Biomedical subjects
Publications and source records attributed to Scott J Miller.
Nucleophilic amines catalyze the 1,4-addition of allenic esters to alpha,beta-unsaturated carbonyl compounds. The reactions proceed under mild conditions. In addition, Baylis-Hillman products serve as appropriate electrophiles for the process such that a one-pot, three-component coupling of aldehydes, acrylates, and allenic esters may be achieved.
[reaction: see text] Nucleophile-loaded peptides and proline have been found to function synergistically as cocatalysts for the asymmetric ketone-based Baylis-Hillman reaction. Although neither compound is effective independently in terms of rate or enantioselectivity, their combination leads to catalysis where enantioselectivities up to 81% have been observed.
The ability to use small peptides as catalysts for asymmetric phosphorylation provides opportunities for rapid syntheses of phosphate-containing compounds and natural products. This short review outlines the genesis of this concept and its reduction to practice in the context of concise syntheses of the enantiomeric D-I-1P and D-I-3P targets. The implications for the development of additional site-selective catalysts are discussed.
An enantioselective synthesis of mitosane core (-)-1 has been achieved. Key steps include a rapid assembly of a key eight-membered-ring intermediate employing ring-closing metathesis. Kinetic resolution of an advanced secondary alcohol was then accomplished by using a peptide-based asymmetric acyl transfer catalyst that was discovered from a parallel screen of catalyst candidates. Optically pure material was then converted to the mitosane core, which was the subject of additional studies on the selective modification to produce several substituted compounds containing a mitosane ring system.
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Peptide-based catalysts have been found that catalyze the enantiodivergent phosphorylation of a meso myo-inositol-derived triol (1). The sequential screening of random peptide libraries, followed by the evaluation of a focused library, led to the identification of two peptides (2 and 24) that are complementary in producing enantiomeric D-myo-inositol-1-phosphate and D-myo-inositol-3-phosphate derivatives. The catalysts were then used to complete efficient total syntheses of both D-I-1P and D-I-3P in optically pure form. Additional information is gleaned from relative rate experiments that unambiguously show the catalysts to afford enantioselection through rate accelerative pathways with respect to simple achiral alkylimidazole catalysts. Furthermore, solvent effect studies show that the two enantiodivergent catalysts exhibit different tolerances of polar media. The systematic discovery of site-selective catalysts establishes a basis for future studies of chiral catalysts that differentiate unique functional groups in polyfunctional molecules.
An approach to the synthesis of dipeptide olefin isosteres using intermolecular olefin cross-metathesis is presented. In particular, a synthesis of the Pro-Gly isostere (1) is reported. Conversion of N-BOC-proline into the corresponding vinyl-substituted carbamate provides the N-terminal cross-metathesis partner (2). Methyl 3-butenoate (3) is employed as the C-terminal component. Treatment of the two partners in an optimized molar ratio affords the cross product 1 (83% yield). Three other examples are demonstrated to evaluate the potential of the approach.
A family of beta-substituted histidine-containing peptides has been synthesized to probe the effect of noncovalent conformational rigidification on catalyst enantioselectivity. Unambiguous enhancement of enantioselectivity in the conjugate addition of azide to alpha,beta-unsaturated carboxylate derivatives has been achieved, enabling application to a sequential asymmetric azidation/cycloaddition for the synthesis of optically enriched triazoles and triazolines.
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.
In recent years, combinatorial chemistry has had a significant impact on catalyst discovery in diverse fields. Proton-activated fluorescence (PAF) has been successfully demonstrated as a technique for effective screening of catalysts for electro-oxidation, enzymatic ester hydrolysis and nonenzymatic acyl transfer reactions. Among the working prototypes are screens for high-throughput assays of arrayed solid-state catalysts, dissolved enzymatic and small-molecule catalysts, as well as catalysts immobilized in solid-phase synthesis beads or polymeric gels. Given the range of reactions that may be set up to provide a change in local pH, the potential of PAF to facilitate catalyst discovery and process development is significant.