Concise route to α-acylamino-β-keto amides: application to the synthesis of a simplified azinomycin A analogue

Condensation of acid chlorides (alkyl, aryl or heteroaryl) with N,N′-dialkyl α-acylamino malonamides in the presence of magnesium ethoxide provides a direct route to α-acylamino-β-keto amides in moderate to good yields (46–95%). Using this method, a concise route to an enantiomerically enriched 1-azabicyclo[3.1.0]hexane containing most of the elements of the ‘right-hand’ domain of azinomycin A has been developed.     

High-performance liquid chromatographic method for the separation of the optical isomers of γ,γ′-di-tert.-butyl- -γ-carboxyglutamic acid and -γ-carboxyglutamic acid

The chemical synthesis of γ,γ′-tert.-butyl-γ-carboxyglutamic acid is accompanied by extensive racemization, and very careful resolution is needed to obtain and -γ,γ′-di-tert.-butyl-γ-carboxyglutamic acids in high chiral purity. A novel method was devised for the separation of enantiomers of γ,γ′-di-tert.-butyl-γ-carboxyglutamic acid and γ-carboxyglutamic acid, applying precolumn derivatization with 1-fluoro-2,4-dinitrophenyl-5- -alanine amide and 2,3,4,6-tetra-O-acetyl-β- -glucopyranosyl isothiocyanate as chiral reagents, with subsequent reversed-phase high-performance liquid chromatographic separation of diastereomeric compounds. The effects of organic modifiers, of the mobile-phase composition and of the pH on the separation of the diastereomers were investigated.     

Reaction of [α-(trimethylsilyl)benzyl]ferrocenes with α-ferrocenylbenzyl cations

Although methanolysis of [α-(trimethylsilyl)benzyl]ferrocene (I) and [p-methyl-α-(trimethylsilyl)benzyl]ferrocene (II) in the presence of anhydrous ferric chloride merely gave α-ferrocenylbenzyl methyl ether (III) and p-methyl-α-ferrocenylbenzyl methyl ether (IV), respectively, acid-catalyzed methanolysis of (I) and (II) in the presence of an equimolar amount of (III) or (IV) afforded 1,2-diferrocenyl-l,2-diarylethanes. It is suggested that one electron oxidation of [α-(trimethylsilyl)benzyl]ferrocene by α-ferrocenylbenzyl cation generated from α-ferrocenylbenzyl methyl ether, and subsequent methanolysis of the resulting substituted ferricenium ion may occur to give the two species of α-ferrocenylbenzyl radical, which in turn undergo an approximately statistical coupling.     

The clemmensen reduction of α,β-unsaturated ketones

The deoxygenation of the α,β-unsaturated ketones (1) and (5) under the Clemmensen condition yielded the olefins (2) and (6) along with their respective dimers (3+4) and (8+9). The α , β-unsaturated ketone (13) under similar treatment yielded the olefin (14) in satisfactory yield but the dimer could not be characterized. The deoxygenation of the α,β-unsaturated ketones (10) and (16) under similar con- ditions afforded the olefins (12) and (15) respectively in satisfactory yield along with the rearranged olefins (11) and (17) respectively. Epox-idation of the olefin (17) followed by heating with p-toluenesulfonic acid yielded the ketone (18).     

Photoinduced transformation of α,β-epoxyketones to β-hydroxyketones by Hantzsch 1,4-dihydropyridine

Irradiation (λ >300 nm) of Hantzsch 1,4-dihydropyridine with aromatic α,β-epoxyketones in acetonitrile selectively breaks the Cα---O bond of the epoxides giving the corresponding β-hydroxyketones in excellent yields.     

Additive Pummerer reactions of vinylic sulfoxides. Synthesis of γ-hydroxy-α,β-unsaturated esters, α-hydroxyketones, and 2-phenylsulfenyl aldehydes and primary alcohols

Treatment of β-monosubstituted vinylic sulfoxides 1 with trifluoroacetic anhydride in dichloromethane gave excellent yields of 1,2-bis(trifluoroacetoxy)thioethers 6. Mildly basic methanolysis of 2-alkyl-substituted 6 gave α-hydroxyaldehydes 11 as monomer-dimer mixtures; similar treatment of the 2-aryl analogues afforded aryl (hydroxymethyl) ketones 12. Compounds 11 underwent Wittig reactions with methoxycarbonylmethylenetriphenylphosphorane to give high yields of γ-hydroxy-α,β-unsaturated esters 13, predominantly as the E-isomers. β-Monosubstituted vinylic sulfoxides 1 possessing a β-aryl group, and β-disubstituted vinylic sulfoxides 3 reacted with trifluoromethanesulfonic anhydride-sodium acetate in acetic anhydride to give 2-(phenylsulfenyl)acylals 14. These gave 2-phenylsulfenyl aldehydes 15 upon basic methanolysis, and the corresponding primary alcohols 16 on reduction with sodium borohydride. Reaction of both geometric isomers of enantiomerically pure vinylic sulfoxide 1o with TFAA gave racemic 6o as a mixture of diastereomers. Reaction of optically pure (E)- and (Z)-1p with trifluoromethanesulfonic anhydride-sodium acetate in acetic anhydride gave acylal 19 in 10.5 and 23% e.e., respectively.     

Preparation of α- or β-trifluoromethylated vinylstannanes and their cross-coupling reactions

α- or β-Trifluoromethylated vinylstannanes 1, 2a, 3 and 4 were prepared form 1,1-bis(phenylthio)-2,2,3,3,3-pentafluoropropylbenzene (5) via several steps. The cross-coupling arylation reactions of 1–4 with aryl iodides bearing a bromo, methoxy, methyl, nitro or trifluoromethyl group on para- or meta-position of benzene ring afforded the corresponding coupling products in good yields. Compounds 1, 2a and 4 underwent the acylation reaction with various types of acyl chlorides to give the corresponding trifluoromethylated enone derivatives in good yields. Reduction of trifluoromethylated enone derivatives with LiAlH₄, followed by Fridel-Craft’s type of cyclization with AlCl₃ provided trifluoromethylated indene derivatives in good yields.     

Powder neutron diffraction of α-UB2C (α-UB2C-type)

The crystal structure of α-UB₂C (low temperature modification below T = 1675(25)°C) was determined from powder X-ray data (RT) and powder neutron diffraction data (at 29 K) employing the Rietveld-Young-Wiles profile analysis method. α-UB₂C crystallizes in the orthorhombic space group Pmma with a = 0.60338(3), B = 0.35177(2), C = 0.41067(2) nm, V = 0.0872 nm³, Z = 2. The residuals of the neutron refinement were R₁ = 0.032 and R_F = 0.043. The crystal structure of α-UB₂C is a new structure type where planar nonregular 6³-U-metal layers alternate with planar nonmetal layers of the type (B₆C₂)³. Boron atoms are in a typical triangular prismatic metal surrounding with a tetrakaidekahedral coordination B[U₆B₂C₁], whereas carbon atoms occupy the center points of rectangular bipyramids C[U₄B₂]. The crystal structure of α-UB₂C derives from the high temperature modification β-UB₂C (ThB₂C-type, ), which reveals a similar stacking of slightly puckered metal layers 6³, alternating with planar layers B₆ · (B₆C₃)². The phase transition from β-UB₂C to α-UB₂C is thus essentially generated by carbon diffusion within the B₆ · (B₆C₃)² layers to form (B₆C₂)³ layers.     

Addition of trimethylsilylmethylmagnesium chloride to α, β-unsaturated carbonyls

Reactions of α,β-unsaturated carbonyl compounds with Me₃SiCH₂MgCl, prepared from chloromethyltrimethylsilane [1], were examined. Unlike its lithium counterpart (Me₃SiCH₂Li), which adds to α,β-unsaturatedketones in the 1,2-sense, the Grignard reagent afforts γ silanes via a 1,4-addition sequence. This tendency is accentuated by the addition of Cu₂Br₂. Addition of the Grignard reagent to α,β-unsaturated aldehydes gives the simple 1,2-addition products.     

Enantioselective synthesis of β,β-dialkyl α-hydroxy γ-butyrolactones

An ephedrine-derived morpholine dione is employed in the synthesis of chiral alkylidene morpholinones that are efficiently converted to β-substituted α,γ-dihydroxy butyramides, precursors of the corresponding butyrolactones. Enantioselective synthesis of a spiro analog of pantolactone as well as a naturally occurring pantolactone homolog is achieved with this protocol.     

Synthesis of novel α,α′,β-trisubstituted β-lactones

A concise and efficient synthesis of α,α′,β-trisubstituted β-lactones is presented. These novel lactones are easily obtained in five steps and will be dedicated to anionic ring opening polymerization.     

Substoichiometric TiCl4-mediated vicinal difunctionalization of α,β-acetylenic ketones for the synthesis of β-halo Baylis–Hillman olefins

A substoichiometric amount of titanium tetrachloride was found to be effective to promote and participate in the tandem α-hydroxyalkylation/β-chlorination of α,β-acetylenic ketones in the presence of (n-Bu)₄NI. This method provides the concise synthesis of (E)-β-halo Baylis–Hillman adducts. No β-iodo products were detected when using this combination of halogen sources. The reaction process involves 1,4-addition of chloro anion released from TiCl₄ onto α,β-acetylenic ketones to give TiCl₃–allenolate intermediates followed by the titanium Lewis acid-promoted carbonyl addition. Modest to good yields (53–77%) and excellent E/Z stereoselectivity (>95%) have been obtained for 10 examples.     

Synthesis of Novel β‐Lactams from Phenothiazin‐10‐ylacetic Acid

The first synthesis of 3‐phenothiazine‐β‐lactams is herein reported. Thirteen new derivatives of β‐lactams were synthesized using various Schiff bases and (phenothiazin‐10‐yl)acetic acid, which in turn was prepared starting from phenothiazine. The sole product of the Staudinger ketene–imine [2 + 2] cycloaddition reaction is the trans‐β‐lactam. All the synthesized compounds were characterized by elemental analyses and spectral (IR, ¹H‐NMR, and ¹³C‐NMR) data.     

Formation of β- and β″-Al2O3 by the solid state reaction between NaAlO2 and γ-Al2O3

The solid state reaction of NaAlO₂ with γ-Al₂O₃ was investigated kinetically. Powdered compacts with various compositions (Al₂O₃/NaAlO₂ = 1–5) were fired at 700–1200°C for 1–768 hr. The amounts of the reaction product were determined by peak heights of X-ray diffraction patterns. β″-Al₂O₃ was formed predominantly from the sample with Al₂O₃/NaAlO₂ = 2. The firing time for the β″-Al₂O₃ formation was shortened as the firing temperature was raised, and the activation energy, E_a, for formation was about 130–135 kcal/mole. The sample of Al₂O₃/NaAlO₂ = 5 formed m-Al₂O₃ with the mullite structure and was observed to transform gradually to β-Al₂O₃. E_a for the m-Al₂O₃ formation and for the transition were about 55–60 and 40 kcal/mole, respectively, which resulted in E_a of about 95–100 kcal/mole for the β-Al₂O₃ formation. The mechanism of the m-Al₂O₃ formation is discussed briefly.     

Spectral correlations for β-chlorovinyl ketones

The IR and UV spectroscopic data of a series of alkyl substituted β-chlorovinyl ketones have been determined. Some of the IR and UV spectroscopic criteria, developed for the S-cis or S-trans conformation of ordinary α,β-unsaturated ketones, seem to be applicable for the β-chlorovinyl ketones: the S-cis conformer shows a low ratio (rⁱ) of the integrated intensities of the carbonyl and double bond stretching vibrations and a relatively low UV ε value; whereas high rⁱ and ε values are found for the S-trans conformer; non-planarity increases the rⁱ value and decreases the ε value.The prefered conformations as determined by the IR and UV spectral data have led to the presentation of benzene solvation models for a series of β-chlorovinyl ketones. These models made it possible to assign thecis ortrans structure to α,β-dialkyl-β-chlorovinyl ketones on the basis of the NMR aromatic solvent induced shifts of the β-alkyl group: high solvent shifts to a higher field (0·31–0·66 ppm) are found forcis-β-chlorovinyl ketones, whereas low solvent shifts (0·040·15) are found for thetrans-β-chlorovinyl ketones. Assignments based on the chemical shifts alone can lead to erroneous interpretations.     

The Amyloid Fibril-Forming β-Sheet Regions of Amyloid β and α-Synuclein Preferentially Interact with the Molecular Chaperone 14-3-3ζ

14-3-3 proteins are abundant, intramolecular proteins that play a pivotal role in cellular signal transduction by interacting with phosphorylated ligands. In addition, they are molecular chaperones that prevent protein unfolding and aggregation under cellular stress conditions in a similar manner to the unrelated small heat-shock proteins. In vivo, amyloid β (Aβ) and α-synuclein (α-syn) form amyloid fibrils in Alzheimer’s and Parkinson’s diseases, respectively, a process that is intimately linked to the diseases’ progression. The 14-3-3ζ isoform potently inhibited in vitro fibril formation of the 40-amino acid form of Aβ (Aβ₄₀) but had little effect on α-syn aggregation. Solution-phase NMR spectroscopy of ¹⁵N-labeled Aβ₄₀ and A53T α-syn determined that unlabeled 14-3-3ζ interacted preferentially with hydrophobic regions of Aβ₄₀ (L11-H21 and G29-V40) and α-syn (V3-K10 and V40-K60). In both proteins, these regions adopt β-strands within the core of the amyloid fibrils prepared in vitro as well as those isolated from the inclusions of diseased individuals. The interaction with 14-3-3ζ is transient and occurs at the early stages of the fibrillar aggregation pathway to maintain the native, monomeric, and unfolded structure of Aβ₄₀ and α-syn. The N-terminal regions of α-syn interacting with 14-3-3ζ correspond with those that interact with other molecular chaperones as monitored by in-cell NMR spectroscopy.     

Catalytic asymmetric epoxidation of α,β-unsaturated carboxylic acid imidazolides and amides by lanthanide–BINOL complexes

Highly enantioselective catalytic asymmetric epoxidation of α,β-unsaturated carboxylic acid imidazolides and simple amides was developed. In the presence of 5–10 mol% of lanthanide–BINOL complexes, the reaction proceeded smoothly with high substrate generality. In particular, in the cases of α,β-unsaturated amides, there was nearly perfect enantioselectivity (>99% ee). The corresponding epoxides were successfully transformed into many types of useful chiral compounds such as α,β-epoxy esters, α,β-epoxy amides, α,β-epoxy aldehydes, α,β-epoxy β-keto ester, and α- and β-hydroxy carbonyl compounds. B3LYP density functional studies were performed to predict substrate reactivity.     

Chemoselective anti-Markovnikov hydroamination of α,β-ethylenic compounds with amines using montmorillonite clay

The catalytic activity of montmorillonite clays as a catalyst for the hydroamination of α,β-ethylenic compounds with amines was tested. Aniline and substituted anilines reacted with α,β-ethylenic compounds in the presence of catalytic amount of commercially available clay to afford exclusively anti-Markovnikov adduct in excellent yields. Aniline reacted with ethyl acrylate to yield only anti-Markovnikov adduct N-[2-(ethoxycarbonyl)ethyl]aniline (mono-addition product). No Markovnikov adduct (N-[1-(ethoxycarbonyl)ethyl]aniline and double addition product N,N-bis[2-(ethoxycarbonyl)ethyl]aniline were formed under selected reaction conditions. For a better exploitation of the catalytic activity in terms of increased activity and improved selectivity for the mono-addition product, the reaction parameters were optimized in terms of temperature, solvent, reactant mole ratio. Under optimized reaction conditions, montmorillonite clay K-10 showed a superior catalytic performance in the hydroamination of ethyl acrylate with aniline with a conversion of aniline to mono-addition product (almost 100% chemoselectivity) with a high rate constant 0.3414 min⁻¹ compared to the reported protocols. The dependence of conversion of aniline over different types of montmorillonite clays (K-10, K-20, K-30, Al-Pillared clay and untreated clay) has also been discussed. The activities of clay for the hydroamination of different aromatic and aliphatic amines have also been investigated. Under harsh reaction conditions (increased temperature and long reaction time) small amounts of di-addition products were observed. The kinetics data has been interpreted using the initial rate approach model.     

Biosynthesis of aristeromycln: Evidence for the intermediacy of a 4β-hydroxymethyl-1α, 2α, 3α-trihydroxycyclopentanetriol.

Evidence for the intermediacy of a 4β-hydroxymethyl-1α, 2α, 3α-trihydroxycyclopentanetdol (5 or6) in the biosynthesis of the nucleoside antibiotic aristeromycin (1) has been obtained by administration of doubly-labeled forms of D-glucose to the fermentation broth ofStreptomyces citricolor followed by trapping of the tetrol5 using isotope dilution methods.     

Diastereoselective SmI2-mediated cyclisation of δ-oxo-α,β-unsaturated esters to cyclopropanols

In the presence of samarium diiodide and a proton source, δ-oxo-γ,γ-disubstituted-α,β-unsaturated esters readily cyclise with complete diastereocontrol to give anti-cyclopropanol products.