Synthesis and application of atropisomeric dihydrobenzofuran-based bisphosphine (BICMAP)

A new atropisomeric dihydrobenzofuran-based bisphosphine ligand 1 was easily prepared from 1,4-dibromo-2-fluorobenzene. This racemic bisphosphine (±)-1 was used as a ligand for the palladium-catalyzed Suzuki-Miyaura reaction of aryl chloride with arylboronic acids and Hartwig-Buchwald amination of aryl bromides with aniline derivatives. The optical resolution of (±)-1 was also carried out by HPLC with a chiral stationary phase column.     

Contrasting chiroptical properties of sparteine lactams and thiolactams

The CD spectra of several mono- and dilactams and thiolactams of sparteine were measured with the purpose of clarifying spectra–structure relations. It is shown that the Cotton effects of lactams are predominantly of the opposite sign to those of the corresponding thiolactams. In bichromophoric molecules 7–9 the observed CD spectra are dominated by exciton type interactions.     

Asymmetric synthesis of new chiral long chain alcohols

Sixteen new chiral alcohols with alkyl (C₁₁–C₁₉) and aryl, substituted aryl, hetero aryl and biaryl groups 2a–2t were synthesized by three different asymmetric reduction methods from their corresponding ketones 1a–1t. Chiral NaBH₄ (method A), chiral BH₃ (method B) and chiral AIP (method C) were used as asymmetric reduction catalysts. Chiral NaBH₄ was modified by four different ligands 3a–3d, chiral BH₃ and chiral AIP by four different ligands 4a–4d. Ligand 4c was synthesized for the first time in this work. Chiral NaBH₄ generated chiral alcohols of (R)-configuration and chiral BH₃ and chiral AIP of (S)-configuration with high enantiomeric excesses, were analysed by chiral HPLC. In order to determine the ee values by chiral HPLC, sixteen corresponding racemic alcohols, synthesized by reducing their corresponding ketones via NaBH₄, were used for chiral resolution on a Daicel OD HPLC column. The sixteen starting ketones were synthesized in this study by Friedel–Craft acylation. The new chiral alcohols were characterized by IR, NMR, (¹H and ¹³C), MS, elemental analyses and specific rotation. The reduction methods A, B and C were applied to these ketones for the first time in this study and were compared with each other. The relationship between the structure of the ketone and the yield and the enantiomeric excess was discussed.     

Resolution of racemic 3-aryloxy-1-nitrooxypropan-2-ols by lipase-catalyzed enantioselective acetylation

Both (R)- and (S)-enantiomers of 3-aryloxy-1-nitrooxypropan-2-ols (R)-(−)-1, (S)-(+)-2 were prepared in high enantiomeric excess by lipase from Pseudomonas cepacia (Amano PS) or Pseudomonas fluorescens (Amano AK)-catalyzed acetylation of racemic alcohols 1a–g with vinyl acetate in n-hexane at 4 or 22°C. The enantioselectivity of this transformation was dependent on the substitution pattern of the aryl ring with E-values ranging from 31 to 111.     

Synthesis of a transition-state analog for the hydrolysis of the zearalenone lactone

The development of a catalytic antibody for the hydrolysis of the lactone functionality in zearalenone (1) is viewed as a potential solution to animal fertility problems associated with the estrogenic mycotoxin. A phosphonomacrolactone is proposed as a hapten for the generation of such antibodies. A suitably functionalized aryl phosphonic acid 4 was condensed with the racemic aliphatic fragment 5 via a Mitsunobu reaction. Macrocyclic formation was achieved via RCM to give advanced intermediate 23, a phosphonate analog of zearalenone, ready for deprotection and conjugation to a carrier protein.     

Oxidative kinetic resolution of racemic alkyl aryl carbinols by an electronically tuned chiral nitroxyl radical

A method for oxidative kinetic resolution of racemic alcohols catalyzed by chiral nitroxyl radical (R,R)-1 has been developed. This method is especially effective for the kinetic resolution of tert-butyl aryl carbinols (s = up to 23).     

Conformational analysis of tetraarylethanes

NMR evidence establishes that both diastereomers of 1,2-diphenyl-1,2-bis(4-pyridyl)ethane (2), identified by optical resolution of the racemic form, exist predominantly in the anti conformation. Furthermore, empirical force field calculations show that the gauche conformer of 1,1,2,2-tetrakis(2,6-dimethylphenyl)ethane (3) is less stable by ca. 10 $\text{kcal}\text{mol}$ than the anti structure. It thus appears that neither polar effects nor steric congestion are effective in reversing the marked preference of 1,1,2,2-tetraphenylethane (1) and other unclamped tetraarylethanes for an anti ground state. In contrast, as predicted by empirical force field calculations and confirmed by X-ray and NMR evidence, the ground state structure of 9,9'-bifluorenyl (4) is gauche. The conformational behavior of 1–4 is discussed in terms of the intramolecular aryl ring stacking in clamped and unclamped tetraarylethanes.     

A highly regio-, diastereo- and enantioselective intramolecular cyclopropanation reaction of a racemic α-diazo ketone catalyzed by chiral ortho-metalated dirhodium(II) compounds

A series of racemic dirhodium(II) compounds with two ortho-metalated aryl phosphine ligands in a head-to-tail arrangement Rh₂(O₂CR)₂(pc)₂ (pc=ortho-metalated aryl phosphine) (1a–k) were tested in the regio- and stereoselective cyclopropanation of racemic 1-diazo-6-methyl-3-(2-propenyl)-5-hepten-2-one 2, which possesses two different reactive CC double bonds for a five-membered-ring formation. The complexes Rh₂(O₂CCH₃)₂(pc)₂ {pc=[(C₆H₄)P(C₆H₅)₂], [(p-CH₃C₆H₃)P(p-CH₃C₆H₄)₂], and [(C₆H₄)P(C₆H₅)(C₆F₅)]} (1a–d) successfully enhanced the cyclopropanation of trisubstituted versus monosubstituted CC bonds to give an 80:20 selectivity ratio. The reaction occurred with excellent diastereoselectivity; the syn-products were the only stereoisomers observed in the whole series of the catalysts. Enantioenriched products were obtained when enantiomerically pure dirhodium(II) complexes were used.     

Synthesis of conformationally restricted acetylcholine analogues. Comparing lipase-mediated resolution with simulated moving bed chromatography of arylated β-hydroxy-pyrrolidines

The enantiodivergent synthesis of new, conformationally restricted acetylcholine analogues was accomplished using arylated endocyclic enecarbamates as key intermediates. Stereoselective hydroboration of the aryl enecarbamates provided the corresponding aryl-β-hydroxy-pyrrolidines. Acetylation, deprotection, followed by N-bismethylation, led to the desired betaine products. The kinetic resolution of the intermediate alcohols was performed by lipase-mediated hydrolysis of its acetate derivatives, resulting in excellent enantioselectivities (E > 100). An enzymatic enantiopreference predicted by the Kazlauskas’s model was confirmed following Riguera’s protocol. Finally, chromatographic resolution of racemic alcohol 5a was evaluated by semi-preparative scale chiral simulated moving bed chromatography and its performance compared with biocatalysis.     

Total synthesis of gliotoxin,dehydrogliotoxin and hyalodendrin

Two general methods, Method A and Method B in Scheme 19, to synthesize epidithiapiperazinediones, are described. A total synthesis of racemic and optically active gliotoxin (1) and of racemic dehydrogliotoxin (53) was achieved by using Method A, whereas a total synthesis of racemic hyalodendrin (52) was completed by using Method B.     

Enzymatic resolution of racemic secondary cyclic allylic alcohols

The resolutions of five racemic cyclic alcohols: 6,6-dimethylcyclohex-2-en-1-ol (±)-5, 4,4-dimethylcyclohex-2-en-1-ol (±)-7, 5,5-dimethylcyclohex-2-en-1-ol (±)-11 and isomeric trans-(±)-13 and cis-piperitols (±)-14 are presented. They were resolved by enzymatic esterification with vinyl esters or by enzymatic hydrolysis of their racemic esters in phosphate buffer. The following lipases were used as biocatalysts: Novozyme 435 (Candida antarctica), Amano PS (Burkholderia cepacia) and lipase from Candida cylindracea. All isomers of alcohols were obtained with at least 96% ee.     

Acyclic stereoselection—13 : Aryl esters: reagents for threo-aldolization

Preformed Li enolates of hindered aryl esters condense with aldehydes to give predominantly threo aldols. The method has been explored with esters 3 (DMP propionate), 4 (BHT propionate), and 5 (DBHA propionate). DMP propionate reacts with benzaldehyde and α-unbranched aliphatic aldehydes to give threo:erythro ratios of about 6.5:1. However, with α-branched aliphatic aldehydes, ester 3 gives only threo-aldols. BHT propionate and DBHA propionate give only threo-aldols with all aldehydes studied. The DMP aldols may be converted into β-hydroxy acids by simple hydrolysis with KOH in aqueous methanol. BHT aldols cannot be hydrolyzed without retroaldolization. However, these aldols can be reduced to diastereomerically pure 1,3-diols. The DBHA aldols can be converted into β-hydroxy acids by a method involving oxidation with ceric ammonium nitrate (CAN) in aqueous acetonitrile. Threo-selectivity is also seen in the condensations of DMP butyrate (15), DBHA butyrate (16), DMP pentenoate (17), and BHT pentenoate (18). The approach has been utilized in a stereoselective synthesis of racemic methyl corynomycolate (30).     

Synthesis of (-)-fortamine and (+)-2-deoxyfortamine from resolved 3S,4S-N-carbomethoxy-3-aminocyclohexen-4-ol

A three step sequence (Scheme I) starting with racemic 3,4-epoxycyclohexene (5) and (S)-α-methylbenzylamine gave 3S,4S-N-carbomethoxy-3-aminocydohexen-4-ol (10) with chromatographic removal of the undesired 3R,4R byproduct. The absolute configuration of 10 was established by x-ray crystallographic analysis of its precursor, 6 (as the HCl salt). Resolved 10 was converted to the aminocyditols (-)-fortamine (1) and (+)-2-deoxyfortamine (2) by efficient routes which parallel those previously developed in the racemic series.     

Resolution of racemic cis-1-amino-2-indanol by diastereomeric salt formation with (S)-2-phenylpropionic acid

Resolution of racemic cis-1-amino-2-indanol 1, a key intermediate for the synthesis of indinavir, is reported. The conditions were optimized for an industrial-scale resolution of racemic cis-1 using (S)-2-phenylpropionic acid 6 as the resolving agent and ethanol as the solvent. The less-soluble diastereomeric salt, (1R,2S)-1·(S)-6, was obtained in 35% yield with 99% de (E >69%) by crystallization. Resolving agent 6 was efficiently recovered from the salt and the mother liquor.     

Enantioselective effects in the association behaviour of optically active alcohols

The association behaviour of four optically active secondary alcohols with chiral C atoms in the α-position was investigated by means of IR spectroscopy and calorimetry CCl₄ was used as a solvent. As compared to the racemic compounds, the corresponding optically active alcohols have slightly higher concentrations of free OH groups, i.e. lower degrees of association, but somewhat higher enthalpy of association. Consequently, the H-bonding of racemic alcohols is favoured by entropy. Differences have been found also in the absorption coefficients of the associated OH groups. Optically active solvents exert some influence on the association behaviour of optically active alcohols. No differences could be observed in the H-bonding of optically active monocarboxylic acids, as compared with the racemic ones     

Efficient synthesis of an optically active tetrahydrozerumbone exhibiting a fragrance and the application of zerumbone derivatives with a medium ring structure

(R)-Tetrahydrozerumbone 2, which has a powerful balmy fragrance, contains a stereogenic carbon at the C2 position and can be easily prepared from zerumbone 1, one of the most important materials displaying an NMRDOS character. The reduction of 2 gave two diastereomers of tetrahydrozerumbol 3, and the optically active (>99%ee) alcohols were obtained by a lipase-catalyzed stereoselective transesterification of each racemic alcohol. A barrier to this development is a long reaction time (about four weeks) and the need to separate the diastereoisomers. The desired (2R)-form of 3 was efficiently obtained by a lipase-catalyzed transesterification under optimized conditions using a diastereomeric mixture of racemic 3 as the starting material without separation of the diastereomers. Using this method, the reaction of other zerumbone derivatives is greatly improved.     

Synthesis and characterization of some pyrimidine–quinoline clubbed molecules and their microbicidal efficacy

The required chalcones 1a–h were prepared by reaction of aryl acetophenone with different aryl aldehydes, which in turn treated with guanidine nitrate, yielded 4-(substituted phenyl)-6-(substituted phenyl)-2-pyrimidinamines 2a–h. Novel pyrimidine–quinoline clubbed molecules 3a–h have been prepared by reaction of 2a–h with 4-chloro-2,6-dimethylquinoline. All the compounds were characterized by elemental analysis and spectral studies. The newly synthesized compounds were evaluated for their antibacterial and antifungal activities.     

Synthesis of enantiomerically enriched α,α-disubstituted β,γ-epoxy esters using hydrolytic kinetic resolution catalyzed by salenCo(III)

Novel α,α-disubstituted epoxy esters were prepared in enantiopure form by hydrolytic kinetic resolution (HKR) of the corresponding racemic mixtures using chiral salenCo(III) as catalyst. The methodology provides a convenient route to enantioenriched β,γ-epoxy esters 2a, 2c and 2d.     

Asymmetric synthesis of triepoxyzerumbol

The achiral sesquiterpene zerumbone 1, which is readily available from wild ginger, has a unique functionality and reactivity making it a convenient starting material for its conversion into useful compounds, such as paclitaxel. Optically active triepoxyzerumbol (−)-3 and its acetate (+)-4 were synthesized by lipase-catalyzed enantioselective transesterification of racemic 3. Under optimized conditions, a lipase from Alcaligenes sp. (Meito QL) catalyzed the reaction of racemic 3 with isopropenyl acetate in THF at 35 °C to afford (1S)-3 and (1R)-4 with an E-value of 79. The absolute configuration of (1R)-4 was determined by single crystal X-ray diffraction of its ester with a chlorine atom using the anomalous dispersion effect.     

Synthesis and use in palladium-catalyzed asymmetric allylic alkylation of new planar chiral chromium complexes of 1,2-disubstituted arenes having pyridine and aryl phosphine groups

Optically active (1,2-disubstituted arene)chromium tricarbonyl complexes 4–7 having pyridine and aryl phosphorus groups were synthesized from (o-disubstituted benzaldehyde)tricarbonylchromium. These chromium complexes have been used as chiral ligands in the asymmetric allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate 8 catalyzed by (η³-allyl)palladium complex. The enantioselectivity increases as the number of electron-withdrawing substituents in the aryl phosphine increases. Significant solvent effects on the enantioselectivity were observed for 4 and 7. By the judicious choice of the planar chiral ligand, high enantioselectivities (90% R, 93% S at 0°C) were observed.