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Four new series of diastereomeric β,γ-di- and β,γ-tetrapeptides derived from conveniently protected (1 R ,2 S )- and (1 S ,2S)-2-aminocyclobutane-1-carboxylic acid and cis - and trans -γ-amino- l -proline joined in alternation have been synthesized. High resolution NMR experiments show that peptides containing trans -cyclobutane amino acid residues adopt a more folded structure in solution than those containing a cis -cyclobutane residue, which adopt a strand-like structure. The cis/trans relative configuration of the cyclobutane residue is the origin of the folding pattern of each peptide due to either intra- or inter-residue hydrogen-bonded ring formation, whereas the cis/trans isomerism of the γ-amino- l -proline residue does not have a significantly relevant role on the folding ability of these peptides. [ABSTRACT FROM AUTHOR]

Abstract: α-(trans-Vinyl) phosphonamides with different substituents at the β-position were stereoselectively synthesized in high yields by treatment of β-substituted α-epoxy-α-trimethylsilyl phosphines with oxidizing agents. The corresponding phosphonamides were unstable in most cases and underwent reductive elimination affording desilylated vinyl derivatives. In turn, α-epoxy phosphines resulted from the [1+2] addition of [bis(diisopropylamino)phosphino](trimethylsilyl)carbene 2 to aliphatic, aromatic, and heteroaromatic aldehydes. In this way, a great variety of vinyl compounds have been efficiently prepared through one-pot procedure. [Copyright &y& Elsevier]

Abstract: The synthesis of a new chiral diaminophosphino(silyl)carbene, based on the use of (R,R)-cyclohexane-trans-1,2-diamine, is described. Its reaction with methyl acrylate afforded a cyclopropane derivative as a single diastereomer. The diastereoselectivity in the addition reactions between olefins and chiral carbenes derived from C 2-symmetric diamines has also been studied by theoretical calculations, which establish that it has a steric origin; we report a rationale to predict the absolute configuration of the adducts. [Copyright &y& Elsevier]

Abstract: A novel and potent family of metallocarboxypeptidase inhibitors based on thioxophosphoranyl oxiranes is presented. These compounds bear aryl or heteroaryl substituents with trans-stereochemistry with respect to the phosphorylated group and they have been synthesized by the addition of [bis(diisopropylamino)phosphino](trimethylsilyl)carbene to the corresponding aldehydes and the subsequent thiolation of the phosphine. These oxiranes contain a tetrahedral P atom harboring shielded N,N-groups. The screening of their biological activity as metallocarboxypeptidase inhibitors and some structural studies, as well as full experimental details for the new compounds, is disclosed. Thus, from the analysis of their activity against the prototypical metallocarboxypeptidases A and B (CPA and CPB), we have observed that hydrophobic phosphorylated oxiranes perform better as CPB inhibitors, reaching K i values comparable to classical synthetic carboxypeptidase inhibitors. X-ray diffraction analysis revealed that the packing in the structure of one phosphorylated oxirane is mediated mainly by hydrophobic contacts and that the N,N-groups are highly flexible. Consequently, phosphorylated oxiranes might constitute an attractive material for subsequent improvements in the design of novel inhibitors against human proteolytic enzymes with enhanced oral availability. [Copyright &y& Elsevier]

Abstract: The highly stereoselective synthesis of enantiopure phosphoranyl alkyl oxiranes has been accomplished by the addition of a nucleophilic stable phosphino(silyl)carbene to chiral aldehydes prepared from (−)-verbenone and d-mannitol, respectively. In the process, two new stereogenic centers are created one of them being on an oxirane quaternary carbon. The excellent π-facial diastereoselection of the aldehydes combined with the diastereoselectivity of the carbene addition allowed us to synthesize the title compounds as single stereoisomers with well defined absolute configuration. [Copyright &y& Elsevier]

The 1,3-dipolar cycloadditions of bis(diisopropylamino)phosphinodiazomethane, 10, to chiral electron-deficient olefins have been investigated for the first time. The results have been compared with those corresponding to the reactions of diazomethane and the same or similar substrates. The experimental observations have been rationalized by DFT theoretical calculations. Diazomethane has been shown to be more reactive than 10 in all cases. The dipolarophiles include compounds synthesized from d-glyceraldehyde acetonide and (−)-verbenone. The latter compounds, bearing a gem-dimethylcyclobutane moiety, are less reactive than those derived from d-glyceraldehyde bearing a dioxolane ring. The influence of the Z/E geometry of the double bond on the reactivity and the π-facial diastereoselectivity has been investigated. Thus, in the reactions of diazomethane, the diastereoselectivity is not dependent on the Z/E stereochemistry but the reactivity is lower for (E)-cyclobutyl derivatives than for their Z isomers. In the reactions between 10 and the glyceraldehyde derivatives, the E isomers are less reactive than the Z ones and afford adducts with poor facial diastereoselectivity due to unfavorable interactions between the reactants in the corresponding transition states. [Copyright &y& Elsevier]

Abstract: New enantiopure cyclobutane derivatives have been synthesized from a chiral precursor derived from (−)-verbenone. The cyclobutane moiety acts as a chiral platform to afford a γ-amino acid function in a branched side-chain containing an additional stereogenic centre as well as additional C 6 or C 16-alkyl chains linked to the ring by means of an amine or an amide function. One of these compounds, obtained as a 1:2 mixture with its TFA salt has been investigated, suggesting behaviour as a good surfactant and its critical micellar concentration has been determined. [Copyright &y& Elsevier]

Abstract Two new conjugates, hcptpyDP and hcptpyTP, of a terpyridine derivative incorporating artificial peptide moieties, have been synthesized and their use in the preparation of metal catalysts and organogelators has been investigated. Ru(II) complexes derived from these ligands showed electrochemical behavior and activity as catalysts in the epoxidation of olefins similar to that of Beller's catalyst. As organogelators, these conjugates were able to gelate a variety of solvents, from toluene to methanol, with satisfactory mgc (minimum gelation concentration) values. The presence of 4′-(4-carboxy)phenylterpyridine (hcptpy) moiety allows tuning the gelling properties and also influences the supramolecular self-assembling mode to produce chiral aggregates with respect to parent peptides DP and TP. In the case of the conjugates, π−π interactions provided by the aromatic moieties cooperate with inter-molecular hydrogen bonding between N H and C O in the amide groups. Further properties of peptide/terpyridine conjugates are under investigation in view of future applications. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Several chiral cyclobutane-containing chemical platforms were synthesized in a stereoselective manner starting from (−)-verbenone as a suitable precursor. These compounds bear three orthogonally protected amine functions, two of them on side-chain and the other directly linked to the cyclobutane ring. Selective deprotection of the latter amine and subsequent coupling with the DOTA macrocycle followed by complexation with Gd(III) allowed the preparation of new GdDO3A monoamides whose potential ability as contrast agents (CAs) in magnetic resonance imaging (MRI) preliminary experiments was tested. Image contrast enhancement was shown to be dependent on the amine substitution and protecting groups (–NH–Cbz, –NH–CO–C 6 H 4 – p -NO 2 , –NH–Ac, and –NMe–Cbz), and in the case of acetamide the corresponding Gd complex manifested a better contrast enhancement than DOTAREM, a Gd-based commercial CA which was used as a reference. Computational studies suggest that water exchange rate in these complexes is associated to the ability of the amido-carbonyl groups in the cyclobutane side-chains to coordinate to Gd. [ABSTRACT FROM AUTHOR]

Divergent and versatile synthetic routes leading to the title compounds are described. They start from a common chiral precursor derived from (-)-(S)-verbenone and afford polyfunctional γ-lactams and γ- and ε-amino acids. The cyclobutane moiety in these molecules acts as a chiral and polyfunctional platform providing stereogenic centres with unambiguous absolute configuration that control the chirality of the newly produced asymmetric carbons. Furthermore, it affords functional groups and carbon chains suitable not only to create the basic skeleton of the desired products but additional functional groups. These features confer on these derivatives a great versatility for further uses in the development of new drugs and as synthetic building blocks. [ABSTRACT FROM AUTHOR]