An Asymmetric Synthesis of (-)-Tetrahydrolipstatin

The Total Synthesis of ( - )-Tetrahydrolipstatin

“…The trichloroethyl (Tce) ester group seemed an ideal candidate as its removal is performed by zinc reduction under mildly acidic conditions. [45] Ester (11) was treated with aqueous potassium hydroxide in tetrahydrofuran to afford the carboxylic acid in 86% yield, which was immediately converted to the trichloroethyl ester (18) in excellent yield (94%, Scheme 4). Synthesis of hydroxy ester (19) from diene (18) proceeded in three steps as described for the ethyl and methyl series (47% overall).…”

“…[3,4] There has been considerable interest in tetrahydrolipstatin due to the growing awareness of obesity-related illness and several syntheses have been reported. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] In each case the construction of the strained trans-β-lactone of (1) emerges as an important synthetic challenge. The majority of previously reported syntheses [5][6][7][8][9][10][11][12][13][14][15][16] use Adams' conditions for formation of the β-lactone from a β-hydroxy carboxylic acid precursor.…”

“…Kocienski and coworkers [17,18] have reported the Lewis acid promoted [2 + 2] cycloaddition of a 2-trimethylsilylketene with a chiral aldehyde, followed by desilylation, to install the trans-β-lactone of (1) in moderate yield and with 9 : 1 diastereoselectivity. Tandem aldol-lactonization sequences have also been applied to good effect for the synthesis of this structural unit.…”

Pharmaceuticals

“…5.110). [256] Some derivatives, e.g. tetrahydrolipstatin, also inhibit the thioesterase domain of the human fatty acid synthase.…”

(3R*,4S*)-4-[(S*)-2-Cyclohexyl-2-(tert-butyldimethylsiloxy)ethyl]-3-hexyl-3-(trimethylsilyl)oxetan-2-one

“…During a synthesis of the pancreatic lipase inhibitor tetrahydrolipstatin, Pommier, Pons, Kocienski & Wong (1994) found high 1,3-asymmetric induction in the analogous cycloaddition of n-hexyl(trimethylsilyl)ketene…”