Alcohol Dehydrogenase‐Catalyzed Synthesis of Enantiomerically Pure δ‐Lactones as Versatile Intermediates for Natural Product Synthesis

Abstract

Starting from ethyl 4-bromobutyrate, the chemoenzymatic synthesis of 6-vinyl-tetrahydropyran-2-one has been accomplished. A screening of a number of available alcohol dehydrogenases and intense optimization of reaction parameters enabled us to establish an efficient synthesis of either enantiomer of the vinyllactone with excellent enantiomeric excess (> 99%). The scope of possible applications of enantiopure vinyllactones has been verified by subjection to cross-metathesis resulting in the total synthesis of the insect pheromone (S)-5-hexadecanolide and the cytotoxic styryllactone goniothalamine as well as derivatives thereof.

Alcohol Dehydrogenases as Catalysts in Organic Synthesis

“…Amongst the chemical NAD(P) + regeneration catalysts redoxactive dyes such as ABTS (Schröder et al, 2003;Aksu et al, 2009) (Wang et al, 2019), [e] YOL151w: Yeast ADH expressed in E. coli (Nowill et al, 2011), [f] [g] (Gonzalez-Martinez et al, 2019) [h] (Fischer and Pietruszka, 2012) [i] TbADH (from Thermoanaerobacter brokii) (Bisterfeld et al, 2017), [j] LbADH (from Lactobacillus brevis) (Holec et al, 2015). [k] engineered LkADH (from Lactobacillus kefir), (Berkessel et al, 2007), [l] overexpressed ADH-A (from Rhodococcus ruber) (Borzecka et al, 2013 ).…”

“…ɣand δ-ketoesters are attractive targets for ADH-catalysed reduction reactions as the corresponding alcohols easily (often spontaneously) undergo intramolecular esterification. The resulting lactones are common motifs in natural products (Korpak and Pietruszka, 2011;Fischer and Pietruszka, 2012;Classen et al, 2014;Díaz-Rodríguez et al, 2014;Kumru et al, 2018; Borowiecki et al, 2020). Starting from synthetically easily accessible substituted conjugated ketoesters bienzymatic cascades comprising ene reductases (ERs) and ADHs enable access to a broad range of chiral ɣ-butyrolactone products (Figure 16) (Korpak and Pietruszka, 2011;Classen et al, 2014;Brenna et al, 2015).…”

The use of the lactone motif in chemical communication

“…53 It has been frequently synthesized as discussed elsewhere. 54 Enantioselective approaches with high ee were recently reported using either an enzymatic approach with alcohol dehydrogenase to form 6-hepten-5-olide, followed by metathesis and hydrogenation, 55 or by stereoselective formation of pentadec-en-4-ol via aldehyde aminooxylation and a RCM strategy. 54 Hydroxylated lactones are used by several insects.…”

Enzymatic aerobic ring rearrangement of optically active furylcarbinols

“…As kinetic resolutions exhibit the general flaw of yield limitation, our aim was to synthesize optically active furylcarbinols via preceding biotransformations to subsequently rearrange them on the basis of the artificial Achmatowicz monooxygenase system. The asymmetric reduction of the corresponding furylketones (3a-k) through alcohol dehydrogenases (ADHs) proved to be an efficient and convenient method 35,36 . Two commercial ADHs in a substrate-coupled system with isopropanol as terminal reducing agent enabled the preparation of alcohol 1a whereby, depending on the employed ADH, both (R)-1a and (S)-1a were obtained in nearly enantiopure form.…”