Conformational Study of N,N′-Diacyl Bispidines and Dioxo Bis-bispidines: Planar Chirality and Molecular Switching

Abstract

N,N'-Diacyl bispidines exhibit chirality in the absence of a chiral center and axis. Conformational analysis indicates planar chirality in the molecular structure as a result of open-ended chiral planes, which has been confirmed by X-ray diffraction studies. Substantial chiral-achiral molecular switching is observed in di(haloacetyl) bispidines upon changing the solvent polarity. Tethering the chiral planes with a bispidine linker alters the planar chirality significantly and renders the resulting bis-bispidine macrocycles achiral.

Bispidine Platform as a Tool for Studying Amide Configuration Stability

“…At the same time, the anti-form would be more stable in less polar solvents and, presumably, in the crystal form since the crystallization of molecules with a smaller dipole moment is more preferable. A CSD search returns 19 structures of bispidine-based bisamides (tricyclic compounds of the cytisine type are excluded) [16][17][18][19][20][21][22][23][24][25], out of which only 3 possess a syn-conformation in the crystal, and all belong to macrocyclic molecules containing two bispidine fragments [13,20,23].…”

“…N,N′-Diacyl bispidines have found various different applications in: medicinal chemistry [26] (a review), [27,28]; crystal engineering [29]; macroheterocycle synthesis [13,[18][19][20]23,[29][30][31]; secondary structure nucleators in peptides [22,32]; conformational switching [12,13]; lipid bilayer modifiers [15,33].…”

“…. C separations found in published papers on bispidine bis-amides range from 3.041 [14] to 4.696 Å [13] (here, we compare only the C . .…”

“…They also established the dependence of the syn/anti ratio on the polarity of the solvent (solvents such as CCl 4 , CDCl 3 , (CD 3 ) 2 CO, (CD 3 ) 2 SO, (CD 3 ) 2 CO/CD 3 OD, CD 3 OD, CD 3 OD/D 2 O, and D 2 O were used). Wang et al called the anti/syn interchange a "chiral-achiral switch" since, in the case R1 = R2 (see Scheme 2), the anti-form possesses C2 symmetry and thus should be chiral, whilst the syn-form has a symmetry plane and is therefore achiral [13]. They also pointed out that incorporation of 3,7-diacylbispidine in a medium-sized macrocycle could affect the total symmetry of the molecule.…”

“…The equilibrium constant for anti/syn interconversion strongly depends on the nature of the solvent: in more polar solvents, the syn-form predominates since it possesses a higher dipole moment compared to the anti-form [12][13][14]. It should be noted here that the presence of a metal ion in a solution could strongly affect the resulting syn/anti ratio towards the prevalence of the syn-form due to chelation of a metal center by two oxygen atoms, which are in close proximity in the syn-form [12,15].…”