Stereodivergent entry to β-branched β-trifluoromethyl α-amino acid derivatives by sequential catalytic asymmetric reactions

Currently, conventional reductive catalytic methodologies do not guarantee general access to enantioenriched β-branched β-trifluoromethyl α-amino acid derivatives. Herein, a one-pot approach to these important α-amino acids, grounded on the reduction – ring opening of Erlenmeyer–Plöchl azlactones, is presented. The configurations of the two chirality centers of the products are established during each of the two catalytic steps, enabling a stereodivergent process.

A one-pot approach to β-branched β-trifluoromethyl α-amino acids, grounded on the reduction – ring opening of Erlenmeyer–Plöchl azlactones, and complementary to conventional catalytic asymmetric hydrogenation, is presented.     

Stereoselective synthesis of unnatural α-amino acid derivatives through photoredox catalysis

A protocol for stereoselective C-radical addition to a chiral glyoxylate-derived N-sulfinyl imine was developed through visible light-promoted photoredox catalysis, providing a convenient method for the synthesis of unnatural α-amino acids. The developed protocol allows the use of ubiquitous carboxylic acids as radical precursors without prior derivatization. The protocol utilizes near-stoichiometric amounts of the imine and the acid radical precursor in combination with a catalytic amount of an organic acridinium-based photocatalyst. Alternative mechanisms for the developed transformation are discussed and corroborated by experimental and computational studies.

A protocol for stereoselective C-radical addition to a chiral glyoxylate-derived N-sulfinyl imine was developed through visible light-promoted photoredox catalysis, providing a convenient method for the synthesis of unnatural α-amino acids.     

anti-Selective synthesis of β-boryl-α-amino acid derivatives by Cu-catalysed borylamination of α,β-unsaturated esters

A copper-catalysed regio- and diastereoselective borylamination of α,β-unsaturated esters with B₂pin₂ and hydroxylamines has been developed to deliver acyclic β-boryl-α-amino acid derivatives with high anti-diastereoselectivity (up to >99 : 1), which is difficult to obtain by the established methods. A chiral phosphoramidite ligand also successfully induces the enantioselectivity, giving the optically active β-borylated α-amino acids. The products can be stereospecifically transformed into β-functionalised α-amino acids, which are of potent interest in medicinal chemistry.

A Cu-catalysed regio-, diastereo-, and enantioselective borylamination of α,β-unsaturated esters with B₂pin₂ and hydroxylamines has been developed. The products can be converted into functionalised α-amino acids with two adjacent stereocentres.     

Catalytic asymmetric synthesis of quaternary trifluoromethyl α- to ε-amino acid derivatives via umpolung allylation/2-aza-Cope rearrangement

In this study, we developed an efficient Ir-catalyzed cascade umpolung allylation/2-aza-Cope rearrangement of tertiary α-trifluoromethyl α-amino acid derivatives for the preparation of a variety of quaternary α-trifluoromethyl α-amino acids in high yields with excellent enantioselectivities. The umpolung reactivity empowered by the activation of the key isatin-ketoimine moiety obviates the intractable enantioselectivity control in Pd-catalyzed asymmetric linear α-allylation. In combination with quasi parallel kinetic resolution or kinetic resolution, the generality of this method is further demonstrated by the first preparation of enantioenriched quaternary trifluoromethyl β-, γ-, δ- and ε-amino acid derivatives.

In this study, we developed an efficient Ir-catalyzed cascade umpolung allylation/2-aza-Cope rearrangement for the preparation of a variety of quaternary trifluoromethyl α-ε-amino acids in high yields with excellent enantioselectivities.     

Solvent directed chemically divergent synthesis of β-lactams and α-amino acid derivatives with chiral isothiourea

A protocol for the chemically divergent synthesis of β-lactams and α-amino acid derivatives with isothiourea (ITU) catalysis by switching solvents was developed. The stereospecific Mannich reaction occurring between imine and C(1)-ammonium enolate generated zwitterionic intermediates, which underwent intramolecular lactamization and afforded β-lactam derivatives when DCM and CH₃CN were used as solvents. However, when EtOH was used as the solvent, the intermediates underwent an intermolecular esterification reaction, and α-amino acid derivatives were produced. Detailed mechanistic experiments were conducted to prove that these two kinds of products came from the same intermediates. Furthermore, chemically diversified transformations of β-lactam and α-amino acid derivatives were achieved.

A protocol for the solvent directed chemically divergent synthesis of β-lactam and α-amino acid derivatives with chiral isothiourea was reported.     

Redox deracemization of β,γ-alkynyl α-amino esters

The first non-enzymatic redox deracemization method using molecular oxygen as the terminal oxidant has been described. The one-pot deracemization of β,γ-alkynyl α-amino esters consisted of a copper-catalyzed aerobic oxidation and chiral phosphoric acid-catalyzed asymmetric transfer hydrogenation with excellent functional group compatibility. By using benzothiazoline as the reducing reagent, an exclusive chemoselectivity at the C N bond over the C C bond was achieved, allowing for efficient deracemization of a series of α-amino esters bearing diverse α-alkynyl substituent patterns. The origins of chemo- and enantio-selectivities were elucidated by experimental and computational mechanistic investigation. The generality of the strategy is further demonstrated by efficient deracemization of β,γ-alkenyl α-amino esters.

A one-pot deracemization of β,γ-alkynyl α-amino esters consisting of an aerobic oxidation and chiral phosphoric acid-catalyzed asymmetric transfer hydrogenation has been described.     

Asymmetric hydroalkylation of alkynes and allenes with imidazolidinone derivatives: α-alkenylation of α-amino acids

This work reports a new method for the synthesis of quaternary α-alkenyl substituted amino acids by the enantio- and diastereoselective addition of imidazolidinone derivatives to alkynes and allenes. Further hydrolysis of the imidazolidinone products under acidic conditions afforded biologically relevant amino acid derivatives. This method is geometry-selective (E-isomer), enantio- and diastereoselective, and products were obtained in good to excellent yields. The utility of this new methodology is proved by its operational simplicity and the successful accomplishment of gram-scale reactions. Experimental and computational studies suggest the key role of Li in terms of selectivity and support the proposed reaction mechanism.

Enantio-, diastereoselective, geometry-selective addition of imidazolidinone derivatives to alkynes and allenes in the presence of LiHMDS in order to obtain quaternary α-alkenyl substituted amino acids in high isolated yields.     

A step-economic and one-pot access to chiral Cα-tetrasubstituted α-amino acid derivatives via a bicyclic imidazole-catalyzed direct enantioselective C-acylation

C^α-Tetrasubstituted α-amino acids are ubiquitous and unique structural units in bioactive natural products and pharmaceutical compounds. The asymmetric synthesis of these molecules has attracted a lot of attention, but a more efficient method is still greatly desired. Here we describe the first sequential four-step acylation reaction for the efficient synthesis of chiral C^α-tetrasubstituted α-amino acid derivatives from simple N-acylated amino acids via an auto-tandem catalysis using a single nucleophilic catalyst. The synthetic efficiency is improved via a direct enantioselective C-acylation; the methodology affords the corresponding C^α-tetrasubstituted α-amino acid derivatives with excellent enantioselectivities (up to 99% ee). This step-economic, one-pot, and auto-tandem strategy provides facile access to important chiral building blocks, such as peptides, serines, and oxazolines, which are often used in medicinal and synthetic chemistry.

The first four-step sequential reaction for the synthesis of C^α-tetrasubstituted chiral α-amino acid derivatives via auto-tandem catalysis has been developed.     

The synthesis of β-heteroarylamino-α,β-dehydro-α-amino acid and β-heteroarylamino-α-amino acid derivatives

From heteroarylaminomethyleneoxazolones 4 , obtained from N-heteroarylformamidines 2 and 2-phenyl-5-oxo-4,5-dihydro-1,3-oxazole ( 3 ), the following β-heteroarylamino-α,β-dehydro-α-amino acid derivatives were prepared: methyl 8 and ethyl esters 9 , amides 10 and 11 , hydrazides 12 , and azides 15 . By catalytic hydrogenation the compounds 4 were converted into β-heteroarylamino substituted amides 18 and β-heteroarylamino-α-amino acids 20 .     

Triarylamine-based porous coordination polymers performing both hydrogen atom transfer and photoredox catalysis for regioselective α-amino C(sp3)–H arylation

Direct functionalization of C(sp³)–H bonds in a predictable, selective and recyclable manner has become a central challenge in modern organic chemistry. Through incorporating different triarylamine-containing ligands into one coordination polymer, we present herein a heterogeneous approach to the combination of hydrogen atom transfer (HAT) and photoredox catalysis for regioselective C–H arylation of benzylamines. The different molecular sizes and coordination modes of the ligands, tricarboxytriphenylamine (H₃TCA) and tris(4-(pyridinyl)phenyl)amine (NPy3), in one coordination polymer consolidate the triarylamine (Ar₃N) moiety into a special structural intermediate, which enhances the chemical and thermal stability of the polymers and diminishes structural relaxation during the catalytic process. The inherent redox potentials of Ar₃N moieties prohibit the in situ formed Ar₃N˙⁺ to earn an electron from C(sp³)–H nucleophiles, but allow the abstraction of a hydrogen atom from C(sp³)–H nucleophiles, enabling the formation of the C(sp³)˙ radical and the cross-coupling reaction to proceed at the most electron-rich sites with excellent regioselectivity. The new heterogeneous photoredox HAT approach skips several interactions between transient species during the typical synergistic SET/HAT cycles, demonstrating a promising redox-economical and reagent-economical heterogeneous platform that has not been reported for α-amino C–H arylation to form benzylamine derivatives. Control experiments based on monoligand coordination polymers suggested that the mixed-ligand approach improved the photochemical and photophysical properties, providing important insight into rational design and optimization of recyclable photocatalysts for rapid access to complex bioactive molecules and late-stage functionalized pharmaceuticals.

The efficiency of photosensitization and hydrogen atom transfer (HAT) catalysis is balanced in a recyclable heterogeneous manner by the modification of the N-central conformation in Cd-MIX.     

N—H⋯π hydrogen bonding in 2‐amino­fluorene

The amino group of the title compound, C₁₃H₁₁N, does not form N—H?N hydrogen bonds, but is engaged only in weaker N—H?Ph and C—H?N interactions. An aromatic ring acts as a double hydrogen‐bond acceptor, leading to an infinite H—N—H?Ph?H—N—H?Ph array.     

A–X⋯σ Interactions—Halogen Bonds with σ-Electrons as the Lewis Base Centre

CCSD(T)/aug-cc-pVTZ//ωB97XD/aug-cc-pVTZ calculations were performed for halogen-bonded complexes. Here, the molecular hydrogen, cyclopropane, cyclobutane and cyclopentane act as Lewis base units that interact through the electrons of the H–H or C–C σ-bond. The FCCH, ClCCH, BrCCH and ICCH species, as well as the F₂, Cl₂, Br₂ and I₂ molecular halogens, act as Lewis acid units in these complexes, interacting through the σ-hole localised at the halogen centre. The Quantum Theory of Atoms in Molecules (QTAIM), the Natural Bond Orbital (NBO) and the Energy Decomposition Analysis (EDA) approaches were applied to analyse these aforementioned complexes. These complexes may be classified as linked by A–X···σ halogen bonds, where A = C, X (halogen). However, distinct properties of these halogen bonds are observed that depend partly on the kind of electron donor: dihydrogen, cyclopropane, or another cycloalkane. Examples of similar interactions that occur in crystals are presented; Cambridge Structural Database (CSD) searches were carried out to find species linked by the A–X···σ halogen bonds.     

The preparation of selenium-containing aromatic and heterocyclic C-substituted α-amino acetic acid derivatives of potential biomedical application

Model selenium-containing aromatic and heterocyclic C-substituted α-amino acid compounds have been synthesized as potential biomedical organ scanning application (external imaging) agents. The synthesis is based on the amidoalkylation of aromatic and heterocyclic compounds with α-hydroxyglyoxylic acid-primary amide adducts (2). The procedure is simple and straightforward, the overall yields are good, and the method appears to be of general use for the preparation of a wide variety of selenium-containing amino acids (4).     

Strong intramolecular O—H⋯O hydrogen bonds in quinaldic acid N‐oxide and picolinic acid N‐oxide

The title compounds contain very short intramolecular hydrogen bonds of the type C—O—H?O—N. The O?O distances are 2.425 (2) Å in picolinic acid N‐oxide (2‐carboxy­pyridine N‐oxide), C₆H₅NO₃, (I), and 2.435 (2) Å in quinaldic acid N‐oxide (2‐carboxy­quinoline N‐oxide), C₁₀H₇NO₃, (II). In (II), this is associated with slight molecular distortion from planarity, while in (I), such an effect cannot be observed because the mol­ecule crystallizes on a mirror plane.     

Enantioselective synthesis of α-amino ketones through palladium-catalyzed asymmetric arylation of α-keto imines

Chiral α-amino ketones are common structural motifs in natural products and pharmaceuticals, as well as important synthons in organic synthesis. Thus, establishing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein we disclose a new catalytic asymmetric approach for the synthesis of chiral α-amino ketones through a chiral palladium-catalyzed arylation reaction of in situ generated challenging α-keto imines from previously unreported C-acyl N-sulfonyl-N,O-aminals, with arylboronic acids. The current reaction offers a straightforward approach to the asymmetric synthesis of acyclic α-amino ketones in a practical and highly stereocontrolled manner. Meanwhile, the multiple roles of the chiral Pd(ii) complex catalyst in the reaction were also reported.

Chiral α-amino ketones are common structural motifs in natural products and pharmaceuticals, as well as important synthons in organic synthesis.     

Three for the Price of One: Concomitant I⋯N,I⋯O,and I⋯π Halogen Bonds in the Same Crystal Structure

The ditopic molecule 3-(1,3,5-trimethyl-1H-4-pyrazolyl)pentane-2,4-dione (HacacMePz) combines two different Lewis basic sites. It forms a crystalline adduct with the popular halogen bond (XB) donor 2,3,5,6-tetrafluoro-1,4-diiodobenzene (TFDIB) with a HacacMePz:TFDIB ratio of 2:3. In a simplified picture, the topology of the adduct corresponds to a hcb net. In addition to the expected acetylacetone keto O and pyrazole N acceptor sites, a third and less common short contact to a TFDIB iodine is observed: The acceptor site is again the most electron-rich site of the pyrazole π-system. This iminic N atom is thus engaged as the acceptor in two orthogonal halogen bonds. Evaluation of the geometric results and of a single-point calculation agree with respect to the strength of the intermolecular contacts: The conventional N⋯I XB is the shortest (2.909(4) Å) and associated with the highest electron density (0.150 eÅ−3) in the bond critical point (BCP), followed by the O⋯I contact (2.929(3) Å, 0.109 eÅ−3), and the π contact (3.2157(3) Å, 0.075 eÅ−3). If one accepts the idea of deducing interaction energies from energy densities at the BCP, the short contacts also follow this sequence. Two more criteria identify the short N⋯I contact as the most relevant: The associated C–I bond is significantly longer than the database average, and it is the only intermolecular interaction with a negative total energy density in the BCP.     

Preparation of α-amino acids via Ni-catalyzed reductive vinylation and arylation of α-pivaloyloxy glycine

This work emphasizes easy access to α-vinyl and aryl amino acids via Ni-catalyzed cross-electrophile coupling of bench-stable N-carbonyl-protected α-pivaloyloxy glycine with vinyl/aryl halides and triflates. The protocol permits the synthesis of α-amino acids bearing hindered branched vinyl groups, which remains a challenge using the current methods. On the basis of experimental and DFT studies, simultaneous addition of glycine α-carbon (Gly) radicals to Ni(0) and Ar–Ni(ii) may occur, with the former being more favored where oxidative addition of a C(sp²) electrophile to the resultant Gly–Ni(i) intermediate gives a key Gly–Ni(iii)–Ar intermediate. The auxiliary chelation of the N-carbonyl oxygen to the Ni center appears to be crucial to stabilize the Gly–Ni(i) intermediate.

We have developed Ni-catalyzed reductive coupling of N-carbonyl protected α-pivaloyloxy glycine with Csp²-electrophiles that enabled facile preparation of α-amino acids, including those bearing hindered branched vinyl groups.     

5‐[N‐(1H‐Benzotriazol‐1‐yl­methyl)­amino]‐3‐tert‐butyl‐1‐phenyl­pyrazole: sheets built from N—H⋯N,C—H⋯N and C—H⋯π(pyrazole) interactions

In the title compound, C₂₀H₂₂N₆, the mol­ecules are linked into a chain of rings by N—H?N [H?N 2.16 Å, N?N 2.950 (3) Å and N—H?N 149°] and C—H?N [H?N 2.55 Å, C?N 3.481 (3) Å and C—H?N 165°] hydrogen bonds, and these chains are linked into sheets by means of C—­H?π(pyrazole) interactions.