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A series of new enantiomerically pure acylnitroso compounds have been prepared and tested as dienophiles for the asymmetric oxyamination of dienes. Very high selectivities were obtained with acylnitroso compounds derived from diphenylmethoxymethyl pyrrolidine 2c, the C-2-symmetric pyrrolidines 2d-e and camphorsultam 2f. (C) 1998 Elsevier Science Ltd. All rights reserved.

1-[(tert-Butyldimethylsilyl)oxy] alkenyl isocyanates 1a and 1b have been conveniently prepared from acetyl or propionyl chloride, silver cyanate and tert-butyldimethylsilyl triflate in the presence of triethylamine. They react with electron-deficient acetylenic dienophiles or with tosyl cyanide to give highly functionalised pyridines or derivatives of uracil or thymine in moderate yields. They also cycloadd with 1-(diethylamino)prop-1-yne, an electron-rich dienophile, to yield glutaconimides and pyridine derivatives.

[3+2] Cycloaddition reactions of (E) and (Z)-1,2-difluorovinylphenylsulfones with diphenylnitrone, ethyl- and mesitylnitrile oxides and diphenylnitrile imine have been studied. The behaviour of these new dipolarophiles has been compared to that of the related phenylvinylsulfone and 1-fluorovinylphenylsulfone.

N-trimethylsilyl-bis(trifluoromethanesulfonyl)imide (TMSNTf2) was readily prepared from allyltrimethylsilane and bis(trifluoromethanesulfonyl)imide. It was shown to complex carbonyl groups much more effectively than trimethylsilyl triflate. As a result, TMSNTF2 was found to be superior to TMSOTf as a catalyst for the Diels-Alder reaction of methyl acrylate with various dienes. (C) 1997 Elsevier Science Ltd.

A series of mercaptoacetic acid thiol esters have been identified as metallo-beta-lactamase inhibitors, Electrospray mass spectrometry (ESMS) has shown that irreversible inhibition of the Bacillus cereus II metallo-beta-lactamase by SB214751, SB214752, and SB213079 was concomitant with a 90-Da increase in mass of the enzyme, Tryptic digestion of the B. cereus II inhibited with SB214751 illustrated that the peptide fragment, containing the only cysteine of the enzyme, had undergone a mass increment of 90 Da. It was further demonstrated that B. cereus II hydrolyzed this type of compound across the thiol ester bond to yield mercaptoacetic acid, Mercaptoacetic acid is the only molecular fragment common to SB214751, SB214752, and SB213079, and free mercaptoacetic acid does not bind covalently to B. cereus II, Therefore, it is concluded that these compounds inhibit B. cereus II by the mechanism-based delivery of mercaptoacetic acid, forming a disulfide linkage with the active site cysteine (predicted mass shift=+90 Da) under the aerobic conditions of the assay. The different thiol esters examined had a broad range of potencies against the metallo-beta-lactamases tested. For example SB214751, SB214752, and SB213079 all had 50% inhibitory concentrations of <10 and >1,000 mu M for the Stenotrophomonas maltophilia L-1 and Bacteroides fragilis CfiA enzymes, respectively. SB216968 was particularly active against the Aeromonas hydrophila CphA metallo-beta-lactamase and was found to be an uncompetitive inhibitor of this enzyme (K-i=3.9 mu M), whereas it exhibited irreversible inhibition of the L-1 enzyme. These observations with this series of compounds have revealed subtle differences between the active sites of different metallo-beta-lactamases. Finally, a novel application for isothermal titration calorimetry for assessing the zinc chelating activity of candidate inhibitors is also presented.

Ketenes have been found to cycloadd with (R)-2-tert-Butyldihydrooxazole 1 and 2 to yield predominantly regioisomers 4 resulting from steric control rather than electronic control. The cycloadditions provide a practical route to enantiomerically pure protected 2-amino-3-hydroxycyclobutanones. (C) 1997 Elsevier Science Ltd.

Doctorat en sciences chimiques -- UCL, 1997

The first part of this paper deals with stereochemical studies related to the Diels-Alder reactions of 2-azadienes. 2-Azadienes could be readily prepared from carboxylic acid chlorides and imine derivatives. Their reactions with electron-poor dienophiles showed an interesting chemical dichotomy : cyclic dienophiles mainly yielded endo-adducts while acyclic dienophiles reacted with a high exo-selectivity, This selectivity could be further increased by using Lewis acids which are compatible with the reactive azadienes. Highly selective asymmetric cycloadditions were observed with unsaturated amides derived from Ct symmetric pyrrolidines. Less satisfactory results were obtained with Evans' and Oppolzer's dienophiles. The second part deals with stereoselective cyclopentannulations of enones. It is shown that a three-carbon reagent bearing an orthoester at C-1 and a sulphone at C-2 reacts as a 1,3-dipole equivalent with enones to give a cyclopentannulation product. The reaction is general and of great synthetic value. Our efforts to develop an asymmetric version of this reaction have been successful : racemic sulphonamide-orthoesters have been shown to effect the cyclopentannulation of cyclic enones with high facial selectivity.

The cine-rearrangement and cine-substitution of a series of 3-allkyl-2,2-dichlorocyclobutanones have been studied in the context of a synthesis of polyfunctitonalized cyclobutanones which were required as synthetic intermediates. Our studies showed that the scope of the rearrangement is limited to substrates bearing bulky substituents at C-3. In other cases, mixtures of isomeric cyclobutanones are obtained. Reaction of 3-butyl-2,2-dichlorocyclobutanone with methanol in the presence of a base yielded a product of double cine-substitution.

Doctorat en sciences chimiques -- UCL, 1996

Doctorat en sciences chimiques -- UCL, 1996

Doctorat en sciences chimiques -- UCL, 1996

Concentrated solutions of lithium trifluoromethanesulfonimide in either acetone or diethyl ether constitute convenient and safe alternatives to lithium perchlorate in diethyl ether for promoting and accelerating [4+2] cycloaddition reactions.

alpha,beta-Unsaturated hydrazones bearing an ester or a nitrile at C-2 position have been synthesized. They are unreactive towards electron-rich dienophiles but react with electron-poor dienophiles. Dramatic rate enhancements have been observed in concentrated organic solutions of LiNTf(2).

Arylacetic esters 1 are converted into the corresponding ketene acetals 2 by O-silylation. Compounds 2 smoothly rearrange in refluxing THF to give the ortho-thiomethylated arylacetic acids 4 after hydrolysis. The sequence can be performed with good yields (63-81%) as a one-pot process.

Doctorat en sciences chimiques -- UCL, 1995

Doctorat en sciences chimiques -- UCL, 1995

Doctorat en sciences chimiques -- UCL, 1995

Doctorat en sciences chimiques -- UCL, 1995

Doctorat en sciences chimiques -- UCL, 1995

The 5-acylamino-3-acetylhydantoin derivatives 8 were designed as potential antibiotics mimicking lactivicin 1. The racemic compounds 19a-c, prepared in six steps from 5-oxohydantoin, were inactive onto bacterial tests.

Chiral 1-azadienes 1 derived from alpha,beta-unsaturated aldehydes and Enders' hydrazines cycloadd to cyclic dienophiles with high facial selectivities. The adducts can be readily converted into enantiomerically pure piperidine derivatives.

Doctorat en sciences chimiques -- UCL, 1994

Doctorat en sciences chimiques -- UCL, 1994

Doctorat en sciences chimiques -- UCL, 1994

Doctorat en sciences chimiques -- UCL, 1994

3-Ethylthiohomopenems 5a and 5b were prepared from alpha-amino-gamma-butyrolactone. Compound 5a showed weak antibacterial properties.

2-cyclopenten-1-ones bearing an acylamino side-chain at C-4 and an acetic acid residue at C-2 were designed as potential alkylating inhibitors of penicillin sensitive enzymes. Compounds 11 and 12 efficiently prepared from the readily available 2-phenylsulfonyl-4-methoxycarbonyl-cyclopentan-1-one 3. They were inactive in all tests.

Trimethylsilyl triflate and t-butyldimethylsilyl triflate can be used as activating reagents in the cycloaddition between chiral oxazoline 1 and cyclopentadiene. However, better results were obtained with a mixture of trifluoroacetic anhydride and trimethylsilyl triflate which gave rise to highly stereoselective cycloaddition. Oxazoline 1 and siloxy-2-azadienes 7, 8, 9 and 10 afforded, in the presence of trimethylsilyl triflate, cycloadducts 11, 12, 13 and 14. Endo adducts were obtained with open chain dienes, whereas exo adducts were the major products with the cyclic diene 10. The diastereoselectivity was highly dependent upon the structure of the diene.

Doctorat en sciences chimiques -- UCL, 1993

Doctorat en sciences chimiques -- UCL, 1993

Doctorat en sciences chimiques -- UCL, 1993

Doctorat en sciences chimiques -- UCL, 1993

Doctorat en sciences chimiques -- UCL, 1993

Doctorat en sciences chimiques -- UCL, 1993

Epoxides (6) and (7), topologically related to the carbapenem antibiotics, were designed as potential alkylating inhibitors of the bacterial D,D-peptidases. The olefinic precursors (8-9) were readily prepared, in three steps, by coupling the Wittig reagent (13) with the aldehyde synthons (10) or (11) resulting from diastereoselective aldol condensations. Epoxide (7) showed a weak anti-beta-lactamase activity.