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

Abstract

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).