Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

An Alternative Enzymatic Route to the Ergogenic Ketone Body Ester (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate

Version 1 : Received: 24 December 2020 / Approved: 25 December 2020 / Online: 25 December 2020 (10:50:32 CET)

How to cite: Zaccone, F.; Venturi, V.; Giovannini, P.P.; Trapella, C.; Narducci, M.; Fournier, H.; Fantinati, A. An Alternative Enzymatic Route to the Ergogenic Ketone Body Ester (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate. Preprints 2020, 2020120653 (doi: 10.20944/preprints202012.0653.v1). Zaccone, F.; Venturi, V.; Giovannini, P.P.; Trapella, C.; Narducci, M.; Fournier, H.; Fantinati, A. An Alternative Enzymatic Route to the Ergogenic Ketone Body Ester (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate. Preprints 2020, 2020120653 (doi: 10.20944/preprints202012.0653.v1).

Abstract

The oral administration of (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate, allows inducing a beneficial level of blood ketone bodies without the adverse effects due to the adhesion to a ketogenic diet. Several studies documented the therapeutic effectiveness of the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in treating neurodegenerative diseases as well as its boosting activity of athletic and cognitive performances during prolonged physical exercises. Further studies considering this ketone body ester for therapy of other pathologies are also underway. In the present work, we describe the synthesis of (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate through the enantioselective transesterification of racemic ethyl 3-hydroxybutyrate with (R)-1,3-butanediol catalyzed by immobilized Candida antarctica lipase B (CAL-B). The enantiopure (R)-1,3-butanediol was in turn obtained from the kinetic resolution of the racemate by CAL-B catalyzed acetylation with vinyl acetate. The economy of the synthetic procedure has been improved by recycling the unreacted (S) enantiomers of the ethyl 3-hydroxybutyrate and 1,3-buatnediol after stereochemical inversion achieved by tosylation and SN2 with ammonium acetate. The overall procedure allows to incorporate up to 70% of the starting racemic reagents into the final product.

Subject Areas

ketone body ester; lipase; kinetic resolution; asymmetric synthesis; configuration inversion.

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