Anti Diastereoisomers Research Articles

Helices with additional H-bonds: crystallographic conformations of α,γ-hybrid peptides helices composed of β-hydroxy γ-amino acids (statines).

β-Hydroxy-γ-amino acids (Statines) are a class of naturally occurring non-ribosomal amino acids frequently found in many peptide natural products. Peptidomimetics constituted with statines have been used as inhibitors for various aspartic acid proteases. In contrast to the synthetic γ-amino acids, very little is known about the folding behavior of these naturally occurring β-hydroxy γ-amino acids. To understand the folding behavior of statines, three α,γ-hybrid peptides P1 (Ac-Aib-γPhe-Aib-(R, S)Phesta-Aib-γPhe-Aib-CONH2 ), P2 (Ac-Aib-γPhe-Aib-(S, S)Phesta-Aib-γPhe-Aib-CONH2 ), and P3 (Ac-Aib-γPhe-Aib-(S, S)Phesta-Aib-(S, S)Phesta-Aib-CONH2 ) were synthesized on solid phase and their helical conformations in single crystals were studied. Results suggest that both syn and anti diastereoisomers of statines can be accommodated into the helix without deviating overall helical conformation of α,γ-hybrid peptides. In comparison with syn diastereoisomer, the anti diastereoisomer was found to be directly involved in the intramolecular H-bonding with the backbone carbonyl groups (i to i + 3) similar to the backbone amide NHs in the helix.

ChemInform Abstract: Sc(OTf)3‐Catalyzed Addition of Bromomagnesium 2‐Vinyloxy Ethoxide to Various Aldehydes Leading to Protected Aldol Products.

The addition of bromomagnesium 2-vinyloxy ethoxide to various aldehydes in the presence of 10 mol% Sc(OTf) 3 provides a broad range of functionalized protected aldol compounds. The enantioselective preparation of these aldols can be achieved via a Swern oxidation–CBS reduction sequence. Use of the dioxolane derived from 2-bromocyclohexanone provides the expected aldol product as the anti diastereoisomer (dr >99:1).

Synthesis of PhTAD-substituted dihydropyrrole derivatives via stereospecific C–H amination

Stereospecific α-amination has been accomplished via addition of N-phenyltriazolinedione (PhTAD) to the allylic position of dihydropyrroles. The aim of this study is to evaluate new PhTAD derivatives of biologically active bicyclic dihydropyrroles. Ene reaction was accomplished via addition of PhTAD to the allylic position to react with syn and anti diastereomers for α-amination. The α-amination depends on the stereochemistry, proceeding faster with syn than anti diastereoisomers. Steric hindrance from sulfide substituent slows down the transformation. Although the results are in accordance with an ene reaction followed by 1,3-shift of the urazole moiety, deuteration at the allylic position by simply stirring the diastereoisomeric dihydropyrroles in MeOD revealed a [1,3-H] shift. The stereospecificity of the transformation is attributed to steric hindrance during the allylic transposition step.

Sc(OTf)3-Catalyzed Addition of Bromomagnesium 2-Vinyloxy Ethoxide to Various Aldehydes Leading to Protected Aldol Products

The addition of bromomagnesium 2-vinyloxy ethoxide to various aldehydes in the presence of 10 mol% Sc(OTf)₃ provides a broad range of functionalized protected aldol compounds. The enantioselective preparation of these aldols can be achieved via a Swern oxidation–CBS reduction sequence. Use of the dioxolane derived from 2-bromocyclohexanone provides the expected aldol product as the anti diastereoisomer (dr >99:1).

Spectroscopic Characterization of 1‐­Naphth­yl Isocyanate Anion Radical and of Tris(1‐naphthyl) Isocyanurate Atropisomers

AbstractRoom‐temperature potassium metal reduction of 1‐naphthyl isocyanate in THF results in a rapid cyclotrimerization (initiated by the 1‐naphthyl isocyanate anion radical) that generates two diastereoisomers (atropisomers) of tris(1‐naphthyl) isocyanurate. The formation of the syn and anti diastereoisomers was monitored by 1H and 13C NMR spectroscopy. Upon completion of the cyclotrimerization, the two diastereoisomers were isolated, and their configuration was assigned by NMR spectroscopy. Both compounds crystallize in the monoclinic C2/c space group, and single‐crystal X‐ray diffraction analyses confirm the structures of both isomeric forms. The results from this study prove that alkali metal reduction of isocyanates is a convenient and rapid method for generating isocyanurate compounds even when a sterically bulky substituent is attached to the NCO moiety.

The organocatalyzed domino Michael–aldol reaction revisited. Synthesis of enantioenriched 3-hydroxycyclohexanone derivatives by reaction of enals with α,α′-diaryl-substituted acetone

The reaction of enals with α,α′-diaryl-substituted acetones (pKa> 18) catalyzed by (S)-1-(2-pyrrolidinylmethyl) pyrrolidine provides direct access to enantioenriched 2,5,6-trisubstituted-3-hydroxy cyclohexanones.

Inverting the Diastereoselectivity of the Mukaiyama–Michael Addition with Graphite-Based Catalysts

Here, we show that graphite-based catalysts, mainly graphite oxide (GO) and exfoliated GO, are effective recyclable catalysts for a relevant stereoselective Mukaiyama–Michael addition, outperforming currently available catalysts. Moreover, the graphite-based catalysts described here invert the diastereoselectivity relative to that observed with known catalysts, with the unprecedented large prevalence of the anti diastereoisomer. This inverted diastereoselectivity is increased when the catalyst concentration is reduced and after catalyst recycling. Density functional theory calculations suggest that the selectivity is determined by two types of supramolecular interactions operating between the catalyst and the substrates at the diastereoselectivity-determining transition state, specifically, the π-stacking of β-nitrostyrene with graphite and the van der Waals interaction between the SiMe3 group of the silyl ether and the graphite.

Atropisomers of Hindered Triarylisocyanurates: Structure, Conformation, Stereodynamics, and Absolute Configuration

The syn and anti diastereoisomers of some 1,3,5-triarylisocyanurate derivatives were isolated and their configuration assigned by NOE experiments and by X-ray diffraction. The kinetics of the syn/anti interconversion were determined, and the experimental activation energies matched satisfactorily the values predicted by DFT computations. Low-temperature NMR spectra were employed to determine the rotation barrier of N-bonded unhindered aryl substituents: these barriers, too, are satisfactorily reproduced by DFT computations. In the case of racemic diastereoisomers, the two expected enantiomers (atropisomers) were isolated by enantioselective HPLC and the absolute configuration established by DFT simulation of the electronic and vibrational circular dichroism spectra.

Resolution of 2,3-dihydro-benzofuran-3-ols

A new method for the preparation of enantiopure 2,2-disubstituted 2,3-dihydro-benzofuran-3-ols is described. A short synthesis is designed for obtaining various 2,2-disubstitued benzofuran-3-ols as racemic mixtures of the two possible syn and anti diastereoisomers, which can be separated after silylation. The major racemic anti isomers were transesterified using (R)-pentolactone, allowing separation of the pure enantiomers. The resolution of benzofuran-3-ols prepared from salicylalehydes has been achieved by the preparation of (R)-pantolactone esters. A general 1H NMR method is proposed to establish the absolute configurations.

Determination of relative configuration of symmetrical bis-Tröger’s base derivatives

Determination of the molecular covalent structure based on spectral analyses is almost routine; however, estimation of stereostructure is still challenging, particularly in case of symmetrical molecules. In this study, various spectral (NMR, IR and Raman) markers revealing relative configuration (syn and anti) of bis-Tröger’s base diastereoisomers are identified. Differences in diastereoisomers 1H chemical shifts seem to be most useful, as they can be interpreted by computations. Vibrational spectra of syn and anti diastereoisomers exhibited systematic differences, too. The relative configuration can be also predicted based on retention on silica, and unambiguously confirmed via chromatographic analysis on a chiral stationary phase.

Stereoselective synthesis of peptidyl trifluoromethyl alcohols and ketones: inhibitory potency against human leucocyte elastase, cathepsin G, porcine pancreatic elastase and HIV-1 protease.

New fluorinated inhibitors have been designed to target two major proteases-human leucocyte elastase and HIV-1 protease. Two series of beta-peptidyl trifluoromethyl alcohols (TFMAs) Z-L-Val-NH-*CH(Y)*CH(OH)-CF3, where *C is the chiral centre, varied in the nature of the substituent Y, a phenylethyl [-(CH2)2-C6H5] or an isopropyl [-CH(CH3)2] group. These TFMAs were first synthesized as two pairs of the syn and anti diastereoisomers. The inhibitory effects of these mixtures were then assessed on three serine proteases chosen on the basis of the aromatic and aliphatic nature of the substituents-human leucocyte elastase (HLE), human cathepsin G (HCG) and porcine pancreatic elastase (PPE). In the presence of detectable inhibition, each epimer at C2 was separated to determine its inhibition constant (Ki) towards HLE, HCG and PPE. The stereoisomerically pure TFMAs were then oxidized into peptidyl trifluoromethyl ketones (TFMKs) for similar inhibition assays. The absolute configuration of the compounds remained unknown. One epimer at C2 of each syn and anti TFMA with the phenylethyl substituent behaved as a competitive inhibitor towards HLE and HCG with inhibition constants below the millimolar range, whereas their TFMK counterparts were non-inhibitors. In the second series, the two ketones inhibited both elastases with Ki values in the micromolar range, whereas only the syn TFMA was active towards HLE (Ki = 5.65 x 10(-4)M). The tested compounds also had structural properties compatible with recognition by HIV-1 protease. The inhibition of the enzyme was observed with TFMK only (IC50 = 15-200 microM). The phenylethyl substituent promoted inhibition by a factor of 10 (IC50 = 15 microM) compared with the isopropyl substituent (IC50 = 200 microM) leading to selective inhibition of HIV-1 protease. Isomerically pure TFMKs were more potent towards HLE than the alcohols from which they were obtained. However, an enantiomerically pure TFMA selectively inhibited HLE unlike its TFMK analogue which also inhibited PPE. This last result together with the selective inhibition of HIV-1 protease by TFMK with a phenylethyl substituent might be relevant to the design of specific HLE and HIV-1 inhibitors as therapeutic agents.

ChemInform Abstract: Diastereofacial Selectivity in 1,3-Dipolar Cycloadditions. Reactions of Diazomethane with endo,cis-5,6-Disubstituted Bicyclo(2.2.2)oct-2- enes.

Abstract The reaction of diazomethane with endo,cis-5,6-diacetoxy, dimesyloxy, bis(methoxycarbonyl) and dihydroxybicyclo[2.2.2]oct-2-ene derivatives, respectively, afforded either only the anti adduct or a mixture of anti and syn adducts wherein the anti diastereoisomer was highly dominant (10:1). The observed facial selectivity provides convincing evidence that direct through space interactions between the attacking 1,3-dipole and acetoxy, hydroxy etc. substituents are, as a whole, repulsive. Steric “non-bonded” repulsions and dipole-dipole interactions override possible stabilizing interactions, e.g. orbital interactions and hydrogen bonding effects.

Synthesis of Enantioenriched 2‐ and 2,6‐Substituted Piperidin‐3‐ols from α‐Dibenzylamino Aldehydes

AbstractHomochiral α‐dibenzylamino aldehydes react with 4‐butenylmagnesium bromide in diethyl ether at 0 °C to yield anti‐β‐amino alcohols in excellent yield and dr. These anti diastereoisomers were transformed into enantioenriched 2‐ and 2,6‐substituted 3‐piperidinols in good yields. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Diastereoselective syntheses of 2-amino propargyl alcohols. Chiral building blocks for enantiopure amino γ-lactones and 5-hydroxy-piperidinone derivatives

α-Dibenzylamino aldehydes, derived from the corresponding natural α-amino acids, react with metal acetylides to yield anti-amino propargyl alcohols in good yield and diastereomeric excess. syn Amino alcohols are prepared from the anti diastereoisomers and all of them are elaborated in few steps to enantiopure amino lactones and hydroxy-piperidin-2-ones.

Highly Stereoselective Benzylation of N‐Sulfinylketimines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly Stereoselective Benzylation of N-Sulfinylketimines

The benzylation of N-sulfinyl ketimines with 2-(p-tolylsulfinyl)ethylbenzene and LDA afford t-alkylamines in good yields. The configuration at each one of the new chiral centers simultaneously created in this reaction is controlled by the configuration of the sulfinyl groups at the nucleophile and electrophile, respectively. Thus, the reactions of the (S)-sulfoxide 6 with the N-(S)-sulfinylketimines 3 only yield the anti diastereoisomers 18, whereas the syn diastereoisomers 19 are exclusively formed in reactions of (S)-6 with N-(R)-sulfinylketimines 3. After a two-step desulfinylation process ((i) TFA, (ii) Ra-Ni), this reaction provides a procedure for synthesizing any epimer of alpha,alpha-dibranched beta-alkylarylamines in optically pure form by choosing the configuration of the starting materials. A similar behavior is observed for carbanions derived from the O-protected 2-(p-tolylsulfinyl) benzyl alcohol 7 thus allowing the synthesis of the optically pure anti- and syn-1,2-amino alcohols containing a chiral quaternary carbon adjacent to the nitrogen.

Synthesis of both syn and anti diastereoisomers of Boc-dolaproine from ( S)-proline through DKR using ruthenium-catalyzed hydrogenation: a dramatic role of N-protecting groups

The natural (2 R,3 R)-Boc-dolaproine and its unnatural (2 S,3 S) diastereoisomer were synthesized involving as key transformation the Ru(II)-promoted hydrogenation of the β-keto-α-methyl ester derived from ( S)- N-Boc-proline. Interestingly, the asymmetric hydrogenation of this β-keto ester N-protected as an amine hydrochloride salt, provided the corresponding anti (2 S,3 R)- and (2 R,3 S)-β-hydroxy-α-methyl esters with significant level of selectivities through dynamic kinetic resolution.

Diastereoselective Synthesis of 3,6‐Disubstituted 3,6‐Dihydropyridin‐2‐ones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Diastereoselective synthesis of 3,6-disubstituted 3,6-dihydropyridin-2-ones

In a short sequence, 5-vinyloxazolidin-2-ones were converted into the 3,6-disubstituted 3,6-dihydropyridin-2-ones via Pd-catalysed carbonylation and enolate alkylation with high diastereoselectivity. Alkylation of 6-substituted N-methylpyridin-2-ones gives stereoselectively the 3,6- anti diastereoisomer with MeI, BuI and i-PrI. Alkylation of the corresponding N-BOC pyridinones gives the 3,6- syn diastereoisomer with high selectivity.

Diastereoselectivity in the Allylation of N-Trialkylsilylimines of O-Protected (2S)-Lactal − Some Unexpected Results

A comparison of the diastereoselective addition of allylMgCl to differently O-protected N-trialkylsilyllactaldimine and to N-benzyllactaldimines is reported. The stereoselectivity strongly depends on the O- and N-protecting groups, on the metal cation, and on the reaction temperature, and varies from predominance of the anti diastereoisomer to predominance of the syn one. O-TBS- and O-TIPS-silyl imines displayed better anti diastereoselectivity than their O-alkyl counterparts. The N-protection produced unexpected results: in particular, the bulky, achiral, N-TIPS group favoured the predominance of the syn diastereoisomer. The temperature dependence of the stereochemical outcome provides evidence of the important role of differential entropies of activation (ΔΔS≠), and the presence of inversion temperatures (Tinv) related to dynamic solvation phenomena. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)