Synthesis and evaluation of chiral bicyclic proline FKBP12 ligands (original) (raw)
2-Aryl-2,2-difluoroacetamide FKBP12 Ligands: Synthesis and X-ray Structural Studies
Organic Letters, 2001
2-Aryl-2,2-difluoroacetamido-proline and pipecolate esters are high affinity FKBP12 ligands whose rotamase inhibitory activity is comparable to that seen for the corresponding ketoamides. X-ray structural studies suggest that the fluorine atoms participate in discrete interactions with the Phe36 phenyl ring and the Tyr26 hydroxyl group, with the latter resembling a moderate-to-weak hydrogen bond.
3-Substituted Prolines: From Synthesis to Structural Applications, from Peptides to Foldamers
Molecules, 2013
Among the twenty natural proteinogenic amino acids, proline is unique as its secondary amine forms a tertiary amide when incorporated into biopolymers, thus preventing hydrogen bond formation. Despite the lack of hydrogen bonds and thanks to conformational restriction of flexibility linked to the pyrrolidine ring, proline is able to stabilize peptide secondary structures such as -turns or polyproline helices. These unique conformational properties have aroused a great interest in the development of proline analogues. Among them, proline chimeras are tools combining the proline restriction of flexibility together with the information brought by natural amino acids side chains. This review will focus on the chemical syntheses of 3-substituted proline chimeras of potential use for peptide syntheses and as potential use as tools for SAR studies of biologically active peptides and the development of secondary structure mimetics. Their influence on peptide structure will be briefly described.
Amino Acids, 2011
The synthesis of unusual cyclic amino acids, that may be envisaged as proline analogs, is an area of great interest for their potential applications as scaffolds for the design of bioactive peptidomimetics or units for the creation of novel foldamers. We have carried out the preparation of cyclic dehydro-b-amino acids starting from allylic carbonates via a two-step allylic amination/ring closing metathesis (RCM) protocol. The introduction of the allylamino moiety has been carried out either without a catalyst, through an S N 2 0 reaction, or in the presence of iridium complexes. The backbone of the allylamino intermediates contains two unsaturations, thus suggesting that RCM could be a valuable tool for the preparation of dihydropyrrole scaffolds. A similar reaction has been already reported in the literature for racemic aromatic-substituted substrates, but no examples of enantiopure derivatives bearing aliphatic chains have been reported. The reaction was optimized by testing different Grubbs' catalysts and carbamate nitrogen protecting groups. Moreover, in view of a future application of these dehydro-b-amino acids as central core of peptidomimetics, the malonate chain was also used to protect nitrogen prior to RCM.
[2.2]Paracyclophane-Derived Chiral P,N-Ligands
With the idea of tuning structural flexibility and rigidity, several [2.2]paracyclophane-derived P,N-ligands were designed and synthesized. A full investigation of the relationship between the ligands' structures and their abilities to induce asymmetry in palladium-catalyzed asymmetric allylic alkylations of malonates with 1,3-diphenyl 2-propenyl acetate was carried out, and high yields and enantioselectivities (i.e., 99% yield, 97% ee) were observed while using ligands bearing matched planar and central chirality.
Organic letters, 2016
A versatile diastereoselective Friedel-Crafts alkylation reaction of heteroaryl systems with a cyclic enecarbamate for the preparation of 5-heteroaryl-substituted proline analogues in good yields has been developed. These heterocyclic tethered cyclic amino acid building blocks constitute important structural motifs in many biologically active molecules. The impact of the substitution on proline cis/trans isomerization was explored by carrying out solution conformational studies by NMR on 5-furanyl-substituted proline-containing peptides. Conformational analysis revealed that the peptide bond is constrained in an exclusively trans conformation.
Synthesis and Characterization of Highly Conjugated, Chiral Bridging Ligands
The Journal of Organic Chemistry, 2004
This paper describes the synthesis of four chiral derivatives of the electronically highly conjugated tetra-2-pyridylpyrazine (TPPZ) bridging ligand, which are denoted (R)-and (S)-4,5-and 5,6-pinenotetra-2-pyridylpyrazine (PTPPZ). Preparation of these ligands was undertaken through the use of commercially available, enantiomerically pure (1R)-and (1S)-R-pinene, which was functionalized and subsequently employed in a Kröhnke pyridine synthesis involving a furan-substituted pyridinium salt to yield a chiral, furan-substituted pyridyl intermediate. Oxidative degradation and subsequent reduction of this furan led to a chiral, substituted 2-pyridylaldehyde, which underwent a pyridoin condensation followed by cyclization to produce the final PTPPZ ligands.
Synthesis of beta-fluoro-beta-proline
Tetrahedron Letters, 2011
A synthetic strategy towards the novel amino acid b-fluoro-b-proline, a fluorinated analogue of b-proline, is elaborated. The synthesis commences from commercially available methyl 2-fluoroacrylate and involves three steps. The overall yield of b-fluoro-b-proline is 57%.