Resolution and determination of the absolute configuration of 3,3′4,4′-tetramethyl-1,1′-diphosphaferrocene-2-carboxylic acid

(±)-3,3′4,4′-Tetramethyl-1,1′-diphosphaferrocene-2-carboxylic acid 1 was resolved via diastereomeric salts with brucine. The (R)-absolute configuration of (+)-1 was determined by X-ray crystallography.     

Resolution and absolute configuration of dimethyl hydroxy-(ferrocenylmethyl)phosphonate

Racemic dimethyl hydroxy-(ferrocenylmethyl)phosphonate rac-1 was resolved via the formation of diastereomeric esters with (S)-α-methoxy-α-phenylacetic acid. The diastereomers, separated by column chromatography, were stereospecifically hydrolyzed by dissolution in trifluoroacetic acid at −30 °C and quenching with water. The absolute configuration of one enantiomer of 1 was assigned by X-ray diffraction.     

1,1′-Spirobiindane-7,7′-diol: a novel,C2-symmetric chiral ligand

A novel, C₂-symmetric chiral diol (16) was prepared in six steps from m-anisaldehyde and resolved via its bis-l-menthoxycarboxylate.     

Efficient oxidative resolution of a P-stereogenic triarylphosphine and asymmetric synthesis of a P-stereogenic atropoisomeric biphenyl diphosphine dioxide

Racemic 3-methoxyphenyl(1-naphthyl)phenylphosphine 1 was effectively resolved via an oxidative resolution procedure utilizing l-menthyl bromoacetate as the resolving agent to give enantiopure 3-methoxyphenyl(1-naphthyl)phenylphosphine oxide (R)-2 in 41% yield. Reduction of the resolved (R)-4 with HSiCl₃/NEt₃ provided the corresponding phosphine (R)-1 in >97% ee. Ortho-iodination of the enantiopure (R)-4 followed by Ullmann coupling of the resulting iodoarylphosphine oxide gave a P-stereogenic and atropoisomeric biphenyl diphosphine dioxide as a single diastereoisomer. The latter transformation constitutes the first example of an effective transfer of a P-centered chirality to an axial chirality of the atropoisomeric biaryl system. The absolute configurations of the resolved phosphine and the atropoisomeric biaryl system have also been established.     

Synthesis and catalytic reactivity of D4-symmetric dinorbornabenzene-derived metallotetraarylporphyrins

The condensation of the resolved C₂-symmetric benzaldehyde, 1,2,3,4,5,6,7,8-octahydro-1:4,5:8-dimethanoanthracene-9-carboxyaldehyde, with pyrrole produced the first chiral tetraarylporphyrin 1 exhibiting D₄-symmetry. The resolved benzaldehyde was synthesized in seven steps from p-benzoquinone and cyclopentadiene and included a resolution via diastereomeric ketals. A manganese chloride complex of porphyrin 1 was used as a catalyst for the asymmetric epoxidation of aromatic substituted alkenes in the presence of excess sodium hypochlorite in up to 7,200 turnovers and up to 76% e.e and >90% yield.     

Resolution of albuterol acetonide

The (R)-enantiomer of albuterol has been isolated via resolution of albuterol acetonide with (2S,3S)-di-O-benzoyl- or (2S,3S)-di-O-toluoyltartaric acid. The absolute configuration of the resolved acetonide was assessed by ¹H NMR analysis of its (R)-Mosher's ester, and confirmed by an X-ray crystal structure determination of the (R)-phenylethylurea derivative of the (S)-enantiomer.     

An efficient synthesis of 3(S)-aminopiperidine-5(R)-carboxylic acid as a cyclic β,γ′-diamino acid

An orthogonally protected β,γ′-diamino acid 6 possessing conformationally-constrained ring system was synthesized as a novel cyclic amino acid analogue. This synthesis involves as key steps chemoselective enzymatic hydrolysis of cis-piperidine-3,5-dicarboxylic ester derivative followed by efficient kinetic resolution of the partially resolved half-acid to afford the C₁-symmetric piperidine-3,5-dicarboxylic acid monoester in high enantiomeric excess (>98% ee). The optically active half-acid was transformed to the cyclic amino acid via Curtius-type rearrangement.     

Resolution and determination of the absolute configuration of 3,3′,4,4′-tetramethyl-1,1′-diphosphaferrocene-2-carboxaldehyde

Racemic 3,3′,4,4′-tetramethyl-1,1′-diphosphaferrocene-2-carboxaldehyde 1 was resolved via the formation of diastereomeric dioxolanes with (S)-(+)-1-phenyl-1,2-ethanediol. Four stereoisomers were separated by column chromatography. The absolute configuration of one of them (2′′R, 4′′S,1R) was established by X-ray diffraction. Acid hydrolysis of the dioxolanes afforded quantitatively (R)- and (S)-enantiomers of 1. Optical rotatory dispersion (ORD) spectra of both enantiomers are also reported.     

Fractional crystallisation of (±)-iso-amarine with mandelic acid: convenient access to (R,R)- and (S,S)-1,2-diamino-1,2-diphenylethanes

(±)-iso-Amarine can be conveniently resolved via 1:1 salt formation with either hand of mandelic acid. Enantiopure iso-amarine can be acetylated and hydrolysed to give enantiopure 1,2-diamino-1,2-diphenylethanes.     

Kinetic resolution of racemic secondary alcohols via oxidation with Yarrowia lipolytica strains

Cyclic and alicyclic racemic secondary alcohols are kinetically resolved via oxidation with Yarrowia lipolytica strains. The comparison of the oxidation reactions with the reductions of the corresponding ketones supports the hypothesis of the presence of two alcohol dehydrogenases with opposite enantioselectivity.     

Efficient preparation of enantiomerically pure (E)-γ-hydroxy-α,β-unsaturated p-tolylsulfoxides using lipase-mediated acylations

(E)-γ-Hydroxy-α,β-unsaturated p-tolylsulfoxides 1 have been efficiently resolved via irreversible enzymatic acylation with lipase PS (Pseudonomas cepacia) and vinyl acetate.     

Chemoenzymatic synthesis of enantiomerically enriched 2-oxobicyclo[m.1.0]alkan-3-yl acetate derivatives

Racemic α′-acetoxy α,β-unsaturated cyclopentanone and cyclohexanone have been resolved into the corresponding enantiomerically enriched α′-hydroxylated and acetoxylated compounds with 96–97% ee via PLE hydrolysis. Stereoselectivity in the palladium(II)-catalyzed reaction between the enantiomerically enriched α′-acetoxylated compounds and diazomethane has been investigated. In the α′-acetoxylated cyclopentenone, preferential cyclopropanation occurs in the anti-form, whereas α′-acetoxylated cyclohexenone affords both syn- and anti-products (syn:anti, 61:36%). The relative configuration of the products was determined by NOE experiments.     

Resolution of racemic 2-amino-1-butanol with immobilised penicillin G acylase

Racemic 2-amino-1-butanol has been resolved to obtain (S)-2-amino-1-butanol with >99% e.e. via enantioselective hydrolysis of its N-phenylacetyl derivative with penicillin G acylase immobilised on Eupergit C.     

Resonant two photon ionization of phenanthrene via its transientS 2 state

We report the vibrationally resolved photoelectron spectrum of phenanthrene obtained by two photon ionization via theS ₂ electronic state. The experiments were performed with picosecond laser pulses with a bandwidth sufficiently large to span a significant fraction of the intermediate resonance state. Therefore the photoelectron spectrum is dominated by signal corresponding to the unrelaxed intermediate resonance, in spite of this state's 420 fs lifetime.     

Determination of the absolute stereochemistry and the activation barriers of thermally interconvertible heterocyclic compounds bearing a naphthyl substituent

The enantiotopic methyl signals of the compounds studied were resolved in the presence of the optically active chiral auxiliary (S)-(+)-2,2,2-trifluoroanthryl ethanol, [(S)-TFAE] via complex formation between (S)-TFAE and the respective compounds. Two different solvation models were proposed for both M and P conformations leading to the assignments of the ¹H NMR signals and thus absolute conformations. The solvation models proposed also explained the strong temperature dependence of the ¹H NMR signals upon cooling. The activation barriers for interconversion between the enantiomers of the compounds studied have been determined by either temperature dependent NMR or enantioresolution on a chiral sorbent via HPLC.     

A practical synthesis of enantiopure β-methyltryptophan ethyl ester for a preparation of diabetes drug

A practical synthesis of (2R,3S)- and (2S,3R)-β-methyltryptophan ethyl ester (β-MeTrp-OEt) has been developed. Racemic threo-β-MeTrp-OEt was diastereoselectively prepared via crystallization-induced diastereomer transformation (CIDT) of the α-nitro equivalent of β-MeTrp-OEt. The enantiomers were resolved via diastereomeric salt formation using a half equivalent of (R)-2-(4-hydroxyphenoxy)propionic acid. The process allowed a diabetes drug candidate N-[(1R,2S)-1-({5-[(dimethylamino)methyl]-2-ethoxyphenyl}aminocarbonyl)-2-(1H-indol-3-yl)propyl]-4-phenyl-1-piperidinecarboxamide to be prepared in good yield with high quality.     

Enzymatic resolution of alicyclic 1,3-amino alcohols in organic media

Racemic cis- and trans-2-aminocyclohexane-1-methanol and cis- and trans-2-amino-4-cyclohexene-1-methanol were resolved via lipase-catalysed O-acylation of their Z derivatives, using vinyl butyrate in different ether solvents. In accordance with the empirical rule, most of the screened lipases preferred the 1S enantiomer.     

New procedures for the resolution of chiral tert-butylphenylphosphine oxide and some of its reactions

Racemic t-butylphenylphosphine oxide was resolved via formation of diastereoisomeric complexes with (+)-(R)-1,1′-binaphthalene-2,2′-diol and (+)-(S)-mandelic acid. With the latter complexing agent, separation of the essentially enantiopure (−)-(S)-enantiomer was achieved in a single complexation process. Addition of paraformaldehyde to this enantiomer gave α-hydroxymethyl-t-butylphenylphosphine oxide with high stereoselectivity and retention of configuration at phosphorus while its reaction with methyl bromoacetate in methanol/sodium methoxide resulted in the formation of methyl t-butylphenylphosphinate with inversion at phosphorus.     

Dielectrically controlled resolution (DCR) of 3-aminopiperidine via diastereomeric salt formation with N-tosyl-(S)-phenylalanine

A useful key intermediate for the dipeptidyl peptidase-4 (DPP-4) inhibitor, 3-aminopiperidine 1, was successfully resolved with an enantiomerically pure resolving agent, N-tosyl-(S)-phenylalanine 2, to give both stereoisomers (R)-1 and (S)-1 as a less-soluble diastereomeric salt with (S)-2, via a dielectrically controlled resolution (DCR) phenomenon.     

An efficient and general method for resolving cyclopropene carboxylic acids

A general method is described for the resolution of cycloprop-2-ene carboxylic acids via diastereomeric N-acyloxazolidines prepared from enantiomerically pure oxazolidinones. Although a number of oxazolidinones were shown to resolve cyclopropene carboxylic acids, the oxazolidinones of S-phenylalaninol, S-phenylglycine and (1S,2R)-cis-1-amino-2-indanol are optimal in terms of resolving power and cost effectiveness. Separations were performed using simple flash chromatography, and because there is typically a large difference in R_f values it is possible to separate gram quantities of pure diastereomers in a single chromatogram. The cycloprop-2-ene carboxylic acids that can be resolved include those that are substituted at the 1-position by H, Ph, α-naphthyl, CO₂Me, CH₂OMOM, and trans-styryl; alkene substituents include Me, n-alkyl, Ph and tethered alkynes. Remarkably, 2-methyl-3-propylcycloprop-2-ene carboxylic acid can also be resolved with ease. The relative configurations of four diastereomerically pure oxazolidines were determined by X-ray crystallography. Reduction of the N-acyloxazolidinones with LiBH₄ give enantiomerically pure derivatives of 3-hydroxymethylcyclopropene that react with either MeMgCl or vinylMgCl and catalytic CuI to give enantiomerically pure products of syn-addition.