Small peptide catalysts containing modified histidine residues are reported that effect enantioselective
acylation reactions. The catalysts described include octapeptide β-hairpins (e.g., 11) that exhibit high selectivities
(up to k
rel = 51), tetrapeptide β-turns (e.g., 7) that afford moderate selectivities (up to k
rel = 28), and several
simple derivatives of the modified histidine amino acid that do not exhibit appreciable enantioselectivity.
Supporting structural studies (1H NMR and X-ray) are presented which lead to the proposal of a model in
which catalyst rigidity and structural complexity contribute to higher degrees of enantioselection. A covalently
rigidified octapeptide (20) is prepared through solid-phase Ru-catalyzed ring-closing metathesis; kinetic
evaluation of this peptide reveals that substituents along the peptide backbone may be more important than
covalent stabilization of a structural motif. Detailed kinetics studies on the most selective peptide catalysts are
presented that suggest the reactions are first order in catalyst and substrate. Additional kinetic studies indicate
unambiguously that enantioselectivities are due to specific acceleration of reaction for one substrate enantiomer,
rather than the deceleration of the reaction for the other. The results are presented in the context of a possible
enantiomer-specific hydrogen-bonding interaction in the stereochemistry-determining step for these processes.
An assay employing a fluorescently labeled split and pool peptide library has been applied to the discovery of a new class of octapeptide catalysts for the kinetic resolution of secondary alcohols. A highly diverse library of peptide-based catalysts was synthesized on solid-phase synthesis beads such that each individual bead was co-functionalized with (i) a uniform loading of a pH-sensitive fluorophore and (ii) a unique peptide-based catalyst. The library was then screened for activity in acylation reactions employing (+/-)-sec-phenylethanol as the substrate and acetic anhydride as the acylation agent. From the most active catalysts, a lead peptide (4) was identified that provides a selectivity-factor (k(rel)) of 8.2 upon resynthesis and evaluation under homogeneous conditions. A "directed" second-generation split and pool peptide library was synthesized such that the new peptide sequences in the library were biased toward the lead structure. Random samples of the second generation library were screened in single bead assays that revealed several new peptide-based catalysts that afford improved selectivities in kinetic resolutions. Peptide catalyst 13 proves effective for the kinetic resolution of sec-phenylethanol (k(rel) = 20), as well as eight other secondary alcohols of a broad substrate scope (k(rel) = 4 to >50).
A technique for high-throughput screening of kinetic resolution catalysts is reported. The method relies on carrying simultaneous kinetic resolutions in a multiwell plate format wherein each well contains a unique catalyst and a small amount of a pH-activated fluorescent sensor (3). By conducting experiments such that each catalyst is evaluated in parallel in the presence of each isolated enantiomer, an indication of catalyst activity is obtained on a per enantiomer basis. Catalysts that are highly active for one enantiomer but modestly active for another are then reevaluated in conventional kinetic resolutions. From these screens, a highly selective (k(rel) = 46) pentapeptide (4) was obtained for a model secondary alcohol (1). In addition, peptide 10 was found to afford excellent selectivities (k(rel) > 20) for a number of alcohol substrates (9a-9f) in the traditionally challenging tertiary class.
Two-photon fluorescence microscopy has been used to interrogate the interior functionality of polymer resin beads. By employing this technique, the spatial distribution of the initial functionality contained within the polymer matrix has been determined. Spatially resolved, concentric shells were then produced synthetically in these polymer spheres via a series of protection/deprotection reactions in which two-photon fluorescence microscopy was employed to monitor each successive step. To demonstrate the potential utility of these techniques in combinatorial screening, a set of beads was prepared containing a unique tripeptide sequence in each of the three concentric shells within each individual bead. The set was then screened for the binding affinity of each tripeptide toward a fluorescent ligand.
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