An efficient synthesis of (R)- and (S)-8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene

Racemic 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-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-2H-chromene. Upon removal of the TBS protecting group, the resolution of the resulting racemic 2-(4-fluorophenyl)-8-hydroxy-3-nitro-2H-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.

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(2R)-2-(4-Fluorophenyl)-3-nitro-8-[(S)-α-methoxyphenylacetoxy]-2H-chromeneC24H18FNO6[α]D20=112.5 (c 0.16, CHCl3)Source of chirality: resolutionAbsolute configuration: (2R,2′S)

(2S)-2-(4-Fluorophenyl)-3-nitro-8-[(S)-α-methoxyphenylacetoxy]-2H-chromeneC24H18FNO6[α]D20=+282 (c 0.11, CHCl3)Source of chirality: resolutionAbsolute configuration: (2S,2′S)

(R)-2-(4-Fluorophenyl)-8-hydroxy-3-nitro-2H-chromeneC15H10FNO4[α]D20=165 (c 0.10, CHCl3)Source of chirality: resolutionAbsolute configuration: (2R)

(R)-8-Ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromeneC17H14FNO4[α]D20=158 (c 0.73, CHCl3)Source of chirality: chemical derivationAbsolute configuration: (2R)