Marlon R. Lutz, E. Ernst, M. Zeller
Aug 22, 2018
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Influential Citations
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Journal
European Journal of Organic Chemistry
Abstract
Chirabite-AR was employed to differentiate enantiomers of the axially chiral cyclotriveratrylene (CTV)-derived macrocyclic lactam with baseline separation of most of the proton NMR resonances enabling enantiomeric purity determination of this supramolecular scaffold. Attachment of menthyloxy acetic acid as a chiral auxiliary to the CTV-Beckmann derived lactam afforded diastereomers that were enriched to a ratio of 87:13, as confirmed by both 1H NMR and single-crystal X-ray diffraction. Basic hydrolysis of the enriched diastereomeric mixture proceeded with rapid bowl inversion to yield racemic CTV-lactam as confirmed by Chirabite-AR NMR analysis. Density functional theory (DFT) calculations (M06 2X /6-31G*) were performed on the crown and saddle conformers of the CTV-lactam. Introduction Chiral cyclophanes have applications in enantiodiscrimination processes including catalysis, recognition and sensing, determination of enantiomeric excess, and signaling chiral information of guests,[1, 2] as with chiral molecular tweezers that exhibit selective binding and chiral recognition of specific guests.[3] Cyclotriveratrylene (CTV, 1)[4] is a natural product and was first isolated from the bark of Zanthoxylum conspersipunctatum found in New Guinea.[5] CTV and its [1.1.1]cyclophane congeners in their rigid crown conformation are unique bowl-shaped molecules that have applications in sensors, self-organized materials, liquid crystals, and metallosupramolecular chemistry.[6] CTV and its cryptophane derivatives are of great interest in molecular recognition.[7] They are members of a larger family of inherently axially chiral concave molecules that have applications in chiral recognition and asymmetric synthesis.[2] A chiral CTV derivative bearing Kemp’s triacid was shown to induce triple helix formation of collagen peptides.[8] A dynamic thermodynamic resolution strategy was recently reported of racemic CTV units by addition of remote stereogenic centers.[9] Helically chiral CTV units have been employed to construct enantiopure molecular cages,[10] along with a host of elegant CTVderived coordination cages.[11] Some of the fascinating supramolecular structures of selfassembled cages derived from CTV-type scaffolds have recently been reviewed,[12] such as a racemic C3-symmetric bipyridyl-bearing CTV ligand with zinc shown to self-assemble into triply interlocked chiral catenanes within an overall chiral crystal.[13] CTV-based host compounds bearing three binaphthol moieties have been reported as chiral sensors with recognition of sugar derivatives.[14] The crown form of cyclotriveratrylene can undergo umbrella inversion that inverts chiral derivatives into their enantiomeric counterpart, as Collet demonstrated by observing the slow racemization of structurally chiral cyclotriveratrylene derivatives.[15] Resolution and NMR studies have been performed on the crown and saddle conformers of a CTV derivative toward chiral liquid crystals.[16] While most work with CTV has focused on peripheral functionalization, we have focused on apical functionalization, enabling attachment of CTV “bowl-out” receptors on surfaces,[17] including desymmetrized C1-symmetric derivatives that are also of interest.[18] The parent 9membered cyclophane 1 (Figure 1) is under ambient conditions locked into the bowl-shaped crown conformer. Elegant high temperature melt and quench experiments by Zimmerman first enabled isolation of the saddle conformer of CTV.[19] In contrast, the corresponding CTV monoketone 2 exists exclusively as the saddle conformer,[4] and resolves upon crystallization in a chiral conformation, as a racemic mixture of enantiomerically pure chiral crystals.[20] We discovered that the corresponding oxime 3 exists as a slowly equilibrating mixture of crown and saddle conformers that are separable,[21] and reported the kinetics and thermodynamics of their interconversion.[20] Furthermore, oxime 3 undergoes facile Beckman rearrangement to afford the macrocyclic lactam 4[22] which is axially chiral and thus potentially resolvable into its atropisomers. Current interest in synthetic macrocyclic receptors includes applications in chiral analysis and separation,[23] as well as in supramolecular chirality in self-assembled systems.[24] Ema has developed chiral selectors with multiple H-bonding sites in macrocyclic cavities[25-27] including the commercially available Chirabite-AR. While the macrocycle of CTV-lactam 4 contains a larger 10-membered ring, amide resonance[28] reduces flexibility through restricting rotation around the carbonyl C-N bond. We were interested if Chirabite-AR, which is designed for determining the enantiomeric purity of small molecules that can ideally be contained within its macrocycle, might be usable to determine the enantiomeric purity of larger supramolecular axially chiral scaffolds such as CTV-derived lactam 4. Furthermore, we addressed the possibility that lactam 4 might be resolvable via attachment of a chiral auxiliary through N-functionalization of lactam 4, given its ability[29] to undergo acylation in high yield to imide derivative 5. MeO OMe MeO MeO OMe OMe