Anti Diastereomers Research Articles

One-pot sequential organocatalytic Michael-Tishchenko-lactonization reactions. Synthesis of enantioenriched 4,5,6-trisubstituted δ-lactones.

Enantioenriched trisubstituted lactones were obtained in good yields and moderate to very good enantioselectivities in one-pot process, which implies a sequential organocatalyzed Michael addition of ketones to enals, followed by catalytic intramolecular diastereoselective Tishchenko reaction and lactonization. The final lactones were obtained as single diastereoisomers, demonstrating that the mixture of the anti and syn diastereomers epimerized to the syn hydroxy ester during the oxido-reduction step.

Three-component anti selective Mannich reactions in a tetrahydro-4-pyranone system by using PDAG-Co catalyst

Abstract Catalytic quantities (2 mol%) of a complex of cobalt containing guanidine and 2,6-pyridinedicarboxylic acid ligands (PDAG-Co) were used for the efficient three-component Mannich reactions of tetrahydro-4-pyranone (1) with different aromatic aldehydes and aniline derivatives in a one-pot process. Reactions rapidly gave high yields of the corresponding three-substituted tetrahydro-4-pyranones at room temperature. Spectroscopic and X-ray analyses support the formation of anti diastereomers as the major or sole products of the reactions.

Simplified synthesis of individual stereoisomers of the 4-hydroxynonenal adducts of deoxyguanosine

We previously reported the synthesis of the 1,N2-deoxyguanosine adducts of 4-hydroxynonenal, an important product of lipid peroxidation, which involved the nucleophilic aromatic substitution reaction of an O6-protected-2-fluoroinosine with 4-amino-1,2,5-trihydroxydecanal followed by periodate oxidation of the vicinal diol.3 An improved synthesis of the amino triols has been developed. The syn and anti diasteromers of a key intermediate, 4-nitro-5-hydroxy-1-decene, were synthesized by a Henry reaction and separated; each diastereomer was further separated into individual enantiomers by chiral supercritical fluid chromatography. Of note, dihydroxylation of the terminal olefin under conventional conditions with catalytic OsO4 and a tertiary amine oxide as the stoichiometric oxidant led to scrambling of stereochemistry at C4. The scrambling was not observed when t-butylhydroperoxide was used as the oxidant.

ChemInform Abstract: Highly Efficient Stereoselective Catalytic C(sp3)—H Insertions with Donor Rhodium Carbenoids Generated from Cyclopropenes.

AbstractThe tetrahydropyrans (II) arise as single anti diastereomers by 1,6‐C—H insertions.

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.

Aldol reactions of 2-thioxotetrahydropyrimidin-4(1H)-ones: stereoregulations from endo- and exocyclic chiral centres

The steric regulations imparted by the substituent at N1 in lithium mediated asymmetric aldol reactions of conformationally restricted 3-aryl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones governed the formation of anti aldol adducts, by a kinetic reaction pathway. The preferential formation of the anti aldol diastereomers was also assisted by the steric effects of the electrophile through diastereofacial selection while the electronic effects of the aryl group at N3 remained subtle. Incorporation of an endocyclic methyl group at C6 witnessed the diastereoselective formation of an anti aldol adduct by regulation of π-facial selectivity. The absolute configurations of the aldol adducts were determined by computational calculations and NMR experiments, and confirmed by single crystal X-ray analysis.

The Stereochemical Course of Intramolecular Michael Reactions

We present a general model for understanding the stereochemical course of intramolecular Michael reactions. We show that the addition of β-ketoester enolates to α,β-unsaturated esters and imides bearing adjacent stereocenters (X, Y = H, Me, OR) leads to high levels of asymmetric induction. Reinforcing and nonreinforcing stereochemical relationships are evaluated from the syn and anti reactant diastereomers. On the basis of synthetic, spectroscopic, and computational studies, we propose that the outcomes of these reactions can be rationalized by a dipole-minimized chair transition-state model.

Stereoregulations of Pyrimidinone Based Chiral Auxiliary in Aldol and Alkylation Reactions: A Convenient Route to Oxyneolignans

(S)-4-Isopropyl-1-phenyltetrahydropyrimidin-2(1H)-one was synthesized and evaluated as a chiral auxiliary for asymmetric acetate and propionate aldol reactions, by generation of titanium and lithium enolates, affording excellent yields and stereoselectivities for syn and anti aldol diastereomers, respectively. High stereoselectivities were also obtained in lithium mediated alkylation reactions. The application of the auxiliary was exemplified in the asymmetric synthesis of a natural oxyneolignan, (+)-(7S,8S)-4-hydroxy-3,3',5'-trimethoxy-8',9'-dinor-8,4'-oxyneoligna-7,9-diol-7'-oic acid.

Copper Complex of Aminoisoborneol Schiff Base Cu2(SBAIB‐d)2: An Efficient Catalyst for Direct Catalytic Asymmetric Nitroaldol (Henry) Reaction

AbstractA new bifunctional copper complex of the aminoisoborneol Schiff base – Cu2(SBAIB‐d)2 – has been developed for the effective direct catalytic asymmetric Henry reaction. One mol% of this catalyst produces the expected Henry products in high yields (up to 99%) with excellent enantioselectivities (up to 98% ee). The utility of the present catalyst was also extended to the Henry reaction with nitroethane and 1‐nitropropane that furnished the corresponding products in moderate to high yields (up to 99%) with moderate to high enantioselectivities of syn (up to 98% ee) and anti (up to 98% ee) diastereomers. The highlights of this catalytic system are easy manipulation, air and moisture tolerance, the need for 1 mol% of an easily synthesizable catalyst and the high enantioselectivities achieved for a wide range of substrates.

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.

Synthesis of 1,3-Diols through Grignard Addition to Isopropenyl Acetate

The 1,3-diol moiety is frequently found in many important natural products and pharmaceuticals. Many methods have been ­developed to synthesize 1,3-diols with both syn- and anti-relative stereochemistry. The authors present a unique and unexpected reaction to form anti-1,3-diols from isopropenyl acetate and aryl Grignard reagents in moderate yield and good ­selectivity for the anti diastereomer.

Highly efficient aldol additions of DHA and DHAP to N-Cbz-amino aldehydes catalyzed by l-rhamnulose-1-phosphate and l-fuculose-1-phosphate aldolases in aqueous borate buffer

Aldol addition reactions of dihydroxyacetone (DHA) to N-Cbz-amino aldehydes catalyzed by L-rhamnulose-1-phosphate aldolase (RhuA) in the presence of borate buffer are reported. High yields of aldol adduct (e.g. 70-90%) were achieved with excellent (>98 : 2 syn/anti) stereoselectivity for most S or R configured acceptors, which compares favorably to the reactions performed with DHAP. The stereochemical outcome was different and depended on the N-Cbz-amino aldehyde enantiomer: the S acceptors gave the syn (3R,4S) aldol adduct whereas the R ones gave the anti (3R,4R) diastereomer. Moreover, the tactical use of Cbz protecting group allows simple and efficient elimination of borate and excess of DHA by reverse phase column chromatography or even by simple extraction. This, in addition to the use of unphosphorylated donor nucleophile, makes a useful and expedient methodology for the synthesis of structurally diverse iminocyclitols. The performance of aldol additions of dihydroxyacetone phosphate (DHAP) to N-Cbz-amino aldehydes using RhuA and L-fuculose-1-phosphate aldolase (FucA) catalyst in borate buffer was also evaluated. For FucA catalysts, including FucA F131A, the initial velocity of the aldol addition reactions using DHAP were between 2 and 10 times faster and the yields between 1.5 and 4 times higher than those in triethanolamine buffer. In this case, the retroaldol velocities measured for some aldol adducts were lower than those without borate buffer indicating some trapping effect that could explain the improvement of yields.

1,3‐Dipolar Cycloaddition of Azomethine Ylides to Aldehydes: Synthesis of anti α‐Amino‐β‐Hydroxy Esters

AbstractA 1,3‐dipolar cycloaddition reaction of azomethine ylides to aldehydes is described. The azomethine ylides, generated by thermal electrocyclic ring opening of aziridines, adds to aldehydes in good yields with moderate to good selectivities to furnish oxazolidines. The oxazolidines were subsequently hydrolyzed to the corresponding amino alcohols, giving the anti diastereomer as the major product.

Enantioselective Synthesis of syn- and anti-1,3-Aminoalcohols via β-Aminoketones and Subsequent Reduction/Dynamic Kinetic Asymmetric Transformation

β-Aminoketones obtained from imines in an organocatalytic Mannich reaction were transformed to enantio- and diastereomerically pure 1,3-aminoalcohols with two stereogenic centers via a combined reduction/dynamic kinetic asymmetric transformation. Both syn and anti diastereomers were obtained in high yield, dr, and ee.

Diastereoselective Conjugate Addition of Organocuprates to Chiral N-Enoyl Oxazolidinethiones

Addition of organocuprates, generated in situ using an excess of a 1:2 mixture of CuI·DMS and Grignard reagent, to N-enoyl oxazolidinethiones in the presence of excess TMSI gave preferentially the anti diastereomer where the addition took place when the conformation of the substrate was syn-s-cis. The reaction was investigated with indene-based and three different phenyl glycine derived oxazolidinethiones.

ChemInform Abstract: Stereochemical Aspects on the Formation of Chiral Allenes from Propargylic Ethers and Epoxides

Chiral propargylic ethers react with organocopper reagents to afford optically active allenes by a u addition to the triple bond followed by an anti p- elimination of the resulting alkenyl copper species. However, the same reaction, run with a Grignard reagent and a catalytic amount of copper (I) salt affords allenes through an anti or svn process. The crucial step is the p-elimination of the intermediate alkenyl metal species, which is of & type with FWa and of type with RMgCJ. Propargylic acetates, which also afford allenes in this reaction, but through a Cu(II1) intermediate, are not sensitive to this halogen effect. By close analogy to ethers, propargylic epoxides react with Grignard reagents and catalytic amount of Cu(1) salt, leading to a-allenic alcohols. The reaction is highly diastereoselective and its stereochemical outcome can be fully controlled.The diastereomer, probably arising through an addition-elimination mechanism, is better obtained with RM&l and copper (I) bromide, whereas the anti diastereomer is best obtained with RM& and a complexed copper (I) salt.

Synthesis, resolution, and applications of 3-amino-2,2-dimethyl-1,3-diphenylpropan-1-ol, a conformationally restricted 1,3-aminoalcohol

Efficient synthetic routes to both syn and anti diastereomers of a conformationally restricted 1,3-aminoalcohol were devised. Resolution of the aminoalcohols was accomplished through diastereomeric salt with R-(−)- O-acetyl mandelic acid. These aminoalcohols were examined as ligands for two standard reactions, namely, enantioselective addition of Et 2Zn to aldehydes and reduction of prochiral ketones with BH 3.

Dual Activity Lysophosphatidic Acid Receptor Pan-Antagonist/Autotaxin Inhibitor Reduces Breast Cancer Cell Migration In vitro and Causes Tumor Regression In vivo

Signal transduction modifiers that modulate the lysophosphatidic acid (LPA) pathway have potential as anticancer agents. Herein, we describe metabolically stabilized LPA analogues that reduce cell migration and invasion and cause regression of orthotopic breast tumors in vivo. Two diastereoisomeric alpha-bromophosphonates (BrP-LPA) were synthesized, and the pharmacology was determined for five LPA G protein-coupled receptors (GPCRs). The syn and anti diastereomers of BrP-LPA are pan-LPA GPCR antagonists and are also nanomolar inhibitors of the lysophospholipase D activity of autotaxin, the dominant biosynthetic source of LPA. Computational models correctly predicted the diastereoselectivity of antagonism for three GPCR isoforms. The anti isomer of BrP-LPA was more effective than syn isomer in reducing migration of MDA-MB-231 cells, and the anti isomer was superior in reducing invasion of these cells. Finally, orthotopic breast cancer xenografts were established in nude mice by injection of MB-231 cells in an in situ cross-linkable extracellular matrix. After 2 weeks, mice were treated with the BrP-LPA alone (10 mg/kg), Taxol alone (10 mg/kg), or Taxol followed by BrP-LPA. All treatments significantly reduced tumor burden, and BrP-LPA was superior to Taxol in reducing blood vessel density in tumors. Moreover, both the anti- and syn-BrP-LPA significantly reduced tumors at 3 mg/kg.

Asymmetric Aldol Reactions Catalyzed by an Activated Primary Amine Catalyst

Da and co-workers report a direct asymmetric aldol reaction using primary amine catalyst 1 and 2,4-dinitrophenol (DNP) as an efficient chiral organocatalytic system. High enantio-selectivities and good to high diastereoselectivities were obtained. Linear ketones and cyclo-­pentanone gave mainly syn products, whereas cyclohexanone gave the anti diastereomer as the major product.

Stereoselective Nucleophilic Addition of Potassium Alkyltrifluoroborates to Cyclic N-Acyliminium Ions: a Simple and Mild Approach to Chiral 5-Alkyl-pyrrolidin-2-ones

The stereoselective nucleophilic addition of potassium alkyltrifluoroborates to cyclic N-acyliminium ions derived from N-benzyl-3,4,5-triacetoxy-pyrrolidin-2-one, which affords 5-substituted-pyrrolidin-2-ones, is described. The products are obtained in moderate to good yields and are produced predominantly as the anti diastereomer.