NMR chiral discrimination of chalcogen containing secondary alcohols

Here, we report the general strategies by which NMR spectroscopy can be used to determine the enantiopurity and absolute configuration of chalcogen containing secondary alcohols, including the evaluation of the use of chiral solvating and chiral derivatizing agents. The BINOL/DMAP ternary complex demonstrated a simple and fast protocol for determining enantiopurity. The drug Naproxen afforded a stable, nonhygroscopic, and readily available chiral derivatizing agent (CDA) for NMR chiral discrimination of chalcogen containing secondary alcohols. The chiral recognition by CDA and chiral solvating agent (CSA) was assessed using ¹H, ⁷⁷Se‐{1H}, and ¹²⁵Te‐{1H} NMR spectroscopy. A simple model for the assignment of the absolute configuration from NMR data is presented.     

Chiral symmetry conservation principle

We show a chiral symmetry conservation principle based on chemical kinetics using stochastic results. Suppose the chiral symmetry conservation is evoked, and our universe can be considered globally asymmetric. In that case, there are at least two mirrored asymmetric universes if all the chiral properties are strongly correlated. However, if the chiral correlations are weak or nonexistent, there are possibly Many-(Chiral-Symmetry)-Worlds. Alternatively, if our universe is only locally asymmetric, there could be a single universe with segregated chiral regions. The possible mechanisms of the primordial chiral symmetry breaking can only be found if the chiral symmetry is not truly conserved by assuming the initial racemic conditions. In that case, our universe is asymmetric and could be alone. On the other hand, if the chiral symmetry is conserved, there is no chance of finding the primordial chiral symmetry breaking. Based on this conservation (or not), it is possible to infer two opposite hypotheses, where two general scenarios about the chiral universes are possible.     

A general criterion for molecular recognition: implications for chiral interactions

A general criterion is formulated for molecular recognition. The criterion for recognition is the inequality of the distance matrices of complexes of different compounds with a resolving agent under ambient experimental conditions. It is shown how this criterion provides for an objective, well-defined, and simple explanation for recognition of chiral compounds. This approach may be used to explain models (e.g., three-point of attachment) and relationships for chiral recognition. It is also shown how one-, two-, or three-point mechanisms are equivalent in this formalism and could result in chiral recognition. Examples are used to illustrate how the so called one- or two-point mechanisms may be operative in many experimental findings. Symmetry requirements of resolving agents may also be derived from considerations of distance matrices. Finally, the reciprocal relationship of chiral resolving agents is easily derived from the present method of analysis.     

A comparison of LC and SFC for cellulose- and amylose-derived chiral stationary phases

This paper presents a systematic comparison of liquid chromatography (LC) and supercritical fluid chromatography (SFC) for Chiralcel OD and Chiralpak AD chiral stationary phases (CSPs), performed using various chiral compounds having a known or potential pharmaceutical activity. The chiral recognition mechanisms involved in LC and SFC for the enantiomeric separation of β-blockers have been studied more particularly. As a general rule, it appears that the presence of polar functions, like primary or secondary hydroxyl or amine functions, may result in marked discrepancies in selectivity between LC and SFC. This result is peculiar to cellulose- and amylose-derived CSPs, for which the interactions involved in chiral recognition mechanism are not always well balanced, contrary to what happens for independent CSPs. In the case of chiral resolution of polar solutes or polymer-type CSPs, the analyst should try both the LC and SFC techniques to be able to choose the more stereoselective one. © 1995 Wiley-Liss, Inc.     

Probability rule for chiral recognition

Molecular Chirality is of central interest in biological studies because enantiomeric compounds, while indistinguishable by most inanimate systems, show profoundly different properties in biochemical environments. Enantioselective separation methods, based on the differential recognition of two optical isomers by a chiral selector, have been amply documented. Also, great effort has been directed towards a theoretical understanding of the fundamental mechanisms underlying the chiral recognition process. Here we report a comprehensive data examination of enantio separation measurements for over 72000 chiral selector-select and pairs from the chiral selection compendium CHIRBASE. The distribution of alpha = k'(D)/k'(L) values was found to follow a power law, equivalent to an exponential decay for chiral differential free energies. This observation is experimentally relevant in terms of the number of different individual or combinatorial selectors that need to be screened in order to observe alpha values higher than a preset minimum. A string model for enantiorecognition (SMED) formalism is proposed to account for this observation on the basis of an extended Ogston three-point interaction model. Partially overlapping molecular interaction domains are analyzed in terms of a string complementarity model for ligand-receptor complementarity. The results suggest that chiral selection statistics may be interpreted in terms of more general concepts related to biomolecular recognition.     

NMR studies of chiral recognition by cyclodextrins

Chiral recognition by cyclodextrins is of considerable importance, especially for pharmaceutical industry, in view of the possible side effects of the second enantiometer of chiral drugs. In general, it manifests itself in all NMR parameters (chemical shifts, coupling constants, NOE and ROE effects, and relaxation rates) on one hand. On the other hand, it allows one to determine the thermodynamic parameters characterizing diastereomeric complexes formed by cyclodextrins with enantiomeric guests. After an introduction and a general discussion of NMR manifestations of chiral recognition by cyclodextrin, the existing literature data on this problem will be discussed herein. Chirality 16:90-105, 2004.     

Performance of brush-type HPLC chiral stationary phases with tertiary amide in the connecting tether

The replacement of the N-H hydrogen of the secondary amide-tethered Pirkle-concept N-(3,5-dinitrobenzoyl)-L-leucine derived chiral stationary phase with various pi-basic or aliphatic groups improved the chiral discrimination ability of new chiral stationary phases, based on the leucine- or alanine-derived chiral selector, for the enantiomers of various racemic neutral analytes with amide functional groups. Retention times decreased while separation and resolution factors increased, thus proving the role of pi-donor aromatic unit as an electron-rich shield in the front of a silica surface. In general, chiral stationary phase (CSP) 5 with the 3,5-dimethylphenyl unit showed best performance, while CSP 3, with phenyl unit, and CSP 7, with 1-naphthyl unit in the tertiary amide connecting tether, were less efficient.     

Electrostatic chiral distinction: Tetrahedral model dimers

Although chiral distinction plays a pervasive role in chemistry, a complete understanding of how this takes place is still lacking. In this work, we expand the earlier described minimal requirement of so called four‐point interactions (vide infra). We focus on chiral point charge model systems as a means to aid in the dissection of the underlying, operative principles. We also construct models with defined symmetry characteristics. By considering extensive constellations of diastereomeric complexes, we are able to identify emerging principles for chiral distinction. As previously postulated, all the diastereomeric complexes, regardless of their nominal contact‐points, possess a chiral distinction energy. In the comparison of complexes, we find that, contrary to chemical intuition, the magnitude of chiral distinction does not correlate with the stability of the complexes, i.e., consideration of low energy complexes may not be an effective way to evaluate chiral distinction. Similarly, we do not find a correlation between the number of contact‐points and chiral distinction. Moreover, favorable interactions and facile chiral distinction appear to be unrelated. We also see some tendency for greater chiral distinction in less symmetric systems, although this may not be general. These studies can now form the basis to fold in higher levels of complexity into the models so as to gain further insights into the nature of chiral distinction. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Liquid chromatographic separation of chiral diarylcarbinols

The direct HPLC separation of three chiral carbinols of general formula Mesityl-CH(OH)-Aryl has been achieved using Pirkle (R)-DNBPG ionic or covalent columns and, for Aryl = o-tolyl, on a Chiralpak OP(+) phase. It is apparent that steric hindrance and hydrogen bonding play important roles in chiral recognition. Two compounds structurally very similar but lacking the hydroxyl group were not resolved in their enantiomeric pairs. © 1992 Wiley-Liss, Inc.     

Axially chiral Ni(II) complexes of α‐amino acids: Separation of enantiomers and kinetics of racemization

Herein we present design, synthesis, chiral HPLC resolution, and kinetics of racemization of axially chiral Ni(II) complexes of glycine and di‐(benzyl)glycine Schiff bases. We found that while the ortho‐fluoro derivatives are configurationally unstable, the pure enantiomers of corresponding axially chiral ortho‐chloro‐containing complexes can be isolated by preparative HPLC and show exceptional configurational stability (t_1/2 from 4 to 216 centuries) at ambient conditions. Synthetic implications of this discovery for the development of new generation of axially chiral auxiliaries, useful for general asymmetric synthesis of α‐amino acids, are discussed.     

Methods of analysis of chiral non-steroidal anti-inflammatory drugs

Although the analysis of the enantiomers of chiral non-steroidal anti-inflammatory drugs (NSAIDs) has been carried out for over 20 years, there often remains a deficit within the pharmaceutical and medical sciences to address this issue. Hence, despite world-wide therapeutic use of chiral NSAIDs the importance of stereoselectivity in pharmacokinetic, pharmacodynamic and pharmacological activity and disposition has often been ignored. This review presents both the general principles that allow separation of chiral NSAID enantiomers, and discusses both the advantages and disadvantages of the available chromatographic assay methods and procedures used to separately quantify NSAID enantiomers in biological matrices.     

Synthesis of hydroxydiamines and triamines via reductive cleavage of N–N bond in substituted pyrazolidines

Aliphatic polyamines, being a versatile class of organic compounds, are widely used in many fields of medicine and organic chemistry. However, the general approach to the synthesis of chiral aliphatic polyamines has been still undeveloped. Here, we describe a new method for the synthesis of chiral trifunctional amino compounds, namely hydroxydiamines and triamines. The initial compounds, namely substituted hydroxy- or aminopyrazolidines and pyrazolines, are readily available using convenient stereoselective methods developed earlier by us. The proposed method allows synthesizing of chiral diaminoalcohols and triamines, which are the analogs of a well-known anti-TB drug, namely ethambutol, and cannot be obtained alternatively. The key step of the synthesis is N-N bond cleavage in substituted hydroxy- or aminopyrazolidines and pyrazolines with borane-tetrahydrofuran complex; other known methods for N-N bond cleavage turned out to be ineffective. The main advantage of the proposed method is the retention of a certain configuration of stereocenters in the course of the reaction. Six new chiral diasteomerically pure substituted hydroxydiamines and triamines and the enantiomerically pure triamine with four chiral centers were synthesized and characterized using NMR, IR and mass spectroscopy, as well as elemental analysis.     

Chiral polyamines from reduction of polypeptides: asymmetric pyridoxamine-mediated transaminations

BH3.THF can reduce polypeptides to polyamines with retention of chirality. The resulting polyamines are intriguing general platforms for asymmetric catalysis, given the diverse structures available and their relative ease of synthesis. We have constructed a number of chiral pyridoxamine catalysts based on reduced peptides. These compounds transaminate alpha-ketoacids with moderate to good enantioselectivity, while their peptidyl counterparts show almost no chiral induction.     

Enzyme catalysed deracemisation and dynamic kinetic resolution reactions

New catalysts and reaction conditions have been developed for the dynamic kinetic resolution or deracemisation of racemic mixtures of chiral compounds. Specific functional groups that lend themselves particularly well to this approach include chiral secondary alcohols, alpha-amino acids, amines and carboxylic acids. A general theme of these processes is the combination of an enantioselective enzyme with a chemical reagent, the latter being used either to racemise the unreactive enantiomer or alternatively recycle an intermediate in the deracemisation process. In some examples of dynamic kinetic resolution, a second enzyme (racemase) is used to interconvert the enantiomers of the starting material.     

Stereochemistry of phosphoryl transfer

A general method has been developed for the synthesis of chiral [16O,17O,18O]phosphate monoesters of known absolute configuration. An analytic method for determining the absolute configuration of chiral phosphate esters has also been developed, which is based on the isotope effects of 17O and 18O at phosphorus in the 31P nuclear magnetic resonance spectrum. These methods have shown that phosphoryl transfer catalysed by hexokinase, phosphofructokinase and pyruvate kinase occurs with inversion of configuration. This is most simply interpreted as an "in-line' transfer of the phosphoryl group between substrates in the enzyme-substrate ternary complex.     

Diphenylethanediamine (DPEDA) derivatives as chiral selectors: IV. A comparison of 3,5-dinitrobenzoylated (S,S)- and (S,R)-DPEDA-derived chiral stationary phases with Pirkle's standard (R)-phenylglycine-derived phase in normal phase HPLC

Undecanoyl bound 3,5-dinitrobenzoyl-(S,R)-1,2-diphenylethane-1,2-diamine [(1S,2R)-DNB-DPEDA] as chiral selector (SO) has been synthesized and used as a chiral stationary phase (CSP II) for normal-phase enantioselective HPLC. It is compared with the already published diastereomeric (1S,2S)-DNB-DPEDA-derived CSP I and with the “standard” Pirkle DNB-(R)-phenylglycine-derived CSP III. Chromatographic data for about 100 racemic analytes reveal that CSP II is able to separate especially well enantiomers of derivatized aromatic carboxylic acids and analytes having a benzyl substituent bound at the chiral center. However, CSP I was found to be superior to CSP II and III in its general applicability and its ability to resolve enantiomers of heterocyclic drugs. © 1994 Wiley-Liss, Inc.     

Evaluation of quantitative structure property relationships necessary for enantioresolution with lambda- and sulfobutylether lambda-carrageenan in capillary electrophoresis

Lambda-carrageenan, a linear, high molecular weight sulfated polysaccharide, was successfully employed in both its native and sulfobutyl derivatized form as a chiral selector in capillary electrophoresis for the separation of enantiomers of basic pharmaceutical compounds. In order to characterize the chiral selectivity properties of this chiral selector, various structurally related racemic compounds were analyzed for enantiomeric interactions using capillary electrophoresis. The results of these studies were then rationalized and analyzed utilizing a general quantitative structure-property relationship (QSPR) evaluation in order to predict critical analyte structural requirements for successful enantiomeric separation. Important structural components of the analytes were found to include the aromatic content, the type of substitution on the aromatic ring, presence of a primary or secondary protonated amine, and an overall positive charge to the molecule.     

Methods of analysis and separation of chiral flavonoids

Although the analysis of the enantiomers and epimers of chiral flavanones has been carried out for over 20 years, there often remains a deficit within the pharmaceutical, agricultural, and medical sciences to address this issue. Hence, despite increased interest in the potential therapeutic uses, plant physiology roles, and health-benefits of chiral flavanones, the importance of stereoselectivity in agricultural, nutrition, pharmacokinetic, pharmacodynamic, pharmacological activity and disposition has often been ignored. This review presents both the general principles that allow separation of chiral flavanones, and discusses both the advantages and disadvantages of the available chromatographic assay methods and procedures used to separately quantify flavanone enantiomers and epimers in biological matrices.