Aromatic architecture. Use of the N-methylamide structure as a molecular splint

Abstract

The stereochemical alteration caused by N-methylation of an aromatic amide structure is an efficient means of changing the biological activity of a molecule, as we have found during the drug design of synthetic retinoids' and synthetic cytokinins.1 2 N-Methylbenzanilide (1) exists predominantly in a cis amide conformation in solution and in the crystal, while benzanilide (2) exists in a trans conformation.3 Though the cis conformation is superficially less favorable, this seems a rather common phenomenon intrinsic to aromatic /V-methylamides. The cause of this real stabilization of the cis structure is unclear and is under study. The cis preference can be used for the fixation of a molecule in a shape that seems less favorable from simple stereochemical considerations. In this paper, we present some examples of molecular construction by using an /V-methylamide structure as a splint or a scantling in a molecule.

Heavily Substituted Atropisomeric Diarylamines by Unactivated Smiles Rearrangement of N‐Aryl Anthranilamides

“…[4a, 5] Expecting similar steric demands in atropisomeric diarylamines,w es ought synthetic methods allowing the construction of ArÀNb onds between 2,6disubstituted anilines 7 and 2,6-disubstituted coupling partners 8 (Scheme 1). N-Methylated benzanilides related to 5 prefer conformations in which the aryl rings lie cis, [19] and anthranilamide 5a was made to test the possibility that intramolecular N-arylation might proceed in such ac ompound by Smiles rearrangement, even of an unactivated ring. [14] Thec lassical Smiles rearrangement proceeds by intramolecular S N Ar: [13,15] an activated, electron-deficient aryl ring migrates from OorSto N, with the heteroatoms in a1,4- [11a-c,15d] or 1,5-relationship.…”

Functional foldamers that target bacterial membranes: The effect of charge, amphiphilicity and conformation

“…[20][21][22][23] In such a case the conformation can be determined by either 1 H NMR (solution state conformation), as evidenced by a diagnostic upfield shift in the aromatic signals, or by obtaining the X-ray crystal structures to determine the conformation in the solid state. 24 The consequence of achieving such conformational control by simple N-substitution has been studied in a number of applications, not least: for facilitating conformational communication via stereogenic axes; 25 for controlling oligourea helicity; 26,27 for designing promising anticancer and anti-bacterial agents; [15][16][17]28 as a molecular splint; 29 for carrying out a so-called 'impossible' macrocyclisation; 30 and for the development of fluorescent sensors. 31 Another way to potentially exploit this conformational switch is to prepare and evaluate compounds, which as a result, differ in their molecular dimensions and functionalities, such that activity can be studied and apportioned to the individual properties of interest in both the trans and cis forms, in this case their ability to lyse bacterial membranes; it is assumed that the pKa of the compounds being prepared, and thus their protonation state in the assay media, would be the same for both conformations.…”

Racemic α,α'-o-Xylylene-1,1'-bis[(3,5-dimethyl-5,6-dihydro-1,3,5-triazine-6-spiro-9'-fluorene)-2,4(1H,3H)-dione]

“…Interactions between aromatic moieties have been postulated as important factors in protein stabilization (Burley & Petsko, 1985). Stabilizing non-covalent interactions between aromatic moieties have been observed in cis-1,4-dihydro-4-tritylbiphenyl and its 4'-bromo derivative (Grossel, Cheetham, Hope & Weston, 1993), dibenzodiazocine esters (Paliwal, Geib & Wilcox, 1994) and a trianilide derivative (Yamaguchi et al, 1991). Calculations aimed at understanding interactions between aromatic rings suggest that benzene rings favor a slightly tilted T-shaped edge-to-face aromatic interaction, with a centroid--centroid distance of 5.5 A (Jorgensen & Severance, 1990).…”