Chemoenzymatic Approach toward the Synthesis of 3- O-(α/β)-Glucosylated 3-Hydroxy-β-lactams

Abstract

Glycosylation significantly alters the biological and physicochemical properties of small molecules. β-Lactam alcohols comprise eligible substrates for such a transformation based on their distinct relevance in the chemical and medicinal community. In this framework, the unprecedented enzymatic glycosylation of the rigid and highly strained four-membered β-lactam azaheterocycle was studied. For this purpose, cis-3-hydroxy-β-lactams were efficiently prepared in three steps by means of a classical organic synthesis approach, while a biocatalytic step was implemented for the selective formation of the corresponding 3-O-α- and -β-glucosides, hence overcoming the complexities typically encountered in synthetic glycochemistry and contributing to the increasing demand for sustainable processes in the framework of green chemistry. Two carbohydrate-active enzymes were selected based on their broad acceptor specificity and subsequently applied for the α- or β-selective formation of β-lactam-sugar adducts, using sucrose as a glucosyl donor.

Figure 1

Bioactive (β-lactam-containing) compounds.

Figure 2

Ezetimibe 7.

Scheme 1. α- and β-Glucosylation of cis-3-Hydroxy-β-lactams 8 by a Mutant Glycoside Phosphorylase from Thermoanaerobacterium thermosaccharolyticum (TtSPP) or by a Glycosyltransferase from Stevia rebaudiana, Respectively

Scheme 2. Synthesis of 3-Hydroxyazetidin-2-ones 8

Scheme 3. Carbohydrate-Active Enzymes Used in Glycosylation Reactions (A = Acceptor; P_i = Inorganic Phosphate; UDP = Uridine Diphosphate)

Scheme 4. Enzymatic Glucosylation of 3-Hydroxy-β-lactams 8 (TtSPP_R134A, Mutant R134A of the Sucrose 6′-Phosphate Phosphorylase from T. thermosaccharolyticum; UGT-76G1Sr, UDP-Glucosyltransferase from S. rebaudiana; SuSy, Sucrose Synthase from Acidithiobacillus caldus)