1,3-Dicarbonyl compounds warfarin anticoagulants

A highly enantioselective organocatalytic Michael addition of 4-hydroxycouma-rines and related compounds to a,p-unsaturated ketones has been also achieved using imidazolidine catalyst 137 [213]. The reaction, which gives high yields and enantioselectivities for a wide range of cyclic 1,3-dicarbonyl compounds and enones, has been successfully employed for the asymmetric synthesis of the anticoagulant warfarin (Scheme 2.78) and derivatives [213], With respect to the reaction mechanism, very recent studies have demonstrated that the truly active catalyst in the process was the chiral diamine 138, which is formed in catalytic amounts under the reaction conditions by reaction with the hydroxycoumarine (Schane 2.79)... 

CATALYTIC ENANTIOSELECTIVE MICHAEL ADDITION OF 1,3-DICARBONYL COMPOUNDS TO ACYCLIC ENONE FOR THE SYNTHESIS OF WARFARIN ANTICOAGULANTS IN ONE STEP... 

Halland N, Hansen T, Jprgensen KA. Organocatalytic asymmetric Michael reaction of cyclic 1,3-dicarbonyl compounds and a, (3-unsaturated ketones - a highly atom-economic catalytic one-step formation of optically active warfarin anticoagulant. Angew. Chem. Int. Ed. 2003 42 (40) 4955-4957. 

The Jprgensen et al. synthesis of warfarin, an anticoagulant, is another example of short drug synthesis (Scheme 11.5). Indeed, the enantioenriched product could be obtained directly by a single-step procedure. The 1,3-dicarbonyl compound 6, a powerful nucleophile, reacted without any need of extra additive on commercially available enone 7 activated by iminium formation with 8 and yielding warfarin in excellent 90% yield and a promising 80% ee. This synthesis further exemplifies the power of iminium catalysis for the fast synthesis of small dmgs. 

Dicarbonyl compounds are versatile stabilized enolate-type nucleophiles in asymmetric Michael addition reactions. In particular, the reaction of 4-hydroxy-2H-chromen-2-one and a,p-enones provided a direct and efficient synthesis of warfarin, a widely prescribed anticoagulant. Recently, Chin reported a simply vicinal... 

---