Enantioselective Epoxidation Reactions Research Articles

Remote Enantioselective Epoxidation Reactions Catalyzed by Chiral Iron Porphyrin Complexes with a Hydrogen-Bonding Site

AbstractIron porphyrin complexes, which were linked via a para-phenylethynyl group to a chiral scaffold with a lactam binding site, were probed as catalysts in the enantioselective epoxidation of 4-(ω-alkenyl)-quinolones. It was found that the 3-butenyl group in the substrate accounts for the highest enantioselectivity (up to 44% ee) and the absolute configuration of an oxirane product was elucidated by electron diffraction. A two-point hydrogen bond of the substrate to the catalyst is likely responsible for enantioface differentiation at a remote position. The study shows chirality transfer to be possible via four nonstereogenic carbon atoms between the binding site of the substrate and its reactive C=C double bond.

Selective Oxidations Using a Cytochrome P450 Enzyme Variant Driven with Surrogate Oxygen Donors and Light.

Cytochrome P450 monooxygenase enzymes are versatile catalysts, which have been adapted for multiple applications in chemical synthesis. Mutation of a highly conserved active site threonine to a glutamate can convert these enzymes into peroxygenases that utilise hydrogen peroxide (H2O2). Here, we use the T252E‐CYP199A4 variant to study peroxide‐driven oxidation activity by using H2O2 and urea‐hydrogen peroxide (UHP). We demonstrate that the T252E variant has a higher stability to H2O2 in the presence of substrate that can undergo carbon‐hydrogen abstraction. This peroxygenase variant could efficiently catalyse O‐demethylation and an enantioselective epoxidation reaction (94 % ee). Neither the monooxygenase nor peroxygenase pathways of the P450 demonstrated a significant kinetic isotope effect (KIE) for the oxidation of deuterated substrates. These new peroxygenase variants offer the possibility of simpler cytochrome P450 systems for selective oxidations. To demonstrate this, a light driven H2O2 generating system was used to support efficient product formation with this peroxygenase enzyme.

Bisguanidinium-Catalyzed Epoxidation of Allylic and Homoallylic Amines under Phase Transfer Conditions

A highly enantioselective epoxidation reaction of allylic and homoallylic amines has been disclosed using an ion pair catalyst, which consists of chiral cationic bisguanidinium [BG]2+ and an achiral tetraperoxyditungstate anion [W2O2(μ-O)(O2)4]2–. The terminal oxidant is a stoichiometric amount of aqueous hydrogen peroxide, an environmentally benign reagent. Up to 96% enantiomeric excess and 99% yields were achieved for 1,1′-disubstituted and 1,2-disubstituted allylic protected amines and 1,2-disubstituted homoallylic protected amines. The identity of the ion pair catalyst was uncovered using X-ray crystallography and revealed that the achiral tetraperoxyditungstate anion species [W2O2(μ-O)(O2)4]2– is nudged nicely into the central cavity of the chiral dication. The ion pair catalyst was also characterized using infrared (IR) and Raman spectroscopies. The synthesis of (−)-venlafaxine was achieved via this reported methodology to demonstrate its usefulness.

Lanthanide complexes combined with chiral salen ligands: application in the enantioselective epoxidation reaction of α,β-unsaturated ketones.

Readily available lanthanide amides Ln[N(SiMe3)2]3 (Ln = Nd (1), Sm (2), Eu (3), Yb (4), La (5)), combined with chiral salen ligands H2La ((S,S)-N,N′-di-(3,5-disubstituted-salicylidene)-1,2-cyclohexanediamine) and H2Lb ((S,S)-N,N′-di-(3,5-disubstituted-salicylidene)-1,2-diphenyl-1,2-ethanediamine) were employed in the enantioselective epoxidation of α,β-unsaturated ketones. It was found that the salen–La complex shows the highest efficiency and enantioselectivity. A relatively broad scope of α,β-unsaturated ketones was investigated, and excellent yields (up to 99%) and moderate to good enantioselectivities (37–87%) of the target molecules were achieved.

(Salen)Mn(III) Catalyzed Asymmetric Epoxidation Reactions by Hydrogen Peroxide in Water: A Green Protocol.

Enantioselective epoxidation reactions of some chosen reactive alkenes by a chiral Mn(III) salen catalyst were performed in H2O employing H2O2 as oxidant and diethyltetradecylamine N-oxide (AOE-14) as surfactant. This procedure represents an environmentally benign protocol which leads to e.e. values ranging from good to excellent (up to 95%).

Novel chiral (salen)Mn(iii) complexes containing a calix[4]arene unit in 1,3-alternate conformation as catalysts for enantioselective epoxidation reactions of (Z)-aryl alkenes

Two new chiral calix[4]arene-salen ligands 1a,b, based on calix[4]arene platforms in 1,3-alternate conformation, have been prepared by a new general synthetic pathway. Their Mn(III) complexes, 3a,b have shown fairly good efficiency in the asymmetric epoxidation of styrene and substituted styrenes, whereas excellent catalytic activity and selectivity were observed with rigid bicyclic alkenes, namely 1,2-dihydro-naphthalene and substituted 2,2'-dimethyl-chromene. The higher catalytic properties of 3a may be ascribed to the more rigid and inherently chiral structure as proved by molecular modelling, NMR spectroscopy and X-ray data of the similarly structured UO2 complexes 2a,b.

Enantio- and Regioselective Epoxidation of Olefinic Double Bonds in Quinolones, Pyridones, and Amides Catalyzed by a Ruthenium Porphyrin Catalyst with a Hydrogen Bonding Site

An array of differently substituted 3-alkenylquinolones was synthesized, and the enantio- and regioselectivity of their Ru-catalyzed epoxidation were studied. A precursor ruthenium(II) complex with a chiral tricyclic γ-lactam skeleton (octahydro-1H-4,7-methanoisoindol-1-one) was available by Sonogashira cross-coupling with a monobromo-substituted ruthenium(II) porphyrin. Enantioselective epoxidation reactions (60-83% yield, 85-98% ee) were achieved with this catalyst, and it was shown that the enantioselectivity depends critically on the presence of a two-point hydrogen bond interaction between the γ-lactam site of the catalyst and the δ-lactam (quinolone) site of the substrate. DFT calculations support the hypothesis that the reaction occurs via a hydrogen-bound transition state, in which the 3-alkenylquinolone adopts an s-trans conformation. The calculations further revealed that this transition state is preferred over a competing s-cis transition state because it exerts less strain in the rigid backbone and because the hydrogen bond interaction is more stable. The catalyst loading required for complete conversion was low (<0.2 mol %), and turnover numbers exceeding 4000 were recorded. It was shown that there is little, if any, inhibition of the catalytic process by other quinolones, which could potentially compete with the binding site. A mechanistic model for the catalytic reaction is presented. In accordance with this model 3-alkenylpyridones reacted with similar enantioselectivities as the respective quinolones. The epoxidation products were unstable, however, and the enantiomeric purity (77-87% ee) of the products could be established only after derivatization. Primary alkenoic acid amides also underwent the epoxidation but gave the respective products in lower enantioselectivities (70% and 45% ee), presumably because the enantioface differentiation is hampered by the increased flexibility of the substrates, which exhibit two or three rotatable single bonds between the binding site and the reactive olefinic double bond.

Asymmetric epoxidation of 2-arylidene-1,3-diketones: facile access to synthetically useful epoxides

In this article the first enantioselective epoxidation reaction of acyclic and cyclic 2-arylidene-1,3-diketones is reported. Easily accessible or commercially available alpha,alpha-diaryl prolinols as the organocatalysts in the presence of tert-butyl hydroperoxide (TBHP) provide the corresponding epoxides in high to excellent yield (up to 99%) and up to 85% ee (ee >90% after crystallisation). These epoxides are pharmaceutically important building blocks and intermediates for the synthesis of densely functionalised epoxide derivatives.

Aspartate-catalyzed asymmetric epoxidation reactions.

We report enantioselective epoxidation reactions that are catalyzed by aspartic acid-containing peptides. The strategy involves the transient conversion of the aspartate carboxylic acid side chain to the corresponding peracid. Reaction of olefin with the activated catalyst regenerates that catalyst, which may be subjected to multiple turnovers through a carbodiimide-mediated dehydration pathway. Enantioselectivities of up to 92% ee are observed for a class of urethane-substituted olefins.

Novel Chiral (Salen)MnIII Complexes Containing a Calix[4]arene Unit as Catalysts for Enantioselective Epoxidation Reactions of (Z)‐Aryl Alkenes

AbstractNew asymmetric (salen)MnIII and UO2 complexes containing a calix[4]arene unit in the ligand framework were synthesized. The UO2 complexes were characterized by 1H‐, 13C‐, 2D TOCSY and T‐ROESY NMR spectroscopy. Furthermore, the structure of one UO2 complex was determined by single‐crystal X‐ray analysis. The data showed that UO2 complexes, which can be considered in first approximation models of the Mn=O oxidant active species, possess a chiral pocket and adopt relevant conformations for the selectivity of the oxygen transfer process. Epoxidation data of model alkenes with the MnIII complexes showed moderate ee values and were not conclusive in indicating that the calix[4]arene unit might be able to influence the selectivity by a molecular recognition mechanism. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2005)

Enantioselective epoxidation of α,β-unsaturated ketones using polymer-supported lanthanoid–BINOL complexes

The immobilization of chiral lanthanum and/or ytterbium complexes using polymer-support is described. The heterogeneous catalysts obtained promote the enantioselective epoxidation of α,β-unsaturated ketones affording the products in good yields with high enantiomeric excess. The catalysts were easily separated from the products by washing with ether and the recovered catalysts promote the enantioselective epoxidation reaction effectively maintaining the high level of enantioselectivity obtained during the first run.

A Kinetic Epoxidation Assay for Chloroperoxidase

Chloroperoxidase exhibits a wide variety of enantioselective epoxidation reactions. Until now, the epoxidation activities have been mainly evaluated using elaborate gas chromatographic methods. This paper reports a rapid and convenient spectrophotometric assay for CPO. The disappearance of indene by catalytic epoxidation is monitored at 250 nm and this is used as an index of enzyme activity. This method will prove to be highly useful in large-scale screening of mutants.

Enantioselective epoxidation reaction of non-functionalised prochiral alkenes using optically resolved [brucine]( R)-[Ru(PDTA-H)Cl] and [brucine]( S)-[Ru(PDTA-H)Cl] complexes

The racemic metal complex K[Ru(PDTA-H)Cl] 1 PDTA=Propylene diaminetetraacetic acid. 1 has been resolved into its optical isomers using brucine as the resolving agent counter ion, [brucine]( S)-[Ru(PDTA-H)Cl] ( 1) and [brucine]( R)-[Ru(PDTA-H)Cl] ( 2) and their structures are determined by single crystal X-ray methods. Longer Ru–Cl bonds in both the complexes (2.3974(13)A in 1 and 2.415(6) in 2 along with one relatively weaker and strained chelation ring could be responsible for their catalytic activity. The CD pattern of the complex 1 shows the presence of the two isomers λ and δ with more contribution of λ form while the complex 2 acquire only λ conformation. Catalytic activity of 1 and 2 for enantioselective epoxidation of non-functionalised alkenes viz. styrene, 4-chloro-, 4-methyl-, 4-nitrostyrene, 1,2-dihydronaphthalene and indene was accomplished by using molecular oxygen and iodosyl benzene as terminal oxidant. Excellent conversions (85–89%) were obtained in case of 1,2-dihydronaphthalene with both the catalysts while catalyst 2 gave good conversion with styrene and 4-methylstyrene. The enantiomeric excess of the epoxide was determined by 1 H NMR using chiral shift reagent Eu(hfc) 3/ by chiral capillary column. The extent of enantioselectivity with respect to the substituents on substrate is shown on Hammet plot. A possible mechanism at the oxo transfer stage is also envisaged.