Marek Chmielewski

The present mini-review concentrates on glycosyl hydroperoxides readily available from sugars, such as 2-deoxy glycosides, 2,3-unsaturated glycosides and glycals, prone to acidic hydrolysis. They represent an interesting, relatively stable family of monosaccharide derivatives of potential antimalarial activity, which can also be used for effective enantioselective epoxidation of allylic alcohols and electrophilic olefins.

The copper(I)-mediated reaction between five-membered cyclic nitrones and terminal acetylenes, leading to the assembly of the basic skeleton of carbapenem antibiotics is described. The diastereoselectivity of this cycloaddition–rearrangement cascade, a process known as the Kinugasa reaction, with respect to the structure and configuration of both substrates, as well as the reaction conditions, are discussed. Application of the described methodology to sugar-derived nitrones offers an attractive entry toward thienamycin and related compounds.

A formal synthesis of a powerful cholesterol inhibitor, ezetymibe 1, is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from acetonide of l-glyceraldehyde and suitable C,N-diarylnitrone. The adduct with (3R,4S) configuration at the azetidinone ring, obtained with high stereoselectivity, was subsequently subjected to deprotection of the diol side chain followed by glycolic cleavage and base-induced isomerization at the C3 carbon atom to afford the (3S,4S) aldehyde, which has been already transformed into ezetimibe by the Schering–Plough group.

The title compounds represent an interesting group of β‐lactam antibiotics and active inhibitors of β‐lactamase enzymes. All these compounds have one structural feature in common, an alkoxy fragment located at C4 of the azetidin‐2‐one ring. The most common strategy for the synthesis of 4‐alkoxyazetidinons involves intramolecular nucleophilic substitution at C4 that leads to ring closure. Such a displacement proceeds via the flat intermediate that suppossedly has the structure of a mezomeric acyl ammonium cation. We herein report a novel and enantioselective, chiral Lewis acid mediated cyclization that affords the corresponding 5‐oxacepham with excellent optical and chemical yields of up to 50 %. This may suggest that the high asymmetric induction is a result of a kinetic resolution of the initially formed racemic oxacepham. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Anomeric hydroperoxides derived from 3,4,6‐tri‐O‐benzyl‐galactose and glucose were used for enantioselective epoxidation of naphthoquinone (12), chalcone (13), (E)‐1,2‐dibenzoyl ethylene (14) and (E)‐iso‐butyryl‐phenyl ethylene (15). In the presence of sodium hydroxide, the epoxidations showed exceptional high asymmetric induction. The exchange of sodium by a potassium ion resulted in a low asymmetric induction. These results pointed to the crucial role of the counterion and strongly suggested that coordination of the alkaline ion occurs in the transition state of the epoxidation process by both reagents, hydroperoxide and the olefin. Theoretical studies of the reaction mechanism at the DFT B3LYP/6‐31G* level fitted very well with experimental results.

The 1,3‐dipolar cycloaddition of unsaturated D‐threo‐hexaldonolactone 3 and a six‐membered cyclic nitrone 11 led to a single adduct 15, which could be transformed into (1S, 2S, 3S, 9aS)‐2,3‐dihydroxy‐1‐hydroxymethyl‐quinolizidine 28 related to epilupinine via a reaction sequence involving rearrangement of the six‐membered lactone ring into a five‐membered one, removal of the terminal carbon atom from the sugar chain, cleavage of the N‐O bond, and the intramolecular alkylation of the nitrogen atom.

1,3‐Dipolar cycloaddition of N‐benzyl nitrone 2 to D‐threo δ‐lactone 15 proceeded with excellent stereoselectivity to provide only one adduct 16. Cycloadduct 16 was subsequently subjected to a sequence of reactions involving rearrangement to γ‐lactone, glycolic cleavage/reduction, protection of the terminal hydroxymethyl group, reduction of the lactone, desilylation/mesylation, and hydrogenolysis of the N‐O bond providing (−)‐isofagomine and its N‐substituted derivatives. The biologic activity of N‐substituted (−)‐isofagomines toward commercially available α‐ and β‐glucosidases, α‐D‐mannosidase, α‐L‐fucosidase, β‐D‐glucuronidase, and β‐D‐galactosidase was tested.