Enantioconvergent Synthesis Research Articles

Enantioconvergent synthesis of axially chiral amides enabled by Pd-catalyzed dynamic kinetic asymmetric aminocarbonylation

Atropisomeric biaryls bearing carbonyl groups have attracted increasing attention due to their prevalence in diverse bioactive molecules and crucial role as efficient organo-catalysts or ligands in asymmetric transformations. However, their preparation often involves tedious multiple steps, and the direct synthesis via asymmetric carbonylation has scarcely been investigated. Herein, we report an efficient palladium-catalyzed enantioconvergent aminocarbonylation of racemic heterobiaryl triflates with amines via dynamic kinetic asymmetric transformation (DyKAT). This protocol features a broad substrate scope and excellent compatibility for rapid construction of axially chiral amides in good to high yields with excellent enantioselectivities. Detailed mechanistic investigations discover that the base can impede the intramolecular hydrogen bond-assisted axis rotation of the products, thus allowing for the success to achieve high enantioselectivity. Moreover, the achieved axially chiral heterobiaryl amides can be directly utilized as N,N,N-pincer ligands in copper-catalyzed enantioselective formation of C(sp3)-N and C(sp3)-P bonds.

Synergistic Photoredox/Palladium Catalyzed Enantioconvergent Carboxylation of Racemic Heterobiaryl (Pseudo)Halides with CO2.

Herein, we report a synergistic photoredox/palladium catalytic system for the efficient enantioconvergent synthesis of axially chiral esters from racemic heterobiaryl (pseudo)halides (bromides/triflates) with CO2 and alkyl bromides under mild conditions. A wide range of axially chiral esters were obtained in good to high yields with excellent enantioselectivities. Detailed mechanistic studies unveiled that the ratio of photocatalyst and palladium catalyst exhibited significant impact on the chemo- and enantioselectivities of the reaction. Kinetic studies and control experiments supported the proposed mechanism involving cascade asymmetric carboxylation followed by SN2 substitution. The achievement of high enantioselectivity relies not only on the choice of synergistic metallaphotoredox catalysts but also on the utilization of alkyl bromides, which trap the generated chiral carboxylic anions in situ, thus preventing their immediate racemization.

Catalytic Eoconvergent C(sp3)−N Coupling to Access Chiral Amines: A Concept Review

AbstractNitrogen containing compounds like chiral amines have been widely used in synthetic medicines, biomass, and fine chemical products because of their particularly valuable motifs and exceedingly broad range of functionality. Enantioconvergent synthesis of chiral amines has high atomic economy and enantioselectivity with theoretically 100 % yield of enantioenriched products. In this concept article, we hope to provide a further understanding of chiral amines enantioconvergent synthesis methodology with an introduction of recent progresses in enantioconvergent amination reactions catalyzed by early transition metals and facilitate the development of enantioconvergent C(sp3)−N coupling for benign and efficient preparation of highly valuable chiral nitrogen‐containing units.

Enantioconvergent synthesis of chiral fluorenols from racemic secondary alcohols via Pd(ii)/chiral norbornene cooperative catalysis.

An efficient protocol for the asymmetric synthesis of fluorenols has been developed through an enantioconvergent process enabled by Pd(ii)/chiral norbornene cooperative catalysis. This approach allows facile access to diverse functionalized chiral fluorenols with constantly excellent enantioselectivities, applying readily available racemic secondary ortho-bromobenzyl alcohols and aryl iodides as the starting materials.

Enantioconvergent Synthesis of α-Amino Acids by Iron-Catalyzed α-C(sp3)–H Amination of Carboxylic Acids

Key words α-amino acids - carboxylic acids - C(sp3)–H amination - enantioconvergent reaction - iron catalysis

Cr-catalyzed chiral allenone synthesisviasequential radical–polar crossover and Oppenauer oxidation

We describe the Cr-catalyzed enantioconvergent synthesis of chiral 2,3-allenones from aldehydes and propargyl bromides, which features an unprecedented cascade of Cr-catalyzed asymmetric reductive radical–polar crossover and Oppenauer oxidation.

Counterion-Mediated Enantioconvergent Synthesis of Axially Chiral Medium Rings.

There are few enantioconvergent reactions in which racemic substrates bearing multiple stereochemical features are converted into products with high levels of diastereo- and enantiocontrol. Here, we disclose a process for the highly enantio- and diastereoselective syntheses of medium ring lactams via an intramolecular counterion-directed C-alkylation reaction. The treatment of racemic biaryl anilides that exist as a complex mixture of enantiomers and diastereoisomeric conformers by virtue of multiple axes of restricted rotation with a quinidine-derived ammonium salt under basic conditions affords medium ring lactams bearing elements of both axial and point chirality via an enolate-driven configurational relaxation process. Thermal equilibration of the syn- and anti-product diasteroisomers has demonstrated that the barriers to bowl inversion are >124 kJ mol-1. We propose that the chiral ammonium salt differentiates between a complex and rapidly equilibrating mixture of enolate and rotational isomers, ultimately leading to highly enantioselective alkylative ring closure. This dynamic and enantioconvergent process offers an operationally simple approach to the synthesis of valuable chiral medium ring lactams for which there are few catalytic and enantioselective approaches.

Ligand‐Promoted, Enantioconvergent Synthesis of Aliphatic Alkanes Bearing Trifluoromethylated Stereocenters via Hydrotrifluoroalkylation of Unactivated Alkenes

Comprehensive SummaryWhile drug chirality remains one of the most important themes in medicinal chemistry and fluorine‐containing drugs have comprised large portion of global pharmaceutical market, the synthesis of fluorine‐containing compounds featuring a trifluoromethylated stereogenic carbon center is still underdeveloped. Recent strategy of enantioconvergent cross‐coupling of trifluoromethylated alkyl halide has significantly updated previous toolbox that is dependent on additional functional group to achieve desired bond formation and highly enantioselective control. However, evident limitations were present in specific coupling candidate (sp2 carbon) and/or prerequisite heteroatom in trifluoroalkyl source for inducing effective stereoconvergent differentiation. Leveraging novel design of sterically hindered bisoxazoline ligand and drastic increase of molecular complexity of in situ generated sp3 coupling partner via metal‐hydride atom transfer, herein, we report a nickel‐catalyzed, highly enantioselective hydrotrifluoroalkylation of unactivated alkenes for diverse synthesis of enantioenriched aliphatic alkanes featuring trifluoromehylated stereogenic carbon. Excellent stereochemical control (mostly >95: 5 er), high catalytic reactivity, mild conditions, and broad substrate scope (40+ examples), enable convenient late‐stage asymmetric trifluoroalkylation of various biologically active complex molecules.

Catalytic Diastereo- and Enantioconvergent Synthesis of Vicinal Diamines from Diols through Borrowing Hydrogen.

We present herein an unprecedented diastereoconvergent synthesis of vicinal diamines from diols through an economical, redox-neutral process. Under cooperative ruthenium and Lewis acid catalysis, readily available anilines and 1,2-diols (as a mixture of diastereomers) couple to forge two C-N bonds in an efficient and diastereoselective fashion. By identifying an effective chiral iridium/phosphoric acid co-catalyzed procedure, the first enantioconvergent double amination of racemic 1,2-diols has also been achieved, resulting in a practical access to highly valuable enantioenriched vicinal diamines.

Catalytic Diastereo‐ and Enantioconvergent Synthesis of Vicinal Diamines from Diols through Borrowing Hydrogen

AbstractWe present herein an unprecedented diastereoconvergent synthesis of vicinal diamines from diols through an economical, redox‐neutral process. Under cooperative ruthenium and Lewis acid catalysis, readily available anilines and 1,2‐diols (as a mixture of diastereomers) couple to forge two C−N bonds in an efficient and diastereoselective fashion. By identifying an effective chiral iridium/phosphoric acid co‐catalyzed procedure, the first enantioconvergent double amination of racemic 1,2‐diols has also been achieved, resulting in a practical access to highly valuable enantioenriched vicinal diamines.

The Asymmetric Synthesis of Amines via Nickel-Catalyzed Enantioconvergent Substitution Reactions.

Chiral dialkyl carbinamines are important in fields such as organic chemistry, pharmaceutical chemistry, and biochemistry, serving for example as bioactive molecules, chiral ligands, and chiral catalysts. Unfortunately, most catalytic asymmetric methods for synthesizing dialkyl carbinamines do not provide general access to amines wherein the two alkyl groups are of similar size (e.g., CH2R versus CH2R1). Herein, we report two mild methods for the catalytic enantioconvergent synthesis of protected dialkyl carbinamines, both of which use a chiral nickel catalyst to couple an alkylzinc reagent (1.1-1.2 equiv) with a racemic partner, specifically, an α-phthalimido alkyl chloride or an N-hydroxyphthalimide (NHP) ester of a protected α-amino acid. The methods are versatile, providing dialkyl carbinamine derivatives that bear an array of functional groups. For couplings of NHP esters, we further describe a one-pot variant wherein the NHP ester is generated in situ, allowing the generation of enantioenriched protected dialkyl carbinamines in one step from commercially available amino acid derivatives; we demonstrate the utility of this method by applying it to the efficient catalytic enantioselective synthesis of a range of interesting target molecules.

Visible‐Light‐Enabled Enantioconvergent Synthesis of α‐Amino Acid Derivatives via Synergistic Brønsted Acid/Photoredox Catalysis

AbstractAn unprecedented radical cross‐coupling reaction was achieved between glycine esters and racemic α‐bromoketones catalyzed by synergistic Brønsted acid/photoredox catalysis, thus serving as an efficient platform for the synthesis of highly valuable enantioenriched unnatural α‐amino acid derivatives. This dual catalysis provides a powerful capability to control the reactive radical intermediate and iminium ion, thereby enabling enantioconvergent bond‐formation in a highly stereochemical manner. An array of valuable enantioenriched unnatural α‐amino acid derivatives bearing two contiguous stereogenic centers are readily accessible with high diastereoselectivity and excellent enantioselectivity, which include α‐amino acids with a unique β‐fluorinated quaternary stereocenter or its β‐all‐carbon counterpart. A strong chiral amplification effect was observed in this dual catalytic system.

Visible-Light-Enabled Enantioconvergent Synthesis of α-Amino Acid Derivatives via Synergistic Brønsted Acid/Photoredox Catalysis.

An unprecedented radical cross-coupling reaction was achieved between glycine esters and racemic α-bromoketones catalyzed by synergistic Brønsted acid/photoredox catalysis, thus serving as an efficient platform for the synthesis of highly valuable enantioenriched unnatural α-amino acid derivatives. This dual catalysis provides a powerful capability to control the reactive radical intermediate and iminium ion, thereby enabling enantioconvergent bond-formation in a highly stereochemical manner. An array of valuable enantioenriched unnatural α-amino acid derivatives bearing two contiguous stereogenic centers are readily accessible with high diastereoselectivity and excellent enantioselectivity, which include α-amino acids with a unique β-fluorinated quaternary stereocenter or its β-all-carbon counterpart. A strong chiral amplification effect was observed in this dual catalytic system.

Organocatalytic Enantioselective Synthesis of Chiral Allenes: Remote Asymmetric 1,8-Addition of Indole Imine Methides.

An organocatalytic enantioconvergent synthesis of chiral tetrasubstituted allenes is disclosed. With suitable chiral phosphoric acid catalysts, a range of racemic indole-substituted propargylic alcohols reacted with nucleophiles to provide efficient access to a series of enantioenriched allenes with high enantioselectivities. Control experiments suggested a mechanism involving remotely controlled asymmetric 1,8-addition of the in situ generated indole imine methide via a bifunctional transition state.

Ir-Catalyzed Enantioconvergent Synthesis of Diversely Protected Allenylic Amines Employing Ammonia Surrogates.

The first iridium catalyzed, enantioconvergent amination of allenylic carbonates is reported. This process utilizes various commercially available carbamates and sulfonamides to generate allenylic amines including commonly employed protected groups (Boc, Fmoc, Cbz, Ts, Ns) in 62-82 % yield and 87-98 % ee. The products generated through this scalable procedure serve as effective linchpins for the rapid, enantiospecific synthesis of a wide range of complex structures.

Ir‐Catalyzed Enantioconvergent Synthesis of Diversely Protected Allenylic Amines Employing Ammonia Surrogates

AbstractThe first iridium catalyzed, enantioconvergent amination of allenylic carbonates is reported. This process utilizes various commercially available carbamates and sulfonamides to generate allenylic amines including commonly employed protected groups (Boc, Fmoc, Cbz, Ts, Ns) in 62–82 % yield and 87–98 % ee. The products generated through this scalable procedure serve as effective linchpins for the rapid, enantiospecific synthesis of a wide range of complex structures.

Manipulating the regioselectivity of a Solanum lycopersicum epoxide hydrolase for the enantioconvergent synthesis of enantiopure alkane- and alkene-1,2-diols

This work engineered a superior double-site mutant SlEH1W106T/F189L used for the enantioconvergent biosynthesis of (R)-1b–6b with high eep values.

Guanidine–Copper Complex Catalyzed Allylic Borylation for the Enantioconvergent Synthesis of Tertiary Cyclic Allylboronates

AbstractAn enantioconvergent synthesis of chiral cyclic allylboronates from racemic allylic bromides was achieved by using a guanidine–copper catalyst. The allylboronates were obtained with high γ/α regioselectivities (up to 99:1) and enantioselectivities (up to 99 % ee), and could be further transformed into diverse functionalized allylic compounds without erosion of optical purity. Experimental and DFT mechanistic studies support an SN2′ borylation process catalyzed by a monodentate guanidine–copper(I) complex that proceeds through a special direct enantioconvergent transformation mechanism.

Guanidine-Copper Complex Catalyzed Allylic Borylation for the Enantioconvergent Synthesis of Tertiary Cyclic Allylboronates.

An enantioconvergent synthesis of chiral cyclic allylboronates from racemic allylic bromides was achieved by using a guanidine-copper catalyst. The allylboronates were obtained with high γ/α regioselectivities (up to 99:1) and enantioselectivities (up to 99 % ee), and could be further transformed into diverse functionalized allylic compounds without erosion of optical purity. Experimental and DFT mechanistic studies support an SN 2' borylation process catalyzed by a monodentate guanidine-copper(I) complex that proceeds through a special direct enantioconvergent transformation mechanism.

Preparing β-blocker (R)-Nifenalol based on enantioconvergent synthesis of (R)-p-nitrophenylglycols in continuous packed bed reactor with epoxide hydrolase

An engineered epoxide hydrolase from Vigna radiate (VrEH2M263N) shows near-perfect enantioconvergence in single enzyme mediated hydrolysis of racemic p-nitrostyrene oxide (pNSO). To explore industrial potential of the promising biocatalyst, we tried to immobilize the VrEH2 variant by covalently linking onto a commercially available amino resin ECR8405F. Then a 5-mL packed bed reactor filled with the immobilized VrEH2M263N was connected with macroporous resin NKA-11 for in situ product adsorption, and the product (R)-p-nitrophenyl glycol (pNPG) was harvested by methanol elution, with 91% isolated yield and 97% ee. The continuous reactor was operated stably for more than 100 h with a space time yield of 20 g⋅L−1⋅h−1. Subsequently, the β-blocker (R)-Nifenalol was prepared by chemically synthesized from (R)-pNPG, affording the product in an overall yield of 61.3% (1.5 g) and an enantiopurity of 99.9% ee after recrystallization.