A Chirality Chain in Phenylglycine, Phenylpropionic Acid, and Ibuprofen

Henri Brunner,Takashi Tsuno,Gábor Balázs

doi:10.3390/sym13010055

Henri Brunner, Takashi Tsuno + Show 1 more

Open Access

https://doi.org/10.3390/sym13010055

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Abstract

Our strategy to analyze the structures of natural amino acids with respect to the interaction of three different elements of chirality within the molecules was applied to the non-natural amino acid (S)-α-phenylglycine, its analogue (S)-α-phenylpropionic acid, and the drug (S)-ibuprofen. The three chirality elements are the configuration at Cα, the conformation at the Cα-C’ bond, and the distortion of the planar carboxylic group to a flat asymmetric tetrahedron. In all three compounds, a given (S) configuration at Cα predominantly induces (M) conformation at the Cα-C’ bond, which in turn preferentially distorts the carboxylic group to a tetrahedron with (R) configuration. Both steps of this chirality chain display high selectivities. Due to varying co-crystallization partners, in all the structures the molecules are in different environments with respect to packing and hydrogen bonding. Nevertheless, the structural pattern and the diaselectivities of the chirality chain persist. For phenylglycine, DFT (Density Functional Theory) calculations confirm the structural results.

Highlights

In amino acids there is chirality and selectivity beyond the configuration at the αcarbon atom
The chirality chain consists of three different elements of chirality: (1) the Cα configuration, which in natural amino acids is L, (2) the conformation concerning rotation around the central C’-Cα bond, and (3) the distortion of the planar carboxylic group CαC’OcisOtrans to a flat asymmetric tetrahedron with four different corners
Data compiled in the Cambridge Structural Database (CSD) have been used to find chemical relationships for a long time

Summary

Introduction

In amino acids there is chirality and selectivity beyond the configuration at the αcarbon atom. The chirality chain consists of three different elements of chirality: (1) the Cα configuration, which in natural amino acids is L, (2) the conformation concerning rotation around the central C’-Cα bond, and (3) the distortion of the planar carboxylic group CαC’OcisOtrans to a flat asymmetric tetrahedron with four different corners. The L configuration at Cα induces preferably (Mψ) conformation at the C’-Cα bond with small negative rotation angles ψ = OcisC’CαN and the (Mψ) conformation distorts the planar carboxylic group preferentially to a flat tetrahedron OcisOtransC’Cα with (Rθ) configuration Stimulated by the progress in X-ray crystallography, today, a wealth of CSD structures is available for exploitation We used this information for an analysis of phenylglycine, α-phenylpropionic acid, and Symmetry 2020, 12, x FOR PEER REViIbEuWprofen with respect to chiral selectivities within the molecules. Formmuullaass ooff ((SS))--pphheennyyllgglylyccininee, ,(S(S)-)α-α-p-phhenenylyplrporpoipoinoincicacaicdi,da,nadnd(S()S-i)b-uibpurpofreonfeannadnd chirality cchhaiirnaloitfythcheaainmoinf othaeciadm(iSn)o-pahciedny(Slg)-lpyhcienney:lgfolyrcaingei:vfeonr (aSg) icvoennfi(gSu) rcaotniofinguartaCtiαon, cahtirCaαl,icnhdiruacltion favors (itMnetdψrua)hccteoidonrnfoofnramvOoacritssOio(tnMranoψsC)f c’tChoαne.fCor’-mCaαtiobnonodf tahnedC(’S-Cθ)α cboonnfidgaunrdat(iSoθn) coofntfhigeuflraattitoentroafhtehderfolnatOcisOtransC’Cα

Results and Discussion

Conclusions

Materials and Methods

Stereoisomerization path for triphenylphosphine oxide and related molecules