Giovanna Mobbili

A convenient approach to diastereomerically pure 1,3,4-trisubstituted pyrrolidin-2-ones by intramolecular cyclisation of N-(2-alken-1-yl)amides mediated by Mn(III). An entry to both (R)- and (S)-3-pyrrolidineacetic acid

The oxidative cyclisation of a series of either (S)-N-(2-alken-1-yl)-N-(1-phenyleth-1-yl)-acetoacetamides5a-d and methoxycarbonylacetamides 6a-b, performed by using Mn(OAc)3 · 2H2) and Cu(OAc)2 · H2O in acetic acid, has been examined. The reaction proceeds regioselectively through a 5-exo-mode, leading to 1,3,4-trisubstituted pyrrolidin-2-ones 7a-d,8a-d and 9a-b,10a-b as diastereomeric mixtures in about 2:1 ratio, which are easily separated by silica gel chromatography. The configuration of the pure diastereomers is assigned from 1H NMR data and confirmed by NOE experiments. The observed asymmetric induction has been explained on the basis of molecular mechanics calculations. This cyclisation constitutes a useful tool for the synthesis of biologically active amino acids containing the pyrrolidine ring in both enantiomerically pure forms, such as (R)- and (S)-3-pyrrolidineacetic acid, 1 and 2.

From 3-aza-2-oxobicyclo[3.1.0]hexane to enantiopure disubstituted cyclopropane: a convenient approach to cis-2,3-methano-GABA

Abstract Starting from the diastereomerically pure 4-ethenyl pyrrolidin-2-one 5 , through simple steps the mesyl derivative 8 was obtained, which underwent intramolecular alkylation to give, in good yield, the 3-aza-2-oxobicyclo[3.1.0]hexane 9 . This compound was subsequently converted into enantiomerically pure (−)- cis -2,3-methano-GABA, 2 .

From pyrrolidin-2-ones to 3-aza-2-oxobicyclo[3.2.0]heptanes. Synthesis of both enantiomers of cis-2-aminomethylcyclobutane carboxylic acid, a conformationally restricted analogue of GABA

Abstract By changing the cyclisation conditions (NaH in THF or NaOEt in EtOH), an enantiopure malonamide containing an enoate acceptor afforded either diastereomeric pyrrolidin-2-one 3 or 4 as the major product of the intramolecular conjugate addition. After separation, both diastereomers were converted through simple steps into the corresponding 3-aza-2-oxobicyclo[3.2.0] heptane which eventually led to each enantiomer of cis -2-aminomethylcyclobutanecarboxylic acid, 1 , a conformationally restricted analogue of GABA, in both enantiomerically pure form.

Cyclisation of (R)- and (S)-N-allyl-N-(1-phenylethyl) methoxycarbonylacetamide mediated by Mn(III): Preparation and structural assignment of 3-aza-2-oxobicyclo[3.1.0]hexanes

Abstract (R)- and (S)-N-allyl-N-(1-phenylethyl)methoxycarbonylacetamide, 5 and 6, underwent oxidative cyclisation mediated by Mn(III), to give easily separable diastereomeric mixtures of 3-aza-2-oxobicyclo[3.1.0]hexanes 8a,b and 9a,b, respectively, whose structures were assigned on the basis of 1H NMR spectra and then confirmed by X-ray diffraction analysis of the derivatives 11b and 14.

STEREOSELECTIVE REDUCTION OF CHIRAL TRANS-3-ACETYL-4-ALKYLPYRROLIDIN-2-ONES

Abstract A number of trans-3-acetyl-4-alkylpyrrolidin-2-ones 8a–d and 11a,b were prepared and reduction of the keto group, carried out with KBH4 in CH3OH, led mainly to 3-hydroxyethylpyrrolidin-2-ones 13a–d and 19a,b with high stereoselection. Configuration of the newly formed stereogenic centre on the hydroxyethyl chain was assigned by 1H NMR data supported by molecular mechanic calculations and eventually confirmed by X-ray diffraction analysis of p-iodobenzoate derivative 15.

Synthesis of a conformationally restricted analog of pregabalin by stereoselective alkylation of a chiral pyrrolidin-2-one

Abstract The 4-benzyloxymethyl pyrrolidin-2-one, 5 , was alkylated leading to 3,4- trans -disubstituted pyrrolidin-2-one 6 in good yield and total diastereoselection, as shown by 1 H NMR data and NOE experiments. After reduction of the carbonyl group to give the trans -3,4-disubstituted pyrrolidine 7 , and removal of the chiral auxiliary, followed by protection of the nitrogen with t -Boc group, the corresponding N -protected pyrrolidine, 8 was obtained. The cleavage of the benzyl ether moiety, followed by oxidation of the hydroxy function, gave in good yield the corresponding pyrrolidine carboxylic acid 2 , a restricted analog of pregabalin.

Steric constraints against [3,3]-sigmatropic rearrangement of allylic azides. A convenient approach to β-l-4-aminopent-2-enoglyceropyranosides

Abstract Starting from alkyl α- d -4- O -methanesulphonylpent-2-eno glycero pyranosides 13a – c , nucleophilic substitution carried out with polymer-supported azide ion led to regioisomeric mixtures of the azides 14a – c and 15a – c . An analogous result, due to a [3,3]-sigmatropic rearrangement, was observed starting from methyl α- d -hex-2-eno erythro pyranoside derivatives 6a and 6b . On the contrary, starting from alkyl β- d -4- O -methanesulphonylpent-2-eno glycero pyranosides 21a – c , azides 22a – c were exclusively obtained, and subsequently converted into the corresponding amino derivatives 23a – c . The behaviour of β-anomers 21a – c was ascribed to steric interactions in the cyclic transition state, as supported by ab initio calculations.

Thermodynamic vs. kinetic control in the stereoselective intramolecular conjugate addition of amide enolates leading to chiral trans-3,4-disubstituted pyrrolidin-2-ones

Abstract Intramolecular conjugate addition of amide enolates to α,β-unsaturated esters was found to give either of the diastereomeric trans-3,4-disubstituted pyrrolidin-2-ones 6, 10 or 7, 11 as the major products, by choosing the appropriate reaction conditions. The cyclisation performed with NaH in THF afforded mainly 6 and 10, whereas by using sodium ethoxide in ethanol the major products of the cyclisation were isomers 7 and 11, with the opposite configuration at both C-3 and C-4. This behaviour was explained by thermodynamic vs. kinetic control and supported by molecular mechanics and quantomechanical calculations.

Neutral liposomes containing crown ether-lipids as potential DNA vectors.

Three crown ether derivatives, 1,2-O-dioleoyl-3-O-{2-[(12-crown-4)methoxy]ethyl}-sn-glycerol (12C4L), 1,2-O-dioleoyl-3-O-{2-[(15-crown-5)methoxy]ethyl}-sn-glycerol (15C5L) and 2,3-naphtho-15-crown-5 (NAP5), have been incorporated into 1-palmitoyl-2-oleoyl-phosphatydilcholine (POPC) liposomes. The size of the crown ether and the lipophilic moiety of 12C4L, 15C5L and NAP5 influence the stability and the properties of the extruded POPC liposomes determined at 25°C in buffered aqueous solution at pH7.4. The investigated liposomes are zwitterionic for POPC headgroups but can be turned into cationic aggregates in the presence of divalent cations. The capability of these systems to complex DNA has been demonstrated by SAXS experiments.

Diastereoselective hetero-diels-alder cycloaddition of a C-nitroso compound prepared starting from a homochiral imidazolidin-2-one

Abstract By Swern oxidation of the hydroxamic acid 3 , prepared from the homochiral imidazolidin-2-one 1 , the transient C-nitroso derivative 4 is obtained, and its cycloaddition to either cyclohexadiene or cyclopentadiene proceeds with high diastereoselection, owing to the conformational stability of 4 . The stereochemical outcome of the reaction is determined from 1 H NMR data and further confirmed by the specific rotation value of 7 , obtained by cleavage of the major cycloadduct 5a .