Syn Diastereomers Research Articles

Chemoenzymatic Synthesis of Enantiomerically Pure syn‐Configured 1‐Aryl‐3‐methylisochroman Derivatives

AbstractA two‐step synthesis of various enantiomerically pure 1‐aryl‐3‐methylisochroman derivatives was accomplished through asymmetric biocatalytic ketone reduction followed by an oxa‐Pictet–Spengler reaction. The compounds were obtained in good to excellent yield (47–92 %) in favor of the syn diastereomers [dr (syn/anti) up to 99:1]. Enantiopure arylpropanols serving as pronucleophiles for the C–C bond‐formation step were obtained by biocatalytic reduction by employing enantiocomplementary alcohol dehydrogenases, which gave access to the (S) and (R) enantiomer with up to >99 % conversion and up to >99 % ee.

Direct Synthesis of β-Hydroxy-α-amino AcidsviaDiastereoselective Decarboxylative Aldol Reaction

A straightforward metal-free synthesis of anti-β-hydroxy-α-amino acids is described. The organic base-mediated decarboxylative aldol reaction of cheap, readily available α-amidohemimalonates with various aldehydes afforded under very mild conditions anti-β-hydroxy-α-amido esters in high yields and complete diastereoselectivity. Simple one-pot subsequent transformations enabled the corresponding anti-β-hydroxy-α-amino acids or in a few examples their syn diastereomers to be obtained directly using epimerization conditions.

Potassium fluoride: A convenient, non-covalent support for the immobilization of organocatalysts through strong hydrogen bonds

The development of potassium fluoride as a practical non-covalent support for a carboxylic acid containing a pyrrolidine substituent with organocatalytic activity in the asymmetric Michael addition is described. The immobilization is carried out by simply treating the catalytic ligand in dichloromethane (DCM) solution with non-anhydrous potassium fluoride (KF). XRD and FTIR results suggest that the organocatalyst is efficiently loaded onto KF through strong hydrogen bond (SHB) formation, affording the KF-supported catalyst (KF-supCAT, 8) for the direct asymmetric Michael addition of carbonyl compounds to trans-β-nitrostyrenes. Good yields, excellent diastereoselectivities (up to 99:1 syn:anti) and excellent enantioselectivities (up to 97% ee for the syn diastereomer) are recorded in the Michael additions of cyclohexanone to trans-β-nitrostyrenes, considerably improving previous results obtained with a closely related catalyst covalently immobilized onto polystyrene. The KF-supCAT could be recovered and recycled three times by increasing the supersaturation degree of the solution.

Asymmetric N-Heterocyclic Carbene Catalyzed Addition of Enals to Nitroalkenes: Controlling Stereochemistry via the Homoenolate Reactivity Pathway To Access δ-Lactams

An asymmetric intermolecular reaction between enals and nitroalkenes to yield δ-nitroesters has been developed, catalyzed by a novel chiral N-heterocyclic carbene. Key to this work was the development of a catalyst that favors the δ-nitroester pathway over the established Stetter pathway. The reaction proceeds in high stereoselectivity and affords the previously unreported syn diastereomer. We also report an operationally facile two-step, one-pot procedure for the synthesis of δ-lactams.

A Theoretical Investigation on the Mechanism and Stereochemical Course of the Addition of (E)-2-Butenyltrimethylsilane to Acetaldehyde by Electrophilic and Nucleophilic Activation

The diastereoselectivity of the addition of (E)-2-butenyltrimethylsilane to acetaldehyde under electrophilic (BF3, H3O(+)) and nucleophilic (F(-)) activation is investigated using density functional theory (M06-2X). The interaction-distortion/activation-strain model of reactivity is used to rationalize the origin of the selectivity. Consistent with experimental model systems, the synclinal transition states are determined to be preferred over the antiperiplanar transition states in the electrophilic-activated manifolds and vice versa for the fluoride-activated manifold. The selectivity for the syn diastereomer in the electrophilic activation manifolds is accounted for by increased electrostatic and orbital interactions for a synclinal transition state (syn-T3) at the expense of increased steric interactions relative to antiperiplanar transition states. The enhanced orbital interactions for the synclinal (syn-T3) versus antiperiplanar transition states can be attributed to increased π→π* interactions. The selectivity for the anti diastereomer in the nucleophilic manifold is explained by the lesser electrostatic repulsion in the antiperiplanar transition states which are favored relative to the synclinal transition states. Additionally, the diastereoselectivity is partly attributed to variation in the distortion of the crotylsilane.

ChemInform Abstract: Stereochemistry Modulates the Catalytic Hydrogenolysis of Nitrile‐Substituted Cyclopropanes.

AbstractThe compound (VI) fails to separate completely.

Insights into the spontaneous emergence of enantioselectivity in an asymmetric Mannich reaction carried out without external catalyst

ESI-MS, chiral HPLC, time-resolved 1H NMR and optical rotation measurements were performed to gain insights into the nature of spontaneous mirror symmetry breaking in the catalyst-free Mannich reaction of PMP protected α-iminoethylglyoxylate with hydroxyacetone. Spontaneous temporary generation of enantiomeric excesses of up to 7.4% in the major syn diastereomer is reproducibly observed in aqueous phosphate buffers, starting from achiral conditions. The syn-product ee values for both enantiomers [(2S,3S) and (2R,3R)], although not with stochastic distribution, have been observed with no clear preference for either enantiomer.

1,2]- and [1,4]-Wittig rearrangements of α-alkoxysilanes: effect of substitutions at both the migrating benzylic carbon and the terminal sp2 carbon of the allyl moiety

Substituted α-alkoxysilanes can be deprotonated by alkyllithium bases and made to undergo Wittig rearrangements to afford the [1,4]- and [1,2]-rearranged products in varying ratios. Substitution at the benzylic migrating carbon and/or at the allylic carbon of the allyl moiety impacts the rearrangement reaction, influencing the reactivity as well as the [1,4]-/[1,2]-selectivity. Diastereomeric α-alkoxysilanes show different reactivities with the syn diastereomer being the more reactive isomer.

Stereochemistry modulates the catalytic hydrogenolysis of nitrile-substituted cyclopropanes

The study of Raney-Ni catalyzed chemo- and regioselective hydrogenolysis of diastereomeric nitrile-substituted spirocyclopropyloxindoles is presented. The chemoselectivity outcome of the reaction is remarkably influenced by the relative stereochemistry of the nitrile-substituted spirocyclopropyloxindoles. Chemo- and high regioselective cyclopropane ring-opening occurs from the syn diastereomers to give the corresponding 3-propylacetamide derivatives. X-ray crystallographic studies together with DFT model chemistry calculations indicate that chemo- and regioselectivity are directly dependent on the bond length asymmetry of the cyclopropane ring.

Unexpected Diastereoselective Acetylation of 1,8‐Dimethoxyanthracene Adducts with Maleic Anhydride and Dimethyl Maleate

AbstractFriedel–Crafts acetylation of adducts between 1,8‐dimethoxyanthracene and maleic anhydride or dimethyl maleate proceeds with a strong preference toward the syn diastereomer. This stereoselectivity is especially prominent for the anhydride counterpart. Dependence of the observed selectivity on the adduct structure is rationalized by the analysis of computed HOMO energies of the reactants and relative energies of the intermediate σ‐complexes. The possible undesired intermolecular condensation of the anhydride did not take place because of steric hindrance. Structures of the reaction products were unambiguously confirmed by single‐crystal X‐ray diffraction (XRD). The reported stereoselectivity of acetylation provides facile access to compounds with the functionalized benzene ring in a syn arrangement with respect to the pendant carboxyl substituents.

Synthesis, Absolute Configuration, and Bacterial Mutagenicity of the 8 Stereoisomeric Vicinal Diol Epoxides at the Terminal Benzo Ring of Carcinogenic Dibenz[a,h]anthracene

The synthesis of the 8 possible stereoisomeric diol epoxides (DEs) at the terminal benzo ring of carcinogenic dibenz[a,h]anthracene (DBA) is reported. trans-3,4-Dihydroxy-3,4-dihydro-DBA (1) afforded the 4 bay region DEs: the enantiomeric pairs of the anti diastereomers (+)-3/(-)-3 and of the syn diastereomers (-)-4/(+)-4, respectively. trans-1,2-Dihydroxy-1,2-dihydro-DBA (2) served as precursor of the 4 reverse DEs: the enantiomeric pairs of the anti diastereomers (+)-5/(-)-5 and of the syn diastereomers (-)-6/(+)-6, respectively. The transformation of the olefinic double bond in the enantiomeric trans-dihydrodiols to epoxides was achieved by either (i) oxidation with m-chloroperoxybenzoic acid or (ii) formation of a bromohydrin with N-bromoacetamide/H(2)O followed by dehydrobromination with an anion exchange resin. Because of the pseudodiequatorial conformation of the hydroxyl groups in 1, both reactions proceeded highly stereoselectively, while the stereoselectivity was impaired by the pseudodiaxial conformation of the hydroxyl groups in 2. Diastereomers and racemic compounds were efficiently separated without derivatization by HPLC on achiral or chiral stationary phases, respectively. The absolute configurations of the DEs were deduced from the absolute configuration of 1 and 2 considering the regio- and stereoselectivity of the subsequent reactions and resulted in (+)-(1R,2S,3S,4R)-3/(-)-(1S,2R,3R,4S)-3, (-)-(1S,2R,3S,4R)-4/(+)-(1R,2S,3R,4S)-4, (+)-(1R,2S,3S,4R)-5/(-)-(1S,2R,3R,4S)-5, and (-)-(1R,2S,3R,4S)-6/(+)-(1S,2R,3S,4R)-6. The bacterial mutagenicity of the 8 stereoisomeric DEs was determined in histidine-dependent strains TA98 and TA100 of Salmonella typhimurium in the absence of a metabolizing system. In general, the bay region DEs of DBA were stronger mutagens than the reverse DEs. In strain TA98, the syn diastereomers of bay region DEs were stronger mutagens than their anti isomers, while in the case of reverse DEs the anti diastereomers were more potent than their syn isomers. In strain TA100, all syn diastereomers surpassed the bacterial mutagenicity of their anti isomers. Concerning the bay region DEs of DBA, this corresponds to the situation described for benzo[a]pyrene: of the 4 enantiomeric bay region DEs of DBA and benzo[a]pyrene, the syn diastereomer with [(R,S)-diol (R,S)-epoxide] absolute configuration is the most potent mutagen in both bacterial strains, while the anti isomer with [(S,R)-diol (R,S)-epoxide] configuration is the weakest mutagen.

Radical and Heck Cyclizations of Diastereomeric o-Haloanilide Atropisomers

The outcomes of radical cyclizations and Heck reactions of N-(cyclohex-2-enyl)-N-(2-iodophenyl)acetamides depend critically on the configurations of the chiral axis and the stereocenter. In substrates without an ortho-methyl group, the diastereomeric precursors interconvert slowly at ambient temperatures. Cyclization of enriched mixtures of diastereomers provided similar yields of acetyl tetrahydrocarbazoles or dihydrocarbazoles, suggesting that interconversion of the radical or organometallic intermediates also occurs. Diastereomers of N-(cyclohex-2-enyl)-N-(2-iodo-4,6-dimethylphenyl)acetamides with an additional ortho-methyl group did not interconvert at ambient temperatures and were readily resolved. In radical cyclizations, syn diastereomers were prone to cyclize, while anti isomers were not. Strikingly, Heck reactions gave the opposite result; anti isomers were prone to cyclization and syn isomers were not. Heck reactions of allylic acetates occur with β-hydride elimination when acetate is trans to palladium and with β-acetoxy elimination when acetate is cis. This is surprising because prior studies have suggested that a trans relationship of palladium and acetoxy is essential for acetate elimination. Analyses of the results provide insights into mechanisms for radical cyclization and for insertion and elimination in the Heck reaction.

Gold Catalysis: Tandem Reactions of Diyne–Diols and External Nucleophiles as an Easy Access to Tricyclic Cage‐Like Structures

Different diyne-diols composed of two terminal homopropargylic alcohol groups were prepared by bi-directional synthesis. Subjection of the syn diastereomers to NAC-gold catalysts (NAC=nitrogen acyclic carbene) in the presence of external nucleophiles such as water or anilines provided substituted and highly rigid heterocyclic cages. The corresponding anti disastereomers polymerised. An intermediate of the reactions of the syn diastereomers could be isolated and even be characterised by crystal structure analysis. Overall, eight new bonds are formed in the reaction, which proceeds by a multistep sequence of highly selective hydroalkoxylations and hydrohydroxylation or hydroaminations. For furyl substituents and for internal alkynes competing reaction pathways could be identified. By the cross-coupling of a product with an iodoaryl substituent, the use of these cage compounds as geometrically defined linking groups by using orthogonal transition-metal-catalysed methodology, namely, gold and palladium catalysis, could be demonstrated.

A Diastereo- and Enantioselective Synthesis of α-Substituted syn-α,β-Diamino Acids

Highly diastereo- and enantioselective additions of substituted alpha-nitroesters to imines have been developed. High diastereoselection relies on the finding that the combination of chiral proton catalyst 2b and alpha-nitro aryl esters bearing 2,6-disubstitution combine to raise substrate-controlled diastereoselection to >20:1 in favor of the syn diastereomer. Furthermore, the chiral catalyst provides enantioselection to the 99% level through control of the addition step in which the azomethine pi-faces are differentiated. The bifunctional chiral protic acid catalyst enables these reactions to proceed without separate preactivation of either substrate, leading to a straightforward synthetic protocol for the formation of alpha,beta-diamino phenyl alanine derivatives.

Nucleophilic addition of potassium organotrifluoroborates to chiral cyclic N-acyliminium ions: stereoselective synthesis of functionalized N-heterocycles

The stereoselective nucleophilic addition of potassium aryl- and alkynyltrifluoroborates to cyclic N-acyliminium ion derivatives from N-benzyl-3,4,5-triacetoxy-2-pyrrolidinone, affording the respective 5-substituted 2-pyrrolidinone is described. The products were obtained in moderate to good yields and with preference for the syn diastereomer.

An Easy Stereoselective Access to β,γ-Aziridino α-Amino Ester Derivatives via Mannich Reaction of Benzophenone Imines of Glycine Esters withN-Sulfonyl α-Chloroaldimines

Mannich-type addition of benzophenone imine glycinates across newly synthesized N-(p-toluenesulfonyl) alpha-chloroaldimines afforded gamma-chloro-alpha,beta-diamino ester derivatives with moderate diastereoselectivity as separable mixtures of anti and syn diastereomers. The gamma-chloro-alpha,beta-diamino esters were efficiently cyclized under basic conditions to the corresponding beta,gamma-aziridino alpha-amino ester derivatives, representing a new class of conformationally constrained heterocyclic alpha,beta-diamino acid derivatives. The relative configuration of the aziridines was determined via X-ray diffraction analysis. Mechanisms and intermediate transition states to explain the stereochemical outcome of the Mannich reaction with different substrates or under different conditions are proposed. The synthetic importance of the beta,gamma-aziridino alpha-amino ester derivatives is demonstrated by their conversion into the corresponding Boc-protected derivatives and ring opening reactions to alpha,beta-diamino esters and a gamma-amino alpha,beta-unsaturated amino ester.

Isolation, Characterization, and Biological Evaluation ofSynandAntiDiastereomers of [99mTc]Technetium Depreotide: a Somatostatin Receptor Binding Tumor Imaging Agent

The early and later eluting [(99m)TcO]depreotide products on RP-HPLC were confirmed to be the anti and syn diastereomers, respectively, based on proton NMR and circular dichroism spectroscopy. NMR provided evidence of a folded, conformationally constrained structure for the syn diastereomer. The syn diastereomer is predominant (anti/syn approximately 10:90) in the [(99m)TcO]depreotide preparation and shows a slightly higher affinity (IC50 = 0.15 nM) for the somatostatin receptor than the anti diastereomer (IC50 = 0.89 nM). Both diastereomers showed higher binding affinities than the free peptide (IC(50) = 7.4 nM). Biodistribution studies in AR42J tumor xenograft nude mice also showed higher tumor uptake for syn [(99m)TcO]depreotide (6.58% ID/g) than for the anti [(99m)TcO]depreotide (3.38% ID/g). Despite the differences in biological efficacy, the favorable binding affinity, tumor uptake, and tumor-to-background ratio results for both diastereomeric species predict that both are effective for imaging somatostatin receptor-positive tumors in vivo.

MO tripeptide diastereomers (M=99/99mTc, Re): models to identify the structure of 99mTc peptide targeted radiopharmaceuticals.

Biologically active molecules, such as many peptides, serve as targeting vectors for radiopharmaceuticals based on 99mTc. Tripeptides can be suitable chelates and are easily and conveniently synthesized and linked to peptide targeting vectors through solid-phase peptide synthesis and form stable TcVO complexes. Upon complexation with [TcO]3+, two products form; these are syn and anti diastereomers, and they often have different biological behavior. This is the case with the approved radiopharmaceutical [99mTcO]depreotide ([99mTcO]P829, NeoTect) that is used to image lung cancer. [99mTcO]depreotide indeed exhibits two product peaks in its HPLC profile, but assignment of the product peaks to the diastereomers has proven to be difficult because the metal peptide complex is difficult to crystallize for structural analysis. In this study, we isolated diastereomers of [99TcO] and [ReO] complexes of several tripeptide ligands that model the metal chelator region of [99mTcO]depreotide. Using X-ray crystallography, we observed that the early eluting peak (A) corresponds to the anti diastereomer, where the Tc=O group is on the opposite side of the plane formed by the ligand backbone relative to the pendant groups of the tripeptide ligand, and the later eluting peak (B) corresponds to the syn diastereomer, where the Tc=O group is on the same side of the plane as the residues of the tripeptide. 1H NMR and circular dichroism (CD) spectroscopy report on the metal environment and prove to be diagnostic for syn or anti diastereomers, and we identified characteristic features from these techniques that can be used to assign the diastereomer profile in 99mTc peptide radiopharmaceuticals like [99mTcO]depreotide and in 188Re peptide radiotherapeutic agents. Crystallography, potentiometric titration, and NMR results presented insights into the chemistry occurring under physiological conditions. The tripeptide complexes where lysine is the second amino acid crystallized in a deprotonated metallo-amide form, possessing a short N1-M bond. The pKa measurements of the N1 amine (pKa approximately 5.6) suggested that this amine is rendered more acidic by both metal complexation and the presence of the lysine residue. Furthermore, peptide chelators incorporating a lysine (like the chelator of [TcO]depreotide) likely exist in the deprotonated form in vivo, comprising a neutral metal center. Deprotonation possibly mediates the interconversion process between the syn and anti diastereomers. The N1 amine group on non-lysine-containing metallopeptides is not as acidic (pKa approximately 6.8) and does not deprotonate and crystallize as do the metallo-amide species. Three of the tripeptide ligands (FGC, FSC, and FKC) were radiolabeled with 99mTc, and the individual syn and anti isomers were isolated for biodistribution studies in normal female nude mice. The main organs of uptake were the liver, intestines, and kidneys, with the FGC compounds exhibiting the highest liver uptake. In comparing the diastereomers, the syn compounds had substantially higher organ uptake and slower blood clearance than the anti compounds.

Experimental Demonstration of Base-Catalyzed Interconversion of Isomeric Betaine Intermediates in the Corey−Chaykovsky Epoxidation

The collapse of hydroxysulfonium salts has been examined as a model for the epoxidation of aldehydes. The anti diastereomer reacted with retention of stereochemistry and no crossover, while the syn diastereomer gave crossover products along with cis and trans epoxides. Deprotonation and reprotonation on the carbon of the alpha-hydroxy sulfonium ylide is presumed responsible for production of the trans epoxide. This reaction pathway has been proposed to explain losses of enantioselectivity but never directly observed.

Synthesis and Characterization of Two Isomeric, Self-Assembled Arsenic−Thiolate Macrocycles

The use of labile As-S bond formation in the self-assembly of discrete supramolecular structures is extended. Macrocyclic structures of chemical formula As2L2Cl2 (H2L=alpha,alpha'-dimercapto-p-xylene) were prepared and characterized. Diastereomeric syn and anti isomers of these macrocycles were selectively crystallized and characterized in the solid state using single-crystal X-ray diffraction. Both the syn and anti macrocycles show close contacts between the arsenic(III) ions and the aromatic carbons, consistent with intramolecular arsenic-pi interactions. The dynamic behavior of the isomers in solution is also investigated. anti-As2L2Cl2.AsCl3 crystallizes in monoclinic space group P2(1)/c (No. 14) with a=10.6194(5) A, b=16.7780(9) A, c=8.5725(4) A, beta=100.6830(10) degrees, and Z=2. syn-As2L2Cl2 crystallizes in orthorhombic space group Pnma (No. 62) with a=10.8881(8) A, b=19.3511(14) A, c=9.9524(7) A, and Z=4.