Uses and production of chiral 3-hydroxy-γ-butyrolactones and structurally related chemicals

Abstract

Enantiopure (S)-3-hydroxy-gamma-butyrolactone (HGB) and its structurally related C3-C4 chemicals are an important target for chiral building blocks in synthetic organic chemistry. For the production of these compounds, more economical and practical synthetic routes are required. To date, chiral HGBs have been produced from petrochemicals and biomass, especially malic acids and carbohydrates. This report provides a short review on the production and application of enantiopure HGBs and their related compounds. Emphasis is focused mainly on synthetic routes using biocatalysis (microbial and chemoenzymatic) and application of these compounds. Biological methods have concentrated on devising different kinds of enzymes for the synthesis of the same compound as shown in the case of hydroxynitrile, a key intermediate of synthetic statins, and integrating unit processes for the optically active HGBs and 4-chloro-3-hydroxybutyrate with recombinant microorganisms expressing multiple enzymes. Chemical methods involve selective hydrogenation of carbohydrate-based starting materials. Both types of pathways will require further improvement to serve as a basis for a scalable route to HGBs and related compounds. Several of their synthetic applications are also introduced.

Functional Screening and In Vitro Analysis Reveal Thioesterases with Enhanced Substrate Specificity Profiles That Improve Short-Chain Fatty Acid Production in Escherichia coli

“…Developing recombinant strains to produce these molecules could lead to production of polymers such as polyhydroxyalkanoates and pharmaceuticals such as statins from fossil fuel alternatives (1,2). Supporting the development of microbially synthesized products are the reduced cost and increased prevalence of genomic sequencing.…”

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

“…Because 3,4-DHBA has a hydroxyl group in the d-position that changes the stereochemical priority of the different atoms of the molecule about its stereocenter, the stereochemistry of 3,4-DHBA formed by PhaB should be (S)-3,4-DHBA while that formed by Hbd should be (R)-3,4-DHBA. PhaB results in significantly higher titres, and fortunately, the (S) stereoisomer is predominately used in the production of pharmaceuticals and high-value compounds 3 . Identification and screening of hbd homologues could identify a reductase with identical stereochemical preference but with an increased substrate tolerance for the production of (R)-3,4-DHBA and (R)-3HBL.…”

“…One such compound, 3-hydroxyg-butyrolactone (3HBL), is widely used in the pharmaceutical industry as a chiral building block for the statin class of cholesterol-reducing drugs such as Crestor and Lipitor, as well as the antibiotic Zyvox, and the antihyperlipidemic medication Zetia 3 . Other pharmaceuticals derived from 3HBL include HIV inhibitors 4 and the nutritional supplement L-carnitine 5 .…”

“…There are no identified natural biochemical routes nor have engineered routes been previously reported for the biosynthesis of 3HBL or its hydrolyzed acid form, 3,4-dihydroxybutyric acid (3,. 3HBL is currently produced as a specialty chemical and sells at a wholesale cost of B$450 per kg.…”

Rapid asymmetric reduction of ethyl 4-chloro-3-oxobutanoate using a thermostabilized mutant of ketoreductase ChKRED20

“…Ethyl (S)-4-chloro-3-hydroxybutanoate ((S)-CHBE) is one of the chiral alcohol intermediates that has been extensively studied using KRED-catalyzed reactions owing to its significance as the key intermediate for the synthesis of chiral pharmaceuticals including blockbuster drug statins, a group of cholesterol-lowering HMG-CoA reductase inhibitors (Kaluzna et al 2005;Kita et al 1999;Lee and Park 2009;Ye et al 2011;You et al 2014). Over the years, a lot of microorganisms or carbonyl reductases have been reported Electronic supplementary material The online version of this article (doi:10.1007/s00253-015-7200-2) contains supplementary material, which is available to authorized users.…”