Chiral Α-aminonitriles Research Articles

Enantioselective Deoxygenative Amino-Cyanation of Carboxylic Acids via Ti-Multicatalysis.

Carboxylic acids are valued synthetic building blocks that offer shelf life stability, structural diversity, and wide commercial availability. Despite the remarkable synthetic utility of carboxylic acids, a direct enantioselective deoxygenative functionalization of carboxylic acids remains rare. We present enantioselective deoxygenative amino-cyanation of carboxylic acids using a novel TiIV-multicatalytic system that catalytically modified each C-O bond of carboxylic acid to C-C, C-N, and C-H bonds, generating enantio-enriched chiral α-amino nitriles (up to 98:2 er).

Direct Asymmetric Synthesis of α-Aminoimines from 1,2-Bis-N-Sulfinylimines by Using Allyl Boronic Acids.

A unique direct asymmetric synthesis of α-aminoimines is realized, through rapid and exclusive mono-allylation of chiral bis-N-sulfinylimines using allylboronic acids. The highly selective allylation was possible as electrophilic imine functional group in the product α-aminoimines remained unreactive towards allyl boronic acid nucleophiles. Notably, by varying the geometry and chiral auxiliary, all four isomers of the α-aminoimines were accessed from readily available precursors. A range of allyl nucleophiles, which are tricky to generate by other means possessing highly reactive functional groups also took part in this reaction, expanding the scope further. The applicability of the products α-aminoimines were further demonstrated by accessing a range of structurally diverse chiral cyclic and acyclic 1,2-diamines bearing adjacent stereocenters through addition of a second nucleophile or aza-Prins-type cyclization by exploiting the nucleophilicity of the tethered alkene moiety. Moreover, the leaving group aptitude of sulfinyl auxiliary attached to imine, was exploited to access valuable chiral α-aminonitriles under thermal conditions without employing any reagents. Detailed DFT calculation revealed a chair-like transition state likely operating for the allylboration reaction across imine.

Front Cover: Catalytic Asymmetric Strecker Reaction of Ketoimines with Potassium Cyanide (Asian J. Org. Chem. 12/2021)

The cover art illustrates the phase-transfer catalysis effective for asymmetric Strecker reaction of ketoimines with potassium cyanide under solid-liquid biphasic conditions. Chiral 1,2,3-triazolium ion featuring prominent hydrogen-bond donating and anion-binding capabilities allows for the establishment of a highly efficient and enantioselective process for the preparation of sterically congested chiral α-amino nitriles. More information can be found in the Communication by Takashi Ooi et al.

Enantioselective Reductive Cyanation and Phosphonylation of Secondary Amides by Iridium and Chiral Thiourea Sequential Catalysis

The combination of transition-metal catalysis and organocatalysis increasingly offers chemists opportunities to realize diverse unprecedented chemical transformations. By combining iridium with chiral thiourea catalysis, direct enantioselective reductive cyanation and phosphonylation of secondary amides have been accomplished for the first time for the synthesis of enantioenriched chiral α-aminonitriles and α-aminophosphonates. The protocol is highly efficient and enantioselective, providing a novel route to the synthesis of optically active α-functionalized amines from the simple, readily available feedstocks. In addition, the reactions are scalable and the thiourea catalyst can be recycled and reused.

Highly Stereoselective Strecker Synthesis Induced by a Slight Modification of Benzhydrylamine from Achiral to Chiral.

2-Methylbenzhydrylamine is a chiral variant of achiral benzhydrylamine; however, the chirality formed from the small difference between the phenyl and o-tolyl groups is not expected to induce sufficient stereoselectivity in conventional homogeneous reactions. Initiated by the spontaneous formation and asymmetric amplification of the enantioenriched N-benzhydryl-α-aminonitrile forming conglomerate, we here report that (S)- and (R)-configured title amine, upon the Strecker reaction with achiral aldehydes and HCN, afford the corresponding α-aminonitriles with up to >99.5 % diastereomeric excess, in conjunction with an enhancement of chirality in the solid state. l-Alanine with 98 % ee was synthesized from the (S)-amine by using the method discussed here. Achiral aromatic and heteroaromatic aldehydes could also be successfully utilized to afford chiral α-aminonitriles in a highly stereoselective manner. The stereodivergent synthesis of styrylglycine nitriles has also been accomplished by using racemic and enantioenriched 2-methylbenzhydrylamine. Thus, accompanied with a small rearrangement of the common substrate from achiral toward chiral, the present reactions induce an enhancement of chirality, and expands the concept of stereoselective synthesis to increase the opportunity to access highly enantioenriched compounds such as α-amino acids.

Rhodium-catalyzed enantioselective hydrogenation of α-amino acrylonitriles: an efficient approach to synthesizing chiral α-amino nitriles.

An efficient rhodium-catalyzed asymmetric hydrogenation of α-amino acrylonitriles has been developed, affording α-acylamino nitriles with high yields and excellent enantioselectivities (up to 99% yield and >99% ee). This novel methodology provides an efficient and concise synthetic route to chiral α-amino nitriles, which are versatile intermediates in organic synthesis.

Small Molecule as a Chiral Organocatalyst for Asymmetric Strecker Reaction

A simple and novel chiral amide-based organocatalyst 6 was synthesized from readily available starting materials for the asymmetric Strecker reaction. A variety of N-benzhydryl- and N-tosyl-substituted imines were found to be suitable substrates with i-PrOH as an additive in the presence of chiral organocatalyst 6 at 0 °C with ethylcyanoformate as a source of cyanide for the synthesis of chiral α-amino nitriles. High yield (up to 91%) with excellent enantioselectivity (ee up to 99% of product) were achieved in 24–30 h in the case of both N-benzhydryl- and N-tosyl-substituted imines. To understand the mechanism of the catalytic Strecker reaction, NMR studies and kinetic investigations were carried out with different concentrations of the catalyst 6, ethylcyanoformate, and substrate. It was found that the asymmetric Strecker reaction was first-order with respect to the concentration of the catalyst, EtOCOCN, and saturation kinetics in substrate. An appropriate stereochemical model for the enantioselective S...

ChemInform Abstract: Asymmetric Strecker Reaction with Chiral Amines: A Catalyst‐Free Protocol Using Acetone Cyanohydrin in Water.

AbstractA new synthesis of a series of new chiral α‐aminonitriles derived from L‐α‐amino acids is described.

The GAP chemistry for chiral N-phosphonyl imine-based Strecker reaction

Chiral N-phosphonyl imines were found to be efficient electrophiles for reaction with diethylaluminium cyanide, a non-volatile and inexpensive cyanide source. The reaction produced chiral Strecker adducts, α-aminonitriles, in excellent chemical yields (94–98%) and diastereoselectivities (95 : 5 to >99%). This synthesis was confirmed to follow the GAP chemistry (group-assistant-purification chemistry) process, which can avoid traditional chromatography and recrystallization purifications, i.e., the pure chiral α-aminonitriles bearing a chiral N-phosphonyl group can be simply obtained by washing the solid crude products with hexane. The chiral N-phosphonyl auxiliary can be easily cleaved under mildly acidic conditions and quantitatively recycled by a one-time extraction with n-butanol.

Dication C(R 1)–N(R 2) 2 Synthons and their use in the Synthesis of Formamidines, Amidines, and α-Aminonitriles

A combination of amides and 2-pyridinesulfonyl chloride was evaluated as synthons of the dication C(R 1)–N(R 2) 2 2+. When the substrates were primary amines, high yields of formamidines and amidines were obtained. When the substrates were α-aminoamides, α-aminonitriles were obtained. Through this process, naturally occurring α-aminoacids can be transformed into chiral α-aminonitriles with complete retention of stereochemical configuration. All reactions proceed rapidly at room temperature, and normally finish within 10 min, with yields ranging from 80 to 95% for most cases. Among the sulfonyl chlorides examined, 2-pyridinesulfonyl chloride stands out in both reaction rate and selectivity of formamidine or amidine versus sulfonyl amide. The scope and limitations of the reaction among different types of amides as synthons and amines as substrates were examined.

A simple preparation of N-protected chiral α-aminonitriles from N-protected α-amino acid amides

N-protected α-amino-acid amides are dehydrated to N-protected α-aminonitriles in good yields and with excellent purities by reaction of the corresponding primary amides with cyanuric chloride in DMF.

Asymmetric synthesis IV. Preparation of chiral α-aminonitriles from a new N-cyanomethyl-1,3-oxazolidine synthon

The synthesis of (−)-N-Cyanomethyl-4-phenyl-1,3-oxazolidine 1 is reported. Good yields and moderate diastereomeric excesses (d.e.s.) of mono- and di-substituted α-aminonitriles were obtained from this simple chiral template.