Grant R. Krow

Nature of amide carbonyl--carbonyl interactions in proteins.

Noncovalent interactions define and modulate biomolecular structure, function, and dynamics. In many protein secondary structures, an intimate interaction exists between adjacent carbonyl groups of the main-chain amide bonds. As this short contact contributes to the energetics of protein conformational stability as well as protein−ligand interactions, understanding its nature is crucial. The intimacy of the carbonyl groups could arise from a charge−charge or dipole−dipole interaction, or n→π * electronic delocalization. This last putative origin, which is reminiscent of the Bürgi−Dunitz trajectory, involves delocalization of the lone pairs (n) of the oxygen (Oi−1) of a peptide bond over the antibonding orbital (π*) of the carbonyl group (Ci=Oi) of the subsequent peptide bond. By installing isosteric chemical substituents in a peptidic model system and using NMR spectroscopy, X-ray diffraction analysis, and ab initio calculations to analyze the consequences, the intimate interaction between adjacent carbonyl groups is shown to arise primarily from n→π* electronic delocalization. This finding has implications for organic, biological, and medicinal chemistry.

Conformational Preferences of Substrates for Human Prolyl 4-Hydroxylase†

Prolyl 4-hydroxylase (P4H) catalyzes the posttranslational hydroxylation of (2 S)-proline (Pro) residues in procollagen strands. The resulting (2 S,4 R)-4-hydroxyproline (Hyp) residues are essential for the folding, secretion, and stability of the collagen triple helix. Even though its product (Hyp) differs from its substrate (Pro) by only a single oxygen atom, no product inhibition has been observed for P4H. Here, we examine the basis for the binding and turnover of substrates by human P4H. Synthetic peptides containing (2 S,4 R)-4-fluoroproline (Flp), (2 S,4 S)-4-fluoroproline (flp), (2 S)-4-ketoproline (Kep), (2 S)-4-thiaproline (Thp), and 3,5-methanoproline (Mtp) were evaluated as substrates for P4H. Peptides containing Pro, flp, and Thp were found to be excellent substrates for P4H, forming Hyp, Kep, and (2 S,4 R)-thiaoxoproline, respectively. Thus, P4H is tolerant to some substitutions on C-4 of the pyrrolidine ring. In contrast, peptides containing Flp, Kep, or Mtp did not even bind to the active site of P4H. Each proline analogue that does bind to P4H is also a substrate, indicating that discrimination occurs at the level of binding rather than turnover. As the iron(IV)-oxo species that forms in the active site of P4H is highly reactive, P4H has an imperative for forming a snug complex with its substrate and appears to do so. Most notably, those proline analogues with a greater preference for a C (gamma)- endo pucker and cis peptide bond were the ones recognized by P4H. As Hyp has a strong preference for C (gamma)- exo pucker and trans peptide bond, P4H appears to discriminate against the conformation of proline residues in a manner that diminishes product inhibition during collagen biosynthesis.

Nitrogen bridge homoepibatidines. syn-6- and syn-5(6-chloro-3-pyridyl)isoquinuclidines

Abstract The N-bridge vicinal-6(6-Cl-3-pyridyl) and distal 6-(6-Cl-3-pyridyl)-2-azabicyclo[2.2.2]octane homologs of the potent nicotinic receptor agonist epibatidine have been synthesized. Key steps involve stereo-selective catalytic hydrogenations of both 6- and 5-(6-Cl-3-pyridyl)-2-azabicyclo[2.2.2]oct-5-enes 12 and 17 on the face anti to the nitrogen containing bridges. The vicinal homolog appears to be a potent nicotinic agonist.

The Baeyer–Villiger Reaction

The oxidation of ketones with organic peroxy acids, hydrogen peroxide or alkyl hydroperoxides to give esters/lactones or derived alcohols and acids is known as the Baeyer–Villiger reaction. Similar oxidations of aldehydes to the corresponding formate esters or their hydrolysis products also belong to this class of reactions. The Baeyer–Villiger reaction is of considerable synthetic use as a component of methods for shortening carbon chains, hydroxylating aromatic rings, converting carbocycles to heterocycles and opening cyclic arrays to prepare functionalized chains and/or rings.

Unusual regiochemistry in a beckmann-like rearrangement of camphor. α-Camphidone via methylene migration.

Abstract Reaction of camphor with hydroxylamine-O-sulfonic acid affords the nitrogen insertion product α-camphidone by migration of the methylene group rather than the bridgehead. Since Beckmann rearrangements of trigonal oximes afford bridgehead cleavage products with camphor, an alternative synchronous rearrangement of a tetrahedral intermediate is proposed for this Beckmann-like reaction.

Oligomers of a 5-Carboxy-methanopyrrolidine β-Amino Acid. A Search for Order

CD spectra for homooligomers (n = 4, 6, 8) of (1S,4R,5R)-5-syn-carboxy-2-azabicyclo[2.1.1]hexane (MPCA), a methano-bridged pyrrolidine β-carboxylic acid, suggest an ordered secondary structure. Even in the absence of internal hydrogen bonding, solution NMR, X-ray, and in silico analyses of the tetramer are indicative of conformations with trans-amides and C(5)-amide-carbonyls oriented toward the C(4) bridgehead. This highly constrained β-amino acid could prove useful in the ongoing development of well-defined foldamers.

Heterodienophiles. 10. Stereoselectivity in the 1,4-cycloaddition of N-(ethoxycarbonyl)-C-alkylaldiminium ions with 1,3-cyclohexadiene

Stereochimie de la reaction alkylidene bis-carbamates avec le cyclohexadiene-1,3 en presence de trifluoroborane

Selectfluor as a nucleofuge in the reactions of azabicyclo[n.2.1]alkane beta-halocarbamic acid esters (n = 2,3).

The ability of Selectfluor to act as a nucleofuge for hydrolysis of beta-anti-halides was investigated with N-alkoxycarbonyl derivatives of 6-anti-Y-7-anti-X-2-azabicyclo[2.2.1]heptanes and 4-anti-Y-8-anti-X-6-azabicyclo[3.2.1]octanes. The azabicycles contained X = I or Br groups in the methano bridge and Y = F, Br, Cl, or OH substituents in the larger bridge. The relative reactivities of the halides were a function of the azabicycle, the halide, and its bridge and the addition of Selectfluor or HgF(2) as a nucleofuge. All halide displacements occurred with retention of stereochemistry. Selectfluor with sodium bromide or sodium chloride, but not sodium iodide, competitively oxidized some haloalcohols to haloketones. A significant 15.6 Hz F...HO NMR coupling was observed with 4-anti-fluoro-8-anti-hydroxy-6-azabicyclo[3.2.1]octane.

Synthesis of 5- and 6-(6-Chloro-3-pyridyl)-2-azabicyclo[2.2.0]hexanes. Epibatidine Analogs

Abstract Synthetic routes to vicinal -6-(6-Cl-3-pyridyl)- and distal -5-(6-Cl-3-pyridyl)-2-azabicyclo-[2.2.0]hexane analogs of the potent nicotinic receptor agonist epibatidine are described. Both exo -regioisomers are available from a readily available 2-azabicyclo[2.2.0]hex-5-ene by way of stereoselective reductive Heck addition of the 6-Cl-3-pyridyl moiety. Stereochemical inversion of the 6- and 5-aryl groups provides entry to the endo isomers.

Synthesis of 3- and 5-endo-(6-Chloro-3-pyridoxy)-methyl-2-azabicyclo[2.2.0]hexane and 3-endo-(6-Chloro-3-pyridoxy)-methyl-2-azabicyclo[2.2.0]hex-5-ene. ABT-594 Analogs

Abstract Stereoselective photochemical ring closure of a 2-hydroxymethyl-1,2-dihydropyridine has been utilized for the syntheses of 3- endo -(6-Cl-3-pyridoxy)-methyl-2-azabicyclo[2.2.0]hex-5-ene and hexane analogs of the nicotinic acetylcholine receptor agonist ABT-594. The photochemical ring closure of a 4-hydroxymethyl-1,2-dihydropyridine has been utilized in the preparation of 5- endo -(6-chloro-3-pyridoxy)-methyl-2-azabicyclo[2.2.0]hexane.