Asymmetric synthesis of Sulindac esters by enantioselective sulfoxidation in the presence of chiral titanium complexes

High ee values (up to 94–96% ee) and moderate isolated yields (48–50%) were achieved in the preparation of Sulindac alkyl esters. These molecules are simple and straightforward precursors of Sulindac, an anti-inflammatory drug that has also been recently investigated in anti-cancer therapy. The key step of the overall procedure was the enantioselective hydroperoxide oxidation of the Sulindac sulfide alkyl esters in the presence of chiral complexes of titanium with either (S,S)- or (R,R)-hydrobenzoin. Various reaction conditions were investigated in order to obtain the best balance between yield and enantioselectivity.

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(S)-Sulindac methyl esterC21H19FO3SEe 94% (HPLC)[α]D25=-60.4(c1.0,CHCl3)Source of chirality: enantioselective oxidationAbsolute configuration: (S)

(S)-Sulindac tert-butyl esterC24H25FO3SEe 96% (HPLC)[α]D25=-42.8(c1.0,CHCl3)Source of chirality: enantioselective oxidationAbsolute configuration: (S)

(R)-SulindacC20H17FO3SEe 96% (HPLC)[α]D25=+56.6(c0.5,CH3OH)Source of chirality: enantioselective oxidationAbsolute configuration: (R)