Transformation of racemic ethyl 3-hydroxybutanoate into the (R)-enantiomer exploiting lipase catalysis and inversion of configuration

Racemic ethyl 3-hydroxybutanoate rac-1 was transformed into ethyl (R)-acetoxybutanoate (ee = 92%) with 85–90% chemical yields using enantioselective acylation with isopropenyl acetate in the presence of Candida antarctica lipase B (CAL-B, Novozym 435) under solvent-free conditions, followed by mesylation of the unreacted (S)-alcohol in the reaction mixture and inversion of configuration with cesium acetate in DMF in one pot. When the (R)-acetoxybutanoate was subjected to alcoholysis with ethanol and CAL-B, enantiopure (R)-1 (ee >99%) was produced.     

A green route to enantioenriched (S)-arylalkyl carbinols by deracemization via combined lipase alkaline-hydrolysis/Mitsunobu esterification

Herein we report results of the chemoenzymatic deracemization of a range of secondary benzylic acetates 1a–9a via a sequence of hydrolysis with CAL-B lipase in non-conventional media, combined with esterification of the recovered alcohol according to the Mitsunobu protocol following an enzymatic kinetic resolution (KR). The KR of racemic acetates 1a–9a via an enzymatic hydrolysis, with CAL-B lipase and Na₂CO₃, in non-aqueous media was optimized and gave high selectivities (E ? 200) at good conversions (C >49%) for all of the substrates studied. This method competes well with the traditional one performed in a phosphate buffer solution. The deracemization using Mitsunobu inversion gave the (S)-acetates in moderate to excellent enantiomeric excess 75% < ee < 99%, in acceptable isolated yields 70% < yield < 89%, and with some variations according to the acetate structure.     

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%).     

The effect of the migrating group structure on enantioselectivity in lipase-catalyzed kinetic resolution of 1-phenylethanol

We have studied the effects of the acyl moiety on the enantioselectivity of three lipases: Candida antarctica B, Pseudomonas cepacia and Candida cylindracea, frequently used in kinetic resolutions by acylation or hydrolysis. The size of the acyl group was examined using various enol esters during the transesterification of 1-phenylethanol and the hydrolysis of the corresponding phenylethylesters. C. antarctica-B lipase showed the highest selectivity in the transesterification of 1-phenylethanol with isopropenyl and vinyl acetate, vinyl decanoate, vinyl laurate, (E > 200). The esters 1-phenyl -ethyl-acetate, decanoate and laurate are also hydrolyzed with high selectivities (E > 150) with CAL-B. The results can be correlated to the three-dimensional form of each lipase. The effect of the migrating group on the reactivity and selectivity of the lipases are discussed for both reactions.     

Enantioselective acylation of rac-2-phenylcycloalkanamines catalyzed by lipases

The kinetic resolution of some 2-phenylcycloalkanamines was performed by means of aminolysis reactions catalyzed by lipases, with Kazlauskas’ rule being obeyed in all cases. The size of the ring and the stereochemistry of the stereogenic centers of the amines had a strong influence on both the enantiomeric ratio and the reaction rate of these aminolysis processes. Lipase B from Candida antarctica (CAL-B) showed excellent enantioselectivities toward trans-2-phenylcyclohexanamine in a variety of reaction conditions (E >150), whereas lipase A from C. antarctica (CAL-A) was the best catalyst for the acylation of cis-2-phenylcyclohexanamine (E = 34) and trans-2-phenylcyclopropanamine (E = 9).     

Do lipases also catalyse the ring cleavage of inactivated cyclic trans-β-lactams?

Twelve-membered cyclic cis- and trans-β-lactams 1b and 2b and the corresponding cyclic cis- and trans-β-amino acid enantiomers, 1a, 1c and 2a, 2c were prepared through the CAL-B-catalysed enantioselective ring cleavage of racemic cis-13-azabicyclo[10.2.0]tetradecan-14-one, (±)-1, and trans-13-azabicyclo[10.2.0]tetradecan-14-one, (±)-2. High enantioselectivities (E >200) were observed for the ring opening of both the cis- and trans-β-lactams when the Lipolase-catalysed reactions were performed with 0.5 equiv of H₂O in i-Pr₂O at 70 °C. The resolved β-lactams 1b and 2b (yield ⩾47%) and β-amino acids 1a and 2a (yield ⩾32%) could be easily separated.     

Enantiomeric resolution by lipase-catalysed esterification of a trans-5,6-dihydro-1,10-phenanthroline possessing helical and central chirality

Lipase-catalysed enantioselective esterification was carried out to obtain the kinetic resolution of (±)-trans-5-hydroxy-6-methoxy-1,10-phenanthroline (±)-1b. Different lipases from Candida cylindracea, Candida antarctica, Rhizomucor miehei, Pseudomonas fluorescens and Pseudomonas cepacia were tested in an unusual methanol/vinyl acetate (8:92 v/v) reaction mixture P. fluorescens lipase showed good enantiodifferentiation (E = 48) and allowed us to prepare both enantiomers (+)-(5S,6S,M)-1b and (−)-(5R,6R,P)-1b with an enantiomeric excess of >97%.     

Asymmetric synthesis of enantiomerically pure zingerols by lipase-catalyzed transesterification and efficient synthesis of their analogues

The achiral zingerone 1, readily available from ginger, can be easily transformed into chiral derivatives. Zingerol 2, a reduced product of zingerone 1 is expected to be an important new medicinal lead compound. We have achieved a concise synthesis of optically active zingerol (R)-2 and (S)-2 by the lipase-catalyzed stereoselective transesterification of racemic 2. Under the optimized conditions, a lipase from Alcaligenes sp. (Meito QLM) and vinyl acetate in i-Pr₂O or hexane at 35 °C within 1 h gave the alcohol (S)-2 and the acetate (R)-9 with high enantioselectivity without producing acetylated by-products. Since optically active (S)-2 and (R)-9 were obtained through lipase-catalyzed transesterification, other enantiomerically pure novel compounds could all be synthesized.     

Photochemical behavior in azobenzene having acidic groups. Preparation of magnetic photoresponsive gels

The photochemistry of three azobenzenes representing contrasting photochemical behaviors is described in the present work. Thus, Methyl Orange (MO, 4-[[(4-dimethylamino)phenyl]-azo]benzenesulfonic acid sodium salt, hereinafter (1) and 4-hydroxyazobenzene-4′-sulfonic acid (2) undergo in water fast photochemical proton shift, with decays in the microsecond timescale. In contrast to the previous cases, azobenzene-4,4′-dicarboxylic acid (3) undergoes photoisomerization in water. This photochemical behavior allows the preparation of aqueous gels with Aerosil as gelating agent (5% weight) exhibiting high cyclability and photoreversible isomerization of the trans to cis (300 nm irradiation) and cis to trans (visible white light irradiation). Gels containing azobenzene 3 as photoresponsive molecule and well-dispersed magnetite (Fe₃O₄) nanoparticles exhibit simultaneously high photoresponse and magnetic properties. Photoisomerization of compound 3 in these gels leads to small but reliable changes (25 G coercive field) in the magnetic hysteresis loop of magnetite nanoparticles. This novel concept of optical modulation of magnetism in iron oxide nanoparticles paves the way for the study of new systems, with a stronger coupling between trans–cis photoisomerization and magnetic properties.     

Formation and isomerization of cis,cis-Ir(H)2(--Ph)(CO)(PPh3)2 and cis,cis-Ir(H)(--Ph)2(CO)(PPh3)2 in oxidative addition of hydrogen and phenylacetylene to trans-Ir(CO)(--Ph)(PPh3)2

Oxidative addition of H–R (H--Ph and H₂) to trans-Ir(--Ph)(CO)(PPh₃)₂ (2) gives the initial products, cis, cis-Ir(H)(--Ph)₂(CO)(PPh₃)₂ (3a) and cis, cis-Ir(H)₂(--Ph)(CO)(PPh₃)₂ (3b), respectively. Both cis-bis(PPh₃) complexes, 3a and 3b undergo isomerization to give the trans-bis(PPh₃) complexes, trans, trans-Ir(H)(--Ph)₂(CO)(PPh₃)₂ (4a) and cis, trans-Ir(H)₂(--Ph)(CO)(PPh₃)₂ (4b). The isomerization, 3b→4b is first order with respect to 3b with k₁=6.37×10⁻⁴ s⁻¹ at 25°C under N₂ in CDCl₃. The reaction rate (k₁) seems independent of the concentration of H₂. A large negative entropy of activation (ΔS^≠=−24.9±5.7 cal deg⁻¹ mol⁻¹) and a relatively small enthalpy of activation (ΔH^≠=14.5±3.3 kcal mol⁻¹) were obtained in the temperature range 15∼35°C for the isomerization, 3b→4b under 1 atm of H₂.     

Lipase-catalyzed asymmetric acylation in the chemoenzymatic synthesis of furan-based alcohols

Eight racemic 1-(furan-2-yl)ethanols were prepared from the corresponding carbonyl compounds for enantioselective acylation studies, and seven of them were used in preparative-scale kinetic resolutions with Candida antarctica lipase B (Novozym 435) and vinyl acetate in dried diisopropyl ether. Mechanism-based competition between the (R)-acetate (enzymatic acylation product), vinyl acetate (added acylating reagent), and acetic acid (enzymatic hydrolysis product) toward CAL-B, together with the residual water of the lipase were shown to be potential reasons for side reactions, which affected the course of the kinetic resolution of 1-[5-(2-chlorophenyl) and (4-bromophenyl)furan-2-yl]ethanols. Clear effects were not observed with the other alcoholic substrates. Alcoholysis of the enantiomerically enriched (R)-acetates with methanol and CAL-B in diisopropyl ether was shown to be a potential method for the deprotection of the (R)-acetates and the formation of (R)-alcohols.     

Enantiomerically enriched cryptone by lipase catalysed kinetic resolution

Thiophenol was added to racemic cryptone (4-isopropyl-2-cyclohexene-1-one) and the resulting 1,4-addition products, cis- and trans-4-isopropyl-3-(phenylsulfanyl)cyclohexanone were separated and the latter reduced to rac-1,3-cis-1,4-trans-4-isopropyl-3-(phenylsulfanyl)cyclohexanol, which was subjected to lipase catalysed resolution by acylation catalysed by CAL-B (Candida antarctica lipase B). The alcohol enantiomers obtained were oxidised. The remaining alcohol was separated from the produced acetate, which was hydrolysed to the alcohol. The initial products, probably sulfoxidoketones spontaneously decomposed to furnish enantiomerically enriched (R)- and (S)-cryptone with up to 76% and 98% ee, respectively.     

Uranium(VI) bis(imido) disulfonamide and dihalide complexes: Synthesis density functional theory analysis

Novel cis- and trans-bis(imido) uranium disulfonamide derivatives have been prepared from iodide metathesis reactions between two equivalents of K[N(Me)(SO₂Ar’)] (Ar’ = 4-Me-C₆H₄) and U(N^tBu)₂(I)₂(L)_x (L = OPPh₃, x = 2; Me₂bpy, x = 1; Me₂bpy = 4,4’-dimethyl-2,2’-bipyridyl). These bis(amide) derivatives serve as useful precursors for the synthesis of the trans-diphenolate complex U(N^tBu)₂(O-2-^tBuC₆H₄)₂(OPPh₃)₂ (5), cis- and trans-dithiolate complexes U(N^tBu)₂(SPh)₂(L)_x (L = OPPh₃ (6); Me₂bpy (7)), and cis- and trans-dihalide complexes with the general formulas U(N^tBu)₂(X)₂(L)_x (X = Cl, L = OPPh₃ (8), L = Me₂bpy (10); X = Br, L = OPPh₃ (9), L = Me₂bpy (11)). DFT calculations performed on the trans-dihalide series U(N^tBu)₂(X)₂(L)₂ and the UO₂²⁺ analogues UO₂X₂(OPPh₃)₂ suggest that the uranium centers in the [U(N^tBu)₂]²⁺ ions possess more covalent character than analogous UO₂²⁺ derivatives but that the U-X bonds in the U(N^tBu)₂X₂L₂ complexes possess a more ionic nature.     

Supramolecular chemistry and the control of the crystallization behavior by the choice of the counter-ion. Part 11. The stereochemistry and crystallization architecture of [(tren)Co(NO2)2]A (I), [(tren)Co(ox)]A (II), [(en)2Co(ox)]A (III) and [trans-(pn)2Co(NO2)2]A (IV), with A = [trans-(NH3)2Co(NO2)4]

In continuation of studies carried out previously [I. Bernal, Inorg. Chim. Acta 96 (1985) 99; I. Bernal, Inorg. Chim. Acta (1986) 121; I. Bernal, E.O. Schlemper, C.K. Fair, Inorg. Chim. Acta 115 (1986) 25; I. Bernal, Inorg. Chim. Acta 101 (1985) 175; I. Bernal, J. Cetrullo, J. Coord. Chem. 20 (1989) 237], we have now expanded the nature and number of cations associated with the [trans-(NH₃)₂Co(NO₂)₄] anion in order to better document when, and how, this helical propeller species crystallizes as a conglomerate.[(tren)Co(NO₂)₂][trans-(NH₃)₂Co(NO₂)₄] (I) crystallizes as a racemate in space group P2₁/n with cell constants of a = 15.8900(2), b = 19.7800(3), c = 26.6200(4) Å, β = 101.970(3)°, z = 15.[(tren)Co(ox)][trans-(NH₃)₂Co(NO₂)₄] (II) crystallizes as a racemate in space group I2/a with cell constants of a = 21.592(11), b = 7.050(4), c = 26.46(2) Å, β = 93.09(6)°, z = 8.[(en)₂Co(ox)][trans-(NH₃)₂Co(NO₂)₄] (III) crystallizes as a racemate in space group P2₁/n with cell constants of a = 6.4740(1), b = 22.8950(6), c = 13.1660(3) Å, β = 97.3310(10)°, z = 4.[trans-(pn)₂Co(NO₂)₂][trans-(NH₃)₂Co(NO₂)₄] (IV) also crystallizes as a racemate in space group P(¯1; no. 2) with cell constants of a = 6.508(2), b = 8.829(5), c = 9.851(5) Å, α = 72.84(2), β = 80.15(3), and γ = 81.45(6)°, z = 1.The most notable results are as follows: (1) all four compounds studied are racemates unlike the previously studied [cis-Co(en)₂(NO₂)₂][trans-(NH₃)₂Co(NO₂)₄] [I. Bernal, Inorg Chim Acta 101 (1985) 175] (V) and K[trans-(NH₃)₂Co(NO₂)₄] (VI) that crystallize as conglomerates. Nevertheless, they share certain crystalline features, which are readily observed in their packing diagrams.In all the four cases the new data were collected at 295 K and 120 K, using Mo Kα radiation; the former with a Nonius CAD-4 diffractometer and the latter with a Nonius CCD instrument. Of primary interest to us are the changes in packing caused by repeated changes in the charge compensating cations. Comparisons with the packing observed previously in [cis-Co(en)₂(NO₂)₂][trans-(NH₃)₂Co(NO₂)₄] (V) and K[trans-(NH₃)₂Co(NO₂)₄] (VI) are made since, at the time of publications of those early papers, no detailed study of the packing characteristics of these anions was published and the existing graphic software were primitive compared with the current packages. This oversight is remedied below.     

Ruthenium(II) and iron(II) complexes of N-pyridyl substituted imidazolin-2-ylidenes

N-mesityl-N′-pyridyl-imidazolium chloride 1a and the corresponding bromide salt 1b have been deprotonated with NaH in THF giving the free N-heterocyclic carbene N-mesityl-N′-pyridyl-imidazolin-2-ylidene 2 in 80% yield (starting from 1a). Imidazolium salt 1a reacts with RuCl₃ · xH₂O to give a racemic mixture of dinuclear di-μ-chloro bridged ruthenium complexes [(κ²-2)₂Ru(μ-Cl)₂Ru(κ²-2)₂]²⁺ [3a]²⁺. The carbene carbon atoms as well as the halides are arranged in cis-positions to each other whereas the nitrogen atoms adopt a trans-configuration. The di-μ-bromo bridged derivative [(κ²-2)₂Ru(μ-Br)₂Ru(κ²-2)₂]²⁺ [3b]²⁺ was obtained from RuCl₃ · xH₂O and 1b. The bridging halide ligands can be removed by the reaction with silver or sodium salts of bidentate Lewis acids. Complex [3a]²⁺ reacts with silver pyridylcarboxylate to give a racemic mixture of the mononuclear complex [4]⁺. Reaction of [3a]²⁺ with the sodium salt of l-proline resulted in a diastereomeric mixture of complexes [5]⁺. The free N-heterocyclic carbene 2 reacts with [FeCl₂(PPh₃)₂] to give after anion exchange with NaBPh₄ cis/cis/trans coordinated [Fe(κ²-2)₂(MeCN)₂](BPh₄)₂ [6](BPh₄)₂. The molecular structures of [3b](PF₆)₂, [4]PF₆ and [6](BPh₄)₂ · H₂O are reported.     

Reactivity of intramolecularly coordinated aluminum compounds to R3EOH (E = Sn,Si). Remarkable migration of N,C,N and O,C,O pincer ligands

The reaction of organoaluminum compounds containing O,C,O or N,C,N chelating (so called pincer) ligands [2,6-(YCH₂)₂C₆H₃]AlⁱBu₂ (Y = MeO 1, ^tBuO 2, Me₂N 3) with R₃SnOH (R = Ph or Me) gives tetraorganotin complexes [2,6-(YCH₂)₂C₆H₃]SnR₃ (Y = MeO, R = Ph 4, Y = MeO, R = Me 5; Y = ^tBuO, R = Ph 6, Y = ^tBuO, R = Me 7; Y = Me₂N, R = Ph 8, Y = Me₂N, R = Me 9) as the result of migration of O,C,O or N,C,N pincer ligands from aluminum to tin atom. Reaction of 1 and 2 with (ⁿBu₃Sn)₂O proceeded in similar fashion resulting in 10 and 11 ([2,6-(YCH₂)₂C₆H₃]SnⁿBu₃, Y = MeO 10; Y = ^tBuO 11) in mixture with ⁿBu₃SnⁱBu. The reaction 1 and 3 with 2 equiv. of Ph₃SiOH followed another reaction path and ([2,6-(YCH₂)₂C₆H₃]Al(OSiPh₃)₂, Y = MeO 12, Me₂N 13) were observed as the products of alkane elimination. The organotin derivatives 4–11 were characterized by the help of elemental analysis, ESI-MS technique, ¹H, ¹³C, ¹¹⁹Sn NMR spectroscopy and in the case 6 and 8 by single crystal X-ray diffraction (XRD). Compounds 12 and 13 were identified using elemental analysis,¹H, ¹³C, ²⁹Si NMR and IR spectroscopy.     

Diterpenoids from the aerial parts of Leonurus macranthus

One cis clerodane-type (1) and three highly oxygenated labdane-type diterpenes (2-4) were isolated from the aerial parts of Leonurus macranthus. Compound 1 represents the first example of cis clerodane-type diterpene in the plants of Leonurus genus.     

Reactions of a hydrido(hydrosilylene)tungsten complex with oxiranes

Reactivity of a hydrido(hydrosilylene)tungsten complex, Cp¹(CO)₂(H)WSi(H)[C(SiMe₃)₃] (1), toward oxiranes was investigated. Treatment of 1 with racemic mono-substituted oxiranes with a substituent R (R = Ph, vinyl, ^tBu, or ⁿBu) at room temperature produced dihydrido(vinyloxysilyl)tungsten complexes, (E)- and/or (Z)-Cp¹(CO)₂(H)₂W{Si(H)(OCHCHR)[C(SiMe₃)₃]} [(E/Z)-2: R = Ph, (E)-3: R = vinyl, (E)-4: R = ^tBu, (E/Z)-5: R = ⁿBu] in high yields via regioselective ring-opening of oxiranes. When the substituent R on oxirane was relatively large, (E)-isomers (2, 3, and 4) were obtained predominantly (87–97%), while the substituent was a relatively small ⁿBu group, an approximately 1:1 mixture of (E)- and (Z)-isomers [(E/Z)-5] was obtained. Reaction of 1 with 2,2-dimethyloxirane afforded the corresponding complex, Cp¹(CO)₂(H)₂W{Si(H)(OCHCMe₂)[C(SiMe₃)₃]} (6), quantitatively. A reaction mechanism is also discussed.     

Lipase-catalyzed kinetic and dynamic kinetic resolution of 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

A dynamic kinetic resolution method for the preparation of enantiopure 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (R)-2 was developed involving the CAL-B-catalyzed enantioselective hydrolysis of the corresponding ethyl ester (±)-1 in toluene/acetonitrile (4:1) containing 1 equiv of added water and 0.25 equiv of dipropylamine. This method allowed the preparation of (R)-2 (ee = 96%) with 80% isolated yield. The kinetic resolution of (±)-1 in diisopropyl ether at 3 °C afforded both enantiomers with ee ⩾92%.     

Heterocycles 35. CaL-B mediated synthesis of enantiomerically pure (R)- and (S)-ethyl 3-(2-arylthiazol-4-yl)-3-hydroxypropanoates

Herein we present the lipase catalyzed synthesis of four new enantiomerically pure (R)- and (S)-ethyl 3-(2-arylthiazol-4-yl)-3-hydroxypropanoates and their butanoates by enzymatic enantioselective acylation of the racemic alcohols rac-1a–d and by ethanolysis of the corresponding racemic esters rac-2a–d mediated by lipase B from Candida antarctica (CaL-B) in organic solvents. In terms of stereoselectivity and activity, both procedures, the acylation and alcoholysis, are successful (50% conversion, E ≫ 200). The absolute configuration of the resolution products was determined by a detailed ¹H NMR study of the Mosher’s derivatives of (S)-1a.