Diastereoisomeric Esters Research Articles

Isothiourea-Catalyzed Enantioselective α-Alkylation of Esters via 1,6-Conjugate Addition to para-Quinone Methides.

The isothiourea-catalyzed enantioselective 1,6-conjugate addition of para-nitrophenyl esters to 2,6-disubstituted para-quinone methides is reported. para-Nitrophenoxide, generated in situ from initial N-acylation of the isothiourea by the para-nitrophenyl ester, is proposed to facilitate catalyst turnover in this transformation. A range of para-nitrophenyl ester products can be isolated, or derivatized in situ by addition of benzylamine to give amides at up to 99% yield. Although low diastereocontrol is observed, the diastereoisomeric ester products are separable and formed with high enantiocontrol (up to 94:6 er).

Evidence of Enantiomers of Spiroglycol. Distinction by Using α,α'-Bis(trifluoromethyl)-9,10-anthracenedimethanol as a Chiral Solvating Agent and by Derivatization with Chiral Acids.

Herein, we perform for the first time a preliminary NMR and computational study of the spiroglycol structure. Spiroglycol is a highly symmetrical molecule, but it should be chiral due to the presence of a chiral axis. The presence of two enantiomers was demonstrated performing NMR enantiodifferentiation experiments using α,α'-bis(trifluoromethyl)-9,10-anthracenedimethanol (ABTE) as a chiral solvating agent (CSA). The addition of 0.6 equiv of ABTE allows the differentiation of several spiroglycol proton signals. The lack of resolution observed in the proton spectrum can be tackled through the corresponding 13C NMR spectrum where a significant enantiodifferentiation at the spirocarbon atom was observed. In order to physically separate both enantiomers, a SPG derivatization with camphorsulfonic acid and Mosher's acid was performed affording the corresponding diastereoisomeric ester mixtures. Computations performed with the Gaussian16 package showed that the enantiodifferentiation is mainly due to the different compound thermodynamics stability.

Optical resolution of racemic 4-hydroxy-3,5-diisobornylbenzaldehyde

Optical resolution of racemic 4-hydroxy-3,5-diisobornylbenzaldehyde was accomplished via transformation into diastereoisomeric esters by treatment with (1S)-camphanoyl chloride. The absolute configuration of the enantiomers was determined on the basis of the X-ray diffraction data for one diastereoisomeric camphanate.

Absolute configuration and parasympathetic action: pharmacodynamics of enantiomorphic and diastereoisomeric esters of beta-methylcholine.

Abstract The parasympathomimetic and atropine-like actions of enantiomorphic esters of β-methylcholine and various esters of choline or β-methylcholine containing an asymmetric centre in the acid moiety have been studied. The potent parasympathomimetic drugs have a configuration identical with that of muscarine, suggesting a close affinity with the receptor. There is a gradual change from agonist to antagonist with increasing molecular size of the acid moiety, antagonism beginning with the butyric ester. Optimal affinity as a mimetic in the lower homologues is obtained with the acetic ester. Maximum affinity as an antagonist is obtained with the ester of the bulky hexahydrobenzilic acid. The configuration of the choline part is irrelevant for high atropine-like potency in the compounds derived from β-methylcholine. Clear differences in affinity are found, however, between stereoisomers of potent antagonists containing an asymmetric centre in the acid moiety, provided the asymmetric carbon atom does not bear isosteric groups. It is concluded that the atropine-like agents, although being competitive antagonists of the parasympathomimetics at best cover the agonistic receptor area only partially.

Enantiomerically Pure Axially Chiral Aminocarbene Complexes of Chromium

Aminocarbene complexes having a methyl group in the ortho-position to the aminocarbene moiety on the aromatic ring, (S)-pentacarbonyl[(N,N-dimethylamino)(3-methoxycarbonyl-2-methylphenyl)carbene]chromium(0) [(S)-6] and (R)-pentacarbonyl[(N,N-dimethylamino)(5-methoxycarbonyl-2-methylphenyl)carbene]chromium(0) [(R)-7], were prepared in enantiomerically pure form by the crystallization of diastereoisomeric esters with (S)-1-(1-naphthyl)ethanol. In the case of (S)-6 the racemization barrier ΔG⧧rac = 121 ± 0.5 kJ·mol−1 was established. The substitution of o-methyl group with an isopropyl group virtually did not change the racemization barrier (ΔG⧧rac = 120.5 ± 0.5 kJ·mol−1), while the introduction of an o-phenyl group led to substantial lowering of ΔG⧧rac. Attempts to transfer chirality in thermal reactions of the complexes (S)-6 and (R)-7 with alkynes, palladium-catalyzed insertion into a C−H bond, and photochemical formation of β-lactams were unsuccessful.

A total synthesis of milbemycin G: approaches to the C(1)–C(10)-fragment and completion of the synthesis

A synthesis of the hydroxybutenolide (-)-6 required for synthesis of alpha-milbemycins and the completion of a total synthesis of milbemycin G 7 is reported. Following preliminary studies, an optimised synthesis of the hydroxybutenolide (-)-6 from the hydroxyketone 38 was developed which involved the resolution of 38 by separation of the 3-(O-chloroacetyl)-(S)-mandelates 80 and 83. Ester 80, which corresponded to the required enantiomer of the hydroxyketone 38, crystallized from the mixture of the diastereoisomeric esters 80 and 83 giving the (-)-hydroxyketone (-)-38 in an overall yield of 47%(based on racemic 38) after ethanolysis. Hydroxyketone (-)-38 was oxidised to the enolic diketone (-)-39 and phenylselenation and stereoselective reduction gave the trihydroxycyclohexyl selenide (-)-43. The regioselective introduction of the non-conjugated double-bond into the six-membered ring was then achieved by esterification of the 4-hydroxyl group using trichloroacetic acid to give the trichloroacetate (-)-69. Oxidative elimination from the trichloroacetate using tert-butyl hydroperoxide was highly regioselective and gave the endo- and exocyclic alkenes (-)-44 and (-)-46 in a ratio of 95 : 5 after ethanolysis of the trichloroacetates. Selective O-methylation of the 4-hydroxyl group via the cyclic stannylene 55 and protection of the 3-hydroxyl group as its 2-trimethylsilylethoxymethyl (SEM) ether gave the ester (-)-57. Following saponification of the ethyl ester, re-esterification using 2-trimethylsilylethanol and oxidation of the 2-trimethylsilylfuryl fragment using singlet oxygen gave the required hydroxybutenolide (-)-6. The Wittig reaction between the phosphonium salt 2 and the hydroxybutenolide (-)-6 gave a ca. 2 : 1 mixture of the (4Z)- and (4E)-isomers of the ester 84 which on treatment with a catalytic amount of iodine was converted into the (4E)-isomer (4E)-84. Deprotection gave the seco-acid 85 but attempts to macrocyclise this were unsuccessful, the elimination product 86 being the only product isolated. The Wittig product 84 was taken through to the butenolide (2'E)-91 by removal of the SEM group, cyclisation to form the butenolide ring and diene isomerization, but this could not be converted into the corresponding seco-acid 92. However, removal of the SEM group from the seco-acid 85 gave the trihydroxy-acid 93 which was cyclized under modified Yamaguchi conditions to give the macrolide 94 together with a small amount of the macrocyclic butenolide 95. Reduction of this mixture using diisobutylaluminium hydride gave (6R)-6-hydroxymilbemycin E 96 which was converted to milbemycin G 7 by cyclisation of the primary chloride 97. The synthetic milbemycin G 7 was identical to a sample prepared by methylation of a commercial sample of milbemycin D 98, 7-O-methylmilbemycin G 99 being a side-product of this methylation.

Use of lactamide diastereoisomers to permit resolution of a racemic modulator of cancer drug resistance

The synthesis of enantiomers of an amidic modulator of cancer multidrug resistance, the chirality of which is not prone to chromatography, has been carried out via formation of the diastereoisomeric esters of the precursor racemic acid with (S)-lactamide and separation of the esters on silica gel.

Enzymic resolution of 2-substituted cyclohexanols through lipase-mediated esterification

Several lipases were used for the kinetic resolution of the racemic cis- and trans-isomers of 2-(4-methoxybenzyl)cyclohexanol, by lipase-mediated esterification of the substrates to the corresponding acetate isomers. Conversion of the products and the remaining deracemized substrates into diastereoisomeric esters of 3,3,3-trifluoromethyl-2-methoxy-2-phenylpropanoic acid, their analysis by chiral HPLC and assignment of their absolute configurations through their 1H and 19F NMR spectra, were the basis of evaluation of the studied enzymic process. Lipase from Rhizomucor miehei (RML) was found to be the most efficient enzyme regarding enantiomeric excess (ee) and yield of the desired products, while resolution by lipase from Rhizopus arrhizus (RAL) resulted in satisfactory ee and lower yields.

Synthesis, resolution, and determination of the absolute configuration of the enantiomers of cis-4,5-dihydroxy-1,2-dithiane 1,1-dioxide, an HIV-1 NCp7 inhibitor

The anti-HIV activity of (±)- cis-4,5-dihydroxy-1,2-dithiane 1,1-dioxide [(±)- cis-1,1-dioxo-[1,2]-dithiane-4,5-diol, NSC-624151] and its attack on the zinc finger domain of the HIV-1 nucleocapsid p7 (NCp7) protein has been established [Rice, W. G.; Baker, D. C.; Schaeffer, C. A.; Graham, L.; Bu, M.; Terpening, S.; Clanton, D.; Schultz, R.; Bader, J. P.; Buckheit, R. W.; Field, L.; Singh, P. K. Turpin, J. A. Antimicrob. Agents Chemother. 1997, 41, 419]. In order to determine which enantiomer of NSC-624151 is the more active component, the compound was resolved via its bis-‘Mosher ester’, which was prepared via its reaction with two equiv of (−)-( R)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride. The diastereoisomeric esters were separated, and each ester was hydrolyzed to yield enantiomers with α D 21 +151° ( c 0.5, MeOH) and α D 21 −146° ( c 0.5, MeOH). Single-crystal X-ray analysis of the (−)-bis-‘Mosher ester’ showed that the (−)-enantiomer is the (4 S, 5 R)-compound. The (−)-enantiomer (NSC 693195) was ca. twice as active (EC 50 8.8±0.2 μM) as its (+)-counterpart (NSC 693194) (EC 50 16.2±2.4 μM) in the XTT assay against HIV-1. All three compounds were found to be approximately equally effective in promoting Zn ejection from the NCp7 zinc finger. As the more anti-HIV active enantiomer is only slightly more active than the racemic form, it appears to offer no advantages over the racemic form.

Crystallization-Induced Asymmetric Transformations. Enantiomerically pure (−)-(R)- and (+)-(S)-2,3-Dibromopropan-1-ol and Epibromohydrins. A Study of Dynamic Resolution via the Formation of Diastereoisomeric Esters

(S)-2,3-Dibromopropan-1-ol of high enantiomer excess was obtained by crystallization-induced asymmetric transformations of racemic 2,3-dibromopropan-1-ol esterified with N-([1,1′-biphenyl]-4-ylcarbonyl-L-alanine; in particular, an asymmetric transformation of the first type (involving bromide exchange to equilibrate the diastereoisomeric esters) and an asymmetric transformation of the second type (involving a transesterification of diastereoisomeric esters with excess racemic alcohol) were devised.

Resolution and absolute configuration of bromofluoroacetic acid

The resolution of racemic bromofluoroacetic acid (BrFHCCO 2H) 1 was effected by crystallisation of its diastereoisomeric α-methylbenzylamine salts. The crystal structure of the p salt (+)- 3a {(+)-BrFHCCO 2H·( R)-(+)-α-methylbenzylamine} was solved by X-ray crystallography and the ( S)-(+)/( R)-(−) absolute configuration was established for 1. Diastereoisomeric esters 5a and 5b, obtained by addition of bromofluoroacetic acid to enantiomerically pure epoxychroman 4, were used to determine the enantiomeric excess of 1 by 19F NMR. Moreover, the diastereoisomerically pure ester 5a, resulting from addition of enantiomerically pure (+)- 1 to 4, gave single crystals and its X-ray crystal structure corroborated the ( S)-(+)/( R)-(−) absolute configuration of 1.

Determination of the enantiomeric excess of ferroelectric liquid crystals derived from three natural amino acids

The synthesis and 1H NMR spectra are presented for diastereoisomeric esters based on chiral alpha-chloro acids which are derived from natural available alpha-amino acids (L-valine, L-leucine and L-isoleucine) and commonly employed for the synthesis of ferroelectric liquid crystals possessing a high spontaneous polarization. Partial racemization is established as occurring within the formation of the chiral alpha-chloro acids and their esterification procedure. The enantiomeric excess exceeds 90% for L-isoleucine and L-valine derivatives, whereas an enantiomeric excess of 60% is found for L-leucine derivatives. On the basis of existing data in the literature, the differences in the spontaneous polarization of these derivatives is discussed with regard to the determined enantiomeric excess and their conformational freedom affecting the average lateral dipole moment of a single molecule.

Stereoselective Synthesis of Chiral (2-Furyl)Amino-Methanephosphonic and Aminophosphonous Acids

Stereoselective synthesis of (2-furyl)-N-methylbenzylaminophosphonate was performed by the addition of dibenzyl phosphate to N-furfurylidene (R)-α-methylbenzylamine[1]. Resulting diastereoisomeric esters were separated and characterised. As both products were oily liquids, the X-ray study could not have been made. So, we determined the absolute configuration on the base of Cram rules and confirmed it according to Riguera's[2] method.

Resolution and conformational analysis of diastereoisomeric esters of cis- and trans-2-(aminomethyl)-1-carboxycyclopropanes

(1 R,2 S)-, (1 S,2 R)-, (1 R,2 R)- and (1 S,2 S)-2-(Aminomethyl)-1-carboxycyclopropanes, conformationally restricted analogues of the neurotransmitter γ-aminobutyric acid (GABA), have been resolved by chromatographic separation of the corresponding diastereoisomeric esters which were formed between the cis- and trans-2-(acetamidomethyl)-1-carboxycyclopropanes with ( R)-(−)-pantolactone. 1H NMR, semi-empirical conformational analysis, ab initio (DFT) structure and NMR shielding tensor calculations of the cis-diastereoisomers allowed the absolute configuration assignments of the cis-amino acids.

Quantitative Analysis of Enzyme‐Mediated Hydrolytic Processes and Their Products Using HPLC and NMR Techniques

AbstractSecond derivatives of the UV spectra of 2‐(4‐alkoxybenzyl)cyclopentan‐1‐ols and their acetates were used for the quantitative analysis of reaction kinetics of enzyme‐mediated hydrolytic process. To determine the enantiomeric purity of the products using non‐chiral HPLC columns, their diastereoisomeric esters of 3,3,3‐trifluoro‐2‐methoxy‐2‐phenylpropanoic acid(MTPA) were prepared. The absolute configuration of the products was established using a combination of the results of a HPLC analysis and 1H/19F‐NMR measurements of the diastereoisomeric MTP esters. The analytical method described consists of an easy routine HPLC analysis which can sometimes be used as a quick on‐line analysis of the reaction kinetics and as a quick stepwise analysis of the optical purity and the absolute configuration of the products.

Design and development of chiral reagents for the chromatographic e.e. determination of chiral alcohols

(S)-Trolox methyl ether is known as a powerful chiral reagent for the e.e. determination of chiral alcohols by separation of the corresponding diastereoisomeric esters on achiral GC and SFC columns. In order to further improve his methodology, five possible candidates resultings from variation of structural elements of parent reagent have been tested for derivatization with selected alcohols and subsequent analysis of the diastereoisomeric pairs of esters. The results of this optimization procedure showing the ways to new potent reagents are discussed. © 1996 Wiley-Liss, Inc.

Design and development of chiral reagents for the chromatographic e.e. determination of chiral alcohols

(S)-Trolox methyl ether is known as a powerful chiral reagent for the e.e. determination of chiral alcohols by separation of the corresponding diastereoisomeric esters on achiral GC and SFC columns. In order to further improve his methodology, five possible candidates resultings from variation of structural elements of parent reagent have been tested for derivatization with selected alcohols and subsequent analysis of the diastereoisomeric pairs of esters. The results of this optimization procedure showing the ways to new potent reagents are discussed. © 1996 Wiley-Liss, Inc.

Fortesyl 2-Phenylpropionate. An Example of a Novel Hydrocarbon Skeleton Containing Three Fused Five-Membered Rings

The title compound is 8,8-dimethyltricyclo[4.2.1.0 3,7 ]nonan-6-yl 2-phenylpropionate, C 20 H 26 O 2 . Fortesol (8,8-dimethyltricyclo[4,2,1,0 3,7 ]nonan-6-ol), derived by acid-catalysed rearrangement of nopyl tosylate, is chiral and forms diastereoisomeric esters with enantiomeric carboxylic and phosphonic acids

The stereochemistry of the major rat hepatic microsomal metabolites of 7,9-dimethylbenz[c]acridine and 7,10-dimethylbenz[c]acridine.

The monofunctionalized dihydrodiol metabolites of 7,9-dimethylbenz[c]acridine and 7,10-dimethylbenz[c]acridine formed in incubations with rat liver microsomes from untreated and phenobarbital and 3-methylcholanthrene-pretreated rats were isolated by reversed-phase high performance liquid chromatography. The relative amounts of each enantiomer were determined by HPLC of diastereoisomeric esters with (+)-(1R,2S,4S)-endo-1,4,5,6,7,7-hexachlorobicyclo-[2.2.1]hept-5 e ne-2- carboxylic acid (HCA). For the K-region dihydrodiols, absolute configurations were determined from their circular dichroic spectra using the empirical method. The absolute configuration of 3,4-dihydrodiol of 7,9-dimethylbenz[c]acridine was determined by the exciton chirality method from the CD spectrum of its bis-4-(dimethylamino)benzoate ester. For the 8,9-dihydrodiol of 7,10-dimethylbenz[c]acridine the absolute configurations were tentatively assigned by normal-phase HPLC comparison of the (+)-HCA esters with literature data. In every case the R,R-configuration predominated with optical purities > 86% for non-K-region dihydrodiols and 56-68% for the K-region dihydrodiols.

A Simplified High-Performance Liquid Chromatographic Method for Direct Determination of Warfarin Enantiomers and Their Protein Binding in Stroke Patients

A simplified method for direct determination of warfarin enantiomers by high-pressure liquid chromatography with fluorescence detection has been developed. This method involves solid phase extraction of warfarin in plasma, precolumn derivatization to form diastereoisomeric esters, and post-column reaction to discriminate each enantiomer separately. Ultrafiltration was employed in the separation of unbound warfarin enantiomers. Twelve plasma samples from six stroke patients taking warfarin regularly were analyzed. The average concentration of total warfarin was 0.47 +/- 0.17 mg/L for the S-isomer and 0.69 +/- 0.18 mg/L for the R-isomer. The average protein binding was 99.67 +/- 0.33% for S-warfarin and 99.44 +/- 0.33% for R-warfarin. This methodology provides a quick and reliable technique for determining enantiomeric protein binding of warfarin in clinical settings.