Asymmetric Strecker Reaction Arising from the Molecular Orientation of an Achiral Imine at the Single‐Crystal Face: Enantioenriched <scp>l</scp>‐ and <scp>d</scp>‐Amino Acids

Miyagawa, Shinobu; Yoshimura, Koji; Yamazaki, Yusuke; Takamatsu, Naoya; Kuraishi, Tetsuya; Aiba, Shohei; Tokunaga, Yuji; Kawasaki, Tsuneomi

doi:10.1002/anie.201611128

Cited by 34 publications

(21 citation statements)

References 53 publications

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“…30 Furthermore, Kawasaki and co-workers have shown how amino nitriles can be synthesized from Strecker reactions and obtained in high ees through crystallization or attack of HCN to a specific imine crystal face. 37,38 We were delighted to find that using 20 mol% of amino nitrile, as before, gave 2-deoxy-D-ribose in similar yields and selectivities to those achieved with the amino ester promoters (compare entries 3 and 9, or 6 and 12). Importantly, we also found that after 24 hours in an aqueous environment there was no observed erosion of the %ee of L-valine nitrile via polarimetry studies.…”

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confidence: 78%

Prebiotic synthesis of 2-deoxy-d-ribose from interstellar building blocks promoted by amino esters or amino nitriles

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confidence: 78%

Prebiotic synthesis of 2-deoxy-d-ribose from interstellar building blocks promoted by amino esters or amino nitriles

et al. 2017

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“…The tiny imbalance of the enantiomorphous aminonitriles could be greatly amplified from ca. 0.05 % enantiomeric excess ( ee ) to near enantiopure (>99.5 % ee ) by thermal dissolution/crystallization cycles . Although this transformation is powerful for the synthesis of large amounts of highly enantioenriched α‐aminonitriles—the chiral intermediates of α‐amino acids—crystallization of aminonitriles in the conglomerates is necessary.…”

Section: Introductionmentioning

confidence: 99%

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

Takamatsu

Aiba

Yamada

et al. 2017

Chemistry A European J

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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.

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“…After this solution was stirred for 5 min, the solvents were removed in vacuo. Again, after the addition of toluene (3.1 mL) and ethanol (1.55 mL), solvents were removed in vacuo to afford the crude imine 42 (455 mg). To a solution of the imine in toluene (4.6 mL) and methanol (4.6 mL) was added HCN (125 μL, 3.1 mmol) at room temperature.…”

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confidence: 99%

Quantitative Difference in Solubility of Diastereomeric (²H/¹H)-Isotopomers

et al. 2021

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Many achiral organic compounds become chiral by an isotopic substitution of one of the enantiotopic moieties in their structures. Although spectroscopic methods can recognize the molecular chirality due to an isotopic substitution, the effects of isotopically chiral compounds in enantioselective reactions have remained unsolved because the small chirality arises only from the difference between the number of neutrons in the atomic nuclei. The difference between the diastereomeric isotopomers of reactive sources should be the key to these effects. However, the energy difference between them is difficult to calculate, even using present computational methods, and differences in physical properties have not yet been reported. Here, we demonstrate that the small energy difference between the diastereomeric isotopomers at the molecular level can be enhanced to appear as a solubility difference between the diastereomeric (2H/1H) isotopomers of α-aminonitriles, synthesized from an isotopically chiral amine, achiral aldehyde, and HCN. This small, but measurable, difference induces the chiral (d/l) imbalance in the suspended α-aminonitrile; therefore, a second enhancement in the solid-state chirality proceeds to afford a highly stereoimproved aminonitrile (>99% selectivity) whose handedness arises completely from the excess enantiomer of isotopically chiral amine, even in a low enantiomeric excess and low deuterium-labeling ratio. Because α-aminonitriles can be hydrolyzed to chiral α-amino acids with the removal of an isotope-labeling moiety, the current sequence of reactions represents a highly enantioselective Strecker amino acid synthesis induced by the chiral hydrogen (2H/1H) isotopomer. Thus, hydrogen isotopic chirality links directly with the homochirality of α-amino acids via a double enhancement of α-aminonitrile, the chiral intermediate of a proposed prebiotic mechanism.

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

Cited by 34 publications

References 53 publications

Prebiotic synthesis of 2-deoxy-d-ribose from interstellar building blocks promoted by amino esters or amino nitriles

Prebiotic synthesis of 2-deoxy-d-ribose from interstellar building blocks promoted by amino esters or amino nitriles

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

Quantitative Difference in Solubility of Diastereomeric (²H/¹H)-Isotopomers

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

Cited by 34 publications

References 53 publications

Prebiotic synthesis of 2-deoxy-d-ribose from interstellar building blocks promoted by amino esters or amino nitriles

Prebiotic synthesis of 2-deoxy-d-ribose from interstellar building blocks promoted by amino esters or amino nitriles

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

Quantitative Difference in Solubility of Diastereomeric (2H/1H)-Isotopomers

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Quantitative Difference in Solubility of Diastereomeric (²H/¹H)-Isotopomers