Organocatalytic Asymmetric Michael Reaction of Cyclic 1,3‐Dicarbonyl Compounds and α,β‐Unsaturated Ketones—A Highly Atom‐Economic Catalytic One‐Step Formation of Optically Active Warfarin Anticoagulant

As optically active drugs become increasingly important for the treatment of diseases in patients, still more enantiopure drugs are introduced to the market either as new drugs or as the result of a racemic switch. An important goal for asymmetric catalysis is to develop new reactions that afford optically active compounds from simple and easily available starting materials and catalysts. However, the ultimate goal would be if the new reaction could be used directly for a onestep synthesis of optically active molecules that have important biological and pharmaceutical activities. Herein we present such an advance and its direct application in an atom-economic synthesis of optically active drugs based on the development of a new organocatalytic enantioselective Michael addition of cyclic 1,3-dicarbonyl compounds to a,bunsaturated ketones. The present development leads to a catalytic enantioselective one-step procedure for the formation of one of the most widely used anticoagulants, warfarin (coumadin), and related important compounds. Warfarin has been prescribed as a racemate for more than 40 years and it is well-known that the anticoagulant activity of the S enantiomer is about 5–8 times higher than of the R enantiomer. Furthermore, the enantiomers are metabolized by different pathways, which is reflected by the different half-lives in the human body, 21–43 and 37–89 h, for (S)and (R)-warfarin, respectively. Due to these very different half-lives, one of the major problems with racemic warfarin is the delivery and maintenance of a stable dose as too high doses might lead to internal hemorrhages in the patient. The dosage problem is further complicated by the fact that the peak pharmacological effect of a single dose is not achieved until after approximately 48 h, and the pharmacological effect lasts 4–5 days. As patients respond differently, it is expected that treatment of patients with optically pure warfarin will reduce the dosage problem. Another advantage of optically pure warfarin would be that weakened patients unable to tolerate the stronger racemic or (S)-warfarin could be treated with the milder (R)-warfarin. However, probably the most important advantage of administering optically pure warfarin is the possibility of eliminating drug–drug interactions, which represents another serious problem with racemic warfarin, as enzymes that are responsible for metabolizing warfarin also metabolize many other drugs. Three different approaches towards the synthesis of optically active warfarin have been reported: Demir et al. used a diastereoselective Michael addition in which chiral enamines of 4-hydroxycoumarin were treated with benzylideneacetone in the presence of LDA and superstoichiometric amounts of Lewis acid to obtain warfarin in moderate yield and enantiomeric excess. Li and co-workers at DuPont Merck Pharmaceutical Company obtained enantioenriched warfarin from racemic warfarin through an oxidation procedure and subsequent asymmetric hydrogenation. The diastereoselective synthesis by Cravotto et al. involved a tandem Knoevenagel/hetero-Diels–Alder approach; however, yields were low owing to the somewhat lengthy synthesis. Herein we present, besides the development of a new organocatalytic enantioselective reaction, a simple, effective and highly atom-economical synthesis of optically active warfarin (1a) from 4-hydroxycoumarin (2a) and benzylideneacetone (3a) in the presence of imidazolidine catalysts (Table 1). Furthermore, the scope and potential of this new one-step, organocatalytic enantioselective Michael addition is demonstrated by the formation of a number of important