Hexacoordinated phosphates: how to teach old chiral anions new asymmetric tricks

Chemical reactions and processes often involve chiral, yet racemic, cationic reagents, intermediates, or products. To afford instead nonracemic or enantiopure compounds, an asymmetric ion pairing of the cations with enantiopure anions can be considered--the counter ions behaving as asymmetric auxiliaries, ligands, or reagents. Detailed herein is a short review of our approach toward gaining reliable and predictable control over stereoselective ion pairing phenomena through the synthesis and use of novel configurationally stable hexacoordinated phosphate anions.     

Recent developments in chiral anion mediated asymmetric chemistry

Chemical reactions and processes often involve cationic prostereogenic or racemic reagents, intermediates or products. To afford instead non-racemic or enantiopure compounds, an asymmetric ion pairing of the cations with chiral anionic counterions can be considered. This review presents recent examples of the synthesis and use of chiral anions for stereoselective purposes.     

Chiral hexacoordinated phosphates: From pioneering studies to modern uses in stereochemistry

Chiral cationic molecular structures and supramolecular assemblies can be effectively analyzed, resolved and stereocontrolled through an asymmetric ion pairing with enantiopure hexacoordinated phosphate anions like TRISPHAT or BINPHAT. After an historical perspective on the development of these anionic reagents, this account describes their synthesis and their use as chiral NMR solvating, resolving and asymmetry-inducing reagents.     

Trimesitylmethylphosphonium cation. Supramolecular stereocontrol and simple enantiomerization mechanism determination

Stereocontrol over the propeller isomerism of trimesitylmethylphosphonium cation was achieved through an ion pairing with chiral hexacoordinated phosphate anions; the asymmetric ion pairing allowed also a most simple experimental proof of the nature of the enantiomerization pathway in solution (two-ring flip).     

Separation and characterization of aluminium malate species by ion chromatography

Aluminium malate complexes have a high relevance in biological systems. The anionic species present in an aqueous aluminium malate mixture can be investigated by ion chromatography coupled online with inductively coupled plasma atomic emission spectroscopy. As malic acid is a chiral ligand, the experiments were carried out using the racemic and the enantiopure forms. In both systems four anionic complexes are observable in the model solutions. One of two crystallized and well-characterized anions, [Al(4)Malate(6)](6-) and [Al(4)Malate(4)](2-), serves as a reference anion for the assignment of one of the species occurring in the model solutions. The main species in the enantiopure aluminium malate model with biological relevance over a wide pH range is the [Al(4)Malate(4)](2-) anion. The [Al(4)Malate(6)](6-) anion is not present in the racemic model solution. This anion suffers complete species disintegration after dissolution. The kinetics of the decay is first order and the activation energy of the decomposition is 74 kJ/mol. A retention model for ion chromatography was used for the determination of the effective charges of the species. The effective charge obtained by the retention model was calibrated in relation to nominal charges of the anions by using several well-defined and differently charged anions and anionic aluminium species.     

Unexpected solids from enantiopure cationic palladium complexes and racemic anions: A structural study of chiral non-discrimination

Enantiomerically pure cationic complexes were obtained via cyclopalladation of primary amines and subsequent addition of a chelating ethylendiamine ligand. No diastereomeric resolution was observed upon combining these cations with racemic mandelate or hydratropate anions, but four less popular products, namely three double salts and a solid solution, were obtained and structurally characterized. For one of the double salts, the alternative ionic compounds based on different stereoisomers of the same residues were synthesized independently: The conventional racemic solid and both diastereomeric salts formed by enantiopure cations and anions were studied by single crystal X-ray diffraction. Lattice energy calculations confirm that the diastereomeric salts differ significantly; formation of the partially racemic double salt, however, is energetically favourable and precludes resolution.     

Asymmetric Ion‐Pairing Catalysis

Charged intermediates and reagents are ubiquitous in organic transformations. The interaction of these ionic species with chiral neutral, anionic, or cationic small molecules has emerged as a powerful strategy for catalytic, enantioselective synthesis. This review describes developments in the burgeoning field of asymmetric ion‐pairing catalysis with an emphasis on the insights that have been gleaned into the structural and mechanistic features that contribute to high asymmetric induction.     

胺及其衍生物的非酰基化动力学拆分

光学纯胺在合成与药物化学领域都有着广泛的应用,发展其高效的合成方法一直以来是有机化学界的研究热点.其中通过N酰基化及去酰基化动力学拆分方法获得光学纯胺化合物,已经成为合成手性胺类化合物的重要方法.近年来,基于非酰基化(或去酰基化)的不对称反应实现外消旋胺的动力学拆分的报道不断涌现,包括一些氨基不参与反应的非酰基化(或去酰基化)不对称反应的外消旋胺的动力学拆分.根据氮原子是否参与反应以及反应类型的不同,总结了外消旋胺的化学催化动力学拆分的研究进展.     

A facile synthesis of enantiopure 2-aziridinesulfinimines and their highly diastereoselective reactions with phosphite anions

Two novel enantiopure 1-benzyl-2-aziridinesulfinimines bearing a chiral group on both sides of the carbon-nitrogen double bond were synthesized from the condensation of racemic 1-benzyl-2-aziridinecarboxaldehyde and enantiopure p-toluenesulfinamide. The addition reaction with phosphite anion followed by the ring-opening reaction with thiophenol provided chiral alpha,beta-diamino-phosphonic acid derivatives. The addition reactions showed the operation of a double-stereodifferentiation effect. The possible transition states of the reaction were proposed, and high diastereoselectivities of the addition reactions of phosphite anions to both aziridinesulfinimines were realized in the presence or absence of zinc bromide.     

Acyclic and cyclic aminophosphonic acids: asymmetric syntheses mediated by chiral sulfinyl auxiliary

Aminophosphonic acids have become increasingly important in different fields of chemistry, medicine and agriculture. This account outlines the results obtained in the author’s laboratory on the asymmetric synthesis of acyclic and cyclic aminophosphonic acids mediated by chiral sulfinyl auxiliary. A key reaction in the synthesis of enantiopure α- and β-aminoalkanephosphonic acids involving a highly diastereoselective addition of phosphite anions or α-phosphonate carbanions to enantiopure sulfinimines is discussed. The asymmetric cyclopropanation of enantiopure α-phosphorylvinyl sulfoxides with sulfur ylides is presented as a platform for developing a new approach to optically active β-aminocyclopropanephosphonic acids. It is exemplified by the total synthesis of enantiopure β-amino-γ-phenylcyclopropanephosphonic acid - a constrained analogue of the GABA_B antagonist phaclofen.     

Enantiodifferentiation of chiral cationic cages using trapped achiral BF4- anions as chirotopic probes

The addition of enantiopure TRISPHAT anions to chiral cationic cages of type [Co(4)(L)(6)(BF(4))](7+) leads to the enantiodifferentiation of the ligands of the racemic salts and, even more effectively, of the achiral tetrafluoroborate anion trapped inside.     

Synthesis of (-)-swainsonine and (-)-8-epi-swainsonine by the addition of allenylmetals to chiral α,β-alkoxy sulfinylimines

The asymmetric synthesis of (-)-swainsonine and (-)-8-epi-swainsonine is reported through the addition of either the allenylzinc or the allenyl lithio cyanocuprate reagents derived from [3-(methoxymethoxy)prop-1-ynyl]trimethylsilane to enantiopure α,β-dialkoxy N-tert-butanesulfinylimines derived from d-erythronolactone.     

Retention of glycopeptides analyzed using hydrophilic interaction chromatography is influenced by charge and carbon chain length of ion‐pairing reagent for mobile phase

Characterization of the glycans of glycoproteins is essential for the development and production of biologics. Numerous methods are available for analyzing the glycans of glycoproteins directly and labeled glycans. Nevertheless, glycopeptides are difficult to resolve because of their exceptional complexity and the microheterogeneity of glycans. These properties represent technical challenges to efforts to insure the accurate characterization of biopharmaceuticals to comply with regulatory requirements. Therefore, we investigated the retention behavior of peptides and glycopeptides in hydrophilic interaction chromatography‐mode HPLC in the presence of ion‐pairing reagents. Anionic ion‐pairing reagents decreased the retention times of glycopeptides and improved resolution in the presence of higher concentrations or hydrophobicities of ion‐pairing reagent. Anionic ion‐pairing reagents increased retention times of larger glycans because of their increased hydrophilicity. In contrast, in the presence of cationic ion‐pairing reagents, the retention times of glycopeptides with greater numbers of sialic acid residues decreased. It is appropriate to add an anionic ion‐pairing reagent to the mobile phase for good separation of glycopeptides. The collision cross‐sectional area values of glycopeptides determined using electrospray ionization‐ion mobility spectrometry‐mass spectrometry correlated with retention times. These findings support the implementation of hydrophilic interaction chromatography‐mode HPLC to improve the characterization of glycosylated biopharmaceuticals.     

Nitrone cycloadditions to isolevoglucosenone: ready access to a new class of directly linked (1-->3)-imino-C-disaccharides

Straightforward access to a new class of d-gulo- and d-allo-derived directly linked (1-->3)-imino-C-disaccharides by means of cycloaddition reactions of enantiopure polyhydroxylated pyrroline N-oxides with isolevoglucosenone is reported. The cycloaddition reactions display a high level of double asymmetric induction, which allows a partial kinetic resolution of a racemic nitrone. [reaction: see text]     

Switching regioselectivity in the allylation of imines by N-side chain tuning

A spectacular inversion of α- to γ-regioselectivity in the allylzincation of imines can be achieved by fine-tuning of the N-side chain. This approach allows easy preparation of regioisomeric amines, in racemic as well as enantiopure forms. The usefulness of the method is illustrated by the parallel asymmetric syntheses of 2,3- and 2,5-diphenylpyrrolidines.     

Synthesis of enantiopure homoallylic ethers by reagent controlled facial selective allylation of chiral ketones

The stereoselective allylation of chiral methyl ketones to give tertiary homoallylic ethers, which can easily be transformed into homoallylic alcohols, is described. Reaction of the enantiopure ketones 8a-d and the racemic ketones 26a-d with the norpseudoephedrine derivative 2 or ent-2 and allylsilane in the presence of a catalytic amount of trifluoromethanesulfonic acid, led to a series of homoallylic ethers with good to excellent diastereoselectivity (85:15 to > 97:3). The allylation is reagent controlled and nearly independent from the stereogenic centers in the substrates. A partial kinetic resolution was observed using the racemic ketones 26a-d. In the reaction of the chiral ketones 8a-d with the achiral reagents ethoxytrimethylsilane and allylsilane only a low diastereoselectivity was observed.     

The evaluation and comparison of trigonal and linear tricationic ion-pairing reagents for the detection of anions in positive mode ESI-MS

A general and sensitive method for detecting divalent anions by ESI-MS and LC/ESI-MS as positive ions has been developed. The anions are paired with tricationic reagents to form positively charged complexes. In this study, four tricationic reagents, 2 trigonal and 2 linear, were used to study a wide variety of anions, such as disulfonates, dicarboxylates, and inorganic anions. The limits of detection for many of the anions studied were often improved by tandem mass spectrometry. Tricationic pairing agents can also be used with chromatography to enhance the detection of anions. The tricationic reagents were also used to detect monovalent anions by monitoring the doubly charged positive complex. The limits of detection for some of the divalent anions by this method are substantially lower than by other current analytical techniques.     

Synthesis and applications of chiral bis-THF in asymmetric synthesis

The synthesis of enantiopure bis-THF is described, starting from d-mannitol. Bis-THF is used as chiral ligand for organolithium reagents in four different reactions. The enantioselectivity provided by this ligand is moderate, and the asymmetric induction is in line with the expected model.     

A new type of C2-symmetric bisphospine ligands with a cyclobutane backbone: practical synthesis and application

[reaction: see text] A highly efficient and practical optical resolution of anti-head-to-head racemic coumarin dimer, (+/-)-5, by molecular complexation with TADDOL (6) through hydrogen bonding and a convenient transformation of enantiopure 5 to a new type of C(2)-symmetric bisphosphine ligand (3) have been achieved. The asymmetric induction efficiency of these chiral bisphosphine ligands was evaluated in Pd-catalyzed asymmetric allylic substitution, affording the allylic substitution products in excellent yield (up to 99%) and enantioselectivity (up to 98.9% ee).     

Asymmetric synthesis of aziridine 2-phosphonates from enantiopure sulfinimines (N-sulfinyl imines). Synthesis of alpha-amino phosphonates

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure sulfinimines, has been developed for the asymmetric synthesis of aziridine 2-phosphonates. Best results involve cyclization of the syn and anti diastereomerically pure alpha-chloro-beta-amino phosphonates to cis- and trans-N-sulfinyl aziridine 2-phosphonates, respectively, with n-BuLi. A transition-state hypothesis is proposed wherein the chloromethylphosphonate anion adds to the C-N bond on the side that is opposite the bulky p-tolyl sulfinyl group. The N-sulfinyl group is easily removed by treatment with MeMgBr or TFA/MeOH, which affords the NH-aziridines in good yield. Using transfer hydrogenation conditions, the NH-aziridines were regioselectively opened to the corresponding enantiopure alpha-amino phosphonates without N-activation and in excellent yield.