Synergistic n → π* and nN → π*Ar interactions in C-terminal modified prolines: effect on Xaa-Pro cis/trans equilibrium.

Carbonyl-carbonyl (CO⋯CO) n → π* interaction often coexists with a hydrogen bond (HB) or another n → π* interaction. Although the interplay between HB and n → π* interaction was previously studied, there is no systematic investigation that shows a synergistic relationship of n → π* with another noncovalent interaction. Herein, we have studied a set of proline-diacylhydrazine (Pro-DAH) molecules and observed that increase in the strength of the nN → π*Ar interaction on their DAH side strengthened the n → π* interaction on the Pro side, which was experimentally determined by measuring the Ktrans/cis of the Xaa-Pro amide bond. Overall, we describe a simple C-terminal modification strategy to stabilize the trans-Pro geometry that could be useful to stabilize PPII helices and collagen triple helices that require Pro to adopt the trans amide geometry.

nN → π*Ar interactions stabilize the E-ac isomers of arylhydrazides and facilitate their SNAr autocyclizations.

We describe a novel mechanism of stabilization of the E-ac isomer of an arylhydrazide via nN → π*Ar interactions. We further show that when a leaving group (F) is present at the ortho-position of the carbonyl group of such an arylhydrazide, the nN → π*Ar interaction facilitates an SNAr autocyclization reaction to produce indazolone, an important heterocycle with biological activity. Faster autocyclization of arylhydrazide is observed when an electron withdrawing group is present in the aryl ring, which is a characteristic of SNAr reactions.

Stabilization of Azapeptides by Namide···H-Namide Hydrogen Bonds.

An unusual Namide···H-Namide hydrogen bond (HB) was previously proposed to stabilize the azapeptide ß-turns. Herein we provide experimental evidence for the Namide···H-Namide HB and show that this HB endows a stabilization of 1-3 kcal·mol-1 and enforces the trans-cis-trans (t-c-t) and cis-cis-trans (c-c-t) amide bond conformations in azapeptides and N-methyl-azapeptides, respectively. Our results indicate that these Namide···H-Namide HBs can have stabilizing contributions even in short azapeptides that cannot fold to form ß-turns.

Evidence of an nN(amide) → π*Ar Interaction in N-Alkyl-N,N'-diacylhydrazines.

1,2-Dibenzoyl-1-tert-butylhydrazine (RH-5849) and related N-alkyl-N,N'-diacylhydrazines are environmentally benign insect growth regulators. Herein, we show that an unusual nN(amide) → π*Ar interaction mediated by a hydrazide amide nitrogen atom plays a crucial role in stabilizing their biologically active trans-cis (t-c) rotameric conformations. We provide NMR and IR spectroscopic evidence for the presence of these interactions, which is also supported by X-ray crystallographic and computational studies.

Conformational control of N-methyl-N,N'-diacylhydrazines by noncovalent carbon bonding in solution.

In recent years, some X-ray structural and computational evidence has emerged for noncovalent carbon bonding (C-bond). However, evidence of C-bonds in solution is limited. Herein, from the conformational analyses of strategically designed N-methyl-N,N'-diacylhydrazines, we for the first time show that C-bonds can be modulated to control the conformational preferences of small molecules in solution. We show that unusual N(amide)C-X noncovalent carbon bonding interactions stabilize the trans-cis (t-c) amide bond rotamers of N-methyl-N,N'-diacylhydrazines over the expected trans-trans (t-t) rotamers.

Solid-Phase Synthesis of Hybrid 2,5-Diketopiperazines Using Acylhydrazide, Carbazate, Semicarbazide, Amino Acid, and Primary Amine Submonomers.

We report the solid-phase synthesis of N,N'-di(acylamino)-2,5-diketopiperazine, an acylhydrazide-based conformationally rigid 2,5-DKP scaffold having exocyclic N-N bonds. We also show that different combinations of acylhydrazides, carbazates, semicarbazides, amino acids, and primary amines can be used to synthesize a highly diverse collection of hybrid DKP molecules via the solid-phase submonomer synthesis route. Finally, we show incorporation of a methyl substituent in one of the carbon atoms of the DKP ring to generate chiral daa- and hybrid-DKPs without compromising the synthetic efficiency.