Stanley M. Roberts

Enzyme-catalysed Baeyer–Villiger oxidations

Abstract Preparative-scale biotransformations of cyclic and bicyclic ketones yielding optically active lactones are illustrated. The use of whole cell systems such as Acinetobacter calcoaceticus to stereoselectively oxidize bicycle[3.2.0]heptanones and bicyclo[2.2.1]heptanones to γ -lactones and δ -lactones respectively is typical of this increasingly popular strategy. Similarly isolated enzymes (e.g. from Pseudomonas putida ) have been used to oxidize monocyclic ketones in an enantioselective fashion. The employment of these biotransformations in the synthesis of natural products such as lipoic acid, multifidene, cyclosarkomycin demonstrate the power of the methodology. A mechanistic rationale and an active site model are discussed.

Development of the biocatalytic resolution of 2-azabicyclo[2.2.1]hept-5-en-3-one as an entry to single-enantiomer carbocyclic nucleosides

Abstract For the resolution of the bicyclic lactam 2-azabicyclo[2.2.1]hept-5-en-3-one, efficient whole cell biocatalysts have been identified and from these, enzymes (lactamases) have been isolated. While the two enzymes obtained act on different enantiomers of the lactam, either can be used in scaleable processes to obtain synthons for carbocyclic nucleosides having the natural configuration.

Chemoenzymatic synthesis of (–)-carbovir utilizing a whole cell catalysed resolution of 2-azabicyclo[2.2.1]hept-5-en-3-one

The resolution of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one (3), a versatile intermediate in the synthesis of carbocyclic nucleosides, is described; both optical forms of the lactam have been obtained in very high optical purity (> 98% enantiomeric excess) in rapid, facile, large-scale biotransformation processes using whole cell catalysts and the laevorotatory enantiomer has been converted into (–)-carbovir.

Polyamino acids as catalysts in asymmetric synthesis

The use of polyamino acids in asymmetric organic synthesis is reviewed. Particular emphasis is placed on the asymmetric epoxidation of alpha,beta-unsaturated ketones with hydrogen peroxide in the presence of polyalanine or polyleucine, and further transformations of the epoxide products.

Studies of lipase-catalyzed polyesterification of an unactivated diacid/diol system

Preliminary enzymatic polymerization studies in the simple stoichiometric adipic acid/butane-1,4-diol system using lipase B from Candida antarctica, immobilized as Novozym 435®, suggest that in solvent-free conditions a step-growth mechanism operates involving the sequential addition of an AB synthon by esterification mode only. Conversely, in toluene as solvent there is a change to the more facile transesterification mode in line with the conventional polyesterification procedure, pointing to a change in specificity of the lipase. Evidence is drawn from qualitative studies using a series of synthetic intermediates, enabling authentication of product mixtures together with an indication of the comparative reactivity of species along the proposed reaction pathway.

Synthesis and enzymatic resolution of carbocyclic 2′-ara-fluoro-guanosine: a potent new anti-herpetic agent

(±)-Carbocyclic-9-(2′-deoxy-2′-β-fluoroarabinofuranosyl) guanine (8) and the corresponding furanose compound (12) have been synthesised; the former compound [which was resolved by formation of the monophosphate (20) and enantioselective hydrolysis using a 5′-nucleotidase] is an extremely potent inhibitor of herpes simplex viruses types 1 and 2.

Polyamino acid-catalysed asymmetric epoxidation: Sodium percarbonate as a source of base and oxidant

Abstract New reaction conditions, using sodium percarbonate, are reported for the polyamino acid-catalysed asymmetric epoxidation of enones. Under these new conditions the rate of the uncatalysed reaction is reduced allowing an increased ratio of substrate to catalyst compared with previous protocols.

Lipase-catalysed Baeyer–Villiger reactions

The Baeyer–Villiger oxidation of some 2- and 3-substituted cyclopentanones and cyclohexanones using myristic acid and hydrogen peroxide is catalysed by Candida anatarctica lipase.

Biological Baeyer–Villiger oxidation of some monocyclic and bicyclic ketones using monooxygenases from Acinetobacter calcoaceticus NCIMB 9871 and Pseudomonas putida NCIMB 10007

A. calcoaceticus NCIMB 9871 and Ps. putida NCIMB 10007 [grown on (+)-camphor] have been utilized as biocatalysts in Baeyer–Villiger oxidations. The former microorganism oxidized the racemic ketone 6 non-selectively but transformed the dihalogeno ketone (±)-8 into optically active lactone 10 and recovered ketone. Ps. putida NCIMB 10007 oxidized the two enantiomers of the ketone 6 at different rates while both enantiomers of ketone (±)-1 were converted into lactones, one enantiomer giving 3-oxabicyclooctenone preferentially, while the other enantiomer gave 2-oxabicyclooctenone. Ps. putida NCIMB 10007 contains two quite different types of monooxygenase enzyme, one using NADH as cofactor (labelled MO1) the other employing NADPH as cofactor (labelled MO2). Monooxygenase MO1 proved to be a selective efficient biocatalyst for the oxidation of bicyclic ketones such as 1 and 6 while monooxygenase MO2 is a useful catalyst for the oxidation of cyclopentanones 15–17. Cofactor recycling was effected using dehydrogenase enzymes in preparative-scale experiments.

PaaSicats: Powerful catalysts for asymmetric epoxidation of enones. Novel syntheses of α-arylpropanoic acids including (S)-fenoprofen

Abstract Application of the recently developed silica-adsorbed polyleucine catalysts to the enantioselective epoxidation of two enones is reported. Treatment of these epoxides with trimethylaluminium in moist dichloromethane generates the α-hydroxy-β-methyl-ketones, with inversion of configuration. Diastereoselective reduction of the ketone moiety followed by oxidative cleavage generates α-arylpropanoic acids.