Advanced procedure for the enzymatic ring opening of unsaturated alicyclic β-lactams

Enantiopure β-amino acids 1a–4a and β-lactams 1b–4b were prepared simultaneously through the lipolase-catalysed enantioselective ring opening of unsaturated racemic β-lactams (±)-1-(±)-4. High enantioselectivities (E>200) were observed when the reactions were performed with 1 equiv of water in iPr₂O at 70 °C. The resolved (1R,2S)-amino acids (yield⩾45%) and (1S,5R)-, (1S,6R)- and (1S,8R)-lactams (yield⩾47%) could be easily separated. The ring opening of lactam enantiomers 1b–4b with 18% HCl afforded the corresponding β-amino acid hydrochlorides 1c·HCl–4c·HCl (ee >95%).     

Approaches to (R)- and (S)-1′-(1-aminoethyl)ferrocene-1-carboxylic acid derivatives

Lipase-catalyzed esterification of (±)-methyl 1′-(1-hydroxyethyl)ferrocene-1-carboxylate 4 afforded its (R)-acetate (−)-5 (ee = 99%) and (S)-(+)-4 (ee = 90%). Stereoretentive azidation/amination/acetylation of (R)-(−)-5 gave (R)-(+)-methyl 1′-(1-acetamidoethyl)ferrocene-1-carboxylate (R)-3 (ee = 98%). In a similar manner (S)-(+)-4 was converted into (S)-(−)-3 (ee = 84%). Both enantiomers of 3 were obtained in high chemical yields without a loss of enantiomeric purity. The title compounds can be coupled with natural amino acids and peptides on both C- and N-termini.     

Synthesis of chiral ligands containing the N-(S)-α-phenylethyl group and their evaluation as activators in the enantioselective addition of Et2Zn to benzaldehyde

The synthesis of chiral ligands 4–18 derived from N-[(S)-α-phenylethyl]-trans-β-aminocyclohexanols (S,S,S)-1a and (R,R,S)-2 is described. Addition of diethylzinc to benzaldehyde catalyzed by ligands 4–18 (6 mol %) proceeds in fair to good yield (45–86%), and low to good enantioselectivities (1–76% ee). Highest enantioselectivities were induced by ligands (S,S,S)-4 and (S,S,S,S,R,R)-18 (76% and 68% ee, respectively). The configuration of the major enantiomer of carbinol 3 is (R) in both cases.     

A new strategy for the synthesis of hydroxylated pyrrolizidinic alkaloids by highly stereoselective indium-mediated allylation of pyrrolidinic aldehydes

Indium-mediated allylation of N-Cbz-l-prolinal 3, under Grignard conditions, was carried out with high yield and stereoselectivity (de = 90%) to afford intermediate (2S,1′R)-N-benzyloxycarbonyl-2-(1′-hydroxybut-3′-en-1′-yl)pyrrolidine 4, which was transformed in two steps into (1R,3R,7aS)-1-hydroxy-3-hydroxymethylpyrrolizidine 9. Commercial Cbz-l-proline was a source of functionalization and chirality.     

Synthesis of rigid and C2-symmetric 18-crown-6 type macrocycles bearing diamide–diester groups: enantiomeric recognition for α-(1-naphthyl)ethylammonium perchlorate salts

A series of rigid and chiral C₂-symmetric 18-crown-6 type macrocycles (S,S)-4, (S,S)-5, (S,S)-6 and (R,R)-2 bearing diamide–ester groups were synthesized. The binding properties of these macrocycles were examined for α-(1-naphthyl)ethylammonium perchlorates salts by an ¹H NMR titration method. Taking into account the host employed, important differences were observed in the K_a values of (R)- and (S)-enantiomers of guests for macrocycles (S,S)-4 and (S,S)-6, K_S/K_R = 3.6, and K_S/K_R = 0.1 (K_R/K_S = 10.3) ΔΔG = 3.19 and ΔΔG = ?5.77 kJ mol^?1, respectively. The results indicated excellent enantioselectivity of macrocyclic (S,S)-6 towards the enantiomers of α-(1-naphthyl)ethylammonium perchlorate salts.     

Synthesis of the (1S,2S)- and (1R,2S)-stereoisomers of the respective E- and Z-isomers of ethyl 4-[(2-hydroxycyclohexyl)methyl]phenoxy-3-methyl-2-butenoate using yeast whole cell bioreduction of the parent ketones

Saccharomyces cerevisiae, strain DBM 2115, was successfully employed in the reduction of the separated Z- and E-isomers of ethyl 4-[(2-oxocyclohexyl)methyl]phenoxy-3-methyl-2-butenoates 1 and 2, in order to prepare the (1S,2S)- and (1R,2S)-enantiomers of the corresponding ethyl 4-[(2-hydroxycyclohexyl)methyl]phenoxy-3-methyl-2-butenoates 3–6. The products were obtained with the required absolute configuration: (1S,2S)-3 (ee = 98%; yield 48%), (1R,2S)-4 (ee = >99%; yield 45%), (1S,2S)-5 (ee = 98.5%; yield 47%), and (1R,2S)-6 (ee = >99%; chemical yield 44%).     

Enthalpic changes on mixing two couples of S- and R-enantiomers of benzyl-(1-phenyl-ethyl)-amine, 1-phenylethylamine, 1-phenyl-ethanol,butyric acid oxiranylmethyl ester, 4-methyl-[1,3]dioxolan-2-one, 2-chloro-methyloxirane and 3-hydroxyisobutyric acid methyl ester at T = 298.15 K

Enthalpies of mixing of (R)- and (S)-enantomers of liquid chiral compounds such as benzyl-(1-phenyl-ethyl)-amine (1), 1-phenylethylamine (2), 1-phenyl-ethanol (3), butyric acid oxiranylmethyl ester (4), 4-methyl-[1,3]dioxolan-2-one (5), 2-Chloromethyloxirane (6) and 3-hydroxyisobutyric acid methyl ester (7) have been measured over the whole range of mole fractions at 298.15 K, albeit very small values. Mixing of heterochiral liquids of R-1 + S-1, R-5 + S-5, and R-7 + S-7 realized enthalpic stabilization over the whole range of mole fractions, whereas that of R-2 + S-2, R-3 + S-3, R-4 + S-4, and R-6 + S-6 realized enthalpic destabilization over entire compositions. The extreme values of enthalpies of mixing and the intermolecular interaction obtained by the molecular mechanics calculations showed a linear correlation, except few the compounds measured.     

Continuous-flow enzymatic resolution strategy for the acylation of amino alcohols with a remote stereogenic centre: synthesis of calycotomine enantiomers

Both enantiomers of calycotomine (R)-5 and (S)-5 were prepared through the CAL-B-catalysed asymmetric O-acylation of N-Boc-protected (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol [(±)-3)]. The optimum conditions for the enzymatic resolution were determined under continuous-flow conditions, while the preparative-scale resolution of (±)-3 was performed as a batch reaction with high enantioselectivity (E >200). The resulting amino alcohol (S)-3 and amino ester (R)-4, obtained with high enantiomeric excess (ee = 99%), were transformed into the desired calycotomine (S)-5 and (R)-5 (ee = 99%). A systematic study was carried out in a continuous-flow system on the O-acylation of tetrahydroisoquinoline amino alcohol homologues (±)-1 to (±)-3 containing a remote stereogenic centre.     

Stereoselective synthesis of novel tetrahydroxypyrrolizidines

N-Benzyloxycarbonyl-2,5-dideoxy-2,5-imino-3,4-O-isopropylidene-l-ribose 12a has been converted into (1R,2S,6R,7S,7aS)-5 and (1R,2S,6S,7R,7aR)-1,2,6,7-tetrahydroxypyrrolidin-5-ones 6 and (1R,2S,6S,7S,7aS)-7 and (1R,2S,6R,7R,7aS)-1,2,6,7-tetrahydroxypyrrolizidines 8 following stereoselective paths. These new compounds have been assayed for their inhibitory activities towards 25 glycosidases. Pyrrolizidines 7 and 8 are moderate but selective inhibitors of amyloglucosidase from Rhizopus mold (7: IC₅₀=130 μM, K_i=120 μM; 8: IC₅₀=200 μM, K_i=180 μM, mixed type of inhibition).     

Synthesis and crystal structure of (S)-pindolol

Racemic 3-(4-indolyloxy)-1,2-propanediol 2 has been effectively resolved into (S)- and (R)-enantiomers by a preferential crystallization procedure. Non-racemic (S)-2 was converted into (S)-4-(2,3-epoxypropoxy)-1H-indole (S)-4 via a Mitsunobu reaction and then into (S)-pindolol (S)-1. The crystalline (S)-1 was studied by single crystal X-ray diffraction. A large number of symmetry independent molecules (Z′ = 6) led to a weakening of the system of strong intermolecular hydrogen bonds, which combined with a loose packing (PI = 64.6%), may be the cause of the abnormally low melting point of (S)-1 as compared with rac-1.     

Second-generation artificial hydrogenases based on the biotin–avidin technology: Improving selectivity and organic solvent tolerance by introduction of an (R)-proline spacer

We report on our efforts to create efficient artificial metalloenzymes for the enantioselective hydrogenation of N-protected dehydroamino acids using streptavidin as host protein. Introduction of an (R)-proline spacer between the biotin anchor and the diphosphine moiety affords a versatile ligand Biot-(R)-Pro-1 which displays good (S)-selectivities in the presence of streptavidin (91% ee). The resulting artificial metalloenzyme [Rh(Biot-(R)-Pro-1)(COD)]⁺ ⊂ WT-Sav displays increased stability against organic solvents.     

Synthesis of chiral C/N-functionalized morpholine alcohols: study of their catalytic ability as ligand in asymmetric diethylzinc addition to aldehyde

A broad variety of chiral C/N-functionalized morpholine alcohols sharing a common structural motif in the 3-(hydroxymethyl)morpholine 6 were prepared from enantiomerically pure serine for the purpose of studying their catalytic ligand properties. The asymmetric addition of diethylzinc to benzaldehyde in the presence of 10 mol % of chiral C/N-functionalized morpholine alcohols gave 1-phenyl-1-propanol in 59–81% yield with 10–30% ee. The addition of 10 mol % of n-butyl lithium to the reaction mixture resulted in a significant enhancement of the stereoselectivity in the case of ligands bearing the two geminal phenyl substituents on the backbone. In the presence of n-butyl lithium and using (S)-3-(hydroxydiphenylmethyl)morpholine (S)-19 as the chiral promoter, (S)-1-phenyl-1-propanol was obtained in 81% yield with 76% ee. The geminal diphenyl-class of morpholine ligands was examined for the diethylzinc addition to four different aldehydes in the presence of n-butyl lithium. (S)-N-Benzyl-3-(hydroxydiphenylmethyl)morpholine (S)-27 was found to be most enantioselective in the case of 4-methoxybenzaldehyde to give (R)-alcohol in 87% yield with 80% ee. Catalysts (S)-19 and its N-methyl derivative (S)-26 gave alcohols with an (S)-absolute configuration while the N-benzylated derivative (S)-27 gave the opposite enantiomeric products. The tentative transition state models to account for the observed product stereoselectivity with morpholine ligands holding the geminal diphenyl group on the β-amino alcohol segment are proposed.     

Sharpless asymmetric dihydroxylation as the key step in the enantioselective synthesis of spirocyclic σ1 receptor ligands

The enantioselective synthesis of fluorinated spirocyclic σ₁ ligands involved three key steps: (1) the Sharpless asymmetric dihydroxylation of 2-bromostyrene 5 provided enantiomerically pure diols (R)-6 and (S)-6 establishing the stereogenic center; (2) the intramolecular opening of the oxirane ring of (R)-11 and (S)-11, which occurred with excellent regioselectivity and complete inversion of configuration giving access to enantiomerically pure alcohols (S)-7a and (R)-7a; (3) the treatment of alcohols (S)-7b and (R)-7b with DAST, which led to the fluoromethyl derivatives (S)-1 and (R)-1 without racemization. X-ray crystal structure analysis of the tosylate (R)-13 confirmed the absolute configuration of the spirocyclic compounds as well as the enantioselectivity during the Sharpless asymmetric dihydroxylation of 5. The (S)-configured fluoromethyl derivative (S)-1 revealed a high σ₁ affinity (K_i = 1.8 nM), high eudismic ratio (factor 8) and high selectivity over the σ₂ subtype (667-fold).     

Asymmetric reductions of ethyl 2-(benzamidomethyl)-3-oxobutanoate by yeasts

The stereoselective reduction of ethyl 2-(benzamidomethyl)-3-oxobutanoate 1 using yeasts was investigated among a restricted number (12) of yeasts. Kluyveromyces marxianus var. lactis CL69 diastereoselectively produced (2R,3S)-ethyl 2-(benzamidomethyl)-3-hydroxybutanoate 2, whereas Pichia glucozyma CBS 5766 gave (2S,3S)-2 as the major stereoisomer. The biotransformations were independently optimized for minimizing by-product formation and maximizing the diastereoselectivity. Under optimized conditions, K. marxianus var. lactis CL 69 gave the (2R,3S)-ethyl 2-(benzamidomethyl)-3-hydroxybutanoate 2 with ee > 99% and de = 98%, while P. glucozyma CBS 5766 allowed for the production of (2S,3S)-2 with ee > 99% and de = 86%.     

The enantiomeric recognition of chiral organic ammonium salts by chiral pyridino-macrocycles bearing aminoalcohol subunits

Pyridine-based macrocycles were prepared by treating 2,6-bis[[2′6′-bis(bromomethyl)-4′-methylphenoxy]methyl]pyridine 3 with the appropriate chiral aminoalcohols. The enantiomeric recognition of these macrocycles bearing aminoalcohol subunits of the pyridinocrown type ligand was evaluated for chiral organic ammonium salts by UV titration. The important differences were observed in the K_a values of (R)-Am2 and (S)-Am2 for (S,S,S)-1, (S,S,S)-2 and (S,S,S)-3 hosts, K_S/K_R = 5.0, K_S/K_R = 2.4 and K_S/K_R = 5.0, respectively. There seems to be a general tendency for hosts to recognise (S)-enantiomers for both Am1 and Am2.     

Biotransformation of 3-azidomethyl-4-phenyl-3-buten-2-one and analogs by Saccharomyces cerevisiae: New evidence for an SN2′ mechanism

(Z)-3-XCH₂-4-(C₆H₅)-3-buten-2-one enones (X = SCN, N₃, SO₂Me, OC₆H₅) were synthesized and submitted to biotransformations using whole Saccharomyces cerevisiae cells. The enone (X = SCN) produced (R)-4-(phenyl)-3-methylbutan-2-one (R)-6 with 93% ee and enones (X = N₃, SO₂Me, OC₆H₅) yielded a mixture of (R)-6 and the corresponding CC bond reduction products. Biotransformation with enone (X = N₃) mediated by Saccharomyces cerevisiae resulted in two products via two different routes: (i) the ketone (R)-4-azido-3-benzylbutan-2-one in 28% yield and with >99% ee by CC bond reduction; (ii) ketone (R)-6 in 51% yield and with 95% ee via cascade reactions beginning with azido group displacement by the formal hydride from flavin mononucleotide in an S_N2′ type reaction followed by reduction of the newly formed CC bond.     

Enzymatic reactions for the preparation of homocalycotomine enantiomers

Homocalycotomine enantiomers (R)-4 and (S)-4 were prepared by the Candida antarctica lipase B (CAL-B)-catalysed asymmetric O-acylation of N-Boc-protected 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)ethanol (±)-1. The preliminary small-scale experiments were performed either in a continuous-flow system or as batch reactions, while the preparative-scale resolution was carried out in two steps with vinyl acetate as the acyl donor in the presence of Et₃N and Na₂SO₄ in toluene at 3 °C, as a batch reaction. Treatment of the resulting amino alcohol (S)-1 and amino ester (R)-3 (ee ?94%) with 18% HCl, and then with 5 M NaOH, furnished the desired (R)-4 and (S)-4 without a decrease in the enantiomeric excess (ee ?94%).     

Enantioselective construction of all-carbon quaternary spirocenters through a Pd-catalyzed asymmetric intramolecular ipso-Friedel–Crafts allylic alkylation of phenols

A novel catalytic asymmetric synthetic method for making spirocyclohexadienones with an all-carbon quaternary spirocenter was developed based on the Pd-catalyzed intramolecular ipso-Friedel–Crafts allylic alkylation of phenols. When 5 mol % of the Pd catalyst and 12 mol % of (?)-9-NapBN (?)-3e were used, the spirocyclic adduct was obtained with up to 93% ee, albeit with low chemical yield. On the other hand, when using 6 mol% of the Trost ligand (R,R)-3k, the spirocyclic adducts were obtained in good yields with up to 89% ee (diastereoselectivity = 9.2:1).     

The stereocontrolled synthesis of polyfunctional organosulfur compounds via chiral azetidinium salts and epoxyamines

The stereocontrolled synthesis of functionalized organosulfur compounds of a general formula: Bn₂NCH(CH₃)CH(OH)CH₂SX [where: X = SO₃Na or SP(S)(OR)₂] was achieved by a regioselective opening of enantiomerically >98% pure (2S,3R)- and (2S,3S)-N,N-dibenzyl-2-hydroxy-3-methylazetidinium bromides and/or (1R)-[1′(S)-dibenzylamino)ethyl]oxiranes with thiosulfate and dithiophosphate anions. The attack of both nucleophiles was directed exclusively at the less substituted carbon atom of the heterocyclic ring.     

Resolution of 1-cyclohexylethylamine via diastereomeric salt formation with enantiopure 2-phenylacetic acids

The resolution of 1-cyclohexylethylamine 1 with enantiopure 2-phenylacetic acids via diastereomeric salt formation was investigated. (R)-2-Methoxy-2-phenylacetic acid 3 and the (S)-2-phenylpropionic acid 5 were found to be efficient resolving agents for obtaining the single enantiomer (S)-1 as the correspondingly less-soluble diastereomeric salt (resolution efficiency = 48% and 52%, respectively).