Role of Association in Chiral Catalysis: From Asymmetric Synthesis to Spin Selectivity

Abstract

The origin of biomolecules in the pre-biological period is still a matter of debate, as is the unclarified nature of the differences in enantiomer properties, especially for the medically important activity of chiral drugs. With regards to the first issue, significant progress was made in the last decade of the 20th century through experimental confirmation of Frank's popular theory on chiral catalysis in spontaneous asymmetric synthesis. Soai examined the chiral catalysis of the alkylation of achiral aldehydes by achiral reagents. Attempts to model this process demonstrated the key role of chiral compounds associates as templates for chiral synthesis. However, the elementary mechanism of alkylation and the role of free radicals in this process are still incompletely understood. Meanwhile, the influence of external magnetic fields on chiral enrichment in the radical path of alkylation has been predicted. In addition, the role of chiral dyad association in another radical process, electron transfer (ET), has been recently demonstrated by the following methods: chemically induced dynamic nuclear polarisation (CIDNP), NMR spectroscopy, XRD and photochemistry. The CIDNP analysis of ET in two dyads has revealed a phenomenon first observed for chiral systems, spin selectivity, which results in the difference between the CIDNP enhancement coefficients of dyad diastereomers. These dyads are linked systems consisting of the widespread drug (S)-naproxen (NPX) or its R analogue and electron donors, namely, (S)-tryptophan and (S)-N-methylpyrrolidine. Because NPX is one of the most striking examples of the difference in the therapeutic properties of enantiomers, the appearance of spin selectivity in dyads with (S)- and (R)-NPX and S donors can shed light on the chemical nature of these differences. This review is devoted to discussing the chemical nature of spin selectivity and the role of chiral associates in the chiral catalysis of an elementary radical reaction: ET in chiral dyads.

Stereoselectivity of Electron and Energy Transfer in the Quenching of (S/R)-Ketoprofen-(S)-Tryptophan Dyad Excited State

“…The difference in spin selectivity in the dyads with naproxen and ketoprofen may be due to differences in the efficiency of back ET in the biradical zwitterions of these dyads. These can be both differences in lifetimes and in the biradical zwitterion configuration [12,13]. The above considerations, as well as the fact that the effective HFI constants of the methylene protons of the tryptophan and methyl protons of the pyrrolidine fragments are of the same order of magnitude, allow one to conclude that it is reasonable to use the data on the spin selectivity of the dyad with ketoprofen and N-methylpyrrolidine.…”

“…In the case of previously studied diastereomers of (S/R)-NPX-(S)-Trp and (S/R)-NPX-(S)-N-methylpyrrolidine dyads, the K values were about two. According to [12,13], this was the result of two-fold difference in the hyperfine coupling constants (HFI) of aromatic protons of NPX and the methyl protons of N-methylpyrrolidine fragment in biradical zwitterions in (R,S) and (S,S) configurations. On the other hand, the proton hyperpolarization of diastereomers of products formed from (S/R)-KP-(S)-N-methylpyrrolidine dyad differ less: the CIDNP of products from (S,S)-diasteromer is only 30% higher than for the (R,S) analogue [17].…”

“…The analyses of CIDNP data, as well as the results of the study of the influence of magnetic field on reaction rates, allow one to establish detailed schemes for the single-electron oxidation of nicotinamide adenine dinucleotide and its analogues of dihydropyridines, occurring in enzymatic Besides the stereodifferentiation, photoinduced intramolecular reversible ET in diastereomers has demonstrated another peculiarity. This is the difference in the efficiency of back ET in intermediates-biradical zwitterions [12,13]. Efficiency is defined as spin selectivity: the difference between the chemically induced dynamic nuclear polarization (CIDNP) enhancement coefficients of protons in a dyad's diastereomers [12,13].…”

“…The important CIDNP peculiarity is the high sensitivity of hyperpolarization to the changes of spin and molecular dynamics in radical intermediates. In the case of chiral systems, the analysis of the difference in spin dynamics of paramagnetic forms of diastereomers, formed as a result of photoinduced ET, has provided new data on chiral drugs reactivity [12,13]. The main result of the application of CIDNP to chiral systems is the conclusion about the difference between hyperfine coupling constants of paramagnetic forms of diastereomers that also suggest a difference in the distribution of electron densities.…”

“…Besides the stereodifferentiation, photoinduced intramolecular reversible ET in diastereomers has demonstrated another peculiarity. This is the difference in the efficiency of back ET in intermediates—biradical zwitterions [ 12 , 13 ]. Efficiency is defined as spin selectivity: the difference between the chemically induced dynamic nuclear polarization (CIDNP) enhancement coefficients of protons in a dyad’s diastereomers [ 12 , 13 ].…”