Diastereoselective synthesis of novel 5-substituted morpholine-3-phosphonic acids: further exploitation of N-acyliminium intermediates

The first diastereoselective total synthesis of 5-substituted morpholine-3-phosphonic acids is reported. The principal feature of the synthesis is the introduction of a dimethyl phosphonate group into 5-substituted morpholin-3-ones. The procedure is based on the preparation of N-Boc-(S)-5-phenyl- and N-Boc-(S)-5-benzylmorpholin-3-one from l-phenylglycine and l-phenylalanine methyl esters, followed by the formation of the 3-methoxylated compounds and subsequent reaction with trimethyl phosphite in the presence of BF₃·OEt₂. Diastereoselectivity in the formation of cis-disubstituted products is in agreement with the nucleophilic addition to other methoxylated derivatives.     

A convenient synthesis of dihydrocoumarins from phenols and cinnamic acid derivatives

A facile procedure for synthesis of dihydrocoumarin derivatives was described. Although the yield of the products in the reaction of phenols with acrylates in trifluoroacetic acid in the presence of Pd(OAc)₂ giving coumarins was found to be very low, dihydrocoumarin derivatives were obtained in good to high yields in the absence of Pd(OAc)₂ when ethyl cinnamates bearing electron-donating groups were employed in this reaction.     

Synthesis of methylated resveratrol and analogues by Heck reactions in organic and aqueous solvents

The Heck reaction under phosphane free conditions using oxime-derived palladacycles or Pd(OAc)₂ as catalysts is a general methodology for the synthesis of methoxylated (E)-stilbene derivatives. Couplings can be performed either with (dicyclohexyl)methylamine as base and TBAB in aqueous DMA or in neat water and with Et₃N as base in DMA in air and under thermal and microwave conditions. The arylation of different styrenes are performed with 3,5-dimethoxyiodobenzene to afford a series of important biologically active (E)-stilbene derivatives containing the 3,5-dimethoxyphenyl moiety, including resveratrol, piceatannol and pinosilvine, which are efficiently prepared with high regioselectivity and total stereoselectivity (TON up to 10⁴).     

Trifluoroacetic acid: a more effective and efficient reagent for the synthesis of 3-arylmethylene-3,4-dihydro-1H-quinolin-2-ones and 3-arylmethyl-2-amino-quinolines from Baylis-Hillman derivatives via Claisen rearrangement

Trifluoroacetic acid has been discovered to be a highly effective and efficient reagent for the tandem Claisen rearrangement and cyclization reaction to yield 3-arylmethylene-3,4-dihydro-1H-quinolin-2-ones from compounds obtained from the S_N2 reaction between anilines and acetyl derivatives of Baylis-Hillman adducts of acrylates in the presence of DABCO. In contrast, similar compounds obtained from the acetyl derivatives of Baylis-Hillman adduct of acrylonitrile on treatment with trifluoroacetic acid directly furnish 3-arylmethyl-2-amino-quinoline via tandem Claisen rearrangement, cyclization and isomerization.     

Regioselective hydroxylation of diverse flavonoids by an aromatic peroxygenase

Aromatic peroxygenases are extracellular fungal biocatalysts that selectively oxidize a variety of organic compounds. We found that the peroxygenase of the fungus Agrocybe aegerita (AaeAPO) catalyzes the H₂O₂-dependent hydroxylation of diverse flavonoids. The reactions proceeded rapidly and regioselectively yielding preferentially monohydroxylated products, e.g., from flavanone, apigenin, luteolin, flavone as well as daidzein, quercetin, kaempferol, and genistein. In addition to hydroxylation, O-demethylation of fully methoxylated tangeretin was catalyzed by AaeAPO. The enzyme was merely lacking activity on the quercetin glycoside rutin, maybe due to sterical hindrance by the bulky sugar substituents. Mechanistic studies indicated the presence of epoxide intermediates during hydroxylation and incorporation of H₂O₂-derived oxygen into the reaction products. Our results raise the possibility that fungal peroxygenases may be useful for versatile, cost-effective, and scalable syntheses of flavonoid metabolites.     

Isomer differentiation via collision‐induced dissociation: The case of protonated α‐, β2‐ and β3‐phenylalanines and their derivatives

A combination of electrospray ionisation (ESI), multistage and high‐resolution mass spectrometry experiments is used to examine the gas‐phase fragmentation reactions of the three isomeric phenylalanine derivatives, α‐phenylalanine, β²‐phenylalanine and β³‐phenylalanine. Under collision‐induced dissociation (CID) conditions, each of the protonated phenylalanine isomers fragmented differently, allowing for differentiation. For example, protonated β³‐phenylalanine fragments almost exclusively via the loss of NH₃, only β²‐phenylalanine via the loss of H₂O, while α‐ and β²‐phenylalanine fragment mainly via the combined losses of H₂O + CO. Density functional theory (DFT) calculations were performed to examine the competition between NH₃ loss and the combined losses of H₂O and CO for each of the protonated phenylalanine isomers. Three potential NH₃ loss pathways were studied: (i) an aryl‐assisted neighbouring group; (ii) 1,2 hydride migration; and (iii) neighbouring group participation by the carboxyl group. Finally, we have shown that isomer differentiation is also possible when CID is performed on the protonated methyl ester and methyl amide derivatives of α‐, β²‐ and β³‐phenylalanines. Copyright © 2010 John Wiley & Sons, Ltd.     

Selective carbometallation of α,β-unsaturated carbonyl compounds and substituted oxacyclopropanes with zirconium-diene complexes

The reactions of zirconium-dience complexes, ZrCp₂(s-cis-diene), with bifunctional electrophiles, i.e. α,β-unsaturated ketones, unsaturated esters and substituted oxacyclopropanes, were investigated. Reaction of ZrCp₂(s-cis-isoprene) with an equivalent of 3-buten-2-one or alkyl acrylates, selectively gives 1,2-addition products. CC bond formation occured at the C(1) atom of the isoprene moiety whereas 1,3-pentadiene-, 2-methyl-1,3-pentadiene- and 2,4-dimethyl-1,3-pentadiene complexes induced the regioselective 1,2-addition at the C(4) position of the diene moiety. Phenyloxacyclopropane and 2-methyl-3-phenyl-oxacyclopropane also react with ZrCp₂(isoprene) leading to CC bond formation from the C(1) atom of isoprene to the oxirane carbon bearing the phenyl group. The corresponding reactions of 2-methyl-2-butene-1,4-diylmagnesium with α,β-unsaturated carbonyl compounds were also studied and found to give quite different products.     

Palladaphosphacyclobutenes as catalysts in Heck and Suzuki reactions

Heck reactions of aryl halides with various olefins and Suzuki reactions of aryl halides with phenylboronic acid catalyzed by palladaphosphacyclobutene have been investigated. The scope of the Heck reaction has been investigated in N,N‐dimethylacetamide at 140 °C using NaOAc as base. Using 0.1% molar ratio of palladaphosphacyclobuyenes, aryl bromides were converted into 1,2‐substitutedethene products in good to high yields through coupling with both vinylarenes and acrylates. Actived aryl chloride reacted with styrene to afford 1,2‐substitutedethene products in moderate yields. The scope of the Suzuki reaction has been conducted in toluene at 110 °C using Cs₂CO₃ as base. Using 0.1% molar ratio of palladaphosphacyclobutene, aryl bromides reacted with phenylboronic acid to afford diaryl derivatives in excellent yield. Copyright © 2008 John Wiley & Sons, Ltd.     

Triphenylphosphine-Catalyzed Michael Addition of Alcohols to Acrylic Compounds

A facile triphenylphosphine-catalyzed Michael addition of alcohols to acrylic compounds was described. The reaction was carried out in open air at refluxing temperature in the presence of 10 mol% PPh3. Michael addition of saturated and unsaturated alcohols to acrylonitrile or acrylates has been examined. The reaction gave β-alkoxy derivatives with isolated yields of 5%-79%. PPh3 is cheaper and more stable than those trialkylphosphines previously used for the similar reactions, and the products can be easily separated from the reaction mixture via distillation.     

Versatile synthesis of chiral 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines as novel scaffolds for peptidomimetic building

The stereocontrolled synthesis of phenylalanine and tryptophan derived 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives is described. This new methodology involves a modified Strecker reaction of N-Boc protected amino aldehydes and methyl anthranilate, reduction of the resulting α-amino nitriles, and lactamization. The resulting 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines were further functionalized at position 4 by alkylation or acylation reactions. One of these new tryptophan-derived 1,4-benzodiazepines showed significant selective binding affinity at cholecystokinin CCK₁ receptors (IC₅₀=156.5±33.2 nM).     

Anodic oxidation of chiral sulfinylamines: a new route to highly diastereoselective α-alkylation of piperidine

The anodic oxidation of some chiral non-racemic N-arylsulfinyl piperidines was investigated and for the first time α methoxylated sulfinyl piperidines were obtained. The so-formed compounds are equivalent of chiral N-sulfinyliminiums and used as new intermediates for the preparation of chiral α-substituted piperidine derivatives in good yield and diastereoselectivity.     

Microwave-promoted <Emphasis Type="Italic">N</Emphasis>-arylation of imidazole and amino acids in the presence of Cu<Subscript>2</Subscript>O and CuO in poly(ethylene glycol)

Copper(I)-catalyzed N-arylation of imidazole with iodobenzene, its derivatives, and bromobenzene in poly(ethylene glycol) under microwave irradiation was studied. The influence of the following factors on the yield of arylation product was investigated: the nature of the source of copper and ligand, type of poly(ethylene glycol) (PEG) used, and substituents in iodoarene. An optimal catalytic system was selected: CuO/l-Hys/Cs₂CO₃/PEG-400, a possibility of recycling of copper-containing catalyst was demonstrated. N-Arylation of eight natural amino acids using catalysis with Cu₂O/Cs₂CO₃/PEG-400 and microwave irradiation was studied, the dependence of the reaction results on temperature, duration of the process, and the ratio of the starting reagents was found. The highest yields of the target products were reached in the case of leucine, valine, and phenylalanine.     

Polymerization of norbornene by palladium(II) complexes bearing ethylene-bridged bisindolinyl- or bis(1,2,3,4-tetrahydroquinolinyl) ligands

Novel moisture and air stable, cationic palladium(II) amine complexes (1–4) of the general type [Pd(N∩N)(X)₂](BF₄)₂, [N∩N=1,2-bis(N-indolinyl)ethane (BIE) 1, 3; 1,2-bis(N-1,2,3,4-tetrahydroquinolinyl)ethane (BTQE) 2, 4; X=NCCH₃, H₂O] were found to catalyze the polymerization reaction of bicyclo[2.2.1]hept-2-ene at room temperature. The amorphous polymer products consist of 2,3-linked norbornene units; no indications for ring opened species could be observed. The polymerization activity of the diaqua-complexes 3, 4 is superior compared to their acetonitrile analogues due to a facile activation by a Wacker-type reaction. The cationic Pd(II)-compounds are inactive towards homo- and copolymerization reactions of polar monomers, like acrylates or carbon monoxide. However, addition of methylacrylate resulted in polynorbornene products with increased molecular weight and narrow molecular weight distributions.     

Peculiarities of the effects of trifluoromethyl and alkoxycarbonyl groups on the structure and reactivity of acrylates

Ab initio quantum-chemical calculations of molecules of CF₃-substituted acrylates and their non-fluorinated analogs were carried out by the restricted Hartree-Fock (RHF) method and at the second-order Møller-Plesset (MP2) level of perturbation theory using the 6–31G^* basis set with full geometry optimization. Peculiarities of their molecular and electronic structure were revealed and the dipole moments, the polarizability and first molecular hyperpolarizability tensors, harmonic vibrational frequencies, electrostatic potentials, and local electron densities in the vicinity of the carbon atoms of the C=C bond were calculated. It was shown that CF₃-substituted acrylates are conjugated systems similar to their nonfluorinated analogs. Peculiarities of the structure and properties of CF₃-substituted acrylates are explained by p-π-interaction between the CF₃ group and the conjugated system.     

Synthetic applications of electrochemically produced α-methoxyamides. Part 2. Oxidation of hydroxyproline derivatives

The electrochemical methoxylation of N-acetyl-4-hydroxyproline esters has been investigated. Both the free alcohol 3 and the corresponding 4-acetoxy derivative 4 as well as the cis-4-acetoxyproline 17 are methoxylated anodically preferentially at C(5), giving a mixture of stereoisomeric methoxy compounds. These mixtures can be used for further substitution as exemplified by the allylation of the methoxylated 4-acetoxy derivatives, giving substitution products preferentially trans to the acetoxy group although with low selectivity. The low selectivity is discussed in terms of kinetic vs. thermodynamic control.     

Enantioselective synthesis of constrained phenylalanine analogues

Constrained phenylalanine derivatives containing hydrophobic groups and hydrogen bond acceptor and/or donor functionalities were synthesized through a tandem palladium-mediated Heck reaction followed by a rhodium(II)-catalyzed asymmetric hydrogenation. Aryl bromides were found to be better substrates in providing products with higher purity and in good yield. The cesium carbonate-mediated cyclization proceeded smoothly in good yield and optical purity. Aryl iodides reacted selectively over bromides under Jeffery-type conditions (Pd(OAc)₂, Bu₄NCl, Et₃N) providing an opportunity for further metal-mediated functionalization.     

Negishi cross-coupling reactions of α-amino acid-derived organozinc reagents and aromatic bromides

The Negishi cross-coupling reaction of organozinc iodides derived from α-amino acids with aromatic bromides to give substituted phenylalanine derivatives is described, using either Pd(OAc)₂ or Pd₂(dba)₃ in combination with P(o-Tol)₃ as catalyst in DMF at 50 °C. Similar results are obtained using Pd[P^tBu₃]₂ as catalyst. The difference in reactivity displayed between aryl iodides and bromides (ArI>ArBr) has been utilised in a short synthesis of an unsymmetrical, orthogonally protected para-phenylene bis-alanine derivative.     

Oxidation of aromatic aldehydes and ketones by H2O2/CH3ReO3 in ionic liquids: a catalytic efficient reaction to achieve dihydric phenols

A convenient and efficient application of hydrogen peroxide/methyltrioxorhenium in ionic liquids [bmim]BF₄ and [bmim]PF₆ for the oxidation of hydroxylated and methoxylated benzaldehydes and acetophenones to the corresponding phenols is described. Good yields of products were obtained in short reaction times.     

Novel approach to 6-alkenyl-substituted pyridoxine derivatives based on the Heck reaction

A new synthetic approach to 6-alkenyl-substituted pyridoxine derivatives was developed based on the Heck reaction. The reaction, which was catalyzed using a mixture of Pd(OAc)₂, (o-Tol)₃P and Bu₃N as a base, led to seven new 6-alkenyl pyridoxine derivatives. When acrylic acid was used the products of decarboxylation and dimerization were formed.     

Synthesis and NMR elucidation of novel amino acid cavitand derivatives

The synthesis of seven novel protected amino acid cavitands is reported. All have four pendant n-undecyl chains and ‘headgroups’ connected by a two-carbon spacer at four positions on the aromatic rings. The amino acids employed are glycine, alanine, phenylalanine, leucine, proline, tryptophan, serine, glutamine and lysine. The structures of the compounds were elucidated using one- and two-dimensional NMR techniques, which verified that all tetra-substituted cavitands have symmetrical C_4v conformation. This is the first example of a complete study for amino acid cavitand derivatives.