Enones and enals as latent enolates in catalytic C-C bond forming processes : total synthesis of (-)-paroxetine (Paxil®)

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2007-05

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Koech, Phillip Kimaiyo, 1974-

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Abstract

Enolates constitute one of the most commonly utilized intermediates in synthetic organic chemistry. However, the regioselective generation of enolates remains a challenge, especially for non-symmetric ketones possessing identical degrees of substitution at the α-positions. Our research has shown that regioselective enolate generation can be achieved by the activation of enones and enals with either 1) nucleophilic phosphine catalysis or 2) transition metal catalysis to generate enolates regioselectively. These enolates can be subsequently trapped with electrophiles. Using nucleophilic phosphine catalysis we have developed the first method for the α-arylation of enones, enals, and nitroalkenes using bismuth(V) reagents. This phosphine-catalyzed arylation methodology is mild in that a strong base is not required. Additionally, the products of this reaction are easily elaborated to complex molecules. This method has been strategically applied in a concise formal and enantioselective total synthesis of the blockbuster antidepressant (-)-paroxetine (PAXIL®). In transition metal catalysis, we have used enantioselective Cu-catalyzed conjugate addition of Grignard reagents to enones to provide magnesium enolates, which can be arylated using bismuth(V) reagents to furnish products of vicinal difunctionalization of enones. These products are obtained in modest to good yields with complete control of both relative and absolute stereochemistry. Another method for regioselective enolate generation is the Rh-catalyzed hydrogenation of enones and enals. Using this method we have developed a reaction that involves addition of metalloaldehyde enolates to ketone acceptors to afford aldol products. This is the first catalytic direct addition of transition metal enolates to ketones.

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