Synthesis and Recognition Properties of Enantiomerically Pure Acyclic Cucurbit[n]uril-Type Molecular Containers Xiaoyong Lu and Lyle Isaacs* Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States * S Supporting Information ABSTRACT: Enantiomerically pure acyclic cucurbit[n]uril containers 1 and 2 were synthesized by the condensation of enantiomerically pure aromatic sidewalls 3b and 4b with glycoluril tetramer 5. Containers 1 and 2 are C 2 -symmetric, feature four arms of the same handedness, and bind to a variety of guests (6-15) in aqueous solution including aliphatic and aromatic ammonium ions, amino acids, dyes, and viologens. The binding constants of hosts 1 Ac and 1 OH toward selected chiral ammonium ions were measured by 1 H NMR and UV/vis spectroscopy. C ucurbit[n]urils (CB[n], Figure 1) are a family 1 of highly symmetric (D nh ) molecular container compounds that feature a hydrodrophobic cavity that is guarded by two symmetry equivalent ureidyl carbonyl portals of highly negative electrostatic potential. 2 CB[n] compounds exhibit remarkable recognition properties toward hydrophobic cations (e.g., alkyl ammonium ions) in water with K a values readily exceeding 10 9 M -1 and also exhibit high levels of selectivity toward structurally similar guests. 3 CB[n] complexes are chemically, electrochemically, and photochemically responsive and have been used therefore as the basis of advanced supramolecular systems including molecular machines, supramolecular materi- als, chemical sensors, drug delivery, gas purification, and (affinity) separations materials. 4 However, because unfunction- alized CB[n] compounds are achiral they are incapable of performing chiral recognition of guest compounds on their own. 5 This is unfortunate, because the high levels of affinity and selectivity exhibited by CB[n] compounds would be expected to translate into high levels of enantioselectivity which could be used to create enantioselective catalysts, sensors, and separations materials. This current limitation of CB[n] synthetic and supramolecular chemistry lead us to ponder how CB[n]-type receptors could be augmented to create enantioselective analogues. Beyond unfunctionalized macrocyclic CB[n], researchers in the field have been synthesizing a variety of CB[n]-type receptors including CB[n] derivatives, 6 hemicucurbit[n]urils, 7 bambus[n]urils, 8 biotin[n]urils, 9 nor-seco-CB[n], 10 and acyclic CB[n]. 11 Macrocyclic CB[n] derivatives are poorly suited for chiral recognition since any substituents are by necessity remote from the binding site. As anion binders, enantiomeri- cally pure hemicucurbit[n]urils, bambus[n]urils, and biotin[n]- urils show potential for the recognition of chiral organic acids. Specifically, enantiomerically pure cyclohexylhemicucurbit[6]- uril has already been shown to bind more strongly to (R)- methoxyphenyl acetic acid (27 M -1 versus 20 M -1 for S) in CDCl 3 . 7b Previously, we have shown that (±)-bis-ns-CB[6] forms complexes with amino acids in water with up to 7:1 diastereoselectivity and affinity up to 10 5 M -1 . 10b In recent years, we have been investigating the preparation of acyclic CB[n] (e.g., M1 and derivatives, Figure 1), their molecular recognition properties in water, and their use as solubilizing agents for insoluble drugs and as agents to reverse neuro- muscular block in vivo. 11c,d,g Container M1 and its derivatives consist of a central glycoluril tetramer to impart a C-shape, aromatic sidewalls to allow it to engage in π-π interactions with guests, and sulfonate-terminated arms to enhance aqueous solubility. In this paper, we explore the synthesis and molecular recognition properties of enantiomerically pure acyclic CB[n] containers 1 and 2. For the preparation of enantiomerically pure acyclic CB[n]- type containers, we decided to utilize aromatic sidewalls containing enantiomerically pure arms. Scheme 1 shows the synthesis of 3b and 4b. Alkylation of hydroquinone or 1,4- dihydroxynaphthalene with enantiomerically pure epichlorohy- drin yields 3a and 4a in moderate yields, respectively. Subsequently, reduction of 3a and 4a with LiAlH 4 delivers sidewalls 3b and 4b in high yield. Received: July 7, 2015 Figure 1. Cucurbit[n]uril and acyclic CB[n]-type containers. Letter pubs.acs.org/OrgLett © XXXX American Chemical Society A DOI: 10.1021/acs.orglett.5b01948 Org. Lett. XXXX, XXX, XXX-XXX