Additional criterion for the determination of the handedness of 2₁ helices in crystals of bile acids: Crystal structure of a tert‐butylphenyl derivative of cholic acid

Abstract

[3β,5β,7α,12α]-3-(4-t-Butylbenzoilamine)-7,12-dihydroxycholan-24-oic acid was synthesized and recrystallized from chlorobenzene and acetone. Orthorhombic P2(1)2(1)2(1) and monoclinic P2(1) crystals were obtained, respectively, and both crystals include solvent and water molecules with a 1:1:1 stoichiometry. In the second case, there are two nonequivalent molecules of the steroid in the unit cell. In both crystals, a crossing structure results for the molecular packing, stabilized by hydrogen bonds between the steroid molecules. In the second crystal, water links steroid molecules of the same type, which are not directly connected through hydrogen bonds. The steroid molecules define helicoidal assemblies along 2(1) screw axes. The handedness in the crystal in chlorobenzene is unambiguously defined by following the criterion proposed by Miyata et al., as the steroids are in a belly-to-belly disposition around the axis. This motif does not appear in the crystal in acetone, and other criterion is required. On the basis of the fact that a staircase and its banister have the same handedness and using the crystal in chlorobenzene as reference, the additional criterion has been established. According to it, in the absence of a belly-to-belly orientation, the handedness must be defined by keeping the bile acid with its right side oriented toward the axis. Pitch angles of the helices and tilt angles of the molecules are also determined.

A Standard Structure for Bile Acids and Derivatives

“…Chemical structure and numbering of the bile acids (R4 = CO2H), bile acid esters (R4 = CO2CH3), and 24-amino derivatives (R4 = NH2) reviewed in this paper. [11] α-OH α-OH CO2H 13 [12] α-OH α-OH CO2H 14 [13] α-OH α-OH CO2H 15 [14] α-OH α-OH CO2H 16 [15] [11] α-OH α-OH CO2H 13 [12] α-OH α-OH CO2H 14 [13] α-OH α-OH CO2H 15 [14] α-OH α-OH CO2H 16 [15] Table 1. Chemical structure and numbering of the bile acids (R4 = CO2H), bile acid esters (R4 = CO2CH3), and 24-amino derivatives (R4 = NH2) reviewed in this paper.…”

“…Chemical structure and numbering of the bile acids (R4 = CO2H), bile acid esters (R4 = CO2CH3), and 24-amino derivatives (R4 = NH2) reviewed in this paper. [11] α-OH α-OH CO2H 13 [12] α-OH α-OH CO2H 14 [13] α-OH α-OH CO2H 15 [14] α-OH α-OH CO2H 16 [15] Modifications of the functional groups lead to a great number of BS derivatives, some naturallyoccurring. For example, typical modifications of the terminal carboxylic acid group are ester (BE) and amide derivatives, while keto and amine groups are common modifications of the hydroxy groups.…”

Crystal Structure of a Cationic Bile Salt Derivative ([3β,5β,7α,12α]-3-(2-naphthyloylamino)-7,12-dihydroxycholan-24-triethylammonium iodide)

“…The angle between the planes formed by the amide linking group and the naphthyl residue is 16.8 • , a value which is close to the one observed for other aromatic amide derivatives of cholic acid. The values of 17.7 • and 18.2 • have been measured for the t-butylphenyl (recrystallized from chlorobenzene) and p-benzoic acid derivatives [3,25], respectively. On the other hand, the angles between the naphthyl plane and the horizontal and vertical planes [24] of 1 are 61.3 and 30.5 • , respectively.…”

“…However, this is not the case for 1 because the hydrogen bonds that take place cause the connected steroid molecules to adopt another spatial disposition. To resolve the problem of situations like this, an additional criterion was stablished [25] and, according to it, the steroid skeleton must be exposing its right side towards the 2 1 axis. Figure 7 is constructed by taking into account this criterion and from it, right-handedness is deduced.…”

“…Figure 7 is constructed by taking into account this criterion and from it, right-handedness is deduced. The measured value for the angle between the horizontal planes of two consecutive molecules used to define the handedness of a helix allows for the determination of the pitch and the tilt in the helical arrangement around the screw axis [25]. The application of this strategy in 1 affords a pitch angle of 57.1 • and a tilt of 32.9 • .…”