Shuguang Yin, Can-Fei Zhang, X. Mao
Mar 31, 2013
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Influential Citations
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Journal
Tetrahedron-asymmetry
Abstract
Abstract Racemic 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2 H -chromene (S14161) was recently identified as a potent inhibitor of phosphoinositide 3-kinase (PI3K). In order to investigate the effects of its two enantiomers on tumor cell lines, we designed a novel synthesis for ( R )-S14161 and ( S )-S14161 using a chemical resolution and derivation strategy. The readily available 3-( tert -butyldimethylsilyloxy)-salicylaldehyde underwent a tandem oxa-Michael–Henry reaction with trans -4-fluoro-β-nitrostyrene in the presence of a catalytic amount of l -proline and triethylamine to give the 3-nitro-2 H -chromene. Upon removal of the TBS protecting group, the resolution of the resulting racemic 2-(4-fluorophenyl)-8-hydroxy-3-nitro-2 H -chromene was achieved via diastereomeric ester formation using ( S )-(+)-α-methoxyphenylacetic acid as the derivatizing agent, followed by aminolysis. Finally, the ethyl ether formation of each enantiomer furnished ( R )-S14161 and ( S )-S14161 in enantiomerically pure forms. The absolute configurations of these chiral molecules were determined by a circular dichroism method. The two enantiomers showed no marked differences in inhibition of growth of human myeloma LP1 and OPM-2 cells.