A simple enantioselective route toward (R)- and (S)-Rolipram via anhydride desymmetrization

A highly enantioselective metal-free synthesis of both enantiomers of Rolipram is reported. The key stereoinductive step is a cinchona alkaloid catalyzed opening of a cyclic anhydride prepared from isovanillin, where both enantiomers are available using the same chiral catalyst in two protocols. An extended one-pot Curtius sequence provides the lactam directly from the desymmetrization product after enrichment in high yield and excellent ee.

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(R)-(−)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)-pyrrolidin-2-oneC16H21NO3ee 95%[α]D26=-29.9 (c 0.586, MeOH)Source of chirality: desymmetrization of anhydride/resolutionAbsolute configuration (R)

(R)-3-(3-Cyclopentyloxy-4-methoxy-phenyl)-pentanedioic acid monobenzyl esterC24H28O6ee 95%[α]D25=+5.2 (c 0.764, CH2Cl2)Source of chirality: desymmetrization of anhydride/resolutionAbsolute configuration: (R)

(R)-3-(3-Cyclopentyloxy-4-methoxy-phenyl)-pentanedioic acid monocinnamyl esterC26H30O6ee 95%[α]D25=-7.3 (c 0.41, MeOH)Source of chirality: desymmetrization of anhydride/resolutionAbsolute configuration: (R)