Yves Dejaegher

SYNTHESIS OF 3-ALKENYLAMINES, 4-ALKENYLAMINES AND 3-ALLENYLAMINES VIA A TRANSAMINATION PROCEDURE

Abstract 3-Alkenylamines, 4-alkenylamines and 3-allenylamines were synthesized conveniently by potassium t-butoxide induced transamination of α-vinylaldimines, α-allylaldimines or α-allenylaldimines followed by hydrolysis with aqueous oxalic acid.

Highly Stereoselective Synthesis of β‐Lactams Utilizing α‐Chloroimines as New and Powerful Chiral Inductors

Due to the biological relevance of b-lactams as antibiotics and their usefulness as synthons for further functionalization, the b-lactam skeleton can be considered as one of the most important azaheterocyclic frameworks in organic chemistry. In recent years, the development of chiral approaches (often catalytic methodologies) towards these attractive compounds has become a key issue and challenge in organic synthesis. The Staudinger reaction, in which a ketene and an imine react in a [2+2]-cycloaddition, is generally acknowledged as the method of choice for the asymmetric synthesis of b-lactams. A first approach in this respect consists of the cycloaddition of a chiral ketene, for example, the Evans–Sjçgren ketene, and an achiral imine. Alternatively, chirality can be induced by using a chiral imine and an achiral ketene. However, the application of chiral imines derived from chiral amines for the Staudinger synthesis of b-lactams generally results in low levels of diastereoselectivity, and only in some exceptional cases (e.g. when imines derived from d-glucosamine or d-threonine and cinnamaldehyde are used) high diastereoselectivities (de >90) have been reported. On the other hand, high stereoselectivities are attained when chiral imines derived from chiral aldehydes (usually a-oxyor a-aminoaldehyde derived imines) are used. Chiral a-alkylimines, derived from chiral a-alkylaldehydes, are known to be unreactive in terms of both chemical reactivity and diastereoselectivity in the Staudinger reaction towards b-lactams. The origin of the asymmetric induction in the Staudinger synthesis of b-lactams has been rationalized on the basis of the magnitude of the stereoelectronic effect exerted by the s* ACHTUNGTRENNUNG(C X) orbital (X being an electronegative atom and C a stereogenic carbon atom) over the HOMO in the transition states. The angular disposition between C3 and the C X bond in transition state 5 minimizes the steric interaction between R and the forming b-lactam ring, but at the cost of loss of efficiency of the stabilizing interaction between the HOMO and the s* ACHTUNGTRENNUNG(C X) orbital. In the case of transition state 3, the aforementioned steric interaction does not occur, and therefore the HOMO–s* ACHTUNGTRENNUNG(C X) stabilization takes place more efficiently, favored by the linear arrangement between C3 and the exocyclic C X bond. Consequently, the latter transition state 3 has a lower energy and is preferred (Scheme 1).

Synthesis of 1-alkyl-2-methylazetidin-3-ones and 1-alkyl-2-methylazetidin-3-ols

Several 1-alkyl-2-methylazetidin-3-ones were prepared in good yield by the hydride-induced cyclization of the corresponding β-bromo-α,α-dimethoxyketimines, the resulting 3,3-dimethoxyazetidines being hydrolyzed by acid. Imination of these 1,2-disubstituted azetidin-3-ones, followed by alkylation under kinetic control conditions resulted in regioisomeric mixtures of 2,4- and 2,2-dialkylated compounds. Analytical samples of the major 2,4-disubstituted derivatives were obtained after extensive chromatographic separation. The cis stereochemistry of the major 2,4-dialkylated isomer was demonstrated on the basis of NMR data.

Novel Diastereoselective Synthesis of Bicyclic β-Lactams through Radical Cyclization and Their Reduction toward 2-(1-Alkoxy-2-hydroxyethyl)piperidines and 2-(1-Alkoxy-2-hydroxyethyl)azepanes

1-Allyl- and 1-(3-phenylallyl)-substituted 4-(2-bromo-1,1-dimethylethyl)azetidin-2-ones were transformed into 3-substituted 7-alkoxy-5,5-dimethyl-1-azabicyclo[4.2.0]octane-8-ones through radical cyclization by means of n-tributyltin hydride and AIBN in toluene with excellent diastereocontrol (>or=99%). The radical cyclization of 4-(2-bromo-1,1-dimethylethyl)-1-(2-methylallyl)azetidin-2-ones afforded 8-alkoxy-3,6,6-trimethyl-1-azabicyclo[5.2.0]nonan-9-ones in good diastereomeric excess (75-78%). The reductive ring opening of 1-azabicyclo[4.2.0]octane-8-ones and 1-azabicyclo[5.2.0]nonan-9-ones with lithium aluminum hydride resulted in novel 2-(1-alkoxy-2-hydroxyethyl)piperidines and -azepanes, which were isolated as single isomers.

A new entry towards the synthesis of 1-substituted 3-azetidinones

The synthesis of 1-substituted 3-azetidinones, starting from readily accessible N-(alkylidene)- or N-(arylidene)-2,2,3-tribromopropylamines, is disclosed.

New reactions of functionalized β-lactams

An easy synthesis of 4-(1- and 2-haloalkyl)azetidin-2-ones by a [2+2] cycloadditon protocol is described. Starting from these functionalized β-lactams, new pathways toward bicyclic β-lactams were developed via intramolecular nucleophilic substitutions and radical cyclizations. 4-(1- and 2-Haloalkyl)azetidin-2-ones also proved to be very useful starting products in the synthesis of various highly substituted aziridines, azetidines, and alkenoates.

A NEW SYNTHESIS OF ALKYL 1-ALKYL-2-METHYLPYRROLE-3-CARBOXYLATES BY RING TRANSFORMATION OF 2-CHLORO-2-ACETIMIDOYLBUTYROLACTONES

Abstract Reaction of 2-chloro-2-acetimidoylbutyrolactones with sodium methoxide or sodium ethoxide in the corresponding alcohol provides a facile one-step synthesis of methyl or ethyl 1-alkyl-2-methylpyrrole-3-carboxylates from readily available starting materials.

The Halogen-Lithium Exchange Reaction of 3,3-Dichloro-2-azetidinones: Application to the Synthesis of cis-4-Aryl-3-chloro-2-azetidinones

A straightforward synthesis of new cis-4-aryl-3-chloro-2-azetidinones was developed, using a halogen-lithium exchange reaction on 4-aryl-3,3-dichloro-2-azetidinones. This methodology was further extended to the use of alkyl halides as electrophiles, while more complex electrophiles could not be introduced.