Combinatorial synthesis of modular chiral cyclophanes

A cationic chiral cyclophane was synthesized and studied as a host for chiral and racemic π-donor molecules. The cyclophane host has a rigid binding cavity flanked by (S)-(valine-leucine-alanine) and N,N′-dibenzyl-4,4′-bipyridinium subunits, which allow for hydrogen-bonding and π-stacking interactions with included aromatic guest molecules. 1 H NMR binding titrations were performed with several different pharmaceutically interesting guest molecules including β-blockers, NSAIDs, and amino acids and amino acid derivatives. The host-guest complexation constants were generally small for neutral and cationic guests (0-39 M -1 at 20 °C in water/acetone mixtures). However, a (R)/(S) enantioselectivity ratio of 13 ( 5 was found for DOPA, a strongly π-donating cationic guest. Two-dimensional NOESY 1 H NMR spectra confirm that (R)-DOPA binds inside the cavity of the host and that there is no measurable interaction of the cavity with (S)-DOPA under the same conditions.

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“…Several groups − have now incorporated chiral amino acids into cyclophane hosts. There are three significant advantages to this approach.…”

Section: Introductionmentioning

confidence: 99%

“…In related work, we recently prepared a small combinatorial library of dipeptide-containing cyclophanes. The affinity of those cyclophanes for chiral guests was unfortunately too low for combinatorial screening of their host−guest interactions …”

Section: Introductionmentioning

confidence: 99%

Chiral Molecular Recognition in a Tripeptide Benzylviologen Cyclophane Host

et al. 1998

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“…The quest for highly enantioselective materials primarily for use in chiral chromatography is an active area of research.Typical methodologies involve structure-based design and empirical modification of known chiral selector molecules . In this paper, we describe a new approach that involves the parallel synthesis and screening of a combinatorial library of potential chiral selectors on polystyrene synthesis beads . Our screen allows picking the most enantioselective library member beads by visual inspection under a low-power microscope.…”

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confidence: 99%

Enantioselective Resolving Resins from a Combinatorial Library. Kinetic Resolution of Cyclic Amino Acid Derivatives

1998

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Solid materials that bind small molecules enantioselectively are valuable as resolving agents in chiral separations. Coupled with modern HPLC, even modestly enantioselective materials (e.g., with separation factors (R) as low as 1.1) are commonly used to resolve small organic compounds. 1,2 While such methods work well for analytical resolutions, large-scale chromatographic resolutions are often less practical. 3 If however a tightly binding and highly enantioselective (e.g., R g 10) resin or other solid material were readily available, then it would be possible to resolve compounds by simply stirring the racemate with such a resin and filtering. 4 The quest for highly enantioselective materials primarily for use in chiral chromatography is an active area of research.Typical methodologies involve structure-based design and empirical modification of known chiral selector molecules. 5 In this paper, we describe a new approach that involves the parallel synthesis and screening of a combinatorial library of potential chiral selectors on polystyrene synthesis beads. 6 Our screen allows picking the most enantioselective library member beads by visual inspection under a low-power microscope. We demonstrate the feasibility of this approach by making and screening a small (60member) combinatorial library of potential resolving resins and showing that enantioselective library members can be readily distinguished and used in a heterogeneous kinetic resolution process that corresponds to resolution by filtration.An Enantioselectivity Screen. To find the most enantioselective members of our chiral selector library, we developed a simple two-color differential binding screen that allows us to estimate the enantioselectivity of each library member visually. 6c,7 The screen employs enantiomeric probe molecules that are labeled with different colored dyes. In this work, we were seeking chiral selectors for resolving amino acid derivatives and suitable probes thus included the blue L-amino acid L-1 and the red D-amino acid D-1.The idea was to treat an equimolar mixture of these colored probe molecules with a library of chiral selectors on synthesis beads in which each bead carried a different selector. The result of such an experiment would be that highly enantioselective binding would yield beads that were red or blue whereas unselective binding would yield beads that were brown. 8The particular probes we used are shown above as 2 and 3. The commercially available Disperse Blue and Red dyes (bound to LPro and DPro derivatives respectively) we used were chosen to be visually distinct and not significantly bound by our selector library members. We also varied linkers (here succinyl and isophthaloyl) connecting the dye labels to the proline derivatives we wished to resolve.A Chiral Selector Library. For our library of chiral selectors, we prepared a library of chiral amines whose members could react with and bind to probes 2 or 3 either by acylation or salt formation, respectively. To promote significant enantioselectivity in the...

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“…Electron deficient systems based on diquat and paraquat have been also instrumental as building blocks for supramolecular chemistry, as well as in the design of electron‐transfer systems . Diquats have helical geometry but typically insufficient configurational stability to allow studies of the two separate enantiomers with opposite helicity (Scheme a, Δ G ≠ theor =37 kJ mol −1 at 20 °C) . In spite of the great general usefulness of diquats, no examples with comfortable configurational stability have been recognized.…”

Section: Methodsmentioning

confidence: 99%

Diquats with Robust Chirality: Facile Resolution, Synthesis of Chiral Dyes, and Application as Selectors in Chiral Analysis

Talele

Koval

Severa

et al. 2018

Chemistry A European J

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Diquats with extremely high racemization barriers with ΔG of 233 kJ mol at 180 °C are described. Reported configurational robustness is due to a combination of two structural features: the rigid o-xylylene tether connecting the nitrogen atoms and the presence of two substituents in the bay region of the bipyridinium scaffold. The straightforward synthesis of diquats, plus facile resolution and derivatization make them attractive for chiral application studies. This is demonstrated by: 1) synthesis of the first non-racemic diquat dyes with pronounced chiroptical properties, and 2) capability of diquats to interact stereospecifically with chiral molecules. This suggests potential for diquat derivatives to be used as chiral selectors in separation methods.

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Combinatorial synthesis of modular chiral cyclophanes

Cited by 22 publications

References 26 publications

Chiral Molecular Recognition in a Tripeptide Benzylviologen Cyclophane Host

Chiral Molecular Recognition in a Tripeptide Benzylviologen Cyclophane Host

Enantioselective Resolving Resins from a Combinatorial Library. Kinetic Resolution of Cyclic Amino Acid Derivatives

Diquats with Robust Chirality: Facile Resolution, Synthesis of Chiral Dyes, and Application as Selectors in Chiral Analysis

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