Anti Diastereomers Research Articles

A simple microscale method for determining the relative stereochemistry of statine units.

A simple method to determine the relative stereochemistry of statine amino acids (gamma-amino-beta-hydroxyacids) by using (1)H NMR spectroscopy is described. Configurational assignment of statine units within complex natural products is possible without degradation or derivatization as the syn and anti diastereomers can be distinguished by using a combination of chemical shift and coupling constant information derived from the alpha-methylene ABX system. Seventy-three examples are provided, demonstrating the scope and limitations of the methodology. These examples range in complexity from simple statine units to cyclic depsipeptides, such as tamandarin B.

Synthesis of Acyl Aminocyclopentenes with Acyl Anion Nucleophiles

The stereoselective ring-opening of diazabicycle 1 with acyl anions yielded only the anti diastereomer of 3. Under the mild reaction conditions, no isomerization of the alkene occurs in the final product. Previous Rh-catalyzed methods of carbonlyation of alkenes involved either high pressures of CO, and/or high temperatures. As a proof of concept, the procedure demonstrated that acyl anion equivalents can be generated under very mild and practical conditions. The methodology reported opens up the door to further study of the Rh-acylanion complex behavior.

Acyclic 1,4-Stereocontrol via Reductive 1,3-Transpositions

One-pot reduction/allylic diazene rearrangement of lactic acid- and mandelic acid-derived alpha,beta-unsaturated tosyl hydrazones leads to 1,4-syn- or 1,4-anti-E-2-alkenyl arrays in high yield and diastereoselectivity. Either the syn or the anti diastereomer can be prepared by choosing the appropriate alkene stereoisomer of the hydrazone. The E-alkenes led to the 1,4-syn isomers, while the Z-alkenes led to the 1,4-anti isomers, both with > or =20:1 diastereoselectivity.

Diastereoselectivity in the Self-Assembly of As2L2Cl2 Macrocycles is Directed by the As−π Interaction

The As-pi interaction, in conjunction with reversible As-thiolate bond formation, is used to direct the self-assembly of dinuclear As2L2Cl2 (L = a dithiolate) macrocycles that exist as equilibrium mixtures of both syn and anti diastereomers. The diastereomeric excess of these self-assembly reactions is controlled in a predictable manner by prudent choice of different achiral, isomeric ligands. A general method for the preparation of As2L2Cl2 macrocycles is established, and strategies to control the diastereoselective self-assembly of regioisomeric macrocycles in solution and the crystalline state are described. A mechanism for the interconversion between diastereomers (a slow process on the NMR time scale) is suggested, and variable-temperature NMR spectroscopic data show that the diastereomeric excess (de) decreases with increasing temperature. anti-As2(L2,6)2Cl2 crystallizes in monoclinic space group P2(1)/n with a = 6.3949(13), b = 19.675(4), c = 10.967(2) A, beta = 106.817(3) degrees , and Z = 2. anti-As2(L1,5)2Cl2 crystallizes in monoclinic space group P2(1)/c with a = 6.813(4), b = 19.085(12), c = 10.277(6) A, beta = 107.788(10) degrees , and Z = 4. syn-As2(L1,4)2Cl2.CHCl3 crystallizes in triclinic space group P(-) with a = 19.313(4), b = 19.923(4), c = 24.508(5) A, alpha = 78.110(4) degrees , beta = 78.860(5) degrees , gamma = 89.183(5) degrees , and Z = 12. As2(L1,4)2Cl2.C6H6 crystallizes in monoclinic space group P2(1)/n with a = 10.3332(7), b = 34.375(2), c = 17.8593(12) A, beta = 98.9650(10) degrees , and Z = 8.

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.

A Heterodinuclear Asymmetric Catalyst for Conjugate Additions of α-Hydroxyketones to β-Substituted Nitroalkenes

[Structure: see text] The bis-ProPhenol ligand was designed to facilitate formation of hetereodinuclear complexes based upon the large difference in pKa of the one phenolic OH group to the tertiary OH groups. In exploring the first example of hydroxyacetophenones as donors in asymmetric Michael reactions with nitroalkene acceptors, the best stereocontrol was observed with a zinc/magnesium dinuclear complex where enantiomeric excesses ranged up to 92% for the major anti diastereomer.

Diastereoselective Ethynylation of Chiral α‐(Dibenzylamino) Aldehydes: Synthesis of meso‐ and Homochiral C2‐Symmetrical 1,6‐Diamino‐2,5‐diols

AbstractHomochiral α‐(dibenzylamino) aldehydes, prepared from the corresponding α‐amino acids, react with ethynylmagnesium bromide in THF/Et2O at 0 °C to afford, in good yields and dr, propargylic 1,2‐amino alcohols; anti diastereomers were always formed as the major products in this reaction. These compounds are versatile intermediates in the synthesis of meso‐ and enantiopure 1,6‐diamino‐2,5‐diols with C2 symmetry. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Diastereoselective synthesis of enantioenriched homopropargyl amino alcohols from α-dibenzylamino aldehydes and their use as chiral synthons

Homochiral α-dibenzylamino aldehydes, prepared from the corresponding α-amino acids, react with propargyl bromide and zinc in DMF/THF (1:1) or DMF/Et 2O (1:1) at 20 °C to afford, in good yields and dr, homopropargylic 1,2-amino alcohols. anti Diastereomers were always formed as major products in this reaction. These compounds are versatile intermediates for a variety of synthetic targets: γ-amino-β-hydroxy-ketones, 4-amino-1,3-diols, 1,7-diamino-2,6-diols, and ω-amino-δ-hydroxy esters.

Synthesis of ethyl and t-butyl (3 R,5 S)-dihydroxy-6-benzyloxy hexanoates via diastereo- and enantioselective microbial reduction

Previously we have demonstrated the reduction of ethyl diketoester 4 to the corresponding dihydroxy ester 6a by Acinetobacter sp. SC13874. Recently we screened more than 100 cultures for microbial reduction of both the ethyl and t-butyl diketoesters 4 and 5. Most yeast cultures showed a preference for reduction at the C-3 with low enantioselectivity. Among the three Acinetobacter strains screened, Acinetobacter sp. SC13874 reduced both compounds 4 and 5 to the corresponding (3 R)- and (5 S)-monohydroxy compounds. Monohydroxy compounds were isolated and their absolute configurations determined. (3 R)- and (5 S)-Monohydroxy compounds were reduced further to the corresponding dihydroxy esters 6a and 8a to provide alternate routes for the synthesis of compounds 14a and 16a, potential intermediates for the synthesis of HMG-CoA reductase inhibitors. Cell suspensions of Acinetobacter sp. SC13874 reduced the ethyl diketoester 4 to a mixture of desired syn and undesired anti diastereomers. The desired syn-(3 R,5 S)-dihydroxy ester 6a was obtained with an enantiomeric excess (ee) of 99% and a diastereomeric excess (de) of 63%. Cell suspensions reduced the t-butyl diketoester 5 to a mixture of mono- and dihydroxy esters with the dihydroxy ester showing an ee of 87% and de of 51% for the desired syn-(3 R,5 S)-dihydroxy ester 8a. Three different ketoreductases were purified to homogeneity, and their biochemical properties compared. Reductase I only catalyzes the reduction of ethyl diketoester 4 to its monohydroxy products 10 and 11, whereas reductase II catalyzes the formation of dihydroxy products 6 and 7 from monohydroxy substrates 10 and 11. A third reductase (III) was identified, which catalyzes the reduction of diketoester 4 to syn-(3 R,5 S)-dihydroxy ester 6a.

Diastereomer-Differentiating Photochemistry of β-Arylbutyrophenones: Yang Cyclization versus Type II Elimination

The diastereomers of ketones 2 and 3 are shown to exhibit distinct photochemical reactivities due to conformational preferences; while the anti isomers of 2 and 3 undergo efficient Yang cyclization in 75-90% yields with a remarkable diastereoselectivity (> 90%), the syn isomers predominantly undergo Norrish Type II elimination. The differences in the product profiles of the diastereomers are consistent with a mechanistic picture involving the formation of precursor diastereomeric triplet 1,4-biradicals in which the substituents at alpha and beta-positions stabilize the cisoid (cyclization) or transoid (elimination) geometry. The fact that such a diastereomeric relationship does indeed ensue at the triplet-excited-state itself is demonstrated via the nanosecond laser-flash photolysis of model ketones 1. The diastereomeric discrimination in the product profiles observed for ketones 2 and 3 as well as in the triplet lifetimes observed for ketones 1 can both be mechanistically traced back to different conformational preferences of the ground-state diastereomeric ketones and the intermediary 1,4-biradicals. Additionally, it emerges from the present study that the syn and anti diastereomers of ketones 2 and 3 represent two extremes of a broad range of widely examined butyrophenones, which lead to varying degrees of Yang photocyclization depending on the alkyl substitution pattern.

Chelation-Controlled Diastereoselective Reduction of α-Fluoroketones

The effect of Ti-based Lewis acids on the reduction of alpha-fluoropropiophenone was examined to determine whether chelation control could be used to direct the diastereoselectivity of conversion to an alpha-fluoro alcohol. Pretreatment of alpha-fluoropropiophenone with TiCl4 followed by reduction with LiBH4 in diethyl ether or methylene chloride provided the syn diastereomer predominantly, while use of Ti(OiPr)4 under identical conditions provided the anti diastereomer as the major product. The products are consistent with a chelation-controlled mechanistic pathway in the former reduction and a nonchelation pathway in the latter case. Detailed 1H, 13C, and 19F NMR studies were consistent with chelation between TiCl4 and alpha-fluoropropiophenone under the reaction conditions utilized in this study. Reduction of other alpha-fluoroketones in the presence of TiCl4 also provided a high degree of diastereoselectivity in the conversion to alpha-fluoro alcohols, showing the generality of this approach.

Metallophosphite‐Induced Nucleophilic Acylation of α,β‐Unsaturated Amides: Facilitated Catalysis by a Diastereoselective Retro [1,4] Brook Rearrangement

Metallophosphite‐Induced Nucleophilic Acylation of α,β‐Unsaturated Amides: Facilitated Catalysis by a Diastereoselective Retro [1,4] Brook Rearrangement

Synthesis of a C20−C26 Segment of Superstolide A by Addition of a Chiral Allenylzinc Reagent to (R)-N-Boc Alaninal

[reaction: see text] Additions of chiral allenylzinc and indium reagents to N-Boc alaninal were examined as a possible route to a C20-C26 segment of superstolide A. Allenylzinc reagents, prepared in situ by palladiozincation of (R)- and (S)-5-pivalyloxy-3-butyn-2-ol mesylate, showed excellent reagent control to afford the anti,syn and anti,anti diastereomers as the nearly exclusive adducts.

Synthesis of Chiral Vicinal Diamines by Highly Diastereoselective Three-Component Phenolic Mannich Reaction: Temperature-Dependent Stereodivergency

[reaction: see text] A diastereoselective three-component synthesis of chiral o-1,2-diaminoalkyl phenols from an electron-rich phenol, an amine, and a chiral alpha-N,N-dibenzylamino aldehyde is developed. The diastereoselectivity of this phenolic Mannich reaction is temperature-dependent,and either anti or syn diastereomer can be prepared by controlling the reaction conditions. Low reaction temperature (-20 degrees C) favors the formation of anti adduct 1, whereas higher temperature (60 degrees C) under otherwise identical conditions produces mainly the syn isomer.

Rapid, Highly Diastereoselective Addition of Dialkylzinc Reagents to Atropisomeric 2‐Formyl Arylamides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Solvent-dependent diastereoselectivities in reductions of beta-hydroxyketones by SmI2.

The reductions of a series of beta-hydroxyketones by SmI(2) were examined in THF, DME, and CH(3)CN using methanol as a proton source. Reductions in THF and DME typically lead to the syn diastereomer with DME providing higher diastereoselectivities. Reductions in CH(3)CN provided the anti diastereomer predominantly. This study reveals that solvation plays an important role in substrate reduction by SmI(2). [reaction: see text]

Diastereoselective Synthesis of β‐Amino‐α‐(trifluoromethyl) Alcohols from Homochiral α‐Dibenzylamino Aldehydes

AbstractHomochiral α‐dibenzylamino aldehydes, prepared from the corresponding α‐amino acids, react with trimethyl(trifluoromethyl)silane in THF at 0 °C to afford, in good yields and dr, β‐amino‐α‐(trifluoromethyl) alcohols; anti diastereomers were formed as major products in the trifluoromethylation reaction whereas syn diastereomers were obtained as single isomers in a two‐step procedure. Swern oxidation of the mixtures formed in the trifluoromethylation leads to the corresponding α‐dibenzylamino trifluoromethyl ketones which undergo diastereoselective reduction with sodium borohydride. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)