Amino acid-derived enaminones: a study in ring formation providing valuable asymmetric synthons

A new reaction for the preparation of enaminones has been discovered. This method employs beta-amino acids as starting materials to allow diversification as well as incorporation of chirality. The beta-amino acids, once converted to ynones, are readily cyclized to the desired six-membered enaminone via a two-step, one-pot protocol. Although disguised as a 6-endo-dig cyclization, the reagents employed in the transformation play a direct role in bond making and bond breaking, thus changing the mode of addition.     

Helical binuclear Co complexes of pyriporphyrin analogue for sensing homochiral carboxylic acids

A hybrid macrocycle composed of two bipyridines and two dipyrrins gave biscobalt complexes of figure eight macrocycle conformation with κ²-carboxylate ligands and water ligands at the axial sites. The axial acetate ligands of the biscobalt complex are readily exchanged with carboxylates of α-hydroxyl acids and α-amino acids. The chiral center of the axial carboxylate ligands controls the helical handedness of the macrocycle as evidenced by a typical CD couplet at 550 nm. The substitution labile nature of the biscobalt complex plays a key role for helical chirality induction on the macrocycle upon co-ordination of chiral carboxylate anions.     

Stereoselective synthesis of beta-benzyl-alpha-alkyl-beta-amino acids from L-aspartic acid

A stereoselective synthesis of beta-benzyl-alpha-alkyl-beta-amino acids 1 and 2 from L-aspartic acid 3 has been developed. Methyl 5-phenyloxazolidin-2-one-4-acetate 4 was prepared from L-aspartic acid 3 through the acylation of benzene or phenyllithium with alpha-amino carboxyl group of L-aspartic acid skeleton. Alkylation of a dianion of 4 with alkyl halides and subsequent hydrogenation afforded anti-disubstituted beta-amino acids 1b and 1c in high stereoselectivities. Complete reversal of the stereoselection was realized by the alkylation of 4-phenyl-3-tert-butoxycarbonylamino-4-butanolide 6 which was obtained in a single step from 4. The 2,3,4-trisubstituted amino lactone 7 thus obtained was hydrogenated to give a syn-disubstituted beta-amino acid 2a. The syn-products 2b, 2c, and 2dwere alternatively prepared via aldol condensation of 6 with aromatic or aliphatic aldehydes followed by stereoselective reduction of the double bond with nickel chloride-sodium borohydride.     

Preparation of protected syn-alpha,beta-dialkyl beta-amino acids that contain polar side chain functionality

We report the synthesis of syn-alpha,beta-dialkyl beta-amino acid derivatives suitably protected for solid-phase synthesis that give rise to residues containing positively charged lysine-like side chains. These amino acids, as well as syn-alpha,beta-dialkyl beta-amino acids that contain diverse hydrophobic side chains, are prepared in good de and ee. The key step in this route involves Davies's protocol for the conjugate addition of a chiral lithium amide to alpha,beta-unsaturated tert-butyl esters (Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 9, 1141). syn-alpha,beta-Dialkyl beta-amino acids are interesting building blocks because of their sheet-forming propensity and because of their presence in bioactive compounds.     

Self‐Assembly of ZnO Nanocrystals in Colloidal Solutions

The self‐organization in solution of ZnO nanocrystals into superlattices is monitored by dynamic light scattering. When long‐alkyl‐chain amines or carboxylic acids are used as stabilizing ligands, no organization is observed. In contrast, when binary mixtures of long‐alkyl‐chain amines and carboxylic acids are used, the presence of a thermodynamic equilibrium between free and organized ZnO nanoparticles is detected in THF or toluene. The superlattices of organized ZnO nanoparticles are independently observed by TEM and SEM. The coordination mode of the ligands at the surface of the ZnO nanoparticles is evidenced by NMR studies. The presence of ion‐paired ammonium carboxylate surrounding the surface of ZnO nanoparticles appears to be a necessary requirement to govern this reversible organization. This is substantiated by the absence of organization of ZnO nanoparticles when either a solvent of high dielectric constant, such as acetone, or a strong hydrogen‐bond acceptor is used.     

The influence of short strong hydrogen bonding on the structure and the physicochemical properties of alkyl-N-iminodiacetic acids in solid state and aqueous systems

Alkyl-N-iminodiacetic acids with varying alkyl chain lengths have been prepared and characterized with respect to structure, acidic properties, and ability to form aggregates in water. The alkyl-N-iminodiacetic acids are the group of ligands with the lowest molecule weight which can be characterized as chelating surfactants, compounds with surface chemical properties which at the same time have a high ability to bind metal ions. The solid alkyl-N-iminodiacetic acids have a unique structure with neutral zwitterionic units linked together to polymer chains through a short strong hydrogen bond, d(O(-H)...O) approximately 2.46 A, and where the nu(O-H) stretching vibration at ca. 720 cm(-1) supports the presence of such a hydrogen bond. The polymer chains are cross-linked together to bilayers through relatively strong hydrogen bonds between ammonium and carboxylate groups, and where the parallel alkyl groups are interdigitating each other; the bilayer surface consists of hydrophilic iminodiacetic acid groups. The acidic properties of monomeric alkyl-N-iminodiacetic acids in water are in the expected ranges with pK(a) values of about 1.7, 2.3, and 10.3. n-Octadecyl-N-iminodiacetic acid, present as aggregates in water, displays very acidic properties of the first proton, and a substantially weakened acidity of the second proton, pK(a2) = 5.5-7.5, depending on ionic strength, and pK(a3) = 9.5-10.5. This pattern of the acidic constants strongly indicates that the polymer structure with short strong hydrogen bonds is maintained in the aggregates and that such bonds can exist in aqueous systems if they are supported by a strong and rigid backbone structure, as the bilayers of well-organized long interdigitating alkyl chains in the studied systems. Hydrogenbis(methyl-N-iminodiacetic acid) perchlorate precipitates from perchloric acidic solutions of methyl-N-iminodiacetic acid. The structure is built up of dimers of zwitterionic methyl-N-iminodiacetic acid units linked together by an extra proton in a short strong hydrogen bond, d(O(-H)...O) approximately 2.456(6) A, and nu(O-H) = 789 cm(-1).     

Carboxylate-imidazole cooperativity in dipeptide-functionalized gold nanoparticles with esterase-like activity

We report here the first example of peptide-functionalized gold nanoparticles hydrolytically active against carboxylate esters. The active units are constituted by His-Phe-OH terminating thiols. The confinement of the catalytic units in the monolayer covering the nanoparticles triggers a cooperative hydrolytic mechanism operative at pH < 7 in which a carboxylate and an imidazolium ion act as general base and general acid, respectively. Such a mechanism is absent with an analogous monomeric dipeptide, and this results in a more than 300-fold rate acceleration of the hydrolytic process at low pH in the presence of the functional nanoparticles.     

CuI-catalyzed coupling reaction of beta-amino acids or esters with aryl halides at temperature lower than that employed in the normal Ullmann reaction. Facile synthesis of SB-214857

[reaction: see text] The CuI-catalyzed coupling reaction of aryl halides with beta-amino acids or beta-amino esters is completed at 100 degrees C in 48 h, which indicates that the structure of the beta-amino acid has an accelerating effect for the Ullmann-type aryl amination reaction. This coupling reaction can be used to prepare enantiopure N-aryl beta-amino acids. An efficient synthetic route to SB214857, a potent GPIIb/IIIa receptor antagonist, is developed using this method.     

IR spectroscopic studies of adsorption of dithiol-containing ligands on CdS nanocrystal films in aqueous solutions

The adsorption of the ligands alpha-lipoic acid, dihydrolipoic acid, and dithiothreitol to films of deposited CdS nanoparticles was studied in situ by ATR-IR spectroscopy. For alpha-lipoic acid and dihydrolipoic acid, the spectra of the adsorbed species closely resemble those of the respective solution species. However, for dithiothreitol, the spectrum of the adsorbed species is significantly different from that of the solution species and is attributed to an interruption of intermolecular hydrogen bonding upon adsorption to the CdS. The S-H stretching absorption of the dihydrolipoic acid solution species at pH=8.6 is observed at 2542 cm(-1). The corresponding absorptions for dithiothreitol occur at 2578 and 2528 cm(-1) and are attributed to monomers and dimers. Adsorption of dihydrolipoic acid and dithiothreitol is found to occur via both thiol functional groups and an additional interaction between the carboxylate and the CdS surface. The adsorption of alpha-lipoic acid to CdS in the presence of light proceeds with photo-oxidation of the CdS surface and reductive cleavage of the disulfide bond of alpha-lipoic acid to produce some adsorbed dihydrolipoic acid and thiosulfate. The adsorption of alpha-lipoic acid to CdS in the absence of visible light shows no photo-oxidation and suggests that adsorption occurs via retention of the disulfide bond. The adsorption isotherm data for dihydrolipoic acid and dithiothreitol gave good fits to the Langmuir isotherm, with adsorption constants higher than those for monothiol-containing ligands on CdS. The Langmuir adsorption constant for n-octanoic acid on CdS indicates that the additional interaction between the carboxylate group of dihydrolipoic acid and the CdS is weak in comparison with the dithiol interaction with CdS.     

An electron paramagnetic resonance study of copper(II)-beta-substituted beta-amino acid systems by the two-dimensional simulation method: first evidence of primarily steric effects of substituents on equilibria of metal complexes

We have studied the complex equilibria of copper(II) with a series of beta-substituted beta-amino acids (R: H, Me, Et, iBu, iPr, cHex, 1-EtPr, and tBu) in aqueous solution by pH potentiometry and electron paramagnetic resonace (EPR) spectroscopy in the range pH = 2-8 at various metal and ligand concentrations. The basicities of the corresponding donor groups differed only slightly in the series of ligands. A purely mathematical method, the matrix rank analysis carried out on the EPR spectrum package recorded in the presence of copper(II), indicated the formation of 6 independent paramagnetic species. Accordingly, Cu(2+) (aqua complex) and the complexes [CuLH](2+), [CuL](+), [CuL(2)H(2)](2+), [CuL(2)H](+), and [CuL(2)] were considered in the subsequent analysis of series of spectra, and also two isomers of [CuL(2)] were identified. The formation constants and the EPR parameters, e.g. the isotropic g-factors and the copper and nitrogen hyperfine couplings for the above species, were determined in the same optimization procedure by the simultaneous evaluation of spectra. The ligands "LH" are suggested to bind in equatorial positions through their carboxylate groups, while the amino acids in the L protonation state are likely to occupy two equatorial sites via the amino and carboxylate groups. For the isomers of [CuL(2)], the donors of the same kind are in the cis or trans position. As far as we know, this is the first reported case in which a strong correlation has been found between the steric effects of substituents characterized by Meyer's steric parameter V(a) and the protonation constants of metal complexes. The observed trend for the preference for nonprotonated complexes [CuL](+) and [CuL(2)] to increase with the steric demand of the substituent was explained by the increasing shielding effect of the substituent hindering protonation of the nonprotonated complex.     

A catalytic asymmetric method for the synthesis of gamma-unsaturated beta-amino acid derivatives

Catalytic enantioselective synthesis of beta-amino acid derivatives is an area of intense interest, due to the importance of these compounds as components in pharmaceutical agents and peptidomimetics. In this report, we present the first catalytic enantioselective method for the synthesis of gamma-unsaturated beta-amino acids and their corresponding 1,3-amino alcohol derivatives. This methodology takes advantage of a highly enantioselective vinylzinc addition to an aldehyde to set chirality. The resulting allylic alcohols are then transformed into the corresponding allylic amines via Overman's [3,3]-sigmatropic imidate rearrangement, and subsequent one-pot deprotection-oxidation of a pendant oxygen leads to the gamma-unsaturated beta-amino acid derivatives of high enantiopurity.     

Synthesis of alpha-trifluoromethyl-beta-lactams and esters of beta-amino acids via 1,3-dipolar cycloaddition of nitrones to fluoroalkenes

Nitrones derived from aromatic or aliphatic aldehydes or ketones react with hexafluoropropene (HFP) or 2H-pentafluoropropene (PFP) to give the respective fluorinated isoxazolidine derivatives in good yields with complete regioselectivity and moderate diastereoselectivity. Catalytic hydrogenolysis of the N-O bond under ambient pressure and temperature leads to fluorides of beta-amino acids that undergo cyclization to alpha-trifluoromethylated beta-lactams or, under acidic conditions, form esters of alpha-trifluoromethylated beta-amino acids.     

Synthesis and characterization of carboxylate complexes of Sn(IV) porphyrin monomers and oligomers

Most of the porphyrin-recognition chemistry we have investigated previously has centred on kinetically labile metal-ligand interactions, such as Z-N and Ru-N. Our interest in the broader scope of molecular recognition required a metal with the ability to specifically recognise non-nitrogen-based ligands, with a significantly different binding interaction to distinguish it from nitrogen-based analogues. In this report we describe interactions of Sn(IV) porphyrins that bind oxygen-based ligands and for which the Sn(IV)bond;O bond is in slow exchange on the NMR timescale. A series of carboxylate complexes is employed to highlight the structural/geometric features of porphyrin monomers and cyclic oligomers. Where more than one porphyrin unit is present in a molecular scaffold, we report the effect of carboxylate binding on the complex when the two porphyrins contain different metals (typically Sn(IV) and Zn(II)). The unexpected spectroscopic and structural properties of the Sn(2)(9-anthroic acid)porphyrin dimer are also reported.     

Analysis of amide bond formation with an alpha-hydroxy-beta-amino acid derivative, 3-amino-2-hydroxy-4-phenylbutanoic acid, as an acyl component: byproduction of homobislactone

In the synthesis of peptidomimetics containing alpha-hydroxy-beta-amino acid, the coupling of this N(beta)-protected beta-amino acid with amine components was generally performed without the protection of its alpha-hydroxyl group. However, the formation of dipeptides in low yield was often observed when sterically hindered amine components were used. Boc-Apns-OH [Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid, allophenylnorstatine] (6), which is one of such beta-amino acid derivatives, is intensively employed as a core structure in the development of HIV-1 protease inhibitors. There have been no precise studies, to date, that have examined amide bond formation with alpha-hydroxy-beta-amino acid derivatives as an acyl component. To determine the cause of this low-yield reaction, we studied the amide bond formation focusing on the activation step of N(beta)-protected alpha-hydroxy-beta-amino acid by using a model coupling reaction between 6 and H-Dmt-OR [Dmt: (R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid] (7). A significant amount of homobislactone 9 was formed through the activation of the carboxyl group of 6 to the benzotriazole-type active esters such as OBt and OAt. In addition, this homobislactone formation was markedly increased in the presence of a catalytic amount of a base, which exhibited good correlation with the low yield of the amide bond formation, suggesting that homobislactone formation is one major reason for the low yield of the amide bond formation. Moreover, homobislactones were also formed in other derivatives of the N(beta)-protected alpha-hydroxy-beta-amino acid, suggesting a common feature of this type of amino acids. The use of a strong activation method like EDC--HOAt without base addition enhanced amide bond formation, although a small amount of homobislactone may be formed during the coupling reaction.     

Stability and acidity constants for ternary ligand-zinc-hydroxo complexes of tetradentate tripodal ligands

Four series of tetradentate tripodal ligands containing pyridyl, 2-imidazolyl, 4-imidazolyl, amino, and/or carboxylic groups were synthesized as hydrolytic zinc enzyme models in order to elucidate the effect of various coordination environments on zinc binding and the acidity of zinc-bound water. In aqueous solution, ligands with same charges showed a good correlation between zinc binding (log K(ZnL)) and zinc-bound water acidity (pK(a) of LZnOH(2)); the stronger the zinc binding, the higher the pK(a). The zinc-bound water acidity decreased as pyridyl groups were replaced by carboxylate groups. However, exchanging amino groups for carboxylate groups gave no change in zinc-bound water acidity regardless of the charge of the atoms in the inner coordination sphere of the metal ion. The results are consistent with the conventional notion that negatively charged carboxylate groups inherently increase zinc binding and result in decreasing zinc-bound water acidity, but also suggest that environmental effects may modulate or dominate control of acidity.     

Residue requirements for helical folding in short alpha/beta-peptides: crystallographic characterization of the 11-helix in an optimized sequence

Design of functional foldamers requires knowledge of the conformational propensities of constituent residues. Here, we explore the effects of variations in both alpha-amino acid and beta-amino acid substitution on alpha/beta-peptide helicity. We also report the first X-ray crystal structure of a helical alpha/beta-peptide. We conclude that a certain amount of conformational preorganization in alpha/beta-peptides (via the inclusion of constrained beta-amino acids or alpha,alpha-disubstituted alpha-amino acids) is needed to promote helical folding; acyclic beta-amino acids and beta-branched alpha-amino acids are tolerated to only a limited extent.     

Carboxylic‐Acid‐Passivated Metal Oxide Nanocrystals: Ligand Exchange Characteristics of a New Binding Motif

Ligand exchange is central in the processing of inorganic nanocrystals (NCs) and requires understanding of surface chemistry. Studying sterically stabilized HfO₂ and ZrO₂ NCs using ¹H solution NMR and IR spectroscopy as well as elemental analysis, this paper demonstrates the reversible exchange of initial oleic acid ligands for octylamine and self‐adsorption of oleic acid at NC surfaces. Both processes are incompatible with an X‐type binding motif of carboxylic acids as reported for sulfide and selenide NCs. We argue that this behavior stems from the dissociative adsorption of carboxylic acids at the oxide surface. Both proton and carboxylate moieties must be regarded as X‐type ligands yielding a combined X₂ binding motif that allows for self‐adsorption and exchange for L‐type ligands.     

Synthesis, characterization, and folding behavior of beta-amino acid derived polyisocyanides

Helical polymers of isocyanopeptides derived from beta-amino acids have been synthesized and their architectures have been studied in detail. Similar to their alpha-amino acid analogues, the helical conformation in these macromolecules is stabilized by internal hydrogen-bonding arrays along the polymeric backbone. Unexpectedly, the flexibility of the beta-peptide side arms results in a rearrangement of the initial macromolecular architecture, leading to a more stable helical structure possessing a better defined hydrogen-bonding pattern, as was concluded from IR and temperature-dependent circular dichroism studies. Based on these results we propose a dynamic helical model for the beta-amino acid derived polyisocyanopeptides; this model is in contrast to the kinetically stable helical macromolecules that are formed upon polymerization of alpha-amino acid based isocyanopeptides.     

Organocatalytic asymmetric direct alkylation of alpha-diazoester via C-H bond cleavage

A new variant of phosphoric acid-catalyzed C-C bond forming reaction, direct alkylation of alpha-diazoester, via C-H bond cleavage is presented. The resulting products, beta-amino-alpha-diazoesters, are highly functionalized and useful synthetic precursors for various types of beta-amino acids.     

Enantioselective addition of ketene silyl acetals to nitrones catalyzed by chiral titanium complexes. Synthesis of optically active beta-amino acids

A chiral titanium complex, Ti(O-i-Pr)(4)/BINOL/tert-butylcatechol, catalyzes enantioselective addition reaction of ketene silyl acetals to nitrones to give optically active beta-amino acid derivatives which are biologically active compounds and useful synthetic intermediates of natural products and pharmaceuticals such as beta-lactam antibiotics. The combined process of catalytic oxidation of secondary amines and enantioselective carbon-carbon bond formation of nitrones thus obtained with ketene silyl acetals provides a useful two-step method for the synthesis of optically active beta-amino acid derivatives and related nitrogen compounds.