Cytochrome P450 Catalyzed Oxidative Hydroxylation of Achiral Organic Compounds with Simultaneous Creation of Two Chirality Centers in a Single C?H Activation Step

Regio‐ and stereoselective oxidative hydroxylation of achiral or chiral organic compounds mediated by synthetic reagents, catalysts, or enzymes generally leads to the formation of one new chiral center that appears in the respective enantiomeric or diastereomeric alcohols. By contrast, when subjecting appropriate achiral compounds to this type of C H activation, the simultaneous creation of two chiral centers with a defined relative and absolute configuration may result, provided that control of the regio‐, diastereo‐, and enantioselectivity is ensured. The present study demonstrates that such control is possible by using wild type or mutant forms of the monooxygenase cytochrome P450 BM3 as catalysts in the oxidative hydroxylation of methylcyclohexane and seven other monosubstituted cyclohexane derivatives.     

Catalytic Enantioselective Olefin Metathesis in Natural Product Synthesis. Chiral Metal‐Based Complexes that Deliver High Enantioselectivity and More

Chiral olefin metathesis catalysts enable chemists to access enantiomerically enriched small molecules with high efficiency; synthesis schemes involving such complexes can be substantially more concise than those that would involve enantiomerically pure substrates and achiral Mo alkylidenes or Ru‐based carbenes. The scope of research towards design and development of chiral catalysts is not limited to discovery of complexes that are merely the chiral versions of the related achiral variants. A chiral olefin metathesis catalyst, in addition to furnishing products of high enantiomeric purity, can offer levels of efficiency, product selectivity and/or olefin stereoselectivity that are unavailable through the achiral variants. Such positive attributes of chiral catalysts (whether utilized in racemic or enantiomerically enriched form) should be considered as general, applicable to other classes of transformations.     

Enantioselective Sequential‐Flow Synthesis of Baclofen Precursor via Asymmetric 1,4‐Addition and Chemoselective Hydrogenation on Platinum/Carbon/Calcium Phosphate Composites

Continuous‐flow synthesis of baclofen precursor ( 2 ) was achieved using achiral and chiral heterogeneous catalysts in high yield with high enantioselectivity. The key steps are chiral calcium‐catalyzed asymmetric 1,4‐addition of a malonate to a nitroalkene and chemoselective reduction of a nitro compound to the corresponding amino compound by using molecular hydrogen. A dimethylpolysilane (DMPS)‐modified platinum catalyst supported on activated carbon (AC) and calcium phosphate (CP) has been developed that has remarkable activity for the selective hydrogenation of nitro compounds.     

Oxygenase‐Catalyzed Desymmetrization of N,N‐Dialkyl‐piperidine‐4‐carboxylic Acids

γ‐Butyrobetaine hydroxylase (BBOX) is a 2‐oxoglutarate dependent oxygenase that catalyzes the final hydroxylation step in the biosynthesis of carnitine. BBOX was shown to catalyze the oxidative desymmetrization of achiral N,N‐dialkyl piperidine‐4‐carboxylates to give products with two or three stereogenic centers.     

Enantioselective Direct Mannich‐Type Reactions Catalyzed by Frustrated Lewis Acid/Brønsted Base Complexes

An enantioselective direct Mannich‐type reaction catalyzed by a sterically frustrated Lewis acid/Brønsted base complex is disclosed. Cooperative functioning of the chiral Lewis acid and achiral Brønsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen‐bond‐activated aldimines delivers β‐aminocarbonyl compounds with high enantiomeric purity.     

Palladium(II)/Brønsted Acid‐Catalyzed Enantioselective Oxidative Carbocyclization–Borylation of Enallenes

An enantioselective oxidative carbocyclization–borylation of enallenes that is catalyzed by palladium(II) and a Brønsted acid was developed. Biphenol‐type chiral phosphoric acids were superior co‐catalysts for inducing the enantioselective cyclization. A number of chiral borylated carbocycles were synthesized in high enantiomeric excess.     

Stereogenic‐Only‐at‐Metal Asymmetric Catalysts

Chirality is an essential feature of asymmetric catalysts. This review summarizes asymmetric catalysts that derive their chirality exclusively from stereogenic metal centers. Reported chiral‐at‐metal catalysts can be divided into two classes, namely, inert metal complexes, in which the metal fulfills a purely structural role, so catalysis is mediated entirely through the ligand sphere, and reactive metal complexes. The latter are particularly appealing because structural simplicity (only achiral ligands) is combined with the prospect of particularly effective asymmetric induction (direct contact of the substrate with the chiral metal center). Challenges and solutions for the design of such reactive stereogenic‐only‐at‐metal asymmetric catalysts are discussed.     

Enantioselective Synthesis of a Chiral Coordination Polymer with Circularly Polarized Visible Laser

Circular dichroism is known to be the feature of a chiral agent which has inspired scientist to study the interesting phenomena of circularly polarized light (CPL) modulated molecular chirality. Although several organic molecules or assemblies have been found to be CPL‐responsive, the influence of CPL on the assembly of chiral coordination compounds remains unknown. Herein, a chiral coordination polymer, which is constructed from achiral agents, was used to study the CPL‐induced enantioselective synthesis. By irradiation with either left‐handed or right‐handed CPL during the reaction and crystallization, enantiomeric excesses of the crystalline product were obtained. Left‐handed CPL resulted in crystals with a left‐handed helical structure, and right‐handed CPL led to crystals with a right‐handed helical structure. It is exciting that the absolute asymmetric synthesis of a chiral coordination polymer could be enantioselective when using CPL, and provides a strategy for the control of the chirality of chiral coordination polymers.     

Chiral Amplification in Nature: Studying Cell‐Extracted Chiral Carotenoid Microcrystals via the Resonance Raman Optical Activity of Model Systems

Carotenoid microcrystals, extracted from cells of carrot roots and consisting of 95 % of achiral β‐carotene, exhibit a very intense chiroptical (ECD and ROA) signal. The preferential chirality of crystalline aggregates that consist mostly of achiral building blocks is a newly observed phenomenon in nature, and may be related to asymmetric information transfer from the chiral seeds (small amount of α‐carotene or lutein) present in carrot cells. To confirm this hypothesis, we synthesized several model aggregates from various achiral and chiral carotenoids. Because of the sergeant‐and‐soldier behavior, a small number of chiral sergeants (α‐carotene or astaxanthin) force the achiral soldier molecules (β‐ or 11,11′‐[D₂]‐β‐carotene) to jointly form supramolecular assemblies of induced chirality. The chiral amplification observed in these model systems confirmed that chiral microcrystals appearing in nature might consist predominantly of achiral building blocks and their supramolecular chirality might result from the co‐crystallization of chiral and achiral analogues.     

Enantioselective supramolecular catalysis induced by remote chiral diols

A new method of creating libraries of chiral diphosphines is presented. Supramolecular coordination compounds based on Ti, Rh, achiral ditopic ligands, and chiral diols were synthesized by in situ mixing and used as catalysts in the asymmetric hydrogenation of (Z)-methyl 2-acetamido-3-phenylacrylate, giving ee's of up to 92%. The ditopic ligands contain a Schiff base that coordinates to the assembly metal Ti and a phosphine as a ligand for Rh. Chirality is introduced by coordination of the chiral diols to Ti. The controlling chiral center and the substrate are separated by as much as 13 ?.     

Asymmetric Transformation Driven by Confinement and Self-Release in Single-Layered Porous Nanosheets

Reported here is the use of single-layered, chiral porous sheets with induced pore chirality for repeatable asymmetric transformations and self-separation without the need for chiral catalysts or chiral auxiliaries. The asymmetric induction is driven by chiral fixation of absorbed achiral substrates inside the chiral pores for transformation into enantiopure products with enantioselectivities of greater than 99 % ee. When the conversion is completed, the products are spontaneously separated out of the pores, enabling the porous sheets to perform repeated cycles of converting achiral substrates into chiral products for release without compromising pore performance. Confinement of achiral substrates into two-dimensional chiral porous materials provides access to a highly efficient alternative to current asymmetric synthesis methodologies.     

Synthesis of chiral iridium complexes immobilized on amphiphilic polymers and their application to asymmetric catalysis

This article details the enantioselective catalytic performance of crosslinked, polymer immobilized, Ir‐based, chiral complexes for transfer hydrogenation of cyclic imines to chiral amines. Polymerization of the achiral vinyl monomer, divinylbenzene, and a polymerizable chiral 1,2‐diamine monosulfonamide ligand followed by complexation with [IrCl₂Cp*]₂ affords the crosslinked polymeric chiral complex, which can be successfully applied to asymmetric transfer hydrogenation of cyclic imines. Polymeric catalysts prepared from amphiphilic achiral monomers have high catalytic activity in the reaction and can be used both in organic solvents and water to give chiral cyclic amines with a high level of enantioselectivity (up to 98% ee). The asymmetric reaction allows for reuse of the heterogeneous catalyst without any loss in activity or enantioselectivity over several runs. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3037–3044     

Determination of the in vitro metabolism of (+)- and (-)-epibatidine

The oxidative in vitro metabolism of epibatidine was investigated using liver microsomes from rat, dog, rhesus monkey and human. Analysis was performed using liquid chromatography-mass spectrometry (LC-MS) using both achiral and chiral stationary phases. Comparison of the metabolism of the (+)- and (-)-enantiomers revealed species differences in the extent of metabolism, with rhesus monkey>dog>rat=human. Furthermore, differences in the routes of metabolism for epibatidine enantiomers were also observed, with mass spectra consistent with hydroxylation of the azabicycle for (-)-epibatidine and with the formation of diastereomeric N-oxides for (+)-epibatidine being obtained. For chiral LC-MS, a volatile ion-pair reagent of heptafluorobutyric acid was used in place of pentanesulphonic acid with no deterioration in chiral selectivity. Analysis of the same samples by chiral LC-MS revealed no evidence for metabolic chiral interconversion and chiral analysis from a metabolic time course of racemic material revealed enantiomers to be metabolised to approximately the same extent. Such findings may be important particularly should epibatidine be investigated in non-rodent species.     

Small amounts of achiral beta-amino alcohols reverse the enantioselectivity of chiral catalysts in cooperative asymmetric autocatalysis

An asymmetric autocatalytic reaction has been catalyzed by a mixture of chiral and achiral beta-amino alcohols. The absolute configuration of the highly enantioenriched obtained product (>98% ee) was shown to depend not only on the absolute configuration of the chiral catalyst but also on the structure and the amount of achiral catalyst. Even in default versus the chiral catalyst, achiral catalysts were shown to be able to reverse the enantioselectivity of the reaction.     

Reactions of alicyclic epoxy compounds with oxygen-centered nucleophiles

The review analyzes the reactions of alicyclic epoxy compounds with oxygen-containing nucleophiles (alcohols, water, and organic acids), describes biologically active products of these reactions, and discusses their mechanisms and results of their simulation by quantum-chemical methods. The regio-and stereoselectivity of nucleophilic reactions of epoxy compounds and the activation of epoxy ring by achiral and chiral catalysts are also considered.     

Chiral monomeric organorhenium(VII) and organomolybdenum(VI) compounds as catalysts for chiral olefin epoxidation reactions

Several attempts have been made to transform the organometallic Re(VII) compound MTO and the (MoO₂)²⁺ moiety to chiral epoxidation catalysts by addition of chiral organic ligands. Being very efficient epoxidation catalysts in achiral reactions, it was hoped that these compounds could be transformed into chiral epoxidation catalysts by adding chiral Lewis base ligands. The major flaw of most of these attempts, however, was the weak coordination of the chiral Lewis base ligands to the metal center, which led either to high ees only at the very beginning of the catalytic reaction (low conversion) or to generally low enantiomeric excesses. The heterogenisation of the Mo(VI) complexes was, at least in some cases, successfully achieved but with the same drawbacks with respect to the ees as in the homogeneous phase. Currently, attempts are being made to synthesize organometallic Re(VII) and Mo(VI) complexes with stronger interactions between the metal containing moiety and the chiral ligand(s).     

Pd‐Catalyzed Allylic Substitution with Enantiomerically Pure Catalysts and Chiral Non‐Racemic Substrates: A New Approach to Catalyst‐Based Regiocontrol,Preliminary Communication

Chiral, enantiomerically pure Pd‐catalysts were used to control the regioselectivity of nucleophilic attack in allylic substitutions with optically active 1,3‐disubstituted allyl acetates (Schemes 4 – 6). In contrast to reactions with achiral catalysts, where the regioselectivity is determined by the steric and electronic effects of the allylic substituents, chiral catalysts allow selective preparation of either one of the two regioisomeric products, depending on which enantiomer of the catalyst is employed. It is not necessary to start from an enantiomerically pure substrate, because the major and minor enantiomers are converted to different regioisomers (not to enantiomeric products; see Scheme 3), resulting in products of very high ee, even when the starting material is only of moderate enantiomer purity.     

The use of mixtures of ligands in the Ir-catalyzed asymmetric reductive amination of 6-methyl-2,3,4,9-tetrahydro-1<Emphasis Type="Italic">H</Emphasis>-carbazol-1-one

A comparative testing of complex catalysts with homo and hetero combinations of chiral and achiral monodentate phosphite- and phosphine-type ligands in the Ir-catalyzed asymmetric direct reductive amination of 2,3,4,9-tetrahydro-1H-сarbozol-1-ones was carried out. A positive effect of the use in the reaction of a mixture of chiral and achiral ligands was demonstrated. This approach makes feasible a one-pot synthesis of valuable biologically active compounds of (tetrahydro-1H-carbazol-1-yl)amine series.     

Atropoenantioselective Redox‐Neutral Amination of Biaryl Compounds through Borrowing Hydrogen and Dynamic Kinetic Resolution

We report herein a novel atropoenantioselective redox‐neutral amination of biaryl compounds triggered by a cascade of borrowing hydrogen and dynamic kinetic resolution under the cooperative catalysis of a chiral iridium complex and an achiral Brønsted acid. This protocol features broad substrate scope and good functional‐group tolerance, and allows the rapid assembly of axially chiral biaryl compounds in good to high yields and with high to excellent enantioselectivity.     

Recent developments in asymmetric catalysis using synthetic polymers with main chain chirality

Some recent developments in the use of main chain chiral polymer catalysts are summarized. These polymers are different from the traditional polymer catalysts that are prepared by anchoring monomeric chiral catalysts to an achiral polymer backbone. Three classes of synthetic main chain chiral polymers are discussed including: (1) helical polymers represented by polypeptides; (2) polymers with flexible chiral chains such as polyesters and polyamides; and (3) polymers of rigid and sterically regular chiral chains represented by chiral conjugated polybinaphthyls. Some of these polymer catalysts have shown high enantioselectivity in asymmetric organic transformations.