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

Abstract

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.

Figure 1

Asymmetric synthesis and evaluation of the enantiopurity of (S)- and (R)-benzhydrylamine-d₅ (1-d₅). (A) Catalytic asymmetric synthesis of (S)- and (R)-benzhydrylamine-d₅ (1-d₅) using the common chiral source (R,R,R)-4. (B) Determination of enantiopurities of asymmetrically synthesized (S)- and (R)-1-d₅ by ¹H NMR of their MTPA amides 5-d₅, respectively.

Figure 2

Strecker synthesis of α-aminonitrile 7-d₅ and the solubility difference between diastereomeric isotopomers of syn- and anti-7-d₅ synthesized from 1-d₅. (A) Schematic outline of the formation of a diastereomerically imbalanced suspension of aminonitrile 7-d₅ induced by a hydrogen isotope chirality. (B) Box and whisker plots of a diastereomeric (enantiomeric) excess of the solution-phase aminonitriles 7-d₅ and 7 in their suspension originating from (S)-, (R)-, rac-1-d₅, and unlabeled 1.

Figure 3

Enantioselective synthesis of α-(p-tolyl)glycine (8) with enantioenriched isotopically (²H/¹H) chiral benzhydrylamine-d₅ (1-d₅) as a source of chirality. (A) Amplification of chirality of α-aminonitrile 7-d₅ by the heating–cooling cycle. The changes in de of the reactions shown in Table 1, entries 3 and 4, were monitored and were described as red and blue lines, respectively. (B) Acidic hydrolysis of anti-d-aminonitrile 7-d₅ to form the α-amino acid d-p-tolylglycine (8).

Figure 4

Double enhancement of hydrogen isotope chirality.