Kinetic Resolution as a General Approach to Enantioenrichment in Prebiotic Chemistry

ConspectusThe origin of the single chirality of the chemical building blocks of life remains an intriguing topic of research, even after decades of experimental and theoretical work proposing processes that may break symmetry and induce chiral amplification, a term that may be defined as the enhancement of enantiomeric excess starting from prochiral substrates or from a racemic mixture or a small imbalance between enantiomers. Studies aimed at understanding prebiotically plausible pathways to these molecules have often neglected the issue of chirality, with a focus on the stereochemical direction of these reactions generally being pursued after reaction discovery. Our work has explored how the stereochemical outcome for the synthesis of amino acids and sugars might be guided to rationalize the origin of biological homochirality. The mechanistic interconnection between enantioenrichment in these two groups of molecules provides insights concerning the handedness extant in modern biology. In five separate examples involving the synthesis of life's building blocks, including sugars, RNA precursors, amino acids, and peptides, kinetic resolution emerges as a key protocol for enantioenrichment from racemic molecules directed by chiral source molecules. Several of these examples involve means not only for chiral amplification but also symmetry breaking and chirality transfer across a range of racemic monomer molecules. Several important implications emerge from these studies: one, kinetic resolution of the primordial chiral sugar, glyceraldehyde, plays a key role in a number of different prebiotically plausible reactions; two, the emergence of homochirality in sugars and amino acids is inherently intertwined, with clear synergy between the biological hand of each molecule class; three, the origin story for the homochirality of enzymes and modern metabolism points toward kinetic resolution of racemic amino acids in networks that later evolved to include sophisticated and complete catalytic and co-catalytic cycles; four, a preference for heterochiral ligation forming product molecules that cannot lead to biologically competent polymers can in fact be a driving force for a route to homochiral polymer chains; and five, enantioenrichment in complex mixtures need not be addressed one compound at a time, because kinetic resolution induces symmetry breaking and chirality transfer that may lead to general protocols rather than specific cases tailored to each individual molecule. Such chirality transfer mechanisms perhaps presage strategies utilized in modern biology.Our latest work extends the study of monomer enantioenrichment to the ligation of these molecules into the extended homochiral chains leading to the complex polymers of modern biology. A central theme in all of these reactions is the key role that kinetic resolution of a racemic mixture of amino acids or sugars plays in enabling enantioenrichment under prebiotically plausible conditions. This work has uncovered important trends in symmetry breaking, chirality transfer, and chiral amplification. Kinetic resolution of racemic mixtures emerges as a general solution for chiral amplification in prebiotic chemistry, leading to the single chirality of complex biological molecules and genetic polymers.