Absolute asymmetric Strecker synthesis in a mixed aqueous medium: reliable access to enantioenriched α-aminonitrile.

Without using chiral sources, the Strecker reaction of achiral hydrogen cyanide, p-tolualdehyde and benzhydrylamine gave enantioenriched l- or d-N-benzhydryl-α-(p-tolyl)glycine nitriles with up to >99% ee in a mixed solvent of water and methanol. Therefore, total spontaneous resolution of α-aminonitriles could occur through a prebiotic mechanism of α-amino acid synthesis. Moreover, it was demonstrated that the repetition of partial dissolution and crystallization of a suspended conglomerate of aminonitrile under solution-phase racemization could generate the enantiomeric imbalance to afford, in combination with the amplification of chirality, an enantioenriched product in every case. Among the 73 experiments that were carried out, d- and l-enriched isomers occurred 36 and 37 times, respectively. This stochastic behavior, under achiral or racemic starting conditions, meets the requirements of the spontaneous absolute asymmetric Strecker synthesis. The implications of the present results for the origin of chirality of α-amino acids are discussed.

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.

Asymmetric Strecker Reaction Arising from the Molecular Orientation of an Achiral Imine at the Single-Crystal Face: Enantioenriched l- and d-Amino Acids.

Strecker synthesis has long been considered one of the prebiotic reactions for the synthesis of α-amino acids. However, the correlation between the origin of chirality and highly enantioenriched α-amino acids through this method remains a puzzle. In the reaction, it may be conceivable that the handedness of amino acids has been determined at the formation stage of the chiral intermediate α-aminonitrile, that is, the enantioselective addition of hydrogen cyanide to an imine. Herein, an enantiotopic crystal surface of an achiral imine acted as an origin of chirality for the enantioselective formation of α-aminonitriles by the addition of HCN. In conjunction with the amplification of the enantiomeric excess and multiplication of enantioenriched aminonitrile, a large amount of near enantiopure α-amino acids, with the l- and d-handedness corresponding to the molecular orientation of the imine, is reported.

Replication of α-amino acids via Strecker synthesis with amplification and multiplication of chiral intermediate aminonitriles.

Replication of chiral l- and d-α-(p-tolyl)glycine has been achieved in combination with the asymmetric induction, amplification and multiplication of their own chiral intermediates, l- and d-aminonitriles, in the solid-phase via the Strecker reaction between three achiral components, which is a plausible prebiotic mechanism for amino acid synthesis.

Spontaneous formation and amplification of an enantioenriched α-amino nitrile: a chiral precursor for Strecker amino acid synthesis.

Without the addition of any chiral substances, the spontaneous formation of an enantioenriched α-amino nitrile (up to 96% ee), which is a chiral precursor for Strecker amino acid synthesis, has been achieved in combination with conglomerate formation. The frequency of the formation of enantiomorphs exhibits an approximate stochastic distribution, i.e., L-form occurred 21 times and D-form occurred 22 times, which fulfils the conditions necessary for spontaneous absolute asymmetric synthesis.