Amino acids as chiral selectors in enantioresolution by liquid chromatography

Amino acids are unique in terms of their structural features and multidimensional uses. With their simple structures and the ready availability of both enantiomers, amino acids not only serve as a chiral pool for synthesis but also provide an inexpensive pool for resolution studies. There has been no attempt to review the application of amino acids as chiral selectors for chromatographic enantioresolution of pharmaceuticals and other compounds. The present paper deals with application of l-amino acids and complexes of l-amino acids with a metal ion, particularly Cu(II), as an impregnating reagent in thin-layer chromatography or as a chiral ligand exchange reagent or a chiral mobile phase additive in both thin-layer chromatography and high-performance liquid chromatography. Enantiomeric resolution of β-blockers, nonsteroidal anti-inflammatories, amino acids (and their derivatives) and certain other compounds is discussed.     

Geometrically selective synthesis of functionalized beta,beta-disubstituted vinylic sulfoxides by Cu-catalyzed conjugate addition of organozinc reagents to 1-alkynyl sulfoxides

[reaction: see text] A new synthetic method of chiral beta,beta-disubstituted vinylic sulfoxides bearing various functionalities has been developed by employing Cu-catalyzed conjugate addition of an organozinc reagent to chiral 1-alkynyl sulfoxide. Since the reaction proceeds with very high syn-selectivity, both geometric beta,beta-disubstituted vinylic sulfoxides were stereoselectively synthesized by changing the combination of 1-alkynyl sulfoxide and the organozinc reagent.     

Highly enantioselective direct alkylation of arylacetic acids with chiral lithium amides as traceless auxiliaries

A direct, highly enantioselective alkylation of arylacetic acids via enediolates using a readily available chiral lithium amide as a stereodirecting reagent has been developed. This approach circumvents the traditional attachment and removal of chiral auxiliaries used currently for this type of transformation. The protocol is operationally simple, and the chiral reagent is readily recoverable.     

An enantiomerically pure 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan- 2-one as 1H NMR shift reagent for the ee determination of chiral lactams, quinolones, and oxazolidinones

The chiral lactam 1 (or its enantiomer ent-1) was shown to be an effective (1)H NMR shift reagent for the ee determination of chiral lactams, quinolones, and oxazolidinones. It was successfully employed in many cases in which a detection of enantiomers by chromatographic methods failed. The method was extended to a broader range of simple substrates bearing a lactam moiety to evaluate its scope. The NH signals of the substrate enantiomers showed the strongest separation and were used for (1)H NMR integration. In most cases, compound 1 (1.5 equiv; 0.06 M solution) induced a baseline separation of the NH signals and it can consequently be regarded as a generally applicable shift reagent for chiral products with a lactam moiety.     

Regio‐ and Stereochemical Studies on the Nitroso‐Diels–Alder Reaction with 1,2‐Disubstituted Dienes

The regioselectivity of the nitroso‐Diels–Alder reaction between unsymmetrical acyclic dienes and Boc‐nitroso (Boc=tert‐butoxycarbonyl) reagent or the Wightman chiral chloronitroso reagents has been studied. With the Boc‐nitroso reagent, the selectivity is a consequence of steric effects at the C1‐position in the diene and electronic effects at the C2‐position in the diene. The combination of an unprotected hydroxyethyl side chain at C1 and an electron‐withdrawing group at C2 allows complete regioselectivity in favour of the proximal isomer. The same isomer was obtained exclusively with the chiral nitroso reagent with high enantioselectivities. A model based on steric effects is proposed.     

(S)-(−)-Fluorenylethylchloroformate (FLEC); preparation using asymmetric transfer hydrogenation and application to the analysis and resolution of amines

Fluorenylethylchoroformate (FLEC) is a valuable chiral derivatisation reagent that is used for the resolution of a wide variety of chiral amines. Herein, we describe an improved preparation of (S)-(−)-FLEC using an efficient asymmetric catalytic transfer hydrogenation as the key step. We also demonstrate the application of FLEC as a chiral Fmoc equivalent for chiral resolution, with facile deprotection, of tetrahydroquinaldines, and its capacity for inducing regioselective outcomes in nitration reactions.     

Direct enantiomeric TLC resolution of dl-penicillamine using (R)-mandelic acid and l-tartaric acid as chiral impregnating reagents and as chiral mobile phase additive

DL-Penicillamine has been resolved into its enantiomers by normal-phase TLC using L-tartaric acid as chiral impregnating reagent as well as chiral mobile phase additive, while (R)-mandelic acid has been found to be successful as a chiral impregnating reagent. The solvent system acetonitrile-methanol-water (5:1:1, v/v) was found to be successful when L-tartaric acid was used as impregnating agent while the solvent combination acetonitrile-methanol-(0.5% l-tartaric acid in water, pH 5)-glacial acetic acid (7:1:1.1:0.7, v/v) was successful as mobile phase as it contained L-tartaric acid as the chiral additive. (R)-mandelic acid was successful as chiral impregnating reagent with ethyl acetate-methanol-water (3:1:1, v/v), as the mobile phase. The effects of concentration of chiral selectors, temperature and pH were examined on enantiomeric resolution. The spots were detected with iodine vapors and the detection limits were found to be 0.12 microg for each enantiomer of penicillamine with L-tartaric acid, under both the conditions, and 0.11 microg with (R)-mandelic acid.     

Asymmetric addition of achiral organomagnesium reagents or organolithiums to achiral aldehydes or ketones: a review

The enantioselective preparation of chiral secondary and tertiary alcohols via addition of an achiral organomagnesium reagent or an organolithium to an achiral aldehyde or ketone in a chiral medium is reviewed. The review is written in chronological order and contains 113 references to literature through late 2008.     

New chiral ionic liquids based on imidazolinium salts

The preparation and application of a new series of chiral ionic liquids are described. The salts are based on imidazolinium cations. Some of the cations also incorporated an axial chirality at the C(2) position next to the central chirality. These cations display a very high rotational barrier along the arene–imidazolinium axis. Furthermore, an analogue with a chiral anion was prepared. The salts have low melting points. Their potential as solvents and as chiral shift reagents was explored, resulting for the first time in an example of a chiral ionic liquid as a shift reagent for a neutral compound.     

Perchloric Acid-Acetic Acid: A Reagent System for Detosylation

Perchloric acid-acetic acid reagent system has been found to be an efficient reagent for deprotection of p-methyl benzene sulfonyl (tosyl) derivatives of primary aromatic amines, secondary aromatic amines and chiral aminoketones.     

(S)‐Naproxen as a platform to develop chiral derivatizing reagent for reversed‐phase high‐performance liquid chromatographic enantioseparation of analytes having a carbonyl functional group

(S)‐Naproxen was used to synthesize a chiral reagent, (S)‐2‐(6‐methoxynaphthalen‐2‐yl)propanehydrazide, by itsreaction with hydrazine hydrate in the presence of dicyclohexylcarbodiimide as coupling agent. The reagent was characterized and its chiral purity was established. It was used as a chiral derivatizing reagent for the synthesis of hydrazone diastereomers, under microwave irradiation, of certain chiral aldehydes and ketones. The respective diastereomers were separated by reversed‐phase high‐performance liquid chromatography using a binary solvent combination containing trifluoroacetic acid. The diastereomers were detected at 231 nm. The method was validated for accuracy, precision, and limit of detection (LOD). For a series of hydrazones the LOD was found to be in the range 1.62–1.65 pmol/mL. Copyright © 2012 John Wiley & Sons, Ltd.     

Highly enantioselective alkynylation of aldehydes catalyzed by a new oxazolidine-titanium complex

The readily available and inexpensive new chiral oxazolidine in combination with Ti(O(i)Pr)(4) was found to catalyze the reaction of an alkynylzinc reagent with various types of aldehydes to generate chiral propargylic alcohols with high enantioselectivities (up to 95%) and excellent yields (up to 98%).     

Remote Central‐to‐Axial Chirality Conversion: Direct Atroposelective Ester to Biaryl Transformation

A strategy for the remote central‐to‐axial chirality conversion by simultaneous planarization of an encoding and a transient stereocenter is presented. Based on a diastereoselective double addition of a chiral 1,5‐bifunctional organomagnesium alkoxide reagent to a broad range of aryl ester substrates, axially chiral biaryls are directly obtained upon in situ reduction. Various structurally distinct atropisomeric biaryl silanes that serve as valuable chiral biaryl anion surrogates are accessible in one step with e.r. values of up to 98:2.     

Synthesis and application of a chiral diborate

A chiral diborate with different counterions is reported whose structure was unambiguously confirmed by X-ray analysis. This chiral dianion was used in the resolution of trans-1,2-diamines and also as a chiral shift reagent for NMR analysis of triphenylphosphonium salts.     

A simple chiral shift reagent for measurement of enantiomeric excesses of phosphine oxides

(R)-(?)-N-(3,5-dinitrobenzoyl)-α-phenylethylamine is a chiral shift reagent which allows ee measurements of various phosphine oxides. Good results were obtained for monophosphine oxides with asymmetric phosphorus centers as well as with an asymmetric carbon in α position of phosphorus. The reagent is also able to differentiate the two enantiomers of racemic DIOP dioxide.     

Acyclic stereoselection in α-amidoalkylation reactions

The chiral reagent 7 provides the first example of an acyclic α-amidoalkylation reagent that generates a new stereogenic center with excellent stereoselectivity, and the stereochemistry of the resulting products provides evidence that the N-acylimine intermediate reacts through the cisoid conformation 12.     

Asymmetric Fluorofunctionalizations with Carboxylate-Based Phase-Transfer Catalysts

Fluorine is an attractive element in the field of pharmaceutical and agrochemical chemistry due to its unique properties. Considering the chiral environment in nature, where enantiomers often show different biological activities, the introduction of fluorine atom(s) into organic molecules to make chiral fluorinated compounds is an important subject. Herein, we describe the story of the development of our chiral carboxylate-based phase-transfer catalysts and their applications for asymmetric fluorocyclizations of alkenes bearing a carboxylic acid, an amide, and an oxime as an internal nucleophile with a dicationic fluorinating reagent, Selectfluor. We also describe dearomative fluorinations of indole derivatives, 2-naphthols, and resorcinols.     

Asymmetric construction of quaternary carbon centers by regio- and enantiocontrolled allylzincation

An allylic zinc reagent bearing a chiral bisoxazoline ligand adds to a substituted cyclopropenone acetal to produce an optically active cyclopropanone acetal possessing a quaternary chiral center in high yield with 97.8-99.8% ee. The steric effects of the bulky bisoxazoline ligand overwhelm the regioselectivity inherent to the electronic property of the olefinic acceptor. High pressure exerts favorable effects on the reaction rate without affecting the high enantio- or regioselectivity.