Peptidyl-Prolyl Model Study: How Does the Electronic Effect Influence the Amide Bond Conformation?

The triple-helical structure of collagen, the most abundant protein in animal bodies, owes its stability to post-translationally installed hydroxyl groups at position 4 of prolyl residues. To shed light on the nature of this phenomenon, we have examined the influence of the 4-substituent on the amide isomerism in peptidyl-prolyl analogues. The rigid bicyclic skeleton of 2,4-methanoprolines allowed us to follow the through-bond impact of the substituent group (electronic effect) without the side-chain conformation being affected by a stereoelectronic effect. These proline analogues were prepared by [2 + 2] photocycloaddition of (2-allylamino)­acrylic acid derivatives. Subsequent p<i>K</i>_a studies demonstrated a remarkable electronic effect of the 4-fluorine substitution, while the effect of the 4-methyl group was negligible. The <i>trans</i>/<i>cis</i> amide ratio was measured in model compounds under low temperature conditions. The observed prevalence for a <i>trans</i>-amide is extraordinary, and in this regard, 2,4-methanoproline is closer to primary α-amino acids than to proline. At the same time the amide rotation velocities were 3−4 orders of magnitude ​higher when compared to <i>N</i>-acetylprolyl. Finally, our results indicate that the electronic effect of the 4-substituent only affects the kinetics of the amide isomerization but not the thermodynamic prevalence for the <i>trans</i>-rotamer

Design and Synthesis of Novel ¹⁹F‑Amino Acid: A Promising ¹⁹F NMR Label for Peptide Studies

Novel aliphatic ¹⁹F-substituted amino acid was designed as a ¹⁹F NMR label for peptide studies. The synthesis was performed in 11 steps and 9% overall yield from a commercially available starting material. The key transformation was a decarboxylative fluorination of an aliphatic carboxylic acid with XeF₂ in C₆F₆

Incorporation of <i>cis</i>- and <i>trans</i>-4,5-Difluoromethanoprolines into Polypeptides

Substituted prolines exert diverse effects on the backbone conformation of proteins. Novel difluoro-analogues were obtained by adding difluorocarbene to N-Boc-4,5-dehydroproline methyl ester, which gave the <i>trans</i>-adduct as the sole product with 71% yield. Upon cleavage of the N-protection group the free amino acid decomposed rapidly. Its incorporation into the proline-rich cell-penetrating “sweet arrow peptide” was thus accomplished using a dipeptide strategy. Two building blocks, containing either <i>cis</i>- or <i>trans</i>-4,5-difluoromethanoproline, were obtained by difluorocyclopropanation of the aminoacyl derivatives of 4,5-dehydroproline. The resulting dipeptides were stable under standard conditions of Fmoc solid phase peptide synthesis and, thus, suitable to study conformational effects

Unexpected Reactivity of Trifluoromethyl Diazomethane (CF₃CHN₂): Electrophilicity of the Terminal N‑Atom

After more than 70 years since its discovery, CF₃CHN₂ was found to possess a novel reactivity mode: <i>N</i>-terminal electrophile. With <i>C</i>-nucleophiles it gives hydrazones that are easily transformed into valuable CF₃-heterocycles

Design, Synthesis, and Characterization of SO₂‑Containing Azabicyclo[3.<i>n</i>.1]alkanes: Promising Building Blocks for Drug Discovery

A set of novel SO₂-containing azabicyclo­[3.<i>n</i>.1]­alkanes has been synthesized by the double-Mannich annulation of of the corresponding monocyclic S-ketones. These compounds have been rationally designed as 3D-shaped, conformationally restricted SO₂-containing building blocks for drug discovery

Photochemical Synthesis of 3‑Azabicyclo[3.2.0]heptanes: Advanced Building Blocks for Drug Discovery

We have developed a rapid two-step synthesis of substituted 3-azabicyclo[3.2.0]­heptanes which are attractive building blocks for drug discovery. This new method utilizes very common chemicals, benzaldehyde, allylamine, and cinnamic acid, via intramolectular [2+2]-photochemical cyclization

Silver(I) and Copper(I) Adducts of a Tris(pyrazolyl)borate Decorated with Nine Trifluoromethyl Groups

Silver and copper ethylene adducts and the silver carbonyl complex of the tris­(pyrazolyl)­borate [HB­(3,4,5-(CF₃)₃Pz)₃]⁻ (which is based on one of the most acidic pyrazoles known) have been synthesized. ¹³C NMR resonance signals of metal-bound ethylene carbon atoms of [HB­(3,4,5-(CF₃)₃Pz)₃]­Ag­(C₂H₄) and [HB­(3,4,5-(CF₃)₃Pz)₃]­Cu­(C₂H₄) appear at δ 111.6 and 94.9, respectively. The CO stretching frequency of the silver adduct [HB­(3,4,5-(CF₃)₃Pz)₃]­Ag­(CO) is significantly higher than that of free CO, but it appears at a region less sensitive to the ligand electronic effects of tris­(azolyl)­borate silver adducts

Sulfonyl Fluorides as Alternative to Sulfonyl Chlorides in Parallel Synthesis of Aliphatic Sulfonamides

Two types of aliphatic sulfonyl halides (Cl versus F) were compared in parallel synthesis of sulfonamides derived from aliphatic amines. Aliphatic sulfonyl fluorides showed good results with amines bearing an additional functionality, while the corresponding chlorides failed. Both sulfonyl halides were effective in the reactions with amines having an easily accessible amino group. Aliphatic sulfonyl chlorides reacted efficiently with amines bearing sterically hindered amino group while the corresponding fluorides showed low activity

A One-Pot Parallel Reductive Amination of Aldehydes with Heteroaromatic Amines

A parallel reductive amination of heteroaromatic amines has been performed using a combination of ZnCl₂–TMSOAc (activating agents) and NaBH­(OAc)₃ (reducing agent). A library of diverse secondary amines was easily prepared on a 50–300 mg scale

Fluorinated Aliphatic Diazirines: Preparation, Characterization, and Model Photolabeling Studies

The previously unknown difluoromethyl diazirines and the previously neglected trifluoromethyl-aliphatic diazirines were synthesized and characterized. Model photolabeling experiments and biological studies showed that these compounds could indeed be used as photoaffinity labels