Conformational preference in aromatic amides bearing chiral ortho substituents: its origin and application to relayed stereocontrol

Abstract

Tertiary aromatic amides bearing stereogenic centres ortho to the amide group may adopt two diastereoisomeric conformations which interconvert slowly on the NMR timescale at ambient temperature, and are therefore detectable by NMR. Certain classes of stereogenic centre--particularly sulfoxides, ephedrine-derived oxazolidines, and proline-derived imidazolidines--strongly bias the population of the two conformers. We propose a model, supported by molecular mechanics calculations, which rationalises the sense and magnitude of the conformational selectivity attained in terms of the steric and electronic properties of the controlling centre. The control over conformation may be exploited either by trapping the favoured conformer as an atropisomer, or by using it to relay information about the stereochemistry of the controlling centre.

Diastereoselective synthesis of atropisomers containing two non-biaryl stereogenic axes: stereochemical relay through stereogenic centres in dihydrostilbene-2,2′-dicarboxamides

“…Comparable imines 15 8 have showed an apparently hydrogenbond directed conformational preference for the isomer shown here as conformer A. 8 However, in compounds 13 and 14 the alkyl substituent at the NHMe-bearing stereogenic centre is significantly larger than the R = methyl or n-butyl group of 15. In the X-ray crystal structure of 14 (Fig.…”

“…A stereogenic amide axis can both control 1-5 and be controlled by 6-8 a nearby stereogenic centre, 9 and in an accompanying publication 8 we reported the details of how relayed stereocontrol may result from combining these two features of amide stereochemistry: a stereogenic axis controls the conformation of the amide, which in turn controls the formation of a new stereogenic centre. In this paper we show that it is also possible to combine these two aspects of stereochemical control in reverse order, i.e.…”

“…5, 14 That centre bears an NHMe group, which we know to be at least moderately effective in governing the conformation of an adjacent atropisomeric amide. 8 We therefore chose to use the addition of laterally lithiated amides 1 and 2 to 2-amidobenzaldimines 9-12 to investigate the potential of an axis-to-axis stereochemical relay.…”

Interrogation of the Structure–Activity Relationship of a Lipophilic Nitroaromatic Prodrug Series Designed for Cancer Gene Therapy Applications

“…Analytical HPLC and 1 H NMR analyses of compounds 2-4 demonstrated that they exist as a mixture of atropisomers [24] at ambient temperature. A well-described phenomena for tertiary aromatic amides bearing an ortho substituent wherein the aromatic ring and the amide plane are near perpendicular [25,26]. Hindered rotation about the amide bond results in two conformations that can interconvert slowly on an NMR timescale at ambient temperature and are hence detectable by NMR and characterized by chemical exchange effects in NMR experiments [27][28][29].…”

Frozen Chirality of Tertiary Aromatic Amides: Access to Enantioenriched Tertiary α‐Amino Acid or Amino Alcohol without Chiral Reagent

“…For our MOC synthesis, we wanted to use the dynamic axial chirality of tertiary aromatic amides . This chirality relies on the fact that the rotation around the Ar−CO bond (and around the N −CO bond) is slow, and that the compound is not planar around this bond (due to steric hindrance, the dihedral angle can be close to 90°).…”