Product Ee Research Articles

Theoretical Prediction and Experimental Verification ofeesVersus Time in Biocatalytic Resolution and its Application in a Bioresolution-inversion Process

A systematic theoretical derivation of bioresolution-inversion process was made. An equation was derived between the maximum ee value of final product ( ee f (max) ) and enantiomeric ratio ( E ) of a reaction. The corresponding equations of conv. (max) , ee p(max), ee s(max) versus E -value were also derivative and the interrelationships among ee f (max) , conv. (max), ee p(max) and ee s(max) were deduced. Furthermore, a simple equation was de-veloped to predict the enantiomeric excess of substrate ( ee s ) at any other time of the whole reaction course based on the ee s value which was determined at a certain reaction time. This equation of ee s versus time was verified by three different experiments. Based on the equation of ee s versus time, a new equation for predicting the time ( t (max) ) needed to reach the maximum enantiomeric excess of the final product ( ee f (max) ) after the resolution-inversion was developed.

Solvent- and phase-controlled photochirogenesis. Enantiodifferentiating photoisomerization of (Z)-cyclooctene sensitized by cyclic nigerosylnigerose-based nanosponges crosslinked by pyromellitate.

Cyclic nigerosylnigerose (CNN), a saucer-shaped cyclic tetrasaccharide with a shallow concave surface, was reacted with pyromellitic dianhydride in 1:2 and 1:4 ratios to give two CNN-based polymers of different degrees of crosslinking, both of which swelled upon soaking in water, acting as a ‘nanosponge’ (NS). These NSs evolved several phases from isotropic solution to flowing and rigid gels via suspension by gradually increasing the concentration in water. The CNN-NSs thus prepared effectively mediated the enantiodifferentiating photoisomerization of (Z)-cyclooctene (1Z) to chiral (E)-isomer (1E). The enantiomeric excess (ee) of 1E obtained was a critical function of the solvent composition and the phase evolved at different CNN-NS concentrations in water. In isotropic solution, the enantioselectivity was generally low (−4% to +6% ee) but the chiral sense of 1E was inverted by increasing the methanol content. Interestingly, the product's ee was controlled more dramatically by the phase evolved, as was the case with the cyclodextrin-based nanosponge (CD-NS) reported previously. Thus, the ee of 1E was low in solution and suspension, but suddenly leaped at the phase border of flowing gel and rigid gel to give the highest ee of 22–24%, which are much higher than those obtained with CD-NSs (6–12% ee), revealing the positive roles of the chiral void space formed upon gelation of the crosslinked saccharide polymer.

Enantioselective Hydrosilylation of Ketones Catalyzed by a Readily Accessible N‐Heterocyclic Carbene–Ir Complex at Room Temperature

AbstractA series of functionalized azolium compounds were synthesized from chiral α‐amino acid derivatives such as β‐amino alcohols. Reaction of hydroxy‐amide‐functionalized azolium salts thus obtained with Ag2O afforded N‐heterocyclic carbene‐Ag (NHC–Ag) complexes. Subsequent treatment of the resulting silver compound with [IrCl(cod)]2 yielded monodentate IrCl(cod)(NHC), which was stable in air. The NHC–Ir complex facilitated efficient asymmetric hydrosilylation of ketones using (EtO)2MeSiH under ambient conditions. A chiral ligand containing an isobutyl stereodirecting group was found to be the best ligand for the functionalized NHC–Ir complexes that were examined. A linear relationship was found between the catalyst ee and the product ee. The hydroxy functional group on the NHC ligand side‐arm not only induced stereocontrol but also enhanced the reaction rate.

Enoyl acyl carrier protein reductase (FabI) catalyzed asymmetric reduction of the C=C double bond of α,β-unsaturated ketones: preparation of (R)-2-alkyl-cyclopentanones.

Enoyl-ACP reductase (FabI) was identified as a non-OYE 'ene'-reductase for asymmetric reduction of the C=C double bond of α, β-unsaturated ketones. Reduction of several 2-alkylidenecyclopentanones with A-FabI and E-FabI gave (R)-2-alkylcyclopentanones in 95-90% and 70-81% ee, respectively. The product ee was improved to 99-98% in high yield by subsequent one-pot biooxidation.

Primary Amine Attached to an N‐(Carboxyalkyl)imidazolium Cation: A Recyclable Organocatalyst for the Asymmetric Michael Reaction

AbstractA (1S,2S)‐1,2‐diphenylethane‐1,2‐diamine derivative modified with an N‐(4‐carboxybutyl)imidazolium cation and PF6– anion has been developed and applied as a recyclable organocatalyst of the asymmetric 1,4‐conjugate addition of 4‐hydroxy‐2H‐chromen‐2‐one to 1‐substituted buten‐3‐ones or cyclohexen‐3‐one to afford corresponding Michael adducts in high yields (up to 97 %) and enantioselectivities (up to 90 % ee). The most active (S) enantiomer of the clinically useful anticoagulant warfarin was prepared in this way. The catalyst exhibited better recyclability than its known analog, which does not contain a carboxy group: it could be recycled 5 times in the reaction without a significant decrease in product yield or ee values. Gradual deactivation of the catalyst was caused by leaching during workup rather than by off‐cycle reactions between the catalyst and reagents.

Using Ionic Liquid in a Biphasic System to Improve Asymmetric Hydrolysis of Styrene Oxide Catalyzed by Cross-Linked Enzyme Aggregates (CLEAs) of Mung Bean Epoxide Hydrolases

The asymmetric hydrolysis of racemic styrene oxide (SO) to (R)-1-phenyl-1,2-ethanediol using cross-linked enzyme aggregates (CLEAs) of epoxide hydrolases (EHs) from mung bean (mbEHs) was successfully conducted using ionic liquids (ILs) as cosolvents in biphasic systems. Of all the tested ILs, the best results were observed in the biphasic system containing [C4MIM][PF6] with better biocompatibility to the CLEAs of mbEHs. In the [C4MIM][PF6]/buffer biphasic system, it was found that the optimal volume ratio of IL to buffer, reaction temperature, buffer pH, and substrate concentration were 1:5, 40 °C, 7.5, and 120 mM, respectively. Under the optimized reaction conditions, the initial reaction rate, yield, product ee, and E value reached 3.35 mmol/min, 49%, 95.8%, and 151, respectively, which were much higher than the corresponding values reported previously. Furthermore, the CLEAs exhibited markedly enhanced operational stability in a [C4MIM][PF6]-based biphasic system as compared with an n-hexane-based biph...

Deracemization by simultaneous bio-oxidative kinetic resolution and stereoinversion.

Deracemization, that is, the transformation of a racemate into a single product enantiomer with theoretically 100 % conversion and 100 % ee, is an appealing but also challenging option for asymmetric synthesis. Herein a novel chemo-enzymatic deracemization concept by a cascade is described: the pathway involves two enantioselective oxidation steps and one non-stereoselective reduction step, enabling stereoinversion and a simultaneous kinetic resolution. The concept was exemplified for the transformation of rac-benzylisoquinolines to optically pure (S)-berbines. The racemic substrates were transformed to optically pure products (ee>97 %) with up to 98 % conversion and up to 88 % yield of isolated product.

Tertiary amine-promoted enone aziridination: investigations into factors influencing enantioselective induction

trans-N-Unsubstituted aziridines were synthesised (up to 77% ee) via a chiral tertiary amine-promoted nucleophilic aziridination of α,β-unsaturated ketones utilising in situ generated N–N ylides (aminimines). A wide range of chiral tertiary amines were synthesised and evaluated, allowing structure–activity relationships to be drawn. The most efficient promoter for asymmetric aziridination, quinine, was assessed with several enones to ascertain the effect of substrate structure on product ee, while the intermediate hydrazinium salt was characterised by X-ray crystallography.

Efficient Synthesis of Imino-methano Tröger Bases by Nitrene Insertions into C–N Bonds

A direct nitrene insertion into C-N bonds is observed upon treatment of methano-Tröger bases with arylsulfonyl iminophenyliodinanes under copper and dirhodium catalysis. Novel cyclic imino-methano Tröger bases are obtained (55-88%). Enantiopure products (ee ≥ 99%) can be obtained with tailored substrates.

Enzymatic production of Cilastatin intermediate via highly enantioselective hydrolysis of methyl (±)-2,2-dimethylcyclopropane carboxylate using newly isolated Rhodococcus sp. ECU1013

(S)-(+)-2,2-Dimethylcyclopropane carboxylic acid [(S)-(+)-DMCPA] is a key chiral intermediate for production of Cilastatin, an excellent renal dehydropeptidase-I inhibitor. In this study, a new method for preparation of (S)-(+)-DMCPA with microbial esterases was investigated. A microbial screening program obtained six esterase-producing isolates that could display relatively high activities and enantioselectivities using racemic ethyl 2,2-dimethylcyclopropane carboxylate (DMCPE) as screening substrate, aiming at forming optically pure (S)-(+)-DMCPA. Further selection was carried out with substrates having different alcohol moieties, including methyl, ethyl, and 2-chloroethyl esters. Finally, one of these strains, numbered ECU1013, with high enantioselectivity toward the hydrolytic resolution of methyl 2,2-dimethylcyclopropane carboxylate (DMCPM), afforded the (S)-product in 92% ee, and was later identified as Rhodococcus sp. According to our research, there were several active esterases to DMCPM in cells of Rhodococcus sp. ECU1013; however, (S)-preferential esterase was selectively enriched based on the time-dependent profile of esterases biosynthesis, thereby the enantiomeric excess of biotransformation product (ee p) was constantly increased, finally maintained at 95% (S). To improve the yield, various organic solvents were employed for better dispersion of the hydrophobic substrate. As a result, (±)-DMCPM of up to 400mM in the organic phase of isooctane was enantioselectively hydrolyzed into (S)-(+)-DMCPA, with an isolation yield of 38% and a further increase of ee p to 99%.

Methylene‐Bridged Bis(imidazoline)‐Derived 2‐Oxopyrimidinium Salts as Catalysts for Asymmetric Michael Reactions

Methylene‐Bridged Bis(imidazoline)‐Derived 2‐Oxopyrimidinium Salts as Catalysts for Asymmetric Michael Reactions

Metal–Ligand Binding Affinity vs Reactivity: Qualitative Studies in Rh(I)-Catalyzed Asymmetric Ring-Opening Reactions

Rh(I)-catalyzed asymmetric ring opening (ARO) of oxabenzonorbornadiene is used as a model system to qualitatively study reactions involving multiple metal-ligand interactions. The key feature of this approach is the use of product ee as an indicator to quickly gain important information such as the relative ligand binding affinity and relative reactivity of catalysts.

Cross- versus Homo-Photocyclodimerization of Anthracene and 2-Anthracenecarboxylic Acid Mediated by a Chiral Hydrogen-Bonding Template. Factors Controlling the Cross-/Homo-Selectivity and Enantioselectivity

Competitive cross-/homo-photocyclodimerization of anthracene (AN) and 2-anthracenecarboxylic acid (AC) mediated by a chiral hydrogen-bonding template (TKS) was investigated under various conditions. The cross-photocyclodimerization was favored by a factor of 4-5 at all temperatures and wavelengths examined to afford the AC-AN cross-dimer in 80-84% yield even at AN/AC = 1 and in 98% yield at AN/AC = 10. The enantiomeric excesses (ee's) obtained were 27-47% for the homo-dimers and 21-24% for the cross-dimer. The absolute configuration of the cross-dimer was determined by comparing the experimental and theoretical circular dichroism spectra and further correlated with the re/si enantiotopic-face selectivity upon AC-TKS complexation in the ground state. Detailed analyses of the complexation behavior and the fluorescence lifetime and cyclodimerization rate of excited re/si complexes revealed that the product's ee is critically controlled not only by the relative abundance of the re/si complexes in the ground and excited states but also by their relative photocyclodimerization rate. Crucially, the ground-state thermodynamics and the excited-state kinetics are not synergistic but offsetting in enantiotopic-face selectivity, and the latter overwhelms the former to give the homo- and cross-dimers in modest ee's. Finally, some practical strategies for enhancing the enantioselectivity in chiral template-mediated photochirogenesis have been proposed.

Epoxidation of linear, branched and cyclic alkenes catalyzed by unspecific peroxygenase

Unspecific peroxygenases (EC 1.11.2.1) represent a group of secreted heme-thiolate proteins that are capable of catalyzing the mono-oxygenation of diverse organic compounds, using only H2O2 as a co-substrate. Here we show that the peroxygenase secreted by the fungus Agrocybe aegerita catalyzed the oxidation of 20 different alkenes. Five branched alkenes, among them 2,3-dimethyl-2-butene and cis-2-butene, as well as propene and butadiene were epoxidized with complete regioselectivity. Longer linear alkenes with a terminal double bond (e.g. 1-octene) and cyclic alkenes (e.g. cyclohexene) were converted into the corresponding epoxides and allylic hydroxylation products; oxidation of the cyclic monoterpene limonene yielded three oxygenation products (two epoxides and an alcohol). In the case of 1-alkenes, the conversion occurred with moderate stereoselectivity, in which the preponderance for the (S)-enantiomer reached up to 72% ee for the epoxide product. The apparent Michaelis–Menten constant (Km) for the epoxidation of the model substrate 2-methyl-2-butene was 5mM, the turnover number (kcat) 1.3×103s−1 and the calculated catalytic efficiency, kcat/Km, was 2.5×105M−1s−1. As epoxides represent chemical building blocks of high relevance, new enzymatic epoxidation pathways are of interest to complement existing chemical and biotechnological approaches. Stable and versatile peroxygenases as that of A. aegerita may form a promising biocatalytic platform for the development of such enzyme-based syntheses.

ChemInform Abstract: Chiral 1,3,2‐Dioxaphospholane Amidophosphite in the Palladium‐Catalyzed Enantioselective Allylation.

Phosphorylation of (S)-1,1,2-triphenylethane-1,2-diol furnishes cyclic P*-chiral amidophosphite, whose application as a ligand in the Pd-catalyzed allyl substitution in 1,3-diphenylallyl acetate provides the products ee up to 70%.

ChemInform Abstract: Highly Enantioselective Synthesis of 3‐Substituted Furanones by Palladium‐Catalyzed Kinetic Resolution of Unsymmetrical Allyl Acetates.

The Pd-catalyzed asymmetric allylic alkylation (AAA) holds a prominent position among the most versatile methods for C C bond formation that are widely applied in natural product synthesis. This transformation typically features broad functional group tolerance and excellent regioand enantioselectivity. In particular, Pd-catalyzed kinetic resolutions of symmetrical allylic substrates and dynamic kinetic transformations have been developed recently, which extends their potential in synthetic chemistry. However, Pd-catalyzed kinetic resolutions of unsymmetrical acyclic allylic substrates with high yield and enantioselectivity are rare. Furthermore, the enantioselective allylic alkylation of silyl enol ethers is still a challenging reaction. Graening and Hartwig reported a highly enantioselective alkylation of monosubstituted allylic substrates with silyl enol ethers catalyzed by an Ir complex. Although excellent results of allylic alkylations have been reported with enolates that are preformed or generated in situ, to the best of our knowledge, Pd-catalyzed AAAwith a nonstabilized silyl enol ether as nucleophile remains an elusive goal (Scheme 1). Herein, we present the Pd-catalyzed kinetic resolution of 1,3-disubstituted unsymmetrical allylic substrates with nonstabilized silyl enol ethers as nucleophiles, which provides a highly regioand enantioselective synthesis of 3-substituted g-butenolides. The g-butyrolactone skeleton is present in more than 13000 natural products, which have attracted considerable attention because of the range of important biological activities associated with this class of compounds. As part of our program to develop catalytic enantioselective methods to access optically active g-butenolides and lactones, we envisioned the possibility of using 2-trimethylsilyloxyfuran (TMSOF) as nucleophile in a Pd-catalyzed AAA reaction. Initially, we examined the allylic substitution of carbonate 1a by utilizing TMSOFas nucleophile and a chiral Pd catalyst based on Trost Ligand L1 (Table 1, entry 1). The 3-substituted product 3 and 5-substituted product 4 were obtained in a 2:1 ratio and in 36% ee for product 3 (Table 1, entry 1). Using a lower temperature (0 8C), the ee value only slightly increased (49% ee, Table 1, entry 2). With tert-butyl carbonate as the leaving group, the regioselectivity shifted in favor of the formation of the 5-substituted product (3/4= 1:2, Table 1,

ChemInform Abstract: A Catalytic Asymmetric Approach to C1‐Chiral 3‐Methylene‐indan‐1‐ols.

Abstract A sequential (R)-BINAP·AgIF (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (6–10 mol %), and (Ph3P)2PdIICl2 (bis(triphenylphosphine)palladium(II) dichloride) (2 mol %) catalyzed asymmetric Sakurai–Hosomi–Yamamoto allylation/Mizoroki–Heck reaction that affords C1-chiral 3-methylene-indan-1-ols with enantiomeric excess (ee) up to 80% is reported. Notably, this protocol allows for the use of various o-substituted benzaldehydes and allyltrimethoxysilane. It was also discovered that the presence of electron-rich groups had no effect on the enantioselectivity of the reaction, whereas electron-withdrawing groups lead to erosion in product ee.

Microenvironmental control of enantiodifferentiating photocyclization of 5‐hydroxy‐1,1‐diphenylpentene through selective solvation

For mechanistic elucidation of the photosensitized cyclization of 5-hydroxy-1,1-diphenylpentene (1), its methyl ether (4) was synthesized as an unreactive "dummy" substrate and used as a quencher of the sensitizer fluorescence to reveal the intervention of an exciplex intermediate that was unable to detect when reactive substrate 1 was used as a quencher/reactant In the enantiodifferentiating photocyclization of 1 to 2-(diphenylmethyl)tetrahydrofuran (2) sensitized by a chiral saccharide ester of 1,4-naphthalenedicarboxylate (3), the enantiomeric excess (ee) of chiral product 2 obtained in methylcyclohexane (MCH) at 25 °C was significantly enhanced from 20% to 35% upon 10-fold dilution of the sample solution by MCH, for which the reduced solvent polarity, discouraging dissociation of the intervening radical ionic exciplex, is likely to be responsible. Further attempts to microenvironmentally control the photochirogenic reaction and enhance the product's ee through selective solvation of polar cosolvent to the diastereomeric exciplex pair in nonpolar solvent were not successful probably due to the inherently high local polarity around the exciplex of saccharide-appended 3 with alcoholic substrate 1.

ChemInform Abstract: Malonate‐Type Bis(oxazoline) Ligands with sp2 Hybridized Bridge Carbon: Synthesis and Application in Friedel—Crafts Alkylation and Allylic Alkylation.

Abstract A series of simple and new C2-symmetric diphenylmethylidene malonate-type bis(oxazoline) ligands were synthesized and applied to the Friedel–Crafts reaction and allylic alkylation. The Cu(II) complex of ligand 4b bearing the benzyl group afforded good to excellent enantioselectivity for the F–C adducts (up to >99% ee) between indole and alkylidene malonate, and the palladium complex of ligand 4c bearing the phenyl group afforded excellent enantioselectivity (up to 94% ee) for the allylic alkylation product.

Optimization Studies on the Hydro-acylation of 1-Alkenes to α-Methylketones using a Homogeneous Palladium/Josiphos Catalyst

The effect of process conditions (temperature, partial pressures of CO and H2) on the product selectivity and ee of the palladium-catalysed asymmetric hydro-acylation of 1-pentene in dichloromethane with the chiral Josiphos ligand (SL-J008-1, L1) was investigated. The highest ee value (73%) for the desired product 4-methyl-5-decanone (1) was obtained at the lowest temperature in the range (30 °C). The selectivity for 1 was between 12 and 20 mol % at 30 °C, though considerably higher at 90 °C (59 mol %). Statistical modeling was applied to quantify the influence of the process conditions on the product selectivity and ee.