Gábor Bernáth

Approach to highly enantiopure β-amino acid esters by using lipase catalysis in organic media

Abstract Ethyl esters of ten alicyclic β-aminocarboxylic acids were resolved by lipase catalysis in organic solvents. The resolution was based on acylation of the amino group at the R-stereogenic centre with various 2,2,2-trifluoroethyl esters. An increase in the hydrophobic nature of the acyl donor enhanced the enantioselectivity and reactivity in the case of lipase SP 526 from Candida antarctica, while the opposite effect was observed with lipase PS from Pseudomonas cepacia. An unexceptional enantioselectivity enhancement was observed when 2,2,2-trifluoroethyl chloroacetate was used in the case of lipase PS catalysis.

Stereochemical studies 83 saturated heterocycles 76. Preparation and conformational study of partially saturated 3,1-benzoxazines, 3,1-benzoxazin-2-ones and 3,1-benzoxazine-2-thiones

Abstract The cis - and trans -2-amino-4-cyclohexene-1-carboxylic acids 1 and 3 react with imidates to give the condensed-skeleton, bicyclic cis - and trans -pyrimidin-4-ones 8 and 9 . The amino acids 1 and 3 were reduced to the cis -and trans -1, 3-aminoalcohoIs 6 and 7 , which were cyclized by means of imidates to the bicyclic tetrahydro-4 H -3,1-benzoxazines 10 and 11 , or were converted, via the corresponding carbamates 14 and 15 into the tetrahydro-4 H -3,1-benzoxazin-2(1 H )-ones 16 and 17 . The 2-thioxo analogues 18 and 19 were prepared by cyclization of the dithiocarbamates obtained from the aminoalcohols 6 and 7 by treatment with carbon disulphide. The trans -aminoalcohol 7 and its saturated analogue reacted with p -chlorobenzaldehyde to furnish the hexahydro 13 and octahydro-4 H -3,1-benzoxazine 13a , respectively. 1 H and 13 C NMR studies showed that, similarly to the earlier-investigated analogues containing oxygen or unsubstituted nitrogen at position 1, the synthesized cis isomrs 8 , 10 , 16 and 18 occurred as the preferred conformer in the heterocyclic twist inverse form of N -inside type ( quasiaxial C 6 -N bond) (B). In the trans isomers containing a saturated C-2 atom ( 13 and 13a ), H-2 and H-6 are in cis relative positions.

Biocatalysis for the preparation of optically active β-lactam precursors of amino acids

Abstract Enantioselective acylation of N -hydroxymethylated β-lactams in the presence of Pseudomonas sp. lipase afforded optically active precursors for the preparation of (1 R ,2)- and (2 S ,2 R )-2-aminocyclopentane- and (1 R ,2 S ,3 R ,4 S )- and (1 S ,2 R ,3 S ,4 R )-3-aminobicyclo[2.2.1]heptanecarboxylic acids. Due to the high enantioselectivity ( E = 90 and 62) and in order to minimize the enzymatic hydrolysis of the acylated products back to the starting alcohol, the reactions were performed in acetone.

Ring-chain tautomerism of 1,3-oxazolidines prepared from norephedrine and norpseudoephedrine

Abstract The reactions of norephedrine and norpseudoephedrine with eleven different aromatic aldehydes led, in each case, to tautomeric equilibria consisting of two ring and one open-chain forms and obeying the equation: log Kx = ϱσ+ + c, where ϱ = 0.54±0.02 and 0.53±0.02 and c = −0.36±0.02 and +0.34±0.02, respectively. A connection was also found between the stereoselectivity of the ring-closures and the Hammett σ+ constants.

Stereochemical studies-XXXIII.1 Saturated heterocycles-IX2: Synthesis and conformations of stereoisomeric cis- and troans-tetramethylene- and pentamethylenedihydro-1,3-oxazines

Abstract By the reaction of cis- and trans-2-aminomethylcyclohexanol (1, 2), cis- and trans-2-hydroxymethyl-cyclohexylamine (3,4) and the homologous cycloheptane derivatives (5-8) with ethyl p-chlorobenzimidate (11), cis- and trans-5,6-tetramethylene- and pentamethylene-2,3,5,6-tetrahydro-4H-1,3-oxazines (12,13,16,17) and cis- and trans-4,5-tetramethylene- and pentaimethylene-4,5-dihydro-6H-1,3-oxazines (14, 15, 18, 19) were prepared. The amidine intermediate of the ring-closure reaction was isolated, and the mechanism of the acid-catalysed reaction is discussed. It follows from the 1H NMR data that in the preferred conformations of the cis-tetramethylene-tetrahydrooxazines the methylene group of the hetero ring is equatorial and the hetero atom (O or N) axial. In contrast, the conformation equilibria of the cis pentamethylene derivatives, in accordance with earlier X-ray analysis, are shifted towards the conformer containing the methylene group in isoclinal and the hetero atom in equatorial position. The preferred conformations 12a and 14a of the tetramethylene derivatives 12 and 14 were also determined by X-ray crystal analysis.

Stereochemical studies — 79 synthesis and kinetic study on the retrodiene decomposition of norbornene-condensed 1,3-oxazin-4-ones

The cis-cxo- amino acid c with norbornene skeleton was converted into 2-aryvl-cis-cxo-1,3-oxazin-4-ones 5a-d. These compounds, similarly to the diendo isomers 1a-d studied by us earlier, undergo retrodiene decomposition under mild conditions to give 2-aryl-62-l,3-oxazin-6-ones (2a-d) in 50-60% yield. The ratio of the decomposition rate constants of the tricyclic diendo and diexo-1,3-oxazin-4-ones, measured in toluene solution, is about 2.

A Simple Synthesis of β-Alkyl-Substituted β-Amino Acids

Abstract By the condensation of branched-chain aliphatic or alicyclic aldehydes with malonic acid in the presence of ammonium acetate, β-alkyl-substituted β-amino acids were prepared.

High-performance liquid chromatographic methods for separation of enantiomers of alicyclic β-amino acids

Abstract Reversed-phase high-performance liquid chromatographic methods were developed for the separation and quantification of the enantiomers of alicyclic β-amino acids: racemic cis - and trans -2-aminocyclohexane-1-carboxylic acids ( cis - and trans -ACHC) and racemic cis - and trans -2-animon-4-cyclohexene-1-carboxylic acids ( cis - and trans -ACHC-ene). The enantioselective separations involved two methods: direct separation on a chiral stationary phase (Crownpak CR(+)) and separation of the diastereomers formed by pre-column derivatization with chiral derivatizing reagents: 1-fluoro-2,4-dinitrophenyl-5- l -alanine amide (Marfeys reagent) and 2,3,4,6-tetra-O-acetyl-β- d -glucopyranosylisothiocyanate. The different methods were compared in systematic chromatographic examinations. The effects of pH, mobile phase composition, organic modifier content and temperature on the separation were also investigated.

Stereochemical studies—76 saturated heterocycles—63 : synthesis of cis- and trans-n-methyl- and n-benzyl-4.5- and 5,6-tetramethylenetetrahydro-1,3-oxazines; an x-ray study of n-benzyl-cis-4,5-tetramethylenetetrahydro-1,-3-oxazinium- picrate

Abstract - The corresponding cis - and trans-N -methyl- and N -benzyl-5,6- and 4,5-tetramethylenetetrahydro-l,3-oxazines (5a,b-8a,b) were synthesized from cis - and trans-N -methyl and N -benzyl-2- aminomethyl-1-cyclohexanols 1a,b,2a,b , from cis - and trans-N -methyl- and N benzyl -2-hydroxymethyl-1-cyclohexylamines (3a,b,4a,b) by reaction with formaldehyde. The aminoalcohols 1a,2a,3a,b and 4a,b were prepared in considerably higher yields than in earlier procedures. NMR spectroscopy showed that the cis isomers of the synthesized oxazines were conformationally homogeneous in solution, and their preferred conformation (inside or outside) depended on the steric requirement of the groups attached to the anellation points, whereas a bulky C-2 substituent had no influence on the predominant conformation. The structure of N -benzyl- cis -4,5-tetramethylenetetrahydro-1,3-oxaziniumpicrate (7b) . determined by X-ray diffraction analysis, was in agreement with the predominant N-outside conformation of the corresponding base, established by means of NMR spectroscopy.

Saturated heterocycless—35 : Synthesis and conformational analysis of stereoisomeric 2-oxo- and 2-thioxo-cis- and trans-5,6-trimethylene-3,4,5,6-tetrahydro-1,3-oxazines

Abstract cis- and trans 5,6-Trimethylene-3,4,5,6-tetrahydro-1,3-oxazin-2-ones ane 2 thiones (11–20) were synthesized from cis and trans-2-aminomethylcyclopentanols (6–10) by reaction with urea ethyl chloroformate, carbon disulphide or thiophosgene. The cyclization reactions were also successful with the trans-amino-alcohols, at variance with earlier literature data relating to 1,2-disubstituted 1,3-bifunctional trans-cyclopentane derivatives X-Ray diffraction analysis of trans-5,6-trimethylene-3,4,5 6-tetrahydro-1,3 oxazine-2-thione (17) shows that the exocyclic CXXXS sp2 bond takes part in a co-planar delocalized pπ-pπ bond system formed on the S(10) O(1), N(3) and C(2) atoms and consequently both the C(2)-N(3) [1.304(7)a] and C(2)-O(1) [1.337(7)a] bonds gain some multiple bond character. The endocyclic bond angles at C(2) and N(3) are significantly opened, compared with those in related heterocycles. Of the bonds in the six membered hetero ring, C(5)-C(6) is significantly shortened [1.448(9)a] The remarkable ring-closure reaction of the trans cyclopentane derivatives can be explained by the above findings. 1H NMR data on compounds 11–20 suggest conformationally homogeneous systems and the predominance of the O-inside conformers of the cis isomers.