Bartłomiej Furman

Asymmetric Kinugasa Reaction of Cyclic Nitrones and Nonracemic Acetylenes

Kinugasa reactions between chiral acetylenes and five-membered nitrones, achiral and bearing a stereogenic center in both enantiomeric forms, proceed in moderate to good yield with high diastereoselectivity affording mostly one dominant product. The first step of the reaction is controlled by the configuration of the nitrone, whereas the protonation of intermediate enolate in the second step depends mainly on the configuration of the bridgehead carbon atom formed in the first step. In the case of the mismatched pair, the configuration at the C-6 center of the carbapenam skeleton may also be affected by the configuration of the stereogenic center in the acetylene portion.

Diastereoselective synthesis of carbapenams via Kinugasa reaction.

A facile approach to carbapenams via Kinugasa reaction between terminal copper acetylides and nonracemic cyclic nitrones derived from malic and tartaric acid is reported. The stereochemical preferences observed in these reactions are explained. The reaction provides an entry to the carbapenams basic skeleton.

A Formal Synthesis of Ezetimibe via Cycloaddition/Rearrangement Cascade Reaction

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.

Synthesis of Polyhydroxylated Piperidine and Pyrrolidine Peptidomimetics via One-Pot Sequential Lactam Reduction/Joullié–Ugi Reaction

A direct approach to the synthesis of polyhydroxylated piperidine and pyrrolidine peptidomimetics is described. The presented strategy is based on one-pot reduction of sugar-derived lactams with Schwartzs reagent followed by a multicomponent Ugi-Joullié reaction.

Strategies for the stereocontrolled formation of oxygen analogues of penicillins and cephalosporins.

The synthesis of oxacephalotin and oxacephamandol, which are more active than natural, sulfur-containing congeners, and the isolation of clavulanic acid, a potent inhibitor of beta-lactamase enzymes, directed attention of many academic and industrial laboratories the synthesis of oxygen analogues of penicillins and cephalosporins. The present review focuses attention on the problem of stereocontrol in the formation of a desired configuration of the bridgehead carbon atom in the title compounds. Five feasible synthetic methods leading to the basic skeletons of clavams and 5-oxacephams are discussed. Three of them involve the nucleophilic substitution at C-4 of the azetidin- 2-ones performed as inter- or intramolecular process and the remaining two involve cycloaddition reactions between ketenes and iminoethers, or between vinyl ethers and isocyanates. Owing to the general application, stereospecificity and high asymmetric induction, the last method seems to be most advantageous. The weak point of the nucleophilic substitution methodology is that a nucleophile approaches the 3-substituted azetidin-2-one ring preferentially anti to the existing substituent and in the case where there is no substituent at C-3, that the stereoselectivity of formation of the new chirality center at C-4 is low. All discussed methods are illustrated by the examples taken from the literature.

Synthesis of polyhydroxylated quinolizidine and indolizidine scaffolds from sugar-derived lactams via a one-pot reduction/Mannich/Michael sequence.

A direct approach to the synthesis of indolizidine and quinolizidine scaffolds of iminosugars is described. The presented strategy is based on a one-pot sugar lactam reduction with Schwartzs reagent followed by a diastereoselective Mannich/Michael tandem reaction of the resulting sugar imine with Danishefskys diene. The stereochemical course of the investigated reaction has been explained in detail. The obtained bicyclic products are attractive building blocks for the synthesis of various naturally occurring polyhydroxylated alkaloids and their derivatives.

Synthesis of Thienamycin methyl ester from 2-deoxy- d -ribose via Kinugasa reaction

A novel synthesis of thienamycin is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from d-lactic acid and suitable, partially protected, five-membered cyclic nitrone obtained from 2-deoxy-d-ribose. The reaction was performed in the presence of tetramethylguanidine as a base to provide 5,6-trans substituted carbapenam as the main product. Thus obtained carbapenam 11 with (5R,6S) configuration at the azetidinone ring was subsequently subjected to oxidation/deprotection/oxidation reaction sequence to afford the β-keto ester 20, which was directly transformed into N,O-protected methyl ester of thienamycin.

Approach to Monobactams and Nocardicins via Diastereoselective Kinugasa Reaction.

A Kinugasa reaction between copper(I) acetylides and cyclic nitrones derived from chiral amino alcohols and glyoxylic acid is reported. The stereochemical preferences observed in this reaction are discussed. The alkyne molecule approaches the nitrone exclusively anti to the large substituent next to the nitrogen atom to provide the cis-substituted β-lactam ring preferentially. The six-membered oxazinone ring can be opened by reduction with lithium borohydride. Deprotection of the β-lactam nitrogen atom can be achieved by lithium in liquid ammonia reduction or by CAN oxidation, depending on the substituents attached to the four-membered azetidinone ring. The adducts obtained by the Kinugasa reaction provide an attractive entry to a variety of monocyclic β-lactam structures related to monobactams and nocardicins.

β-Lactams from Carbohydrates

Since more then thirty years carbohydrates have gained much attention as chiral starting materials in stereocontrolled target oriented synthesis. Among variety of applications, synthesis of β-lactam antibiotics from carbohydrate precursors played a special role owing to the importance of these class of compounds in modern chemotherapy. In 1994 we published a review article on the synthesis of β-lactams from carbohydrate precursors. The present survey reports literature published after that date. The streaking feature of the syntheses performed during the last decade is domination of the highly stereoselective direct formation of a four-membered β-lactam ring via [2 + 2]cycloaddition of ketenes to imines and of chlorosulfonyl isocyanate to olefins. Particularly attractive substrates are: in former method, imines derived from glyceraldehyde and in latter one, vinyl ethers of acetal protected sugars.