Design and synthesis of conformationally constrained glycosylated amino acids

To probe the conformational requirements of O-linked glycoproteins for binding to various enzymes and receptors, two conformationally constrained glycosylated amino acids, 2 and 3, were designed. The analogues were found to represent two potential low energy conformations of the parent conjugate, 1, by molecular modeling. A convergent synthesis of both 2 and 3 from D-galactose and L-methionine is presented.     

Stereoselective synthesis of conformationally constrained glycosylated amino acids using an enzyme-catalyzed desymmetrization

As part of an effort to probe the mechanism by which glycosyltransferases recognize glycoproteins and assemble the core structures of O-linked oligosaccharides, constrained glycopeptides, compounds 2 and 3, based on the alpha-N-acetylgalactosaminyl serine substructure 1, were designed. In this paper we describe a stereoselective preparation of protected versions of these compounds. A pig liver esterase-catalyzed enzymatic desymmetrization of a diacetate substrate, 10, was employed as a key component in the synthesis.     

A hybrid foldamer with unique architecture from conformationally constrained aliphatic-aromatic amino acid conjugate

In this paper, we describe the design and synthesis of a novel hybrid foldamer, derived from a conformationally constrained aliphatic-aromatic amino acid conjugate that adopts a well-defined, compact, three-dimensional structure, governed by a combined conformational restriction imposed by the individual amino acids from which the foldamer is composed. Conformational investigations confirmed the prevalence of a unique doubly bent conformation for the foldamer, in both solid and solution states, as evidenced from single crystal X-ray and 2D NOESY studies, respectively. The findings suggest that constrained aliphatic-aromatic amino acid conjugates offer new avenues for the de novo design of hybrid foldamers with distinctive structural architectures. Furthermore, the de novo design strategy disclosed herein has the potential for significantly augmenting the ‘tool-box’ of the modern day peptidomimetic chemist, as well as providing a novel approach to the field of rational design.     

Asymmetric synthesis of 4-substituted prolines as conformationally constrained amino acid analogues

Treatment of readily available chiral building block 1 with (2R)-2,3-O-isopropylideneglyceraldehyde (5) provides a new route for asymmetric synthesis of 2,4-disubstituted pyrrolidines. Several proline-amino acid chimeras: proline-leucine, proline-lysine, proline-arginine and proline-glutamic acid, are synthesized in highly diastereomerically pure forms.     

Enantiomeric analysis of the common protein amino acids by liquid chromatography

Methods for resolving amino acids into their enantiomers are of importance in the preparation of peptides, drugs, food additives, and in other areas where optical purity is important. HPLC methods of separation are particularly useful.     

Simple access to novel azetidine-containing conformationally restricted amino acids by chemoselective reduction of β-lactams

Reduction with diphenylsilane and catalytic amounts of tris(triphenylphosphine)rhodium(I) carbonyl hydride resulted in an efficient, chemoselective method for the transformation of amino-acid-derived β-lactams into the corresponding azetidines, which after removal of the p-methoxybenzyl group, afforded a new family of conformationally restricted amino acids. Phe-derived compounds were obtained in enantiopure form by combining HPLC resolution of the β-lactam precursor and the above-mentioned procedure.     

Total synthesis of a conformationally constrained didemnin B analog

The total synthesis of a didemnin B analogue containing a conformationally constrained replacement for the isostatine moiety is reported. Synthetic highlights include an improved preparation of 2-hydroxy-3-cyclohexenecarboxylic acid and a new strategy for accessing the macrocycle.     

Synthesis of conformationally constrained adamantane imidazolines with trypanocidal activity

Aiming at the development of new adamantano building blocks for treating African trypanosomiasis, we report on the synthesis of spiro adamantane 2‐imidazolines 8a‐f and 9a‐c , and their congeneric 5‐(1‐adamantyl)imidazolines 14 and 15 . The potency of these compounds against Trypanosoma brucei was compared to that of rimantadine and found, in the case of compound 14e , to be three fold higher. Together with the other active compounds, 14b and 15b , which were equipotent to rimantadine, the new molecules illustrate the synergistic effect of the lipophilic character of adamantane and the C1 amidine functionality on trypanocidal activity.     

Synthesis of novel non-natural conformationally restricted cyclopropane amino acids of spirane series

Russian Chemical Bulletin - New conformationally rigid spirane analogues of γ-aminobutyric acid, namely, 4-aminospiro[2.2]pentanecarboxylic and 1-aminospiro[2.3]hexane-5-carboxylic acids were...     

Synthesis of a new conformationally constrained glycoamino acid building block

The synthesis of a suitably protected β-d-glucopyranosyl-(S)-α-methylserine derivative—a new conformationally constrained glycosylated quaternary amino acid analogue of β-d-glucopyranosyl-l-serine—is described. This compound can be used as an attractive building block for the synthesis of new, constrained glycopeptides.     

Synthesis of alkylated sugar amino acids: conformationally restricted L-Xaa-L-Ser/Thr mimics

Two synthetic strategies for the generation of delta-substituted pyranoid sugar amino acids (SAAs) are evaluated. The first employs chiral nonracemic tert-butane sulfinamides as key reagents. Regardless of the stereochemistry of the applied sulfinamide, the product formed has a stereochemistry resembling that of a d amino acid at C7. Direct Grignard reaction on formyl-tetra-O-benzyl-beta-D-C-glucopyranoside in the second strategy and subsequent Mitsunobu inversion, yields the l,l-dipeptide isosters.     

Structural arrangement of DNA constrained by a cross-linker

Self-complementary cross-linked oligonucleotides with a disulfide linkage were designed and synthesized. Double helix and hairpin structures were controlled using the different diastereochemistry of phosphoramidate where the cross-linker was introduced. The structures of the strained cross-linked DNAs were estimated by gel mobility, circular dichroism spectra, and melting profiles.     

Synthesis of conformationally constrained C-glycosyl alpha- and beta-amino acids and sugar-carbamino sugar hybrids via Diels-Alder reaction

[structure: see text] Sugar-derived dienes undergo Diels-Alder reactions with methyl alpha-nitro acrylate and ethyl beta-nitro acrylate to form the corresponding cycloadducts which have been converted into conformationally constrained C-glycosyl alpha- and beta-amino acids. Further, these beta-amino acids are converted into sugar-carbamino sugar hybrid molecules.     

Synthesis of a new stable conformationally constrained 2,7-anhydrosialic acid derivative

A stereoseletive synthesis of 2,7-anhydrosialic acid derivative 18 was achieved from d-glucono-delta-lactone. A highly syn-selective addition of Grignard reagent to theN-benzylimine 8 served as a key step.     

New pyrrole-based amino acids for the synthesis of peptidomimetic constrained scaffolds

A new family of pyrrole-based amino acids have been prepared through the microwave assisted Paal-Knorr reaction of 1-4 ketoesters derived from the corresponding β-ketoester with a functional homologation. The carboxylic group is located in position 3 of the pyrrole, whereas the amino group, protected with the Cbz moiety, is present on the side chain in positions 1 or 2. These compounds were used to prepare constrained oligopeptides.     

Total syntheses of conformationally constrained didemnin B analogues. replacements of N,O-dimethyltyrosine with L-1,2,3,4-tetrahydroisoquinoline and L-1,2,3,4-tetrahydro-7-methoxyisoquinoline.

The design and synthesis of two conformationally constrained analogues of didemnin B are described. The [N,O-Me(2)Tyr(5)]residue of didemnin B was replaced with L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) and L-1,2,3,4-tetrahydro-7-methoxyisoquinoline-3-carboxylic acid (MeO-Tic), which mimic the N,O-dimethylated tyrosine while constraining the conformation of the molecule. Preliminary results indicate that the conformation of the [N,O-Me(2)Tyr(5)]residue closely matches the conformation imposed by the Tic replacement.     

Stereocontrolled synthesis of cyclopropanol amino acids from allylic sulfones: conformationally restricted building blocks

[reaction: see text] A new amino acid methyl ester with a cyclopropanol has been synthesized starting from the allyl sulfone 10. The starting material, 10, could be obtained in both enantiomeric forms. The stereoselectivity of the cyclopropane formation has been studied by molecular modeling.