl)-2-nonene and a Lewi s acid. This advanced intermediate was further elaborated to the targe t compound in good overall yield. The second approach utilized laurald ehyde as a starting material and capitalizes on an asymmetric allylbor onation (91 % ee). The product could be obtained enantiomerically pure by conversion to the (R)-acetoxymandelate ester and hydrolysis. Oxida tive cleavage of the terminal double bond led to 11 which was further extended using 1,3- and 1,2-asymmetric induction based on existing nei ghboring chirality. The synthesis of tetrahydrolipstatin using the sec ond approach comprises seven steps from 11 and proceeds in 38 % overal l yield.