Synthesis of Enantiopure 1,2-Diaminobicyclo[2.2.2]octane Derivatives, C 1 -Symmetric Chiral 1,2-Diamines with a Rigid Bicyclic Backbone

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Crystal structure of Boc-(S)-ABOC-(S)-Ala-(S)ABOC-(S)-Phe-OBn chloroform monosolvate

International audienceIn the title compound, phenyl (S)-2-[(S)-(1-\2-[(S)-(1-\[(tert-butoxy)carbonyl]amino\bicycloĂ [2.2.2]octan-2-yl)formamido]propanamido\bicyclo[2.2.2]octan-2-yl)for mamido]-3-phenylpropanoate chloroform monosolvate, C42H56N4O7-CHCl3, the alpha,beta-hybrid peptide contains two non-proteinogenic amino acid residues of (S)-1-aminobicyclo[2.2.2]octane-2-carboxylic acid [(S)-ABOC], two amino acid residues of (S)-2-aminopropanoic acid [(S)-Ala] and (S)-2-amino-3-phenylpropanoic acid [(S)-Phe], and protecting groups of tert-butoxycarbonyl (Boc) and benzyl ester (OBn). The tetramer folds into a right-handed mixed 11/9 helix stabilized by intramolecular i, i +3 and i, i-1 C=O center dot center dot center dot H-N hydrogen bonds. In the crystal, the oligomers are linked by N-H center dot center dot center dot O=C hydrogen bonds into chains along the a-axis direction. The chloroform solvent molecules are intercalated between the folded chains via C-H center dot center dot center dot O=C interactions

C 1 -Symmetric 1,2-Diaminobicyclo[2.2.2]octane Ligands in Copper-Catalyzed Asymmetric Henry Reaction: Catalyst Development and DFT Studies

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Synthesis, characterisation and cytotoxic activity evaluation of new metal-salen complexes based on the 1,2-bicyclo[2.2.2]octane bridge

International audience(R)-1,2-Diaminobicyclo[2.2.2]octane was used as a starting material for the preparation, in solution or in a ball mill, of a salen ligand. Five metal salen complexes were prepared in high yield and their cytotoxic activities were evaluated against the Human Colon cancer HCT116 cell lines. The original manganese salen complex displayed the highest activity with a potency 16 fold higher than that of cisplatin, demonstrating the benefit of the bridging backbone compared to other salen systems. An alternative preparation route for this complex by mechanochemistry was also performed

N-Pyrrolidine-based alpha/beta-peptides incorporating ABOC, a constrained bicyclic beta-amino acid, for asymmetric aldol reaction catalysis

International audienceA series of N-pyrrolidine-based alpha,beta-peptide catalysts incorporating a constrained 2-aminobicyclo[2.2.2] octane carboxylic acid (ABOC) residue were synthesized and evaluated in the asymmetric aldol reaction from acetone and some p-substituted benzaldehydes. Their catalytic properties were shown to be highly dependent on the amino acid sequences and on the absolute configuration of the ABOC residue that played a determinant role. Among the peptides tested, the heterochiral tripeptide H-Pro-(R)-ABOC-Asp-OCH3 13, that adopts a turn conformation in the solid state, proved to be the most efficient catalyst affording beta-hydroxy ketones in high yields and good enantioselectivities (up to 87%)

Synthesis, Characterisation and Cytotoxic Activity Evaluation of New Metalsalen Complexes Based on the 1,2-bicyclo[2.2.2]octane Bridge

Diaminobicyclo[2.2.2]octane was used as starting material for the preparation, in solution or in a ball-mill, of a salen ligand. Five metal salen complexes were prepared in high yield and their cytotoxic activities were evaluated against HCT116 cell lines. Original manganese salen complex displayed the highest activity with a potency 16 fold higher than the one of cisplatin, demonstrating the benefit of the bridging backbone, compared to other salen systems. An alternative preparation route for this complex by mechanochemistry was also performed.<br /

12/14/14-Helix Formation in 2:1 alpha/beta-Hybrid Peptides Containing Bicyclo[2.2.2]octane Ring Constraints

International audienceThe highly constrained b-amino acid ABOC induces different types of helices in b urea and 1:1 a/b amide oligomers. The latter can adopt 11/9- and 18/16-helical folds depending on the chain length in solution. Short peptides alternating proteinogenic a-amino acids and ABOC in a 2:1 a/b repeat pattern adopted an unprecedented and stable 12/14/14-helix. The structure was established through extensive NMR, molecular dynamics, and IR studies. While the 1:1 a-AA/ABOC helices diverged from the canonical a-helix, the helix formed by the 9-mer 2:1 a/b-peptide allowed the projection of the a-aminoacid side chains in a spatial arrangement according to the a-helix. Such a finding constitutes an important step toward the conception of functional tools that use the ABOC residue as a potent helix inducer for biological applications

Synthesis of Enantiopure 1,2-Diaminobicyclo[2.2.2]octane Derivatives, <i>C</i>₁‑Symmetric Chiral 1,2-Diamines with a Rigid Bicyclic Backbone

The synthesis of enantiopure 1,2-diaminobicyclo[2.2.2]­octane (DABO, <b>1</b>) and its two selectively <i>N</i>-Boc monoprotected derivatives <b>15</b> and <b>16</b> is described. Starting from bicyclic β-amino acid <b>3</b> or <b>5</b>, strategies involving Curtius and Hofmann rearrangements were explored, demonstrating the unprecedented influence of the bicyclic backbone unsaturation for the preparation of the corresponding diamines that could be only obtained in good yield using the Hofmann rearrangement of unsaturated compound <b>3</b>. The divergent outcome observed during the Hofmann rearrangement of <b>3</b> and <b>5</b> was investigated by DFT calculations

Synthesis of Enantiopure 1,2-Diaminobicyclo[2.2.2]octane Derivatives, <i>C</i>₁‑Symmetric Chiral 1,2-Diamines with a Rigid Bicyclic Backbone

The synthesis of enantiopure 1,2-diaminobicyclo[2.2.2]­octane (DABO, <b>1</b>) and its two selectively <i>N</i>-Boc monoprotected derivatives <b>15</b> and <b>16</b> is described. Starting from bicyclic β-amino acid <b>3</b> or <b>5</b>, strategies involving Curtius and Hofmann rearrangements were explored, demonstrating the unprecedented influence of the bicyclic backbone unsaturation for the preparation of the corresponding diamines that could be only obtained in good yield using the Hofmann rearrangement of unsaturated compound <b>3</b>. The divergent outcome observed during the Hofmann rearrangement of <b>3</b> and <b>5</b> was investigated by DFT calculations

Mixed oligoureas based on constrained bicyclic and acyclic β-amino acids derivatives: on the significance of the subunit configuration for folding.

International audienceThe combination of a non-functionalized constrained bicyclo[2.2.2]octane motif along with urea linkages allowed the formation of a highly rigid 2.5(12/14) helical system both in solution and the solid state. In this work, we aimed at developing stable and functionalized systems as promising materials for biological applications in investigating the impact of this constrained motif and its configuration on homo and heterochiral mixed-oligourea helix formation. Di-, tetra-, hexa-, and octa-oligoureas alternating the highly constrained bicyclic motif of (R) or (S) configuration with acyclic (S)-β(3)-amino acid derivatives were constructed. Circular dichroism (CD), NMR experiments, and the X-ray crystal structure of the octamer unequivocally proved that the alternating heterochiral R/S sequences form a stable left-handed 2.5-helix in contrast to the mixed (S/S)-oligoureas, which did not adopt any defined secondary structure. We observed that the (-)-synclinal conformation around the C(α)-C(β) bond of the acyclic residues, although sterically less favorable than the (+)-synclinal conformation, was imposed by the (R)-bicyclic amino carbamoyl (BAC) residue. This highlighted the strong ability of the BAC residue to drive helical folding in heterochiral compounds. The role of the stereochemistry of the BAC unit was assessed and a model was proposed to explain the misfolding of the S/S sequences