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Scott J Miller

Publications and source records attributed to Scott J Miller.

At least 19 recordsLinked to original sources
PubMed2006

Remote desymmetrization at near-nanometer group separation catalyzed by a miniaturized enzyme mimic.

The chirality of biological receptors often requires syntheses of therapeutic compounds in single enantiomer form. The field of asymmetric catalysis addresses enantioselective synthesis with chiral catalysts. Chemical differentiation of sites within molecules that are separated in space by long distances presents special challenges to chiral catalysts. As the distance between enantiotopic sites increases within a substrate, so too may the requirements for size and complexity for the catalyst. The extreme of catalyst complexity could be defined by macromolecular enzymes and their amazing capacity to effect stereospecific reactions over long distances between reactive sites and enzyme-substrate contacts. We report here a synthetic, miniaturized enzyme mimic that catalyzes a desymmetrization reaction over a very long distance.

Biphenyl Compounds↗
PubMed2006

Streamlined synthesis of phosphatidylinositol (PI), PI3P, PI3,5P2, and deoxygenated analogues as potential biological probes.

Highly direct total syntheses of phosphatidylinositol (PI), phosphatidylinositol-3-phosphate (PI3P), phosphatidylinositol-3,5-bisphosphate (PI3,5P2), and a range of deoxygenated versions are reported. Each synthesis is carried out to deliver the target in optically pure form. The key step for each synthesis is a catalytic asymmetric phosphorylation reaction that affects desymmetrization of an appropriate myo-inositol precursor. Elaboration to each target compound is then carried out employing a diversity-oriented strategy from the common precursors. In addition to three natural products, several additional streamlined total syntheses of deoxygenated PI analogues are reported. These syntheses set the stage for high-precision biological investigations of polar headgroup/biological target interactions of these membrane-associated signaling molecules.

Fluorescent Dyes↗
PubMed2006

The temperature dependence of the inositol monophosphatase Km correlates with accumulation of di-myo-inositol 1,1'-phosphate in Archaeoglobus fulgidus.

Di-myo-inositol 1,1'-phosphate (DIP) accumulates as a compatible solute in many hyperthermophilic archaea (e.g., Archaeoglobus fulgidus) when the cells are grown above 80 degrees C. Recent microarray analysis of A. fulgidus transcripts [Rohlin, L., et al. (2005) J. Bacteriol. 187, 6046] indicates that neither the myo-inositol-1-phosphate synthase, the first step in inositol biosynthesis, nor the inositol monophosphatase (IMPase), which generates myo-inositol, are significantly upregulated upon thermal stress. Although other factors could contribute to regulation of DIP synthesis in cells, there is an 8-10-fold decrease in the K(m) of the IMPase for inositol phosphates between 75 and 85 degrees C (for l-I-1-P, the K(m) decreased from 13.2 to 1.67 mM) that correlates with the observed accumulation of DIP in cells. Between 55 and 75 degrees C, K(m) values decreased 2.3-fold at most. The enzyme also exhibits fructose bisphosphatase activity. However, the K(m) for fructose 1,6-bisphosphate was low and the same (0.15 +/- 0.01 mM) at 55 and 70 degrees C. This indicates that the unusual temperature dependence of K(m) is specific for I-1-P substrates. (31)P NMR studies confirmed that the affinity of inositol 1-phosphate for the enzyme was indeed weak (K(D) >or= 5 mM) below but increased significantly at 80 degrees C. In contrast, the IMPase from Methanococcus jannaschii, an organism in which DIP does not accumulate, had a low K(m) for I-1-P over the entire temperature range. A structural comparison of the two archaeal IMPases identified a hydrogen bonding network present in the active site of the A. fulgidus enzyme and not in the M. jannaschii IMPase, the disruption (e.g., A. fulgidus IMPase S171A or T174L) of which prevented the drop in K(m) at high temperatures. We suggest that the temperature-dependent synthesis and accumulation of DIP in A. fulgidus are regulated in part by the temperature dependence of the K(m) of the IMPase activity in the cells.

Amino Acids↗
PubMed2006

Studies of folded peptide-based catalysts for asymmetric organic synthesis.

Folded peptides have proven to be a fertile area for discovery of catalysts for reactions in organic synthesis. Both combinatorial chemistry and rational design have fueled these discoveries. In both lines of research, mechanistic studies following the discovery of selective reactions have led to structural information that has stimulated attempts to correlate peptide structure and the relay of stereochemical information. Thus, key elements of the design of peptide-based catalysts include the identification of catalytically competent functional groups and their incorporation into three-dimensional structures that provide an appropriate chiral environment. Of note, turns, helices, nonobvious folds, and still undetermined secondary structures characterize the structural and functionally diverse motifs that enable peptide-catalyzed asymmetric reactions to occur.

Acylation↗
PubMed2005

Dual catalyst control in the enantioselective intramolecular Morita-Baylis-Hillman reaction.

The intramolecular Morita-Baylis-Hillman (MBH) reaction has been achieved with unprecedented levels of enantioselectivity. Using a co-catalyst system involving pipecolinic acid and N-methylimidazole, cyclic MBH products have been obtained with enantiomer ratios of 92:8 (84% ee). In addition, reactions may be carried out with a "kinetic resolution quench" involving acetic anhydride and an asymmetric acylation catalyst such that ee enhancement occurs to deliver products with >98% ee with an isolated yield of 50%. [reaction: see text]

Journal Article↗
PubMed2005

Desymmetrization of glycerol derivatives with peptide-based acylation catalysts.

[reaction: see text] Nucleophile-loaded peptides have been evaluated as catalysts for the desymmetrization of glycerol derivatives through an enantioselective acylation process. Enantiomeric excesses of up to 97% have been obtained for the monoacylated products. A range of other substrates have been examined that shed light on the mechanistic basis of the desymmetrizations.

Acylation↗
PubMed2005

Peptide bond isosteres: ester or (E)-alkene in the backbone of the collagen triple helix.

[structure: see text] Collagen is the most abundant protein in animals. Interstrand N-H...O=C hydrogen bonds between backbone amide groups form a ladder in the middle of the collagen triple helix. Isosteric replacement of the hydrogen-bond-donating amide with an ester or (E)-alkene markedly decreases the conformational stability of the triple helix. Thus, this recurring hydrogen bond is critical to the structural integrity of collagen. In this context, an ester isostere confers more stability than does an (E)-alkene.

Alkenes↗
PubMed2005

Thiazolylalanine-derived catalysts for enantioselective intermolecular aldehyde-imine cross-couplings.

Catalytic asymmetric cross-coupling reactions between aldehydes and N-acylimines have been discovered that employ thiazolylalanine derivatives as catalysts. Alkylation of the thiazolyl moiety, followed by in situ generation of the derived thiazolium ylide using a tertiary amine base, leads to the active catalyst. alpha-Amidoketone products are isolated in up to 90% yield with up to 87% enantiomeric excess (>98% ee after a single recrystallization). The use of a hindered base to suppress product racemization was stimulated by a mechanistic study that revealed an isotope effect on the racemization rate of the product.

Alanine↗
PubMed2004

Chemistry and biology of deoxy-myo-inositol phosphates: stereospecificity of substrate interactions within an archaeal and a bacterial IMPase.

Six enantiomerically pure myo-inositol-monophosphates, including four deoxygenated analogues, have been synthesized by employing catalytic asymmetric phosphorylation methodology. These compounds were then evaluated as substrates for the direct interrogation of the stereospecificity of enzyme-substrate interactions with two inositol-monophosphatases (IMPases), one of which (from Archaeoglobus fulgidus) is characterized by an X-ray crystal structure with its substrate (d-I-1P) bound. The kinetic results lead to the finding that certain hydroxyl group contacts are actually destabilizing, while others have little effect. These new probes also allow a prediction of the active site binding mode of the substrate for the Escherichia coli IMPase for which no crystal structure exists.

5'-Nucleotidase↗
PubMed2004

A peptide-catalyzed asymmetric Stetter reaction.

Thiazolylalanine, in appropriately functionalized form, has been found to function as an enantioselective catalyst for an intramolecular Stetter reaction. Incorporation of the residue in a number of environments has resulted in a family of catalysts that promote the cyclization of a test substrate with up to 81% enantiomeric excess.

Alanine↗
PubMed2004

Asymmetric syntheses of phosphatidylinositol-3-phosphates with saturated and unsaturated side chains through catalytic asymmetric phosphorylation.

Highly direct asymmetric syntheses of phosphatidylinositol-3-phosphate (PI3P) in each enantiomerically pure form have been achieved. The key step involves catalytic asymmetric phosphorylation of meso-myo-inositol derivatives through desymmetrization. Protecting group schemes have been employed that allow for synthesis of PI3P with either saturated or arachidonate side chains, in analogy to the naturally occurring systems. Syntheses in each enantiomeric series are reported that rely on the choice of enantioselective peptide-based catalyst to define the enantiomeric series in which the syntheses are carried out.

Phosphatidylinositol Phosphates↗
PubMed2004

Catalytic enantioselective synthesis of sulfinate esters through the dynamic resolution of tert-butanesulfinyl chloride.

Development of a new synthetic route to obtain enantiomerically enriched tert-butanesulfinate esters in excellent yields through catalytic enantioselective sulfinyl transfer is described. As little as 0.5 mol % of chiral amine catalysts was used to couple racemic tert-butanesulfinyl chloride with arylmethyl alcohols to provide sulfinate esters in near quantitative yields and with enantiomeric excesses up to 81%. The method represents the first example of the catalytic dynamic resolution of sulfinyl derivatives.

Journal Article↗
PubMed2004

Structure-selectivity relationships and structure for a peptide-based enantioselective acylation catalyst.

Studies of analogues of a recently discovered enantioselective peptide-based catalyst for enantioselective acylation reactions have led to mechanistic insight and improved catalysts. Systematic replacement of each residue within the parent peptide with alanine of the appropriate stereochemistry allows for an unambiguous evaluation of the kinetic role of each amino acid side chain in the catalyst. The results of the alanine scan support a bifunctional catalysis mechanism at the heart of the origin of enantioselectivity. In addition, an experimentally derived solution structure of the peptide-based catalyst is presented that supports a key role for each residue within the peptide chain.

Acylation↗
PubMed2004

In search of peptide-based catalysts for asymmetric organic synthesis.

The discovery of short peptide sequences that function as asymmetric catalysts for a variety of reactions is documented. The evolution of the project from an exercise in rational design to an endeavor that combines combinatorial screening with various mechanism-based experiments is presented. The specific development of catalysts for enantioselective acylation, phosphorylation, conjugate addition, and Morita-Baylis-Hillman reactions is described.

Journal Article↗