Control Of Enantioselectivity Research Articles

Zn-ProPhenol Catalyzed Enantioselective Mannich Reaction of 2H-Azirines with Alkynyl Ketones.

The enantioselective Mannich reaction of 2H-azirines with alkynyl ketones is achieved under Zn-ProPhenol catalysis, delivering various aziridines with vicinal tetrasubstituted stereocenters in high yields with excellent enantioselectivities. The bimetallic Zn-ProPhenol complexes activate both the nucleophile and the electrophile in the same chiral pocket. A unique intramolecular hydrogen bond is observed in the obtained Mannich adducts, which lowers the basicity of the product's aziridine nitrogen thus favoring enantioselective control and allowing catalyst turnover.

Enantioselective Intermolecular Radical C-H Amination.

Radical reactions hold a number of inherent advantages in organic synthesis that may potentially impact the planning and practice for construction of organic molecules. However, the control of enantioselectivity in radical processes remains one of the longstanding challenges. While significant advances have recently been achieved in intramolecular radical reactions, the governing of asymmetric induction in intermolecular radical reactions still poses challenging issues. We herein report a catalytic approach that is highly effective for controlling enantioselectivity as well as reactivity of the intermolecular radical C-H amination of carboxylic acid esters with organic azides via Co(II)-based metalloradical catalysis (MRC). The key to the success lies in the catalyst development to maximize noncovalent attractive interactions through fine-tuning of the remote substituents of the D2-symmetric chiral amidoporphyrin ligand. This noncovalent interaction strategy presents a solution that may be generally applicable in controlling reactivity and enantioselectivity in intermolecular radical reactions. The Co(II)-catalyzed intermolecular C-H amination, which operates under mild conditions with the C-H substrate as the limiting reagent, exhibits a broad substrate scope with high chemoselectivity, providing effective access to valuable chiral amino acid derivatives with high enantioselectivities. Systematic mechanistic studies shed light into the working details of the underlying stepwise radical pathway for the Co(II)-based C-H amination.

Exploiting attractive non-covalent interactions for the enantioselective catalysis of reactions involving radical intermediates

The past decade has seen unprecedented growth in the development of new chemical methods that proceed by mechanisms involving radical intermediates. This new attention has served to highlight a long-standing challenge in the field of radical chemistry - that of controlling absolute stereochemistry. This Review will examine developments using a strategy that offers enormous potential, in which attractive non-covalent interactions between a chiral catalyst and the substrate are leveraged to exert enantiocontrol. In a simplistic sense, such an approach mimics the modes of activation and control in enzyme catalysis and the realization that this can be achieved in the context of small-molecule catalysts has had sizable impact on the field of asymmetric catalysis in recent years. This strategy is now starting to quickly gather pace as a powerful approach for control of enantioselectivity in radical reactions and we hope that this focused survey of progress so far will inspire future developments in the area.

Enantioselective hydrogenation of dialkyl ketones

Chiral catalyst development is a key to asymmetric catalysis research. The enantioselectivity of a chiral catalyst relies on its ability to distinguish the prochiral centres or faces of substrates, which is difficult when the two groups attached to the centre or face are spatially and electronically similar. For example, dialkyl ketones are difficult to reduce enantioselectively. Here we report a protocol for the highly enantioselective hydrogenation of dialkyl ketones catalysed by a rationally designed chiral spiro iridium complex. The tridentate spiro structure and the bulky phosphino groups of the chiral ligand imparted a remarkable stability and enantioselectivity to the catalyst. The protocol is highly efficient for generating chiral aliphatic alcohols, and has potential for a wide application in pharmaceuticals and fine chemicals. Achieving high enantioselective control in the hydrogenation of aliphatic ketones is a long-standing challenge. Now, the design of a spiro iridium catalyst with a narrow, crowded chiral pocket allows highly enantioselective hydrogenation of these compounds.

Enantioselective Copper-Catalyzed Remote C(sp3)-H Alkynylation of Linear Primary Sulfonamides.

The highly efficient copper-catalyzed enantioselective alkynylation of the remote C(sp3)-H bond on linear primary sulfonamides is presented here using a radical relay strategy. The chiral box-copper complex, which is used to recapture the in-situ-generated alkyl radical via a 1,5-HAT strategy, is the key to success, affording the chiral alkynes after a following reductive elimination. A general substrate scope, mild conditions, and excellent regio- and enantioselective control are demonstrated in this method.

Control of enantioselectivity in the enzymatic reduction of halogenated acetophenone analogs by substituent positions and sizes

We utilized acetophenone reductase from Geotrichum candidum NBRC 4597 (GcAPRD), wild type and Trp288Ala mutant, to reduce halogenated acetophenone analogs to their corresponding (S)- and (R)-alcohols beneficial as pharmaceutical intermediates. Reduction by wild type resulted in excellent (S)-enantioselectivity for all of the substrates tested. Meanwhile, reduction by Trp288Ala resulted in high (R)-enantioselectivity for the reduction of 4′ substituted acetophenone and 2′-trifluoromethylacetophenone. In addition to that, we were able to control the enantioselectivity of Trp288Ala by the positions and sizes of the halogen substituents.

Observation of persistent orientation of chiral molecules by a laser field with twisted polarization

Molecular chirality is an omnipresent phenomenon of fundamental significance in physics, chemistry and biology. For this reason, search for novel techniques for enantioselective control, detection and separation of chiral molecules is of particular importance. It has been recently predicted that laser fields with twisted polarization may induce persistent enantioselective field-free orientation of chiral molecules. Here we report the first experimental observation of this phenomenon using propylene oxide molecules ($\mathrm{CH_{3}CHCH_{2}O}$, or PPO) spun by an optical centrifuge - a laser pulse, whose linear polarization undergoes an accelerated rotation around its propagation direction. We show that PPO molecules remain oriented on a time scale exceeding the duration of the centrifuge pulse by several orders of magnitude. The demonstrated long-time field-free enantioselective orientation opens new avenues for optical manipulation, discrimination, and, potentially, separation of molecular enantiomers.

Asymmetric hydrogenation of an α-unsaturated carboxylic acid catalyzed by intact chiral transition metal carbonyl clusters - diastereomeric control of enantioselectivity.

Twenty clusters of the general formula [(μ-H)2Ru3(μ3-S)(CO)7(μ-P-P*)] (P-P* = chiral diphosphine of the ferrocene-based Walphos or Josiphos families) have been synthesised and characterised. The clusters have been tested as catalysts for asymmetric hydrogenation of tiglic acid [trans-2-methyl-2-butenoic acid]. The observed enantioselectivities and conversion rates strongly support catalysis by intact Ru3 clusters. A catalytic mechanism involving an active Ru3 catalyst generated by CO loss from [(μ-H)2Ru3(μ3-S)(CO)7(μ-P-P*)] has been investigated by DFT calculations.

Chiral discrimination of amlodipine from pharmaceutical products using capillary electrophoresis

The present work describes the development of a capillary electrophoresis (CE) method for the chiral discrimination of amlodipine (AML) enantiomers using cyclodextrine (CD) derivatives as chiral selectors. A large number of native and derivatized, neutral and ionized CD derivatives were screened to find the optimal chiral selector; and carboximethyl-β-CD (CM-β-CD) was selected for the enantiomeric discrimination. A factorial analysis study was performed by orthogonal experimental design in which several factors were varied at the same time to optimize the separation method. The optimized method (25 mM phosphate buffer, pH = 9.0, 15 mM CM-β-CD, 15 °C, + 25 kV, 30 mbar/1 second, detection wavelength 230 nm) was successfully applied for the baseline separation of AML enantiomers within 5 minutes. Successful validation and application of the proposed CE method suggest its routine use in enantioselective control of AML in pharmaceutical preparations.

Enantioselective Palladium(II)-Catalyzed Oxidative Aminofluorination of Unactivated Alkenes with Et4 NF⋅3 HF as a Fluoride Source.

The first asymmetric PdII -catalyzed aminofluorination of unactivated alkenes using chiral quinoline-oxazolines (Quox) as ligands has been developed. This reaction provides easy access to a wide array of enantiomerically enriched β-fluoropiperidines in good yields and with excellent enantioselectivity. Notably, Et4 NF⋅3 HF as a readily accessible nucleophilic fluoride source was found to play an essential role in the enantioselective control, and CsOCF3 also acts a key additive to improve the excellent ee value of products.

Enantioselective Palladium(II)‐Catalyzed Oxidative Aminofluorination of Unactivated Alkenes with Et4NF⋅3 HF as a Fluoride Source

AbstractThe first asymmetric PdII‐catalyzed aminofluorination of unactivated alkenes using chiral quinoline‐oxazolines (Quox) as ligands has been developed. This reaction provides easy access to a wide array of enantiomerically enriched β‐fluoropiperidines in good yields and with excellent enantioselectivity. Notably, Et4NF⋅3 HF as a readily accessible nucleophilic fluoride source was found to play an essential role in the enantioselective control, and CsOCF3 also acts a key additive to improve the excellent ee value of products.

Reversible control of enantioselectivity by the length of ketone substituent in biocatalytic reduction.

Enzyme engineering has been widely employed to tailor the substrate specificity and enantioselectivity of enzymes. In this study, we mutated Trp288, an unconserved residue in the small binding pocket of an acetophenone reductase from Geotrichum candidum NBRC 4597 (GcAPRD). Trp288 mutants showed substrate specificity expansion towards bulky-bulky ketones and enantioselectivity alteration which was highly dependent on the substrate substituent length. In aliphatic ketone reduction, enantioselectivity inverted from (S) to (R) when one of the substituents to the carbonyl carbon was elongated from propyl to butyl or pentyl. The best (R)-selective mutant, Trp288Val, achieved the reduction of 3-heptanone to its corresponding (R)-alcohol with 97% ee. Our docking simulation suggested that when enantioselectivity inverted to (R), only pro-R binding poses were productive. Gly94 played an important role to stabilize the butyl or pentyl group for their productive pro-R poses. Interestingly, when the substituent was further elongated, the enantioselectivity inverted back to the (S) form.

Enantioselective Control of Both Helical and Axial Stereogenic Elements though an Organocatalytic Approach

A highly diastereo- and enantio-selective method for the asymmetric synthesis of molecules containing helicenes and stereogenic axes was developed based on organocatalysis. Various compounds bearing both helical and axial stereogenic elements were obtained in excellent enantioselectivities. The mechanism study revealed that the reaction proceeded through two stages: 1) The first cyclization produces a reaction intermediate containing a stereogenic axis. 2) The dynamic kinetic resolution of helix reaction intermediate following with cyclization generates a helix and another stereogenic axis.

Enantioselective Control of Both Helical and Axial Stereogenic Elements though an Organocatalytic Approach

AbstractA highly diastereo‐ and enantio‐selective method for the asymmetric synthesis of molecules containing helicenes and stereogenic axes was developed based on organocatalysis. Various compounds bearing both helical and axial stereogenic elements were obtained in excellent enantioselectivities. The mechanism study revealed that the reaction proceeded through two stages: 1) The first cyclization produces a reaction intermediate containing a stereogenic axis. 2) The dynamic kinetic resolution of helix reaction intermediate following with cyclization generates a helix and another stereogenic axis.

Enantioselective Copper-Catalyzed 1,5-Cyanotrifluoromethylation of Vinylcyclopropanes.

A copper-catalyzed enantioselective 1,5-cyanotrifluoromethylation of vinylcyclopropanes has been developed using a radical relay strategy. This asymmetric reaction has demonstrated high enantioselective control, broad substrate scope, and mild conditions. Initiated by the in situ generated CF3 radical from Togni's reagent, this method offers a new solution for remote enantioselective bifunctionalization of alkenes and thus provides a straightforward way for the synthesis of chiral CF3-containing internal alkenylnitriles.

Pd-Catalyzed Stereoselective 1,2-Aryboration of Alkenylarenes.

The palladium-catalyzed highly regio- and diastereoselective arylboration of alkenylarenes has been developed. This chemistry afforded the benzylic boronic esters with a broad substrate scope, which are valuable synthetic intermediates for organic synthesis. The chiral anion phase-transfer strategy was designed for this transformation to realize the regio-, diastereo-, and enantioselective control of this reaction simultaneously.

Novel β‐amino Amide Organocatalysts for the Synthesis of Pharmaceutically Relevant Oxindoles

AbstractIn this work, a series of novel organocatalysts derived from unique unnatural β‐amino acid scaffold were synthesized and further developed to enhance the desired catalytic properties. Their evaluation was carried out in the asymmetric crossed‐aldol condensation of isatin and enolizable ketone donors. Following a systematic study of the reaction parameters including variations of additive, solvent, temperature, catalyst loading and substrate scope, (1R,2R)‐2‐amino‐N‐((R)‐1‐phenylethyl)cyclohexane carboxamide 9 proved particularly successful, affording the corresponding 3‐hydroxy‐3‐alkyl‐2‐oxindole in excellent yield (>99%) and distereoselectivity (>99% dr) with good enantioselective control (up to 52% ee) in the presence of p‐nitrophenol and EtOH in <24 h. An added benefit of this catalyst was its catalytic activity and selectivity at room temperature eliminating the requirement of reduced reaction temperatures. This scaffold, comprising of β‐amino amide, has not yet been applied in organocatalysis, thus, this is the first reported in this growing area. In mechanistic studies, direct infusion ESI‐MS proved a valuable tool forproposal of the catalytic cycle, confirming the formation of 2 key reaction intermediates.

Rhodium-Catalyzed Asymmetric Allylic Dearomatization of β-Naphthols: Enantioselective Control of Prochiral Nucleophiles.

A highly enantioselective rhodium-catalyzed allylic dearomatization of β-naphthols with racemic aryl vinyl carbinol is described. In the presence of a Rh-catalyst derived from [Rh(C2H4)Cl]2 and chiral (P, olefin)-ligand with TFA as an additive, the functionalized β-naphthalenone compounds bearing an all-carbon-substituted quaternary stereogenic center were obtained in good yields with excellent enantioselectivity. In addition, this protocol features the enantioselective control of prochiral nucleophiles and provides the first illustration of Rh-catalyzed asymmetric allylic dearomatization.

Asymmetric Induction and Enantiodivergence in Catalytic Radical C–H Amination via Enantiodifferentiative H-Atom Abstraction and Stereoretentive Radical Substitution

Control of enantioselectivity remains a major challenge in radical chemistry. The emergence of metalloradical catalysis (MRC) offers a conceptually new strategy for addressing this and other outstanding issues. Through the employment of D2-symmetric chiral amidoporphyrins as the supporting ligands, Co(II)-based MRC has enabled the development of new catalytic systems for asymmetric radical transformations with a unique profile of reactivity and selectivity. With the support of new-generation HuPhyrin chiral ligands whose cavity environment can be fine-tuned, the Co-centered d-radicals enable to address challenging issues that require exquisite control of fundamental radical processes. As showcased with asymmetric 1,5-C-H amination of sulfamoyl azides, the enantiocontrol of which has proven difficult, the judicious use of HuPhyrin ligand by tuning the bridge length and other remote nonchiral elements allows for controlling both the degree and sense of asymmetric induction in a systematic manner. This effort leads to successful development of new Co(II)-based catalytic systems that are highly effective for enantiodivergent radical 1,5-C-H amination, producing both enantiomers of the strained five-membered cyclic sulfamides with excellent enantioselectivities. Detailed deuterium-labeling studies, together with DFT computation, have revealed an unprecedented mode of asymmetric induction that consists of enantiodifferentiative H-atom abstraction and stereoretentive radical substitution.

Controlled Enantioselective Orientation of Chiral Molecules with an Optical Centrifuge.

We report on the first experimental demonstration of enantioselective rotational control of chiral molecules with a laser field. In our experiments, two enantiomers of propylene oxide are brought to accelerated unidirectional rotation by means of an optical centrifuge. Using Coulomb explosion imaging, we show that the centrifuged molecules acquire preferential orientation perpendicular to the plane of rotation, and that the direction of this orientation depends on the relative handedness of the enantiomer and the rotating centrifuge field. The observed effect is in agreement with theoretical predictions and is reproduced in numerical simulations of the centrifuge excitation followed by Coulomb explosion of the centrifuged molecules. The demonstrated technique opens new avenues in optical enantioselective control of chiral molecules with a plethora of potential applications in differentiation, separation, and purification of chiral mixtures.