Spherical Amides with C3 Symmetry: Improved Synthetic Approach and Structural/Optical Analysis

Abstract

A spherical amide with C₃ symmetry was synthesized by a one-step cyclization reaction using triphenylphosphine and hexachloroethane as coupling reagents. This method enabled synthesis of N-benzyl and N-allyl derivatives, which could not be obtained by the previously reported method. The optical resolution of each compound was measured, and their electronic circular dichroism spectra revealed that they were mirror images. The high structural symmetry resulted in a higher Δε (molar absorption difference against right or left circular polarization: ε_L - ε_R value compared to that of another structural isomer synthesized previously. The absolute structure of the enantiopure crystal of the N-benzyl derivative was determined using the Flack parameter obtained by X-ray crystallographic analysis.

Keywords: chiral macrocycle; cyclic amide; molecular scaffold; organic cage.

Figure 1

(a) Equilibrium of racemization of m-calix[3]amide. When m-calix[3]amide and a benzene ring are connected through amide bonds, spherical molecule 1, in which the racemization is suppressed, is obtained. (b) Four structural isomers (1–4) of the spherical amide. Each component is colored as follows. a: Red: trimesic acid; b: green: 3,5-bis(alkylamino)benzoic acid; c: black: 3-(alkylamino)isophthalic acid; d: blue: 1,3,5-tri(alkylamino)benzene. R: alkyl group.

Figure 2

Synthetic routes to spherical amide 1 [37].

Scheme 1

Synthesis of isomer 1 with ethyl groups (1a).

Scheme 2

Synthesis of monomer (a) 8b: N-benzyl and (b) 8c: N-allyl.

Scheme 3

Synthesis of spherical amide 1b and 1c.

Figure 3

¹H NMR spectrum of 1b. The benzene or benzyl units in the structure are indicated as follows. Red: trimesic acid (core); green: 3,5-diamino benzoic acid (core); pink: N-benzyl groups at the side; blue: N-benzyl groups at the bottom.

Figure 4

ECD spectra of 1a (N-ethyl), 1b (N-benzyl), and 1c (N-allyl) in acetonitrile solution. The sign of (+) or (−) was determined by optical rotation at 589 nm in acetonitrile solution.

Figure 5

Comparison of ECD spectra of (a) 1a and 2a (N-ethyl), (b) 1b and 2b (N-benzyl), and (c) 2a and 2b in acetonitrile solution. (d) UV absorption spectra of the same compounds in acetonitrile solution.

Figure 6

Crystal structures of chiral (+)-1b. (a) Molecular structure. (b) Superimposed structures. Pink: molecule A with benzene rings numbered C1–C6; pale blue: molecule B with benzene rings numbered C101–C106.

Figure 7

Molecular arrangements in the crystals of (+)-1a (R = Et, CCDC code: LOJMIH) and (+)-1b (R = Bn). (a) Crystal structures of (+)-1a. The view is along the a axis. Green: molecule C; pale green: molecule D. (b) Crystal structures of (+)-1b. The view is along the c axis. Pink: molecule A; pale blue: molecule B.