Asymmetric Alkylation Research Articles

Asymmetric Alkylation of Ketones Catalyzed by Engineered TrpB.

The β-subunit of tryptophan synthase (TrpB) catalyzes a PLP-mediated β-substitution reaction between indole and serine to form L-Trp. A succession of TrpB protein engineering campaigns to expand the enzyme's nucleophile substrate range has enabled the biocatalytic production of diverse non-canonical amino acids (ncAAs). Here, we show that ketone-derived enolates can serve as nucleophiles in the TrpB reaction to achieve the asymmetric alkylation of ketones, an outstanding challenge in synthetic chemistry. We engineered TrpB by directed evolution to catalyze the asymmetric alkylation of propiophenone and 2-fluoroacetophenone with a high degree of selectivity. In reactions with propiophenone, preference for the opposite product diastereomer emerges over the course of evolution, demonstrating that full control over the stereochemistry at the new chiral center can be achieved. The addition of this new reaction to the TrpB platform is a crucial first step toward the development of efficient methods to synthesize non-canonical prolines and other chirally dense nitrogen heterocycles.

Catalytic Enantioselective Alkylation of Prochiral Enolates.

The asymmetric alkylation of enolates is a particularly versatile method for the construction of α-stereogenic carbonyl motifs, which are ubiquitous in synthetic chemistry. Over the past several decades, the focus has shifted to the development of new catalytic methods that depart from classical stoichiometric stereoinduction strategies (e.g., chiral auxiliaries, chiral alkali metal amide bases, chiral electrophiles, etc.). In this way, the enantioselective alkylation of prochiral enolates greatly improves the step- and redox-economy of this process, in addition to enhancing the scope and selectivity of these reactions. In this review, we summarize the origin and advancement of catalytic enantioselective enolate alkylation methods, with a directed emphasis on the union of prochiral nucleophiles with carbon-centered electrophiles for the construction of α-stereogenic carbonyl derivatives. Hence, the transformative developments for each distinct class of nucleophile (e.g., ketone enolates, ester enolates, amide enolates, etc.) are presented in a modular format to highlight the state-of-the-art methods and current limitations in each area.

Design and synthesis of HFCA‐based plasticizers with asymmetrical alkyl chains for poly(vinyl chloride)

AbstractA series of bio‐based diester plasticizers with various alkyl chain asymmetry and the same molecular weight were designed and synthesized, using renewable 5‐hydroxymethyl‐2‐furancarboxylic acid (HFCA) as the raw material. The chemical structures of the HFCA‐based plasticizers were characterized by Fourier transform infrared and nuclear magnetic resonance (1H NMR and 13C NMR). Besides, the influence of alkyl chain asymmetry on plasticization properties of the HFCA‐based plasticizers in poly(vinyl chloride) (PVC) blends was also investigated. It was found that increasing the alkyl chain asymmetry of the diester plasticizer and keeping the molecular weight unchanged simultaneously could further improve its plasticizing efficiency, without sacrificing its volatility resistance and exudation resistance. The results showed that this study provided a new approach for further optimizing the overall properties of the asymmetric diester plasticizers.

Stereodivergent Pd/Cu Catalysis for Asymmetric Desymmetric Alkylation of Allylic Geminal Dicarboxylates

A stereodivergent Pd/Cu catalyst system for asymmetric desymmetric alkylation of allylic geminal dicarboxylates has been developed, which was successfully applied to the asymmetric synthesis of β-h...

A new tricomponent reaction for the synthesis of symmetric and asymmetric alkyl bisphosphoramidates

A novel three-component one-pot reaction procedure was designed for the synthesis of symmetric and asymmetric bisphosphoramidate derivatives. Our key reactants were a set of four aliphatic diamines, which individually react with two different phosphoryl chloride derivatives (N,N,N′,N′-tetramethylphosphorodiamide chloride and diphenyl phosphoryl chloride). A total of 10 products, six of them none reported before, were synthetized. The proposed experimental procedure does not involve any catalyst and proceeds under routine experimental conditions (room temperature and 1 atm). Each synthesized compound was characterized by NMR (1H, 13C, and 31P) spectroscopy and mass spectrometry.

Copper(I)-Catalyzed Asymmetric Alkylation of Unsymmetrical Secondary Phosphines.

A copper(I)-catalyzed asymmetric alkylation of HPAr1Ar2 with alkyl halides is uncovered, which provides an array of P-stereogenic phosphines in generally high yield and enantioselectivity. The electrophilic alkyl halides enjoy a broad substrate scope, including allyl bromides, propargyl bromide, benzyl bromides, and alkyl iodides. Moreover, 11 unsymmetrical diarylphosphines (HPAr1Ar2) serve as competent pronucleophiles. The present methodology is also successfully applied to catalytic asymmetric double and triple alkylation, and the corresponding products were obtained in moderate diastereo- and excellent enantioselectivities. Some 31P NMR experiments indicate that bulky HPPhMes exhibits weak competitively coordinating ability to the Cu(I)-bisphosphine complex, and thus the presence of stoichiometric HPAr1Ar2 does not affect the enantioselectivity significantly. Therefore, the high enantioselectivity in this reaction is attributed to the high performance of the unique Cu(I)-(R,RP)-TANIAPHOS complex in asymmetric induction. Finally, one monophosphine and two bisphosphines prepared by the present reaction are employed as efficient chiral ligands to afford three structurally diversified Cu(I) complexes, which demonstrates the synthetic utility of the present methodology.

Asymmetric Synthesis of N‐Fmoc‐(S)‐7‐aza‐tryptophan via Alkylation of Chiral Nucleophilic Glycine Equivalent

AbstractNi(II)‐complexes, derived from glycine Schiff bases with chiral tridentate ligands, have been used as powerful tools for the synthesis of structurally diverse tailor‐made amino acids. In this manuscript, asymmetric alkylation reaction between chiral nucleophilic glycine derived Ni‐complex and 3‐(chloromethyl)‐1H‐pyrrolo[2,3‐b]pyridine has been developed under convenient conditions, which affords the corresponding alkylated Ni‐complex in 74 % yield and excellent diastereoselectivity (only one isomer). This reaction features convenient conditions and completely controlled diastereoselectivity, which provides a highly valuable approach for asymmetric synthesis of 7‐aza‐tryptophan.

Radical Mechanism of Ir III /Ni II -Metallaphotoredox-Catalyzed C(sp 3 )–H Functionalization Triggered by Proton-Coupled Electron Transfer: Theoretical Insight

Photoredox catalysis can be induced to activate organic substrates or to modulate the oxidation state of transition-metal catalysts via unique single-electron transfer processes, so as to achieve c...

Asymmetric Alkyl and Aryl/Azolation of Alkenes via a Single Cu(I) Complex

The copper-catalyzed, highly enantioselective alkyl and aryl/azolation of alkenes is reported. The employment of the chiral carbazole-based bisoxazoline (Cbzbox) ligand is critical to the success o...

Development of C2-Symmetric Chiral Spirocyclic Phase-Transfer Catalysts: Synthesis and Application to Asymmetric Alkylation of Glycinate Schiff Base.

A class of C2-symmetric chiral spirocyclic phase-transfer catalysts based on tetramethyl-1,1'-spirobiindane scaffold was synthesized from commercially available bisphenol A in 12 steps with 22-25% total yields, which features a more rigid and stable backbone and smaller dihedral angles and can be easily modified. These catalysts show high catalytic performance in the asymmetric alkylation of tert-butyl glycinate Schiff base at only 2 mol % catalyst loading, giving the target products with up to 92% yield and 98% ee.

PH-Sensitive Polycations for siRNA Delivery: Effect of Asymmetric Structures of Tertiary Amine Groups.

pH-sensitive polyelectrolytes provide enormous opportunity for siRNA delivery. Especially, their tertiary amine structures can not only bind genes but also act as pH-sensitive hydrophobic structure to control genes release. However, the influence of molecular structures on siRNA delivery still remains elusive, especially for the asymmetric alkyl substituents of the tertiary amine groups. Herein, a library of N-methyl-N-alkyl aminoethyl methacrylate monomers (MsAM) with asymmetric alkyl substituents on the tertiary amine group is synthesized and used to prepare a series of tri-block polycationic copolymers poly(aminoethyl methacrylate)-block-poly (N-methyl-N-alkyl aminoethyl methacrylate)-block-poly(ethylene glycol methacrylate) (PAMA-PMsMA-PEG). And the properties of these polycations and their self-assembled micelles are characterized, including molecular structure, proton buffering capacity, pH-sensitivity, size, and zeta potential. With the length increase of one alkyl substituent, the proton buffering capacity of both monomers and polycations is demonstrated to be narrowed down. The siRNA delivery efficiency and cytotoxicity of these micelles are also evaluated on HepG2 cells. In particular, poly(aminoethyl methacrylate)-block-poly(N-methyl-N-ethyl aminoethyl methacrylate)-block-poly(ethylene glycol methacrylate) (PAMA-PMEMA-PEG) elicited the best luciferase knockdown efficiency and low cytotoxicity. Besides, PAMA-PMEMA-PEG/siRRM2 also induced significant anti-tumor activity in vitro. These results indicated PAMA-PMEMA-PEG has potential for further use in the design of gene vehicles with the improved efficiency of siRNA delivery.

Stereoselective protonation of 2-methyl-1-tetralone lithium enolate catalyzed by salan-type diamines

Asymmetric protonation of ketone enolates is a convenient alternative to asymmetric alkylation of enolates that allows to convert racemic ketones into their optically active form. Here, we have reported an efficient enantioselective protonation of 2-methyl-1-tetralone lithium enolate catalyzed by salan-type diamines. A broad series of salan-type catalysts were synthesized, including several previously unknown, and subsequently tested in the title reaction. For the first time, a chiral amine used as organocatalyst has shown better results than as stoichiometric protonating agent. Application of only 10 mol% of salan allows to obtain the title ketone with high yield and enantiomeric excess up to 75%. The DFT calculations of the structure of the catalyst and its complex with lithium enolate were conducted, which makes it possible to propose a likely reaction mechanism.

Ni-catalyzed enantioselective [2 + 2 + 2] cycloaddition of malononitriles with alkynes

Summary Efficient strategies to assemble enantioenriched pyridine derivatives are highly important, given their significance in both synthetic and medicinal chemistry. Here, we report an enantioselective nickel-catalyzed intermolecular [2 + 2 + 2] cycloaddition of alkyne-tethered malononitriles with alkynes for the synthesis of densely substituted pyridines. The α-all-carbon quaternary center adjacent to pyridine is introduced by desymmetrizing the two cyano groups of disubstituted malononitriles. Notably, terminal alkynes are also tolerated with good regioselectivity to afford tetrasubstituted pyridines. Zinc halide is essential to enable the occurrence of the transformation by promoting the hetero-cyclometallation step. The reaction uses bio-renewable 2-MeTHF as the solvent and features mild reaction conditions, good functional group compatibilities, and enantioselectivities. This study offers a straightforward approach to the valuable enantioenriched heteroarenes from feedstock chemicals by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step.

Direct Catalytic Asymmetric α-Allylic Alkylation of Aza-aryl Methylamines by Chiral-Aldehyde-Involved Ternary Catalysis System

A ternary catalytic system comprising a chiral aldehyde, a transition metal, and a Lewis acid is rationally designed for the asymmetric α-allylic alkylation reaction of aza-aryl methylamines and π-allylmetal electrophiles. Structural diversity chiral amines bearing carbon-carbon double bonds and aza-heterocycles are produced in moderate to good yields with good to excellent enantioselectivities. These products can be readily converted into other chiral amines without the loss of enantioselectivity. A reasonable reaction mechanism is proposed to illustrate the stereoselective control results.

Stereodivergent Pd/Cu catalysis: asymmetric alkylation of racemic symmetrical 1,3-diphenyl allyl acetates.

We report a stereodivergent Pd/Cu catalyst system that was successfully applied to the asymmetric allylic alkylation of symmetrical 1,3-disubstituted allyl acetates with prochiral imino esters, providing efficient access to enantiopure products bearing vicinal stereocenters in a fully stereodivergent manner. The protocol proceeds smoothly under mild reaction conditions and can accommodate a range of imino esters, delivering the substituted products in high yields and with excellent diastereoselectivities (up to >20 : 1 dr) and enantioselectivities (up to >99% ee).

Dinuclear helicate or mononuclear pincer lanthanide complexes from one ligand: stereo-controlled assembly and catalysis

By varying the metal/ligand ratio, either dinuclear triple helicate or mononuclear pincer can be stereo-selectively obtained from the same chiral ligand. Their catalytic properties have been demonstrated with the asymmetric FC alkylation reactions.

Squaramide-catalysed asymmetric Friedel-Crafts alkylation of naphthol and unsaturated pyrazolones.

The first method for highly efficient asymmetric Michael-type Friedel-Crafts alkylation of naphthol and unsaturated pyrazolones has been accomplished under mild reaction conditions. In the presence of the chiral squaramide catalyst, a wide range of substrates are tolerated in excellent yields (up to 99%) with reasonable enantioselectivities (up to 96% ee).

Enantioselective Synthesis of 3-Allylindolizines via Sequential Rh-Catalyzed Asymmetric Allylation and Tschitschibabin Reaction.

The first highly regio- and enantioselective synthesis of 3-allylindolizines has been developed by the sequential Rh-catalyzed asymmetric allylation and Tschitschibabin reaction. Above the 20:1 branch/linear ratio, up to a 96% yield and 99% ee could be obtained with the help of tert-butyl-substituted chiral bisoxazolinephosphine ligand. In situ generated highly nucleophilic 2-alkylpyridinium ylides are utilized to undergo the asymmetric alkylation reaction before cyclization.

Asymmetric Alkoxy and Alkyl Substitution on Nonfullerene Acceptors Enabling High‐Performance Organic Solar Cells

AbstractIn this paper, a strategy of asymmetric alkyl and alkoxy substitution is applied to state‐of‐the‐art Y‐series nonfullerene acceptors (NFAs), and it achieves great performance in organic solar cell (OSC) devices. Since alkoxy groups can have a significant influence on the material properties of NFAs, alkoxy substitution is applied to the Y6 molecule in a symmetric manner. The resulting molecule (named Y6‐2O), despite showing improved open‐circuit voltage (Voc), yields extremely poor performance due to low solubility and excessive aggregation properties, a change that is due to the conformational locking effect of alkoxy groups. In contrast, asymmetric alkyl and alkoxy substitution on Y6, yields a molecule named Y6‐1O that can maintain the positive effect of Voc improvement and obtain reasonably good solubility. The resulting molecule Y6‐1O enables highly efficient nonfullerene OSCs with 17.6% efficiency and the asymmetric side‐chain strategy has the potential to be applied to other NFA‐material systems to further improve their performance.

Light‐Promoted Copper‐Catalyzed Enantioselective Alkylation of Azoles

AbstractA catalytic asymmetric alkylation of azoles with secondary 1‐arylalkyl bromides through direct C−H functionalization is reported. Under blue‐light photoexcitation, a copper(I)/carbazole‐based bisoxazoline (CbzBox) catalytic system exhibits good reactivity and high stereoselectivity, thus offering an efficient strategy for the construction of chiral alkyl azoles. These reactions proceed at low temperature and are compatible with a wide range of azoles.