Diastereoselective Research Articles

Enantioseparation of (RS)-Bupropion and determination of configuration

ABSTRACTRacemate of (RS)-Bupropion (Bup) has been separated by derivatization approach and thin layer chromatography (TLC). It was extracted from commercially available tablets, purified, and characterized. A new chiral derivatization reagent (CDR) was synthesized by introducing L-leucine amide and butoxy group in cyanuric chloride (CC) moiety. Derivatization reaction was carried out using a two-fold molar excess of CDR under microwave irradiation (MWI). The diastereomeric pair was separated by TLC and the same were recovered by the preparative method; these were purified and characterized. Absolute configuration of the Bup moiety in the diastereomeric derivatives was confirmed by recording their 1HNMR spectra and thus elution order was also established.

Palladium-Catalyzed Diastereoselective 1,4-Addition

Palladium-Catalyzed Diastereoselective 1,4-Addition

Cheap and Diastereoselective ß-Lactam Formation

Cheap and Diastereoselective ß-Lactam Formation

Memory of Chiral Molecules Define Their Interactions and the Results of Resolution Processes

The preparation of pure enantiomers has an increasing demand both for academic and industrial (pharmaceutical) practice. This is not surprising, because the active ingredients of a main part of medicines (about 70-80%) are pure enantiomers. Several selective methods are known for preparation of pure enantiomers but the more economical and usual method is the resolution, when the pure enantiomers are obtained from diastereomeric salts formed due the reaction of the racemic compound and resolving agent in adequate conditions (solvent, temperature crystallization time). Since the first resolution effectuated by Pasteur the researchers have tried to explain what is happening during resolution, but this has not yet been fully accomplished, it is still a mystery. In this paper is described our proposal for resolution’s mechanism, based on systematization of our results and observations made during the resolution, taking into consideration the principal characteristics of enantiomeric mixtures, namely the eutectic composition and their helicity. We suppose that the enantiomers have a memory and they used it during the resolution processes, tending to form their stable symmetric conformation.

Synthesis and reactivity of β-stannylated phenylalanines

Abstract The free radical hydrostannation of a series of N-benzoyl and N-acetyl dehydrophenylalanine esters 2a – h yields β-stannylated phenylalanine derivatives 3 and 4. This addition of tin hydride to such unsaturated compounds simultaneously creates two new chiral centers leading to mixtures of two diastereomeric pairs of enantiomers. The reaction of 3-stannylated phenylalanine 3 with methanolic HCl yields chlorostannyl-substituted compounds 5 and 6 and, with one equivalent of bromine, the bromostannylated compounds 7 and 8 are formed. The bromostannylated phenylalanine derivative 7 reacts with one further equivalent of bromine to produce the dibromostannylated compound 9. Even the chlorostannylated phenylalanine derivative 5 reacts with one further equivalent of HCl to give the dichlorostannylated compound 10. The products were characterized by elemental analysis, infrared (IR), and multinuclear (1H, 13C, 119Sn) nuclear magnetic resonance (NMR) spectroscopy. Attempts were made to assign the preferred conformation of the stannylated phenylalanine derivatives using Karplus-type relationship of coupling constants 3 J(H,H), 3 J(Sn,H), and 3 J(Sn,C=O). The results of these analyses have been confirmed by three crystal structure determinations.

Diastereoselective [3+2] Annulation

Diastereoselective [3+2] Annulation

Efficient resolution of venlafaxine and mechanism study via X-ray crystallography.

Numbers of resolving factors were investigated to improve resolution of venlafaxine 1. An effective resolving agent, O,O'-di-p-toluoyl-(R, R)-tartaric acid 2, was screened using similar method of 'Dutch resolution' from tartaric acid derivatives. The resolution efficiency was up to 88.4%, when the ratio of rac-1 and 2 was 1:0.8 in THF with little water (10:1v/v). Enantiomerically pure venlafaxine was prepared with 99.1% ee in 82.2% yield. The chiral resolution mechanism was first explained through X-ray crystallographic study. One diastereomeric salt with well solubility forms a columnar supramolecular structure as the acidic salt (R)-1·2, while the other diastereomeric salt with less solubility forms a multilayered sandwich supramolecular structure by enantio-differentiation self-assembly as the neutral salt 2(S)-1·2. The water molecules play a key role in the optical resolution, as indicated by the special structures of the diastereomeric salts.

Development of a Practical Synthesis of a Peripherally Selective Noradrenaline Reuptake Inhibitor Possessing a Chiral 6,7-trans-Disubstituted-1,4-oxazepane as a Scaffold

A practical synthesis of a peripherally selective noradrenaline reuptake inhibitor that has a chiral 6,7-trans-disubstituted-1,4-oxazepane as a new class of scaffold is described. The amino alcohol possessing the desired stereochemistry was obtained with excellent dr and ee, starting from a commercially available aldehyde via a Morita–Baylis–Hillman reaction, Michael addition, isolation as maleic acid salt, reduction, and diastereomeric salt formation with (+)-10-camphorsulfonic acid. The desired single stereoisomer obtained at an early stage of the synthesis was used for seven-membered ring formation in fully telescoped processes, providing the chiral 6,7-trans-disubstituted-1,4-oxazepane efficiently. In addition to controls of dr and ee of the chiral 1,4-oxazepane, and control of N,O-selectivity in SN2 reaction of the intermediate mesylate with a pyridone derivative, finding appropriate intermediates that were amenable to isolation and upgrade of purity enabled a practical chiral HPLC separation-free, c...

Crystal structure of (1S,2R)-2-hy-droxy-1,2-di-phenyl-ethan-1-aminium (S)-2-aza-niumyl-butane-dioate monohydrate.

The title diastereomeric salt, formed between 2-amino-1,2-di-phenyl-ethanol (ADE) and aspartic acid (ASP), C14H16NO+·C4H6NO4-·H2O, crystallizes as a monohydrate. The 1,2-di-phenyl-ethyl group in the cation has a cis conformation, and the aspartic acid anion is in the zwitterionic form. In the crystal, the ASP anions are linked via N-H⋯O hydrogen bonds to form a 21 helix along the b-axis direction. The helices are linked by the ADE cations via O-H⋯O and N-H⋯O hydrogen bonds, forming layers parallel to the bc plane. There are channels in the layers that are occupied by water mol-ecules, which link to both the anions and cations via Owater-H⋯O and N-H⋯Owater hydrogen bonds. There are also C-H⋯O and C-H⋯π inter-actions present within the layers.

Practical Isolation of the (1R,2R)-Enantiomer from a Racemic cis/trans Mixture of 2-Methyl-1-cyclohexanamine

2-Methyl-1-cyclohexanamine exists in four stereoisomeric forms. Although it is a simple compound, none of the stereoisomers is readily available in its pure form. We herein described a crystallization method identified by a salt screen (diastereomeric salt formation) allowing the isolation of a single trans enantiomer from a readily available commercial source consisting of a mixture of all four stereoisomers.

Iridium-Catalyzed Enantio- and Diastereoselective Spiroketalization

Iridium-Catalyzed Enantio- and Diastereoselective Spiroketalization

Discrimination and Enantiomeric Excess Determination of Chiral Primary Amines Based on a Chiral-at-Metal Ir(III) Complex Using NMR Spectroscopy.

A three-component protocol involving enantiopure Δ-[Ir(ppy)2(MeCN)2](PF6) (ppy is 2-phenylpyridine) and salicylaldehyde as chiral auxiliaries was successfully applied to discriminate the absolute configuration and determine the enantiopurity of primary amines and amine alcohols via 1H NMR spectroscopy. The assembly reaction is rapid and quantitative, generating a pair of diastereomers that can be determined directly without physical separation. Single crystal structural analyses indicate that the shielding effects on the ligands imposed by a pair of diastereomers are different and generate sufficient resolution NMR signals for identification. The enhancement of stability via chelating coordination to Ir(III) ion and more than one pair of diastereotopic resonances in different detection regions of the three-component protocol ensure a high degree of accuracy in quantifying the ee value of chiral amines. The absolute errors in the ee determinations by 1H NMR spectroscopy in different detection windows are within 2.0%. The linear relationship between the experimentally measured ee values and the gravimetrically prepared samples is found to be excellent. This finding would provide a complementary method for the discrimination and determination of the enantiopurity of chiral primary amines and amine alcohols in the screening of asymmetric reactions.

β-Lactam-Synthon-Interceded Metal/Acid-Free Diastereoselective Access to Highly Functionalized Oxazol-5-ones and Dihydroimidazoles

Facile diastereoselective access to functionalized oxazol-5-ones and dihydroimidazoles was accomplished through base-promoted intramolecular amidolysis and methoxide-assisted tandem intramolecular amidolysis/ring opening/intramolecular cyclization, respectively, of C-3-functionalized azetidin-2-ones.

Fast further purification of diastereomeric salts of a nonracemic acid by gas antisolvent fractionation.

A novel, green possibility of the further purification of the diastereomeric salt of 4-chloromandelic acid and 1-phenylethane-1-amine was developed. Gas antisolvent method using supercritical carbon dioxide was applied for the first time to precipitate the diastereomeric salts with increased purity followed by the supercritical fluid extraction of the dissolved diastereomers. The RR-salt can be purified to >99%, while fractionation-based purification of the SR-salt is limited to ~80%. The limiting initial diastereomeric excess correlates strongly with the atmospheric melting eutectic composition of the same salts, which suggests that despite the fast precipitation, the diastereomeric excess of the solid product is not kinetically determined. The efficiency of the diastereomeric enrichment is in the same range as that of the atmospheric reference experiments; however, technological advantages provided by the antisolvent precipitation method such as fast processing and dry product obtained suggest that this novel procedure is a promising alternative to the atmospheric methods.

Chiral bis(mandelato)borate salts for resolution via metathesis crystallization.

Spiroborate anions have potential for crystallization or resolution and chiral bis(mandelato)borate anions can be used for the efficient resolution of a diverse range of racemic cations via diastereomeric salt formation. The syntheses, X-ray crystal structures and solubilities of three chiral bis(mandelato)borate salts, namely poly[[aqua-μ3-bis[(R)-mandelato]borato-lithium(I)] monohydrate], [Li(C16H12BO6)(H2O)]n or Li[B(R-Man)2]·H2O, (1), ammonium bis[(R)-mandelato]borate, NH4+·C16H12BO6- or NH4[B(R-Man)2], (2), and tetra-n-butylammonium bis[(R)-mandelato]borate, C16H36N+·C16H12BO6- or NBu4[B(R-Man)2], (3), are reported. They all have a BS configuration and show a reasonably well-conserved anion geometry. The main conformational variation is the orientation of the two phenyl groups, supporting the idea that [B(Man)2]- is a semi-rigid anion. The salts are differentially soluble in a range of solvents, meaning they could be useful as reagents for resolution via a metathesis crystallization approach.

Circular dichroism of R- and S-enantiomers of Ugi´s amine and their conjugates with l-tartaric acid

Circular dichroism spectra of the optically active (R)- and (S)-enantiomers of N,N-(dimethylamino)ethylferrocene (Ugi´s amine) were studied for a free form and for their diastereomeric salts with с l(+)-tartaric acid.

Structure elucidation of metabolite x17299 by interpretation of mass spectrometric data

IntroductionA major bottleneck in metabolomic studies is metabolite identification from accurate mass spectrometric data. Metabolite x17299 was identified in plasma as an unknown in a metabolomic study using a compound-centric approach where the associated ion features of the compound were used to determine the true molecular mass.ObjectivesThe aim of this work is to elucidate the chemical structure of x17299, a new compound by de novo interpretation of mass spectrometric data.MethodsAn Orbitrap Elite mass spectrometer was used for acquisition of mass spectra up to MS4 at high resolution. Synthetic standards of N,N,N-trimethyl-l-alanyl-l-proline betaine (l,l-TMAP), a diastereomer, and an enantiomer were chemically prepared.ResultsThe planar structure of x17299 was successfully proposed by de novo mechanistic interpretation of mass spectrometric data without any laborious purification and nuclear magnetic resonance spectroscopic analysis. The proposed structure was verified by deuterium exchanged mass spectrometric analysis and confirmed by comparison to a synthetic standard. Relative configuration of x17299 was determined by direct chromatographic comparison to a pair of synthetic diastereomers. Absolute configuration was assigned after derivatization of x17299 with a chiral auxiliary group followed by its chromatographic comparison to a pair of synthetic standards.ConclusionThe chemical structure of metabolite x17299 was determined to be l,l-TMAP.

Enantioselective Additions of Stabilized Carbanions to Imines Generated from α-Amido Sulfones By Using Lipophilic Salts of Chiral Tris(1,2-diphenylethylenediamine) Cobalt(III) Trications as Hydrogen Bond Donor Catalysts

The enantiopure salt ∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf – [BArf = B(3,5-C6H3(CF3)2)4] is an effective hydrogen bond donor catalyst (10 mol%, r.t., CH2Cl2) for enantioselective additions of dialkyl malonates to Boc-derivatized aryl imines generated from sulfones [ArCH(SO2Ph)NHBoc] in the presence of K2CO3 (ten examples, 91–97% isolated yields, 87–99% ee). The diastereomeric salt Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20 – [BArf20 – = B(C6F5)4 –] is similarly applied to additions of nitroalkanes (four examples, 89–93% isolated yields, 79–91% ee). Precautions to exclude air or moisture are unnecessary.

Conformationally rigid chiral ferrocene derivative: Synthesis, resolution and stereochemical assignment

A conformationally rigid chiral molecule LB-I with Lewis basic site has been designed and synthesized in racemic form from ferrocene via Lewis acid mediated diastereoselective cyclization of hydroxy lactam. Both isomers were successfully obtained in enantiomerically pure form through classical resolution using dibenzoyl-d-tartaric acid as the chiral resolving agent in acetone. The nature of the diastereomeric salt formed in the resolution process was investigated by single crystal X-ray crystallographic studies. The absolute configuration of (+)-LB-I was unambiguously assigned as (S,Rp) by single crystal analysis of the salt I obtained from precipitate fraction containing (+)-LB-I and dibenzoyl-d-tartaric acid.

Development of a Process Route to the FAK/ALK Dual Inhibitor TEV-37440

The development of a scalable route to TEV-37440, a dual inhibitor of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK), is presented. The medicinal chemistry route used to support this target through nomination is reviewed, along with the early process chemistry route to support IND (inversigational new drug) enabling activities within CMC (Chemistry, Manufacturing, and Controls). The identification and development of an improved route that was performed in the pilot plant to supply early phase clinical supplies are discussed. Details surrounding the use of a novel ring expansion, a selective nitration through a para-blocking group strategy, a single-pot amination–hydrogenation, a diastereomeric salt resolution, a through-process step to avoid a hazardous intermediate, and a practical formation of a trihydrochloride dihydrate salt are disclosed.