Enantioface Discrimination Research Articles

Chiral Macrocyclic Catalysts for the Enantioselective Addition of Lithium Acetylides to Ketones.

Alkynyl addition to carbonyl compounds is a valuable synthetic method for the preparation of versatile chiral alcohols that are widely found in pharmaceuticals and natural products. Although a variety of enantioselective variations have been reported, alkynyl addition to simple ketones remains an unmet challenge due to their low reactivity and difficult enantiofacial discrimination. Here, we report a method for the catalytic enantioselective addition of lithium acetylide to a variety of ketones using macrocyclic lithium binaphtholates as catalysts. These reactions generally suffer from facile aggregation of lithium species, which leads to less active and selective catalysts. The macrocyclic structure designed in this study prevents such aggregation, affording a monomeric and highly active catalyst that can furnish enantioenriched tertiary alcohols from a variety of ketones within 5-30 min. Moreover, the confined cavity and lipophilicity of the macrocycle confer substrate specificity on the system, demonstrating a multiselectivity similar to that of enzymatic reactions. Thus, these findings offer new insights into the rational design of small-molecule artificial enzymes that exhibit high levels of reactivity and multiselectivity.

Cross-assembly confined bifunctional catalysis via non-covalent interactions for asymmetric halogenation

•Assembling bifunctional catalysts via non-covalent interactions •Enantioselectivity is largely optimized by changing the achiral catalytic species •Asymmetric halogenation to give various valuable building blocks •Access to the advanced intermediates of drugs and natural products Bifunctional catalysis plays a key role in the synthesis of useful compounds. By offering a sterically confined environment, chiral bifunctional catalysts can achieve highly enantioselective reactions. However, introducing suitable substituents to create a confined microenvironment for asymmetric catalysis on many occasions involves tedious procedures, leading to inefficient reaction optimization. Herein, we report a proof-of-concept study on formulating confined bifunctional catalysts by linking catalytic species via non-covalent interactions (NCIs). Chiral phosphate and achiral cyclopropenium cations cross-assembled to give a confined bifunctional system for asymmetric bromo-semipinacol rearrangement. By changing the achiral catalyst to aminopyridine, the system can be applied to asymmetric bromocycloetherification. These reactions are largely optimized by simply changing the achiral catalyst. A computational study revealed that the strength of the NCI donor is crucial in creating tighter catalytic pockets to amplify the effect of enantiofacial discrimination of substrates. Bifunctional catalysis plays a key role in the synthesis of useful compounds. By offering a sterically confined environment, chiral bifunctional catalysts can achieve highly enantioselective reactions. However, introducing suitable substituents to create a confined microenvironment for asymmetric catalysis on many occasions involves tedious procedures, leading to inefficient reaction optimization. Herein, we report a proof-of-concept study on formulating confined bifunctional catalysts by linking catalytic species via non-covalent interactions (NCIs). Chiral phosphate and achiral cyclopropenium cations cross-assembled to give a confined bifunctional system for asymmetric bromo-semipinacol rearrangement. By changing the achiral catalyst to aminopyridine, the system can be applied to asymmetric bromocycloetherification. These reactions are largely optimized by simply changing the achiral catalyst. A computational study revealed that the strength of the NCI donor is crucial in creating tighter catalytic pockets to amplify the effect of enantiofacial discrimination of substrates.

Carbene-catalyzed enantioselective oxidative coupling of enals and di(hetero)arylmethanes.

Di(hetero)arylmethane is a unique structural motif for natural and synthetic functional molecules. To date, it remains challenging to functionalize the diaryl methyl sp3 carbon-hydrogen bond directly in an enantioselective manner. This is likely due to the relatively inert nature of the carbon-hydrogen bond and the difficult enantiofacial discrimination of two sterically similar aryl substituents. Here we disclose an N-heterocyclic carbene-catalyzed direct oxidative coupling of enals and di(hetero)arylmethanes. Our method allows for highly enantioselective transformation of diaryl methanes and quick access to benzimidazole fused lactams.

Diastereo- and enantioselective phase-transfer alkylation of 3-substituted oxindoles with racemic secondary alkyl halides.

A catalytic asymmetric alkylation of fully substituted enolates with racemic, non-activated secondary alkyl halides is described. The chiral 1,2,3-triazolium ion enables excellent diastereo- and enantiocontrol via enantiofacial discrimination of prochiral enolates and kinetic resolution of secondary halides.

The origin of the stereoselective alkylation of 3-substituted-2-oxopiperazines: A computational investigation

2-Oxopiperazines and their derivatives are important pharmacophores found in numerous bioactive products. The potency of these compounds depends on the nature and/or position of their substituent(s) as well as on their chirality. Hence, it is important to develop, control and optimize synthetic routes leading to enantiomerically pure substituted 2-oxopiperazines. In this work we report on the origin of this stereoselectivity, upon alkylation of 2-oxopiperazines at position C3, studied by means of quantum chemistry calculations. Indeed, this alkylation with methyl chloride is predicted to afford mainly the exo product with a 98:2 ratio. To this purpose, we model the reaction path leading to both enantiomers by scrutinizing the structures and energetics of the pre-reaction complexes, the transition states and the post-reaction complexes. The computational results are in good agreement with the experimental observations, and provide valuable insights into the origins of this specificity. From the conformational analysis of the piperazine ring and of intramolecular interaction patterns, we show that the enantiofacial discrimination is achieved by a subtle balance between sterical hindrance and control of the conformation of the piperazine ring.

Unique syndio-selectivity in CO/styrene copolymerization reaction catalyzed by palladium complexes with 2-(2′-oxazolinyl)-1,10-phenanthrolines

The reaction of the neutral Pd complex [Pd(CH(3))Cl(cod)] with the potentially terdentate 2-oxazolinyl phenanthroline ligands 1-3 affords the corresponding cationic dinuclear Pd-complexes 1a-3a, which can be isolated in the solid state in good yields. By treatment with AgPF(6) the complexes 1a-3a were converted into the corresponding hexafluorophosphate derivatives 1b-3b, where both the ligand units feature a terdentate coordination around the two Pd-centres with the phenanthroline fragment of each unit displaying a chelate coordination to one Pd-centre, while the corresponding oxazolinyl pendant acts as a bridging ligand towards the second Pd-centre. The persistence of this dimeric structure of 1b-3b in CD(2)Cl(2) solution was confirmed by (15)N-NMR experiments at natural abundance, which clearly show the binding to the metal of all of the nitrogen donors, as well as the overall C(2) symmetry of the compound. In consequence of the different strengths of the relevant ion-pair, the dimeric structure of the complex undergoes partial fragmentation in the case of the chloride derivatives 1a-3a, as evidenced from the (15)N-NMR spectra. Complexes 1b-3b are active catalysts in styrene alternate carbonylation, where, under very mild conditions (30 °C and 1 atm of CO), they provide oligomers with 3-5 repetitive units as the exclusive or prevailing product. When traces of the CO/styrene polyketones are also formed, their (13)C-NMR characterization shows that they are stereochemically homogeneous with a unique syndio-tacticity. This result implies that Pd-complexes able to induce a complete enantioface discrimination in the insertion step of the alkene during the catalytic cycle of the styrene alternate carbonylation have been produced for the first time.

Synthesis of (R)-Ofloxacin

The key step in the small-scale synthesis of (R)-ofloxacin depicted here is the first step, a chiral Brønsted acid catalyzed transfer ­hydrogenation in which the hydride source is the dihydropyridine C. These reactions give excellent enantiofacial discrimination with low catalyst loadings under mild conditions. A synthesis of the simpler fluoroquinolone antibiotic flumequine is also described.

Binding of Serotonin to the Human Serotonin Transporter. Molecular Modeling and Experimental Validation

Molecular modeling and structure-activity relationship studies were performed to propose a model for binding of the neurotransmitter serotonin (5-HT) to the human serotonin transporter (hSERT). Homology models were constructed using the crystal structure of a bacterial homologue, the leucine transporter from Aquifex aeolicus, as the template and three slightly different sequence alignments. Induced fit docking of 5-HT into hSERT homology models resulted in two different binding modes. Both show a salt bridge between Asp98 and the charged primary amine of 5-HT, and both have the 5-HT C6 position of the indole ring pointing toward Ala173. The difference between the two orientations of 5-HT is an enantiofacial discrimination of the indole ring, resulting in the 5-hydroxyl group of 5-HT being vicinal to either Ser438/Thr439 or Ala169/Ile172/Ala173. To assess the binding experimentally, binding affinities for 5-HT and 17 analogues toward wild type and 13 single point mutants of hSERT were measured using an approach termed paired mutant-ligand analogue complementation (PaMLAC). The proposed ligand-protein interaction was systematically examined by disrupting it through site-directed mutagenesis and re-establishing another interaction via a ligand analogue matching the mutated residue, thereby minimizing the risk of identifying indirect effects. The interactions between Asp98 and the primary amine of 5-HT and the interaction between the C6-position of 5-HT and hSERT position 173 was confirmed using PaMLAC. The measured binding affinities of various mutants and 5-HT analogues allowed for a distinction between the two proposed binding modes of 5-HT and biochemically support the model for 5-HT binding in hSERT where the 5-hydroxyl group is in close proximity to Thr439.

(R)‐1,1′‐Binaphthyl‐2‐bis(pentafluorophenyl)borane Lewis Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Direct Assignment of Enantiofacial Discrimination on Single Heterocyclic Substrates by Self‐induced CD

The first direct assignment of highly dynamic enantiofacial discrimination acting on a single heterocyclic substrate has been achieved by a combination of experimental and theoretical CD spectroscopy. The interaction of chirally modified hosts based on triphenylene ketals with appropriate prochiral guests can lead to the preferential formation of one diastereomeric host-guest complex. This reversible stereoselective binding transmits the chiral information from remote chiral groups in the host to the strongly absorbing triphenylene chromophore, which gives rise to self-induced CD. This effect was exploited for the determination of the enantiofacial recognition in various host-guest systems. Inversion of the steric demand either of the chiral substituents at the host or of the prochiral guest leads to almost complete inversion of the resulting CD spectra. For the assignment of the absolute stereochemistry of the complexes, a combined molecular dynamics/quantum-chemical approach was successfully employed. Despite the size and the highly dynamic character of the supramolecular systems, fundamental properties of the systems and details of the spectra were simulated accurately, providing access to fast and reliable assignment of the enantiofacial preference. The results are highly consistent with available X-ray data.

(R)-1,1′-Binaphthyl-2-bis(pentafluorophenyl)borane Lewis Acids

A practical and high yielding synthetic route was developed for the preparation of optically pure (R)-(+)-2-bis(pentafluorophenyl)boryl-, (R)-(+)-1a,b, and (R)-2-difluoroboryl-1,1′-binaphthyls, (R)-5a,b. Chiral boranes (R)-1a and (R)-5a are active catalysts for the allylstannation of aromatic aldehydes although enantioselectivities for R products were low. A structural investigation of the adduct (±)-1a·o-anisaldehyde suggested that substituents in the 2′-position of the binaphthyl backbone could increase enantiofacial discrimination. Consistent with this structural study, the 2′-Me derivative (R)-1b gave slightly higher enantioselectivities and opposite configuration S of homoallylic alcohol products.

Highly Enantioselective Reformatsky Reaction of Ketones: Chelation‐Assisted Enantioface Discrimination.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly enantioselective reformatsky reaction of ketones: chelation-assisted enantioface discrimination.

[reaction: see text] Highly enantioselective Reformatsky reaction of ketones was accomplished using cinchona alkaloids as chiral ligands. Chelation with the sp(2)-nitrogen adjacent to the reactive carbonyl center contributed the enantioface discrimination for the high enantioselectivities.

Bidentate Lewis acid catalysts in asymmetric synthesis

Abstract The chemistry of bidentate Lewis acids belongs to an unexplored field of science, and so far has been only poorly studied. This paper illustrates the design of several bidentate Al and Ti Lewis acids, and their successful application to selective organic synthesis, particularly to asymmetric synthesis. For example, a new, chiral bidentate Ti(IV) complex is successfully designed by adding commercially available Ti(OPri)4 and (S)-binaphthol sequentially to 2,2'-bis(tritylamino)-4,4'-dichlorobenzophenone in CH2Cl2, and can be utilized for simultaneous coordination to aldehyde carbonyls, thereby allowing the precise enantioface discrimination of such carbonyls for a new catalytic, practical enantioselective allylation of aldehydes with allyltributyltin. This chiral bidentate Ti(IV) catalyst exhibits uniformly high asymmetric induction as well as high chemical yields for various aldehydes. The present enantioselective allylation is highly chemoselective in the presence of other carbonyl moieties.

Practical approach for catalytic asymmetric allylation of aldehydes with a chiral bidentate titanium(IV) complex

A new, chiral bidentate Ti(IV) complex of type 1 was successfully designed and can be utilized for simultaneous coordination to aldehyde carbonyls, thereby allowing the precise enantioface discrimination of such carbonyls for a new catalytic, practical enantioselective allylation of aldehydes with allyltributyltin.

Directed Evolution of a New Catalytic Site in 2-Keto-3-Deoxy-6-Phosphogluconate Aldolase from Escherichia coli

Background: Aldolases are carbon bond-forming enzymes that have long been identified as useful tools for the organic chemist. However, their utility is limited in part by their narrow substrate utilization. Site-directed mutagenesis of various enzymes to alter their specificity has been performed for many years, typically without the desired effect. More recently directed evolution has been employed to engineer new activities onto existing scaffoldings. This approach allows random mutation of the gene and then selects for fitness to purpose those proteins with the desired activity. To date such approaches have furnished novel activities through multiple mutations of residues involved in recognition; in no instance has a key catalytic residue been altered while activity is retained. Results: We report a double mutant of E. coli 2-keto-3-deoxy-6-phosphogluconate aldolase with reduced but measurable enzyme activity and a synthetically useful substrate profile. The mutant was identified from directed-evolution experiments. Modification of substrate specificity is achieved by altering the position of the active site lysine from one β strand to a neighboring strand rather than by modification of the substrate recognition site. The new enzyme is different to all other existing aldolases with respect to the location of its active site to secondary structure. The new enzyme still displays enantiofacial discrimination during aldol addition. We have determined the crystal structure of the wild-type enzyme (by multiple wavelength methods) to 2.17 Å and the double mutant enzyme to 2.7 Å resolution. Conclusions: These results suggest that the scope of directed evolution is substantially larger than previously envisioned in that it is possible to perturb the active site residues themselves as well as surrounding loops to alter specificity. The structure of the double mutant shows how catalytic competency is maintained despite spatial reorganization of the active site with respect to substrate.

Effects of Ligands and Additive Alcohols on Enantioselection in Highly Efficient Asymmetric Borohydride Reduction of Ketones Catalyzed by Optically Active Aldiminato Cobalt(II) Complexes

Highly enantioselective reduction of ketones with sodium borohydride was achieved in the presence of a catalytic amount of optically active aldiminato cobalt(II) complexes to afford the corresponding secondary alcohols in quantitative yields with high enantiomeric excesses. The effects of ligands of the cobalt(II) complexes and of the additive alcohol pairs used for modification of the borohydride on the present reduction were described. The enantiofacial discrimination in the present asymmetric reduction was discussed based on the conformation of the cobalt complex determined by X-ray analysis.

Enantioface discriminating carbonylations of styrene with cationic palladium(II) catalyst precursors

The enantioface discriminating copolymerization of styrene with carbon monoxide using palladium complexes [(L ∧L′)Pd(S) 2](X) 2 of the C 1-symmetric ligands ( S, S)-2-[2-(diphenylphosphino)phenyl]-3-phenyl-4-methoxymethyl-4,5-dihydrooxazole or ( S, S)-2-(2-pyridyl)-3-phenyl-4-methoxymethyl-4,5-dihydrooxazole gives highly isotactic or syndiotactic poly(1-oxo-2-phenyl-1,3-propanediyl), respectively. With the former catalytic system, efficient enantioface discrimination takes place only after the first insertion step and is only slightly influenced by the growing chain, as shown by the chiroptical properties of terpolymers with ethene. Similar terpolymerization experiments with the latter catalyst precursor show that the fairly good enantioface discrimination due to the catalyst is in opposition to the influence of the chirality of the growing chain. The latter effect predominates resulting in the formation of the overwhelmingly syndiotactic copolymer.

Palladium-catalyzed asymmetric intermolecular arylation of cyclic or acyclic alkenes using phosphinite-oxazoline ligands derived from d-glucosamine

Chiral phosphinite-oxazolines, 2-alkyl- or 2-aryl-4,5-(4,6- O-benzylidene-3- O-(diphenylphosphino)-1,2-di-deoxy-α- d-glucopyranosyl)-[2,1- d]-2-oxazolines 1a– f derived from d-glucosamine hydrochloride, are revealed to work as effective P, N-bidentate ligands in the palladium-catalyzed enantioselective arylation of 2,3-dihydrofuran to give 2-aryl-2,5-dihydrofuran selectively in high yield with up to 96% ee. The first asymmetric phenylation reaction of trans- and cis-crotyl alcohols as acyclic alkenes with iodobenzene is also carried out to afford 3-phenylbutanal in moderate chemical yield with up to 17% ee. The complex [PdCl 2( 1b)] is newly prepared and its structure is characterized by X-ray crystallography. Structures of the new complex [( p-MeO 2CC 6H 4)PdI( 1a)] ( 8) and its cationic complex [( p-MeO 2CC 6H 4)Pd( 1a)] +OTf − ( 9) are also elucidated on the basis of 1H-, 13C-, and 31P-NMR spectra, p-MeO 2CC 6H 4 moiety on the palladium being located trans to the nitrogen of 1a. This configuration might be responsible for an enantiofacial discrimination of 2,3-dihydrofuran to produce ( R) isomer predominantly. The stoichiometric reaction of [PhPd( 1f)] +OTf − ( 11) with 2,3-dihydrofuran has provided the mechanistic aspect for the arylation using P, N-ligands, in which the base-promoted deprotonation at β-position leading to an alkene(2-aryl-2,5-dihydrofuran)–palladium(0) complex has been shown to be an important step for the selective formation of the product.

Stereoselective Dihapto-Binding of Prochiral Aromatic Compounds by {TpRe(CO)(PMe3)}: Synthesis, Characterization, Stability, and Enantiofacial Discrimination (Tp = Hydrido(tris)pyrazolylborate)

Synthetic access to {TpRe(CO)(PMe3)} and the ability of this fragment to bind unsaturated compounds are reported. A variety of complexes of the type TpRe(CO)(PMe3)(η2-L) (L = cyclohexene, cyclopentene, naphthalene, phenanthrene, thiophene, 2-methylthiophene, furan, or acetone) have been isolated and characterized, and stereochemical and stability issues of aromatic molecules bound to {TpRe(CO)(PMe3)} are discussed in detail. In particular, a solid-state structural study of TpRe(CO)(PMe3)(η2-cyclohexene) has provided a foundation for a discussion of the stereoelectronic features of the Re(I) fragment, and substitution reactions of an aromatic ligand by acetone provide insight into the stability of these aromatic complexes. In addition, a solid-state X-ray diffraction study of the Re(II) complex TpRe(CO)(PMe3)(OTf) (OTf = trifluoromethanesulfonate) is presented.