Production of biorenewable, enantiopure (S)-3-hydroxy-γ-butyrolactone for pharmaceutical applications

Many pharmaceuticals include chiral centers, which are introduced using high-cost building blocks such as (S)-3-hydroxy-γ-butyrolactone, (S)-HBL. This species is used in the synthesis of many important drugs, including statins, antibiotics, and HIV inhibitors, and it is currently produced from fossil resources via a high-cost, high-emission process. Here, we show that a nearly quantitative yield of enantiopure (S)-HBL can be obtained from glucose at ambient temperature, using a combination of biological and chemical catalysis. Whole-cell enzyme catalysis converts glucose to a labile intermediate (denoted as trione) that is subsequently reacted to (S)-HBL by metal-free homogeneous acid/base catalysis. These reactions do not involve the C5 of glucose, leading to enantiopure (S)-HBL, produced at less than half the present cost. This approach can also be used to produce other commercially important building blocks from sustainable feedstocks: the enzymes used for trione production are active in converting xylose, leading to the acrylate co-monomer 3-hydroxypropionic acid.