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 CDCl. Binding constants ( K) determined in CDCl by NMR titrations indicated that ( R)-1d was the most enantioselective ( K( S)/ K( R) = 5.4). Interestingly, the K 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).

Synthesis ofα‐Hydroxyphosphonates Containing Functionalized 1,2,3‐Triazoles

“…Among the tested solvating agents, only the Kagan's amide ( C4 ) resulted in a good discrimination of the 3 a enantiomers by 1 H NMR and 31 P‐{ 1 H} NMR experiments (Figures S56 and S57). This chiral amide derived from 3,5‐dinitrobenzoic acid, called Kagan's amide, is one of the oldest and well‐studied CSA, being non‐hygroscopic, stable, and effective for chiral discrimination of different organic structures in mild conditions [83–86] . Additionally, the use of harsh conditions could provide the formation of oxidation‐byproducts derived from the α ‐hydroxyphosphonate degradation, [87–88] as observed when the reaction was carried out for longer periods.…”

Efficient Enantiodifferentiation of Carboxylic Acids Using BINOL-Based Amino Alcohol as a Chiral NMR Solvating Agent

“…The chiral binaphthyl units and multiple hydrogen bonding sites containing hydroxyl, or amino groups, can provide an excellent candidate for chiral receptor sensors development (Yu and Pu, 2015;Pu, 2017), especially, they are broadly applicable CSA. For instance, commercially available (R)-or (S)-BINOL and derivatives as chiral-solvating agents to assign the enantiomeric excess (ee) of enantiomeric hydroxy carboxylic acids, synthetic drugs, natural alkaloids, or flavanones via 1 H NMR spectroscopy (Ardej-Jakubisiak and Kawecki, 2008;Freire et al, 2008;Klika et al, 2010;Redondo et al, 2010Redondo et al, , 2013Chaudhari and Suryaprakash, 2013;Mishra et al, 2014;Yuste et al, 2014;Borowiecki, 2015;Du et al, 2015;Yi et al, 2016;Monteagudo et al, 2017) and bifunctional BINOL-macrocycles containing diacylaminopyridine moieties were developed by Ema et al (2007Ema et al ( , 2008Ema et al ( , 2018; BINOL-derived disulfonimide extends the concept of CSA sensing to chiral recognition of O-heterocycles (Couffin et al, 2014); the crownophane and strapped calix[4]pyrrole containing built-in chiral BINOL were used for the enantioselective recognition of chiral amines and carboxylate anions, respectively (Tokuhisa et al, 2001;Miyaji et al, 2007). Chiral BINOL Brönsted acids were selected for determination of various indoloquinazoline alkaloid-type tertiary alcohols and various 3-arylquinazolinones (Liu et al, 2017;Wu et al, 2018), binaphthalene skeleton ureas as sensor for scanned various sulfoxides, phenylethanol, and arylpropanoic acids (Holakovský et al, 2015;Curínová et al, 2018Curínová et al, , 2019.…”

Chiral Tetraaryl‐ and Tetraalkynylborates as Chiral Solvating Agents for Tetraalkylammonium Salts

“…Frequently, the UV‐active substituent is introduced by further synthetic transformations of the chiral compounds. Consequently, developments of chiral solvating agents such as chiral acids, metal complexes, and cyclic receptors have been studied to allow the determination of ee by NMR analysis, even in the absence of a UV‐active substituent, …”