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Cross-Coupling Approach to an Array of Macrocyclic Receptors Functioning as Chiral Solvating Agents

Ema, Tadashi, Yamasaki, Takayuki, Watanabe, Sagiri, Hiyoshi, Mahoko, Takaishi, Kazuto
Journal of organic chemistry 2018 v.83 no.18 pp. 10762-10769
Suzuki reaction, crystal structure, enantioselectivity, hydrogen bonding, moieties, nuclear magnetic resonance spectroscopy, organic compounds, receptors
Chiral macrocyclic receptors 1 with multiple hydrogen-bonding sites in the cavity were synthesized and used as NMR chiral solvating agents (CSAs). The Suzuki–Miyaura cross-coupling reaction gave rapid access to a series of variants 1b–p of unsubstituted parent compound 1a. Among them, 1d with the 4-cyanophenyl group at the 3,3′-positions of the binaphthyl moiety was the most excellent CSA for a benchmark analyte compound, 2-chloropropionic acid (CPA); both of the quartet and doublet signals of CPA were split most completely in CDCl₃. Binding constants (Kₐ) determined in CDCl₃ by NMR titrations indicated that (R)-1d was the most enantioselective (Kₐ(S)/Kₐ(R) = 5.4). Interestingly, the Kₐ value of (R)-1d for (S)-CPA (5900) was greater than that of (R)-1a for (S)-CPA (3080), which strongly suggests an attractive interaction between the 4-cyanophenyl group of (R)-1d and (S)-CPA. The X-ray crystal structure of 1d indicates that one of the two H atoms meta to the cyano group is directed toward the cavity. DFT calculations suggested that this H atom of the 4-cyanophenyl group of (R)-1d forms a weak hydrogen bond with the Cl atom of (S)-CPA (C–H···Cl–C hydrogen bond).