Enikő Forró

Synthesis of 4-aryl-substituted β-lactam enantiomers by enzyme-catalyzed kinetic resolution

Abstract Enantiopure 4-phenyl- and 4-( p -tolyl)-2-azetidinones 3a , 3b , 4a and 4b (with e.e.s of ≥96%) were prepared through lipase-catalyzed asymmetric butyrylation of the primary OH group of N -hydroxymethylated β-lactams (±)- 5 and (±)- 6 at the ( R )-stereogenic centre or by lipase-catalyzed asymmetric debutyrylation of O- butyryloxymethyl-2-azetidinones (±)-7 and (±)- 8 at the ( R )-stereogenic centre. The ring-opening of lactams 5a , 5b , 6b and 8a with HCl/EtOH afforded the corresponding β-amino ester enantiomers 9a , 9b , 10a and 10b with e.e.s of ≥92%.

New gas chromatographic method for the enantioseparation of β-amino acids by a rapid double derivatization technique

A novel gas chromatographic method was developed for the enantioseparation of valuable acyclic and carbocyclic cis- and trans-beta-amino acids, including cispentacin and a number of its analogues and homologues. Excellent (in most cases baseline) separation was achieved for the racemates of these beta-amino acids on CP-Chirasil-Dex CB or CP-Chirasil L-Val columns after a simple and rapid double derivatization (esterification followed by N-acylation). The elution sequences were determined in all cases.

Enzymatic resolution of alicyclic β-lactams

Abstract Racemates of N -hydroxymethylated β-lactams 4 – 6 were resolved through the lipase-catalyzed asymmetric acylation of the primary hydroxy group at the 6 S stereogenic centre. High enantioselectivity (E>200) was observed when the enzymatic reactions were performed in acetone with lipase PS as catalyst and vinyl butyrate as acyl donor. The hydrolysis of the enantiomeric azetidinones 4a – 6a and 4b – 6b resulted in the enantiomerically pure alicyclic β-amino acids 4c – 6c and 4d – 6d . When the less reactive enantiomers 4b – 6b were treated with NH 4 OH/MeOH, enantiomerically pure β-lactams 4e – 6e were formed.

Preparation of (1R,8S)- and (1S,8R)-9-azabicyclo[6.2.0]dec-4-en-10-one: Potential starting compounds for the synthesis of anatoxin-a

Abstract 9-Azabicyclo[6.2.0]dec-4-en-10-one (±)- 2 , obtained from cyclooctadiene by addition of chlorosulfonyl isocyanate, was N -hydroxymethylated to (±)- 3 and then resolved by lipase-catalysed asymmetric acylation of the primary OH group at the ( S )-stereogenic centre. High enantioselectivity ( E =94) was observed when lipase PS and vinyl butyrate were used in di- iso -propyl ether at −15°C, resulting in the enantiomerically enriched ester 3a and alcohol 3b (e.e. ≥92%). Treatment of 3a and 3b with NH 4 OH/MeOH afforded the corresponding β-lactams (1 R ,8 S )- 2a and (1 S ,8 R )- 2b (e.e. ≥93%), potential starting compounds in anatoxin- a synthesis. The ring opening of lactams (±)- 2 , (±)- 7 , 3a and 3b , followed by reduction, resulted in racemic 4 – 6 and 8 and enantiomeric 4a , 4b , 5a and 5b eight-membered cyclic β-amino acid derivatives.

Recent lipase-catalyzed hydrolytic approaches to pharmacologically important β- and γ-amino acids.

Kinetic and sequential kinetic enzymatic routes for the synthesis of enantiomeric β- and γ-amino acids through enzymatic ring cleavage of the corresponding lactams in organic solvents or solvent-free systems or a supercritical CO(2) medium, and for the enantioselective hydrolysis of the corresponding amino esters in organic solvents are reviewed. In the frame of a practical guide, a simple and rapid GC enantioseparation technique for amino acids, including exact descriptions of selected enzymatic reactions, is additionally presented.

Regio- and diastereoselective fluorination of alicyclic β-amino acids

A regio- and stereoselective approach to fluorinated β-aminocyclohexene or cyclohexane esters has been developed, starting from a bicyclic β-lactam (1). The procedure involves six or seven steps, based on regio- and stereoselective iodolactonization, lactone opening and hydroxy-fluorine exchange. The method has been extended to the synthesis of fluorinated amino ester enantiomers.

Separation of enantiomers of β-lactams by HPLC using cyclodextrin-based chiral stationary phases

Abstract The enantiomeric separation of 12 β‐lactam compounds on 3 native cyclodextrin and 6 derivatized β‐cyclodextrin stationary phases was evaluated using high performance liquid chromatography (HPLC). The dimethylphenyl carbamate functionalized chiral stationary phase (CSP) (Cyclobond I 2000 DMP) separated 11 of the 12 β‐lactams in the reversed phase mode. The dimethylated β‐cyclodextrin column (Cyclobond I 2000 DM) was the second most effective CSP and it separated 8 of the 12 compounds. The reversed phase separation mode was the most effective approach. The effects of the composition and the flow rate on enantioseparations were studied. The effect of the structure of the substituents on the β‐lactams was examined.

A New Access Route to Functionalized Cispentacins from Norbornene β-Amino Acids

An efficient and simple new stereocontrolled access route to novel disubstituted cispentacin derivatives with multiple stereogenic centers from norbornene β-lactam has been developed. The synthesis involves olefinic bond functionalization by dihydroxylation followed by oxidative ring cleavage and transformation of the dialdehyde intermediate through a Wittig reaction.

Separation of cis-β-lactam enantiomers by capillary electrophoresis using cyclodextrin derivatives

Chiral separation of 19 pairs of cis-beta-lactam (BL) stereoisomers of pharmacological importance was examined by capillary electrophoresis using cyclodextrin (CD) derivatives. In order to select the most effective conditions separating the highest number of stereoisomers of BLs, single carboxymethyl alpha-, beta- and gamma-, as well as sulfobutyl beta-CD derivatives were applied. Additionally, carboxymethyl and sulfobutyl beta-CD derivatives complemented with neutral beta-CD derivatives as dual CD systems were tested. Both the composition and concentration of applied selectors and the pH of background electrolyte were selected. In single systems the structural characteristics of BLs and the complex forming affinity were correlated. Most BLs provided optimal complexation with beta-CD derivatives. In conclusion, the efficiency of combining sulfobutyl-beta-CD and permethylated beta-CD was superior to other single and dual CD systems applied. This method successfully separated each pair of stereoisomers investigated.

Synthesis and stereochemistry of 1,3,2-oxazaphosphorino [4,3-A]isoquinolines

Abstract 1,3,2-Oxazaphosphorino[4,3- a ]isoquinolines 8a,b, 9a,b and 10a were synthesized by the reactions of homocalycotomine 7 with appropriate dichlorophosphorus derivatives, such as phenylphosphonic dichloride, bis(2-chloroethyl)phosphonic dichloride or phosphoryl chloride. In spite of the blocking effect of the connecting isoquinoline ring system, the oxazaphosphorinane moiety exists as a chair–twist equilibrium, where the conformer ratios are strongly dependent on the P-4 configuration and the stereoelectronic properties of the substituents.