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.
Highlights
Since Pasteur discovered molecular asymmetry,[1] the origin of biological chirality in nature has been an attractive mystery.[2,3] Among the theories,[4−9] isotopic chirality is a possibility[10] because many apparently achiral organic compounds become chiral when taking isotopic substitutions into consideration.[11−14] A higher deuterium-labeling ratio of meteoritic compounds than found in the same terrestrial compounds has been reported;[15] extra-terrestrial organic compounds may have isotopic chirality
When (S)-amine 1-d5 with a low labeling ratio by mixing with unlabeled 1 was submitted to the Strecker reaction, after the enhancement of chirality, 7-d5 including unlabeled 7 with an L configuration was synthesized in the same stereochemical relationship
A highly enantioselective Strecker amino acid synthesis has been achieved by utilizing chiral benzhydrylamine arising from hydrogen isotope (2H/1H) substitution
Summary
Since Pasteur discovered molecular asymmetry,[1] the origin of biological chirality in nature has been an attractive mystery.[2,3] Among the theories,[4−9] isotopic chirality is a possibility[10] because many apparently achiral organic compounds become chiral when taking isotopic substitutions into consideration.[11−14] A higher deuterium-labeling ratio of meteoritic compounds than found in the same terrestrial compounds has been reported;[15] extra-terrestrial organic compounds may have isotopic chirality. The present amplification of solid-state chirality originated from the small but measurable solubility difference between the isotopomers. It is the first example to demonstrate quantitatively a solubility difference between the diastereomeric (2H/1H) isotopomers and their asymmetric amplification. These effects may be the key to understand the asymmetric induction by enantioenriched chiral compounds arising from hydrogen isotope substitution
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