Click-chemistry approach to isoxazole-containing α-CF3-substituted α-aminocarboxylates and α-aminophosphonates

A convenient strategy for the synthesis of isoxazole-containing α-CF(3)-substituted α-aminocarboxylates and α-aminophosphonates have been developed. The method is based on copper-catalyzed 1,3-dipolar cycloaddition of different aromatic nitrile oxides to functionalized acetylenes.     

A straightforward and general access to α-phthalimido-α′-substituted propan-2-ones

The regioselective ring opening of the commercially available N-(2,3-epoxypropyl)phthalimide with different nucleophiles, to obtain the corresponding phthalimidopropan-2-ols (including a challenging fluorohydrin) followed by the Dess-Martin periodinane oxidation, constitutes a general and widely applicable protocol for the preparation of differently functionalized α-phthalimido-α′-substituted propan-2-ones. The incorporation of the substituent in the α′ position takes place in an early stage of the process, thus furnishing a divergent and valuable approach.     

A novel approach to α-keto acid derivatives via palladium-catalyzed arylation and vinylation of methyl α-methoxyacrylate

Methyl α-methoxyacrylate reacts stereoselectively with aryl iodides and vinyl triflates under palladium catalysis to give enol ethers of arylpyruvates and of β,γ-unsaturated α-keto esters in good to moderate yields.     

Nitrobenzylation of α-carbonyl ester derivatives using TDAE approach

A series of 2-hydroxy-propionic acid ethyl ester derivatives was prepared in good yields by reaction of o- and p-nitrobenzyl chlorides (1, 8) with various α-carbonyl esters in presence of tetrakis(dimethylamino)ethylene (TDAE). This reaction was generalized to α-ketolactam and α-ketomalonate.     

Kinetic asymmetric protonation as a stereochemistry determining step in theMichael addition of acetic acid derivatives to α-substituted cinnamic acid derivatives

Summary The reaction between acetic acid derivatives and -substituted cinnamic acid derivatives has been studied inTHF andTHF:HMPT (80:20) as an alternative pathway of theMichael addition of phenylacetic and cinnamic acid derivatives. The regioselectivity observed is found to depend on the acceptor functional group and its geometry but not on the solvent used. The diastereoselectivity of the conjugate addition results from kinetic protonation of diastereotopic enolates (1,2-asymmetric induction). It varies from low in the presence ofHMPT to considerable or even high in pureTHF. The favouredanti orsyn configuration inTHF depends on the nature of the enolate. The results obtained are rationalized in terms of protonationvia transition structures different in type (openvs. chelated) and geometry.

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Kinetische asymmetrische Protonierung als bestimmender Schritt für die Stereochemie bei derMichael-Addition von Essigsäurederivaten an -substitutierte Zimtsäurederivate

Zusammenfassung Die Reaktion zwischen Essigsäurederivaten und -substitutierten Zimtsäurederivaten wurde inTHF undTHF:HMPT=80:20 als ein alternative Weg derMichael-Addition von Phenylessigsäure und Zimtsäurederivaten untersucht. Es wurde gefunden, daß die beobachtete Stereoselektivität von der Akzeptorgruppe und ihrer Geometrie, nicht jedoch vom Lösungsmittel abhängig ist. Die Diastereoselektivität der konjugierten Addition folgt aus der kinetischen Protonierung der diastereotopen Enolate (1,2-asymmetrische Induktion). Sie variiert von klein (bei Anwesenheit vonHMPT) bis bedeutend oder sogar groß (in reinemTHF). Die bevorzugteanti odersyn Konfiguration inTHF hängt von der Natur der Enolate ab. Die Ergebnisse werden durch eine Protonierungvia bezüglich Typ (offen oder chelatiert) und Geometrie unterschiedliche Strukturen des Übergangszustands erklärt.

     

Facile access to α,β-dehydroalanine and α,β-dehydroamino butyric acid derivatives from DL-serines and threonines

Not only α,β-dehydroamino acids are important constituents for a number of bioactive peptides in nature, but also they are important building blocks for a variety of synthetic amino acids in organic synthesis. Methods to prepare dehydroamino acids have been reported extensively in the literature; however, efficient and convenient protocols are still required. Here we have developed a convenient method to prepare dehydroalanine (ΔAla) and dehydroamino butyric acid (ΔAbu) derivatives derived from DL-serines and DL-threonines, respectively. 4-Toluenesulfonyl chloride (TsCl) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were employed in this procedure, which carried out activation of hydroxyl group and β-elimination in one pot. Because it is convenient and easy to handle, this method will attract the attention of synthetic chemists.     

Novel carbonyl complexes of ruthenium with α-substituted oxime derivatives of terpenes

The reactions of Ru₃(CO)₁₂ with 1R,4S,6S-4-dimethylamino-4,7,7-trimethylbicyclo[4.1.0]heptane-3-one oxime (dimethylaminocaraneoxime) (I), 1R,4S,6S-4-methylamino-4,7,7-trimethylbicyclo[4.1.0]heptane-3-one oxime (methylaminocarane oxime) (II), and 1R,2R,5R-2-benzylthio-2,6,6-trimethylbicyclo[3.1.1]heptane-3-one oxime (benzylthiopinaneoxime) (III) were studied. The binuclear complex Ru₂(CO)₄{μ-η³(O,N,X)-L}₂ was formed as the main product in every reaction, when Ru₃(CO)₁₂ was heated with terpenoid to 80°C. In the above complex, two terpene ligands are coordinated in the form of ‘head-to tail’ bridge by the oxime groups at a binuclear metal fragment Ru-Ru. The heteroatom of the second functional group of every bridging ligand (nitrogen of amino group in I and II, sulfur of the thio group in III) is additionally coordinated to the ruthenium atom to give the chelate five-membered ring. Also the reactions of terpenoids I, II, III with Ru₃(CO)₁₂ were performed at room temperature using Me₃NO. In this case, as in the thermal reactions, the main product was the binuclear complex. However, in the reactions of Ru₃(CO)₁₂ with I and II, the trinuclear clusters were isolated that readily transformed to binuclear complexes in a solution. The complexes synthesized can exist as two diasteromers due to their chiral metal core. However, in all the cases, only one diastereomer was isolated, which indicates stereospecific nature of the above reactions. The compounds obtained were characterized by IR, ¹H-, ¹³C{¹H}-, COSY, and HXCOBI-NMR spectroscopy, the specific optical rotation angles were measured. For the binuclear complexes with ligands I, III and for trinuclear cluster with ligand II, single crystals were obtained and studied by X-ray diffraction.     

Synthesis of α-CF3-substituted γ,δ-didehydro lysine derivatives

An efficient and selective access to novel α-CF₃-substituted γ,δ-didehydro lysine derivatives and their phosphorus analogues has been developed via the Cu-catalyzed Mannich reaction of α-amino α-propargyl α-trifluoromethyl carboxylates or phosphonates with different secondary amines and paraformaldehyde.     

Ruthenium carbonyl complexes with α-substituted oxime derivatives of terpenes as ligands

The reactions of Ru₃(CO)₁₂ with oximes of α-substituted caran-4-one, lemonen-5- and pinan-3-one derivatives were studied. The reactions at elevated temperatures yield binu-clear complexes Ru₂(CO)₄L₂, with two ruthenium atoms bridging two terpenoid ligands (L) through the oxime groups and coordinated additionally to a nitrogen or sulfur atom of the NR₂ or SR groups respectively. The reactions carried out at room temperature in the presense of Me₃NO yield trinuclear complexes Ru₃(CO)₈L₂ with analogous coordination of the terpenoid ligands. In a solution at room temperature these clusters readily transform to binuclear complexes. The NMR spectroscopy shows the stereochemical nonrigidity of the complexes with the S-CH₂-Ph fragment: at room temperature in a solution the benzyl radical undergoes slow rotation about the S-C bond and a change of the conformation of carane and pinane carbocycles occurs more rapidly. The reactions with pinane and carane derivatives are stereospecific yielding only one of the possible diastereoisomers. More flexible limonene derivative form both diastereoisomers.     

Synthesis of pyrrolidines and piperidines from ω-azidoalkylboronic esters. Stereocontrolled access to chiral nonracemic 2-and 3-substituted derivatives

The conversion of ω-azidoalkylboronic esters 1 into the corresponding pyrrolidines or piperidines was achieved by oxidation with hydrogen peroxide followed by successive mesylation and catalytic hydrogénation. Homologation reactions were used as key steps of the syntheses of a chiral non-racemic 2-substituted pyrrolidine and a 3-substituted piperidine.     

Organocatalytic asymmetric tandem condensation-intramolecular rearrangement-protonation: an approach to optically active α-amino thioester derivatives

An unprecedented and conceptually novel chiral Br?nsted base/Br?nsted acid catalytic method for the enantioselective synthesis of α-amino thioesters through a tandem condensation-intramolecular rearrangement-protonation has been developed which provides a number of important synthetic building blocks in good yield and with moderate to good enantioselectivities.     

Synthesis of α-substituted iminodiacetate ligands: α-hexadienyl derivatives for the selection of lipoxygenase mimics

Derivatives of iminodiacetic acid (IDA) are important as ligands for metal ions, having numerous applications in separations, sensing, catalysis and medicine. This report describes the preparation of two types of IDA derivatives (1, 2) that could be covalently attached to a polymer or protein surface via a variable length spacer chain. The parent compounds 1 (R′=H) were easily prepared via N-alkylation of dimethyl iminodiacetate with esters of 6-bromo-hexanoic acid and subsequent selective ester hydrolysis. Metal complexes of IDA derivatives having an α-dienyl side chain are required for the selection of histidine-rich proteins with potential lipoxygenase activity. The α-hexadienyl side chain of IDA derivative 2 was selectively introduced in the reaction of (2,4-hexadienyl acetate)Fe(CO)₃ with a glycine-derived TMS-enol ester. Subsequent demetallation, followed by N-carboxymethylation, N-deacylation, N-alkylation with a trichloroethyl 6-halohexanoate, and TCE-ester cleavage provided the desired α-hexadienyl IDA derivative 2. Amide formation with IDA acid 1b demonstrates the feasibility of conjugating the IDA ligands to polymers and proteins while Ni(II)-complexation with the derived IDA triacid 1e shows the complexing ability of the tethered IDA ligand.     

Secondary amine catalyzed retro-aldol reactions of enals and enones: one-pot conversion of enals to α-substituted derivatives

A practical synthetic procedure to hydrolytically cleave the C,C-double bond of α,β-unsaturated aldehydes and ketones has been developed. Secondary amines are employed as organocatalysts for the retro-aldol process under simple and mild reaction conditions. Beside the generation of the parent aromatic aldehydes, the synthetic procedure has been successfully used in a one-pot reaction sequence to convert simple cinnamaldehydes into their α-aryl/alkyl substituted derivatives.     

An approach to α-keto vinyl carbinols

Adducts from the radical addition of xanthates to ethyl vinyl sulfide readily undergo elimination of the xanthate group upon thermolysis to give vinylic and/or allylic sulfides, depending on the structure. In the case of α-xanthyl ketones, the adducts are converted into α-keto vinyl carbinols by rearrangement of the sulfoxides derived from the vinylic and allylic sulfides.     

New approach to the functionalization of δ-carboline derivatives

The possibility of transformation of 3-cyano-1-p-nitrophenyl--carbolin-2-one into 2-amino-3-cyano-1-p-nitrophenyl-1H-pyrido[3,2-b]indole derivatives and 2-imino-3-cyano-1-p-nitrophenyl-5H-pyrido[3,2-b]indole derivatives (-carbolines) is demonstrated. Methylation of 1-p-nitrophenyl-2-piperidino-1H--carboline followed by treatment with acetone in an alkaline medium yields 4-acetonyl-5-methyl-1,4-dihydro-5H-pyrido[3,2-b]indole derivative. The rearrangement of 2-arylimino-3-cyano-1-p-nitrophenyl-5H-pyrido[3,2-b]indoles into 2-(aryl)nitrophenylamino-3-cyano-5H-pyrido[3,2-b]indoles was accomplished on heating above the melting point or on treatment with potassium tert-butoxide. The structures of the resulting compounds were proved by ¹H and ¹³C NMR spectroscopy and X-ray diffraction analysis.     

Thiourea-catalyzed asymmetric conjugate addition of α-substituted cyanoacetates to maleimides

Chiral isosteviol-derived tertiary amine-thiourea was proven to be effective in catalyzing the asymmetric conjugate addition between α-substituted cyanoacetate and maleimides. Diverse succinimides bearing vicinal quaternary-tertiary stereocenters were obtained in excellent yields, excellent diastereoselectivities, and with good to high enantioselectivities. This catalytic system can be used efficiently in large-scale reactions with the yields and stereoselectivities being maintained at the same level.     

Organocatalytic asymmetric conjugate addition of α-substituted cyanoacetates to maleimides

The asymmetric conjugate addition of α-substituted cyanoacetates to N-substituted maleimides has been developed. A number of cinchona alkaloids and amine thioureas were evaluated as catalysts. Takemoto’s catalyst was found to be the most efficient for the transformation. Chiral succinimides with two adjacent quaternary and tertiary stereogenic carbon centers were obtained in good yields, enantioselectivities, and diastereoselectivities. The products were converted to chiral γ-lactams conveniently without a loss in the enantioselectivity.     

Michael addition of α-azido ketones on iminocoumarin derivatives: an efficient access to new functionalized azido chromenes

A facile one-pot synthesis of functionalized azido chromenes was achieved by Michael addition of α-azido ketones on iminocoumarin derivatives obtained from salicylaldehydes and malononitrile. Synthesized azido chromenes were successfully transformed into triazolyl chromenes by the [3+2] cycloaddition reaction.     

Hydroxymethylation of α-substituted nitroacetates

Only 1 mol % of K₃PO₄ is efficient enough to catalyze the hydroxymethylation of α-substituted nitroacetates in good to excellent yield. Both aliphatic and aryl substituted nitroacetates work well under this reaction. The first catalytic asymmetric version of this reaction also reported that 10 mol % of cupreidine could catalyze this reaction up to 71% ee and 89% yield. Paraformaldehyde and formalin could both serve as the hydroxymethylation C1 unit. The synthetic application of products is also demonstrated.