A chemoenzymatic approach to the synthesis of enantiomerically pure (S)-3-hydroxy-γ-butyrolactone

Abstract

Optically pure (S)-3-hydroxy-gamma-butyrolactone, an important chiral building block in the pharmaceutical industry, was synthesized from L: -malic acid by combining a selective hydrogenation and a lipase-catalyzed hydrolysis. Lipase from Candida rugosa was found to be the most efficient enzyme for the hydrolysis of (S)-beta-benzoyloxy-gamma-butyrolactone. The use of organic solvent-aqueous two-phase system was employed to extract benzoic acid generated from enzymatic hydrolysis of the substrate. Tert-butyl methyl ether as an organic solvent was effective to extract the reaction product, benzoic acid, and stably maintained the enzyme activity of Lipase OF immobilized on polymeric supports Amberlite XAD-7. The immobilization made the recovery of the product simpler and prevented the formation of the emulsion. The pH adjustment was unnecessary with the immobilized Lipase OF. The scale-up of the enzymatic hydrolysis of S-BBL at 1,850-kg scale was carried out without problems to give 728.5 kg of S-HGB at 80% isolated yield. The scale-up results are similar to those of bench scale reactions. Racemic (R,S)-beta-benzoyloxy-gamma-butyrolactone was prepared from D-, L: -malic acid and was found to be hydrolyzed nonselectively by the enzyme.

Highly selective/enantioselective Pt-ReO /C catalyst for hydrogenation of L-malic acid at mild conditions

“…However, we found only two examples of selective L-malic acid hydrogenation to ( S ) −3-HBL and ( S ) −1,2,4-butanetriol using mono-and bimetallic catalysts [28,29] . In addition, optically pure ( S ) −3-HBL can be produced by chemoenzymatic method, i.e., via selective hydrogenation of malic acid over zinc borohydride catalyst followed by hydrolysis with enzymes [30] or via direct biosynthesis from glucose [31] .…”

A platform pathway for production of 3-hydroxyacids provides a biosynthetic route to 3-hydroxy-γ-butyrolactone

“…A continuous chemical synthesis process employing high pressure hydrogenation of L-malic acid over a ruthenium-based catalyst in a fixed-bed reactor has been developed for the commercial synthesis of (S)-3HBL at a capacity of 120 tonnes per year 8,9 ; however, this process employs hazardous processing conditions and expensive catalyst and purification processes. The various other chemical and chemoenzymatic routes developed for 3HBL synthesis 3 also suffer from similar disadvantages including the use of hazardous materials and processing conditions 10,11 , expensive starting materials, reagents and catalysts [11][12][13][14][15] , and poor yield and difficult to separate by-products 10,12,13,16 , driving up the cost of the product. Biosynthesis is expected to alleviate many of these problems and offer an elegant solution towards economical production of this valuable chemical; however, this requires the design of a novel biosynthetic pathway 17,18 .…”

A Review on Synthesis and Applications of Statin Family Drugs as a New Generations of Anti-Blood Medicines

“…); however, when the process is at a yield More than 40% is in operation, the enantiomeric purity of 24 is diminished. Lee et al [50] from the LG chemical company recently reported the synthesis of 24, which uses three synthesis steps (Scheme 24). The two initial steps of this synthesis were done directly.…”