Promiscuous enzyme‐catalyzed Michael addition: synthesis of warfarin and derivatives

Abstract

BACKGROUND: Biocatalytic promiscuity has attracted much attention from chemists and biochemists in recent years. Warfarin, one of the most effective anticoagulants, has been introduced for clinical use as a racemate for more than half a century. Although some different chemical strategies towards the synthesis of optically active warfarin have been reported, biocatalytic preparation of warfarin remains unexploited. RESULTS: Lipase from porcine pancreas (PPL) was used as a biocatalyst to catalyze the Michael addition of 4‐hydroxycoumarin to α,β‐unsaturated enones in organic medium in the presence of water to synthesize warfarin and derivatives. The products were obtained in moderate to high yields (up to 95%) with none or low enantioselectivities (up to 28% ee). The influence of reaction conditions including solvents, temperature and molar ratio of substrates was systematically investigated. CONCLUSION: Among the many reported lipase‐catalyzed Michael additions, only a few showed enantioselectivity. Therefore, this Michael addition activity of, for example, PPL is a valuable case of enantioselective lipase catalytic promiscuity. In addition, it was the first time warfarin and derivatives were prepared using a biocatalyst. Copyright © 2012 Society of Chemical Industry

NMR and DFT Insight into the Synergistic Role of Bovine Serum Albumin–Ionic Liquid for Multicomponent Cascade Aldol/Knoevenagel–thia‐Michael/Michael Reactions in One Pot

“…Herein, we report a mild, economical, one‐pot, and green protocol for an AC–TMA cascade reaction, and a combination of experimental ( 1 H NMR spectroscopy) and theoretical calculations (DFT) revealed for the first time that the “synergistic effect” of BSA with 1‐butyl‐3‐methylimidazolium bromide ([bmim]Br) promoted the multicomponent chemoselective synthesis of β‐aryl‐β‐sulfido carbonyl compounds (construction of C−C and C−S bonds) without the formation of undesired bisadducts. Further, this catalytic system was exploited for the synthesis of the drug warfarin (construction of two C−C bonds) from acetone, benzaldehyde, and 4‐hydroxycoumarin through sequential aldol–Michael addition reactions and the synthesis of potent pyridine analogues (construction of two C−C bonds, one C−S bond, and one C−N bond) from aromatic aldehydes, thiophenol, and malononitrile through Knoevenagel–Michael reactions in one pot.…”

“…Similarly, the BSA–[bmim]Br catalytic system was exploited to catalyze a MCR between 4‐hydroxycoumarin, a carbon nucleophile, and an aryl aldehyde and acetone to generate the anticoagulant drug warfarin ( 8 a ) and analogue 8 b in good yields through sequential aldol–Michael reactions (Scheme ) in one pot. On the other side, it was previously reported that BSA alone is unable to catalyze the synthesis of warfarin, which thus strengthens the importance of the synergism of the BSA–[bmim]Br catalyst.…”

Engineered MOFs and Enzymes for the Synthesis of Active Pharmaceutical Ingredients

“…after 7 days of reaction in anhydrous DMSO at room temperature (see Table 3). [44] The α,β-unsaturated benzylideneacetone binds to the oxyanion hole of the enzyme, where Gln-106 and Thr-40 stabilize the formation of an enolate by three hydrogen bonds with the carbonyl oxygen of the α,β-unsaturated compound (see Figure 10 left). [45] His-224 acts as a general base to activate the carbon nucleophile of 4-hydroxycoumarin by removing one of its α-H.…”

Recent Advances in Biocatalytic Promiscuity: Hydrolase‐Catalyzed Reactions for Nonconventional Transformations

“…In the reaction between acetylacetone and thienyl nitroolefin (3 equiv) an 83% ee was attained (Scheme ), although a dramatic loss in yield and stereoselectivity was observed when the enzyme was recycled. Furthermore, the asymmetric Michael addition of 4‐hydroxycoumarin to α,β‐unsaturated ketones was reported using PPL, although even after optimization of the reaction conditions poor enantioselectivities were also observed (up to 28% ee ) towards the formation of warfarins (Scheme ), which are effective anticoagulants …”