Asymmetric Synthesis and some Reactions

Abstract

This thesis describes the asymmetric phase-transfer catalysed (PTC) Darzens condensation of aldehydes and ketones with the chiral reagents 1-menthyl chloromethanesulphonate, (S)-(-)-N-chloromethylsulphony l-2 -thoxymethylpyrrolidine,(S)-(-)-tert-butyl N-(chloromethylsulphonyl)prolinate and (+)-0-methyl-N-(chloromethylsulphonyl)ephedrine using triethylbenzylammonium chloride (TEBA) as the phase-transfer catalyst.The chiral reagent 1-menthyl chloromethanesulphonate was obtained by the sulphonation of I-menthol with chloromethanesulphonyl chloride . The chloromethanesulphonamides were similarly obtained from suitable derivatives of (S)-(-)-proline and (+)-ephedrine, ~respectively.The diastereomeric a,8-epoxysulphonate esters from 1-menthyl chloromethanesulphonate and the a,$-epoxysulphonamides from the hloromethanesulphonamides were obtained in good chemical yields, showing a diastereomeric excess (d.e.) ranging from 10-18% for the epoxysulphonate esters and from 10-50% for the proline epoxysulphonamides . The d.e. values for the ephedrine epoxysulphonamides were rather low (4-83, with one positive exception of 203). The improved degree of asymmetric induction using proline derived chloromethanesulphonamides as chiral reagents was based on the better defined and conformationally less flexible stereostructures of the transition states leading to proton abstraction by base to form intermediate diastereomeric a-sulphonyl carbanions. Reaction of these anions with the carbonyl compounds gave the desired epoxysulphonamides. The lower d,e . valuesfor epoxysulphonylephedrines support the dependence of the chiral induction on the conformational flexibility of the stereostructure of a chiral reagent. The dependence of the extent of asymmetric induction on the steric b ul k of the st a rting carbonyl compound was demonstrated in all the cases. The rationale for the better d.e. values when (S)-(-)-N-chloromethylsulphonyl-2-ethoxymethylpyrrolidine was used as the chiral reagent instead of tert-butyl N-(chloro thylsulphonyl)prolinate is also discussed.A discussion of the stereochemical course for the stereoselective formation of (E)-epoxysulphones in the Darzens condensation of aldehydes with chloromethanesulphones, which is based on the Curtin-Hammett principle, is presented together with a survey of some literature pertinent in the discussion of the experimental results.An account is given on the attempted and successful reactions of a,$-epoxysulphones and epoxysulphonamides. In this respect an approach to the asymmetric synthesis of a-methyl-aaminoacids from the reaction of the intermediate epoxysulphonamides with sodium azide is described. The enantiomeric excess of the thus-obtained a -met~yl amino alcohols, which in principle can be converted to the desired a-methyl-a-aminoacids with retent i on of stereochemistry, was about 30%. Reductive desulphonylation and reactions wi t h organometallic reagents failed to take place with epoxysulphones and epoxysulphonamides .Attempted reaction with magnesium bromide led to the rearrangement of the epoxysulphonamides derived from the 2-methoxymethylpyrrolidine sulphonamide.