Amyloid-like Nanofibrillation of Metal-Organic Complex Arrays Ruled by Their Precisely Designed Metal Sequences.

Self-assembly of a series of dimetallic sequences constructed on a backbone with two successive tyrosine moieties (Fmoc-M1 -M2 -CO2 H) revealed that the resultant morphology is clearly dependent on the metal sequence, where Re-containing sequences such as homometallic Fmoc-Re-Re-CO2 H specifically afforded amyloid-like nanofibers. These findings further allowed to achieve the fibrillation of a longer metal sequence containing three different metals (Fmoc-Rh-Pt-Re-Re-CO2 H). Cyclic voltammetry of the fibrillated Fmoc-Re-Re-CO2 H demonstrated that the redox activity of the metal complexes in the sequence is preserved in the nanofibrous forms.

Chemical approach for interconversion of (S)- and (R)-α-amino acids.

Here we report a general method for the preparation of unnatural (R)-α-amino acids via complexation of α-(phenyl)ethylamine derived chiral reagent (S)- with various (S)-α-amino acids. The reactions proceed with synthetically useful chemical yields and thermodynamically controlled diastereoselectivity. Chiral reagent (S)- can be conveniently recovered and reused without any loss of enantiomeric purity and reactivity.

Design and synthesis of quasi-diastereomeric molecules with unchanging central, regenerating axial and switchable helical chirality via cleavage and formation of Ni(II)-O and Ni(II)-N coordination bonds.

We describe herein the design and synthesis of asymmetric, pentadentate ligands, which are able to coordinate to Ni(II) cations leading to quasi-diastereomeric complexes displaying two new elements of chirality: stereogenic axis and helix along with configurational stabilization of the stereogenic center on the nitrogen. Due to the stereocongested structural characteristics of the corresponding Ni(II) complexes, the formation of quasi-diastereomeric products is highly stereoselective providing formation of only two, (R(a)*,M(h)*,R(c)*) and (R(a)*,P(h)*,R(c)*), out of the four possible stereochemical combinations. The reversible quasi-diastereomeric transformation between the products (R(a)*,M(h)*,R(c)*) and (R(a)*,P(h)*,R(c)*) occurs by intramolecular trans-coordination of Ni-NH and Ni-O bonds providing a basis for a chiral switch model.

Synthesis of metal−organic complex arrays.

The Merrifield solid-phase peptide synthesis technique has been adapted to the synthesis of homo- and heterometallic metal−organic complex arrays (MOCAs). A terpyridine-appended and Fmoc-protected L-tyrosine derivative was metalated with Pt(II), Rh(III), or Ru(II) ions in solution and sequentially coupled at the surface of functionalized polymeric resin to give a metal complex triad (Rh−Pt−Ru), tetrad (Ru−Rh−Pt−Pt), pentad (Rh−Pt−Ru−Pt−Rh), and hexad (Rh−Pt−Ru−Pt−Rh−Pt) with specific metal sequence arrangements. These were cleaved from the resin, and their character was confirmed by mass spectrometry.

Ridge-tile-like chiral topology: synthesis, resolution, and complete chiroptical characterization of enantiomers of edge-sharing binuclear square planar complexes of Ni(II) bearing achiral ligands.

Binuclear square planar Ni(II) complexes are described, formed by two tridentate ligands with two imine-nitrogens coordinating two nickel atoms. Such complexes are synthetically readily available with great structural variety and present new types of ridge-tile-like chiral compounds that are reasonably stable in the appropriate "bent" conformation. Enantiomerically pure samples of these compounds have been obtained for the first time using HPLC with a chiral stationary phase. Absolute configurations and chiroptical properties are fully characterized by ECD, VCD, ORD spectroscopy, and theoretical calculations. These new compounds with ridge-tile-like chiral topology are configurationally reasonably stable [DeltaG(double dagger) = 121.4 kJ mol(-1), t(1/2) = 14.9 h (78 degrees C, ethanol)], and therefore their chemistry, physical properties, and applications can be systematically studied.

Reactive sulfur species: kinetics and mechanism of the oxidation of aryl sulfinates with hypochlorous acid.

The mechanism of oxidation of ArSO(2)(-) (PhSO(2)(-) and 5-sulfinato-2-nitrobenzoic acid = TNBO(2)(1-/2-)) with HOCl/OCl(-) has been investigated using the kinetic method. In contrast to previous reports for PhSO(2)(-) (for which it was suggested that OCl(-) and not HOCl was the reactant), the reaction proceeds through a conventional pathway: nucleophilic attack by ArSO(2)(-) on HOCl with concomitant Cl(+) transfer to give a sulfonyl chloride intermediate (ArSO(2)Cl), which we have identified spectrophotometrically. Remarkably, the rate constant for the reaction of HOCl with ArSO(2)(-) is on the order of 10(9) M(-1) s(-1), larger than the rate constants for corresponding thiolates, and is nearly diffusion-controlled. In contrast, the rate constant for the reaction of OCl(-) with ArSO(2)(-) is approximately 7 orders of magnitude smaller.

Resolution/deracemization of chiral alpha-amino acids using resolving reagents with flexible stereogenic centers.

This work has demonstrated that a previously unexplored approach to separation of enantiomers via formation of diastereomeric derivatives with three stereogenic centers has obvious practical potential and deserves further systematic study. The design reported here is based on the unusual application of a configurationally unstable stereogenic nitrogen, which plays a key role in setting up the stereochemical match between the three stereogenic centers in the corresponding products.

New sterically driven mode for generation of helical chirality.

The presented results and the available literature data convincingly suggest that there is a new sterically driven mechanism for the formation of supramolecular helicity in the solid state. This mechanism requires the presence of sterically bulky groups, such as tert-butyl, for which the spiral arrangement in uninterrupted hydrogen-bonding chains, serving as an axis for helical structure and maximizing the repulsive stereochemical interactions, provide for the most efficient, spatially economical accommodation of these groups in a crystallographic unit cell.

Efficient asymmetric synthesis of novel 4-substituted and configurationally stable analogues of thalidomide.

The preparation of new thalidomide derivatives 4-methyl-(3S,4R)-3a and 4-phenyl-(3S,4S)-3b starting from pyroglutamic acids (2R,3R)-7a and (2R,3S)-7b, possessing an inappropriate stereochemistry, was successfully realized due to stereochemically complete epimerization at the alpha-stereogenic center upon formation of the corresponding N-phthaloyl anhydrides 9a,b. The demonstrated conformational stability of these new thalidomide derivatives provides solid experimental evidence for practical feasibility of the approach described here to overcome the inherent problem of configurational instability of thalidomide by introducing an alkyl or aryl group in the C4 position. [reaction: see text].

Design, synthesis, and evaluation of a new generation of modular nucleophilic glycine equivalents for the efficient synthesis of sterically constrained alpha-amino acids.

A new generation of modular achiral glycine equivalents have been evaluated with respect to their synthetic utility for the production of tailor-made, sterically constrained alpha-amino acids, which proved to be the most efficient approach developed to date for the synthesis of symmetrical alpha,alpha-disubstituted-alpha-amino acids. Among the new series of achiral glycine equivalents, one was found to be a superior glycine derivative for the Michael additions with various (R)- or (S)-N-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones representing a general and practical synthesis of sterically constrained beta-substituted pyroglutamic acids. In particular, the application of these complexes allowed for the preparation of several beta-substituted pyroglutamic acids which include electron-releasing and sterically demanding substituents in the structure thus increasing the synthetic efficiency and expanding the generality of these Michael addition reactions.

Synthesis of trifluoro- or difluoromethylated olefins by regio- and stereocontrolled S(N)2' reactions of gem-difluorinated vinyloxiranes.

This paper presents a highly stereoselective synthesis of trifluoro- or difluoromethylated olefins via an S(N)2' type fluorination or reductions of gem-difluorinated vinyloxiranes. Their fluorination with HF-Py furnished trifluoromethylated allylic alcohols with exclusive E selectivity. On the other hand, their reduction with DIBAL-H afforded difluoromethylated E-allylic alcohols predominantly, whereas the corresponding Z isomers were formed exclusively by treatment with BH3.THF.

Regio- and stereoselective reactions of gem-difluorinated vinyloxiranes with heteronucleophiles.

[Reaction: see text]. Regio- and stereoselectivity in reactions of gem-difluorinated vinyloxiranes with heteronucleophiles were successfully controlled. Halogen atoms were introduced regioselectively at the allylic epoxide carbon with an inversion in stereochemistry using MgBr2*Et2O or Li2CuCl4 to produce anti-vic-halohydrine. The other diastereomers were obtained selectively using LiBr/AcOH or BCl3, and SN2' type products were formed selectively with excellent E preference by changing the reaction temperature. Moreover, a further investigation led us to find that a regio- and stereoselective SN2' addition of several Brnsted acids was dependent on the pKa values of the acids. Under strong acidic conditions, we exclusively obtained E allylic alcohols.

Michael addition reactions between chiral equivalents of a nucleophilic glycine and (S)- or (R)-3-[(E)-enoyl]-4-phenyl-1,3-oxazolidin-2-ones as a general method for efficient preparation of beta-substituted pyroglutamic acids. Case of topographically controlled stereoselectivity.

This paper describes a systematic study of addition reactions between the chiral Ni(II) complex of the Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone and (S)- or (R)-3-[(E)-enoyl]-4-phenyl-1,3-oxazolidin-2-ones as a general and synthetically efficient approach to beta-substituted pyroglutamic acids and relevant compounds. These reactions were shown to occur at room temperature in the presence of nonchelating organic bases and, most notably, with very high (>98% diastereomeric excess (de)) stereoselectivity at both newly formed stereogenic centers. The stereochemical outcome of the reactions was found to be overwhelmingly controlled by the stereochemical preferences of the Michael acceptors, and the chirality of the glycine complex influenced only the reaction rate. Thus, in the reactions of both the (S)-configured Ni(II) complex and the Michael acceptors, the reaction rates were exceptionally high, allowing preparation of the corresponding products with virtually quantitative (>98%) chemical and stereochemical yields. In contrast, reactions of the (S)-configured Ni(II) complex and (R)-configured Michael acceptors proceeded at noticeably lower rates, but the addition products were obtained in high diastereo- and enantiomeric purity. To rationalize the remarkably high and robust stereoselectivity observed in these reactions, we consider an enzyme-substrate-like mode of interaction involving a topographical match or mismatch of two geometric figures. Excellent chemical and stereochemical yields, combined with the simplicity and operational convenience of the experimental procedures, render the present method of immediate use for preparing various beta-substituted pyroglutamic acids and related compounds.

Regio- and stereoselective reductions of gem-difluorinated vinyloxiranes.

[reaction: see text] gem-Difluorinated vinyloxiranes are versatile building blocks for the synthesis of fluorinated compounds. Investigations of their reactions with nucleophiles resulted in highly regio- and stereoselective reductions. In their reactions with LiAlH4, hydride reacted at the allylic epoxide carbon to produce homoallylic alcohols exclusively. Moreover, regio- and stereoselective S(N)2' reactions were observed with DIBAL-H and BH3 x THF; the former afforded E allylic alcohols, whereas the latter furnished the corresponding Z isomers with excellent selectivities.

Preparation and regioselective SN2' reaction of novel gem-difluorinated vinyloxiranes with RLi.

A series of hitherto unknown 3,4-epoxy-1,1-difluorobutenes were prepared from the readily accessible alpha,beta-epoxy ketones and these compounds were found to undergo regioselective S(N)2' reactions with hard RLi nucleophiles occurring at the highly positively charged terminal fluorine-possessing sp(2) carbon atom in quite sharp contrast to the cases of the corresponding nonfluorinated vinyloxiranes which only attained a low level of regioselectivity. Addition of HMPA substantially improved the products' olefinic stereoselectivity. Theoretical calculations were used to qualitatively explore the nature of selectivity in these reactions.

Virtually complete control of simple and face diastereoselectivity in the Michael addition reactions between achiral equivalents of a nucleophilic glycine and (S)- or (R)-3-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones: practical method for preparation of beta-substituted pyroglutamic acids and prolines.

This study demonstrates a new strategy for controlling the stereochemical outcome of the Michael addition reactions between nucleophilic glycine equivalents and alpha,beta-unsaturated carboxylic acid derivatives: The addition reactions between achiral Ni(II)-complex of the Schiff base of glycine with o-[N-alpha-pycolylamino]acetophenone and (S)- or (R)-3-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones were shown to occur at room temperature in the presence of nonchelating organic bases and, most notably, with very high stereoselectivity at both newly formed stereogenic centers. Thus, the chiral 4-phenyl-1,3-oxazolidin-2-one moiety was found to control efficiently both face diastereoselectivities of the glycine derived enolate and the C,C double bond of the Michael acceptor. The new strategy developed in this work is methodologically superior to previous methods, most notably in terms of generality and synthetic efficiency. Excellent chemical yields and diastereoselectivities, combined with the simplicity of the experimental procedures, render the present method of immediate use for preparing various 3-substituted pyroglutamic acids and related amino acids (glutamic acids, glutamines, prolines, etc.) available via conventional transformations of the former.

Efficient synthesis of serically constrained smmetrically alpha,alpha-disubstituted alpha-amino acids under operationally convenient conditions.

Homologation of the nucleophilic glycine equivalent Ni-Gly-PABP [Ni(II) complex of glycine Schiff base with 2-[N-(alpha-picolyl)amino]benzophenone (PABP)] 2 via alkyl halide alkylations and Michael addition reactions was systematically studied as a general method for preparing symmetrically alpha,alpha-disubstituted alpha-amino acids (sym-alpha,alpha-AA). The dialkylation reactions are conducted under operationally convenient conditions without recourse to inert atmosphere, dried solvents, and low temperatures, thus enjoying key advantages of the experimental simplicity and attractive cost structure. The method has been shown to be particularly successful for the dialkylation of complex 2 with activated and nonactivated alkyl halides, including propargyl derivatives, affording a generalized and practical access to the corresponding sym-alpha,alpha-AA. This study has also shown some limitation of the method, as it cannot be extended to alpha- or beta-branched alkyl halides or Michael acceptors to be used for the dialkylation of glycine equivalent 2. High chemical yields of the dialkylated products, combined with the simplicity of the experimental procedure, render this method worth immediate use for multigram scale preparation of the sym-alpha,alpha-AA.