Paroxetine, asymmetric synthesis

Scheme 14- Synthesis of (-)-paroxetine using an asymmetric desymmetrization of a glutanc ester via enzymatic hydrolysis.

Hynes PS, Stupple PA, Dixon DJ (2008) Organocatalytic Asymmetric Total Synthesis of (R)-Rolipram and Formal Synthesis of (3S,4/f)-Paroxetine. Org Lett 10 1389... 

Brandau S, Landa A, Franzen J, Marigo M, Jprgensen KA (2006) Organocatalytic Conjugate Addition of Malonates to a,(3-Unsaturated Aldehydes Asymmetric Formal Synthesis of (-)-Paroxetine, Chiral Lactams, and Lactones. Angew Chem Int Ed 45 4305... 

SCHEME 4.16. Catal3ftic asymmetric total synthesis of (—)-paroxetine. 

The catalytic enantioselective synthesis of ( )-paroxetine (69, Paxil GlaxoSmithKline, London, U.K.), which is a selective serotonin reuptake inhibitor being used for the treatment of depression, anxiety, and panic disorders, was executed as an application of the catalytic asymmetric mono -a-alkylation of 1,3-amide esters (Scheme 4.16). The characteristic feature of this protocol is the introduction of the C3-stereocenter first by the asymmetric phase-transfer alkylation before installing the C4-center by a diastereoselective Michael addition. Af,A -Di-p-methoxyphenyl malonamide... 

Park and coworkers reported the synthesis of (—)-paroxetine (103) [59], an antidepressant drug from the class of drugs known as selective serotonin reuptake inhibitors (SSRIs) [60]. In their approach. Park and coworkers synthesized 103 by an asymmetric alkylation of malonic ester 104 in the presence of PTC 105. The key intermediate 106 was obtained in 92% yield and 95% ee. 

Buchwald reported asymmetric copper-catalyzed conjugate reductions of a variety of a,/i-unsaturated acceptors [175, 176]. The reactions were demonstrated to proceed with optimal enantioinduction in the presence of a chiral copper catalyst incorporating p-tol-BINAP (240, Scheme 12.20). A convenient feature of these reductions is the use of the inexpensive polymeric polymethyl-hydrosiloxane (PMHS) as the stoichiometric reductant. Unsaturated lactam 239 undergoes reduction in 90% yield and 90% ee to give 241, a key intermediate in a synthesis of the antidepressant (-)-paroxetine (242) [176]. 

The use of lithiated reactants obtained with the aid of sparteine have been utilized by Beak in other key asymmetric transformations [56, 57]. Deprotonation in the presence of sparteine followed by conjugate addition to nitro-olefins was shown to provide expeditious access to piperidine derivatives. This strategy was elegantly exemplified in the synthesis of (-)-paroxetine, a selective serotonin reuptake inhibitor (68, Scheme 13.11) [57]. 

Scheme 12.16 Asymmetric total synthesis of (—)-paroxetine and (—)-isonitramine by phase-transfer catalytic alkylations of 1,3-dicarbonyl compounds 90a and 90b.

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