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author:("guze, Ilia A.")
1.  New Preorganized γ-Amino Acids as Foldamer Building Blocks 
Organic letters  2012;14(10):2582-2585.
An asymmetric synthesis of two new diastereomeric γ-amino acids is described. Both molecules contain a cyclohexyl ring to limit conformational flexibility about the Cα-Cβ bond; they differ in having cis vs. trans stereochemistry on the ring. Residues derived from the cis γ isomer are shown to support helical secondary structures in α/γ-peptide oligomers.
PMCID: PMC3445736  PMID: 22568480
2.  Characterization of DMSO Coordination to Palladium(II) in Solution and Insights into the Aerobic Oxidation Catalyst, Pd(DMSO)2(TFA)2 
Inorganic chemistry  2012;51(21):11898-11909.
Recent studies have shown that Pd(DMSO)2(TFA)2 (TFA = trifluoroacetate) is an effective catalyst for a number of different aerobic oxidation reactions. Here, we provide insights into the coordination properties of DMSO to palladium(II) in both the solid state and in solution. A crystal structure of Pd(DMSO)2(TFA)2 confirms that the solid-state structure of this species has one O-bound and one S-bound DMSO ligand, and a crystallographically characterized mono-DMSO complex, trans-Pd(DMSO)(OH2)(TFA)2, exhibits an S-bound DMSO ligand. 1H and 19F NMR spectroscopic studies show that, in EtOAc and THF-d8, Pd(DMSO)2(TFA)2 consists of an equilibrium mixture of Pd(S-DMSO)(O-DMSO)(TFA)2 and Pd(S-DMSO)2(TFA)2. The O-bound DMSO is determined to be more labile than the S-bound DMSO ligand, and both DMSO ligands are more labile in THF relative to EtOAc as the solvent. DMSO coordination to PdII is substantially less favorable when the TFA ligands are replaced with acetate. An analogous carboxylate ligand effect is observed in the coordination of PdII to the bidentate sulfoxide ligand, 1,2-bis(phenylsulfinyl)ethane. DMSO coordination to Pd(TFA)2 is shown to be incomplete in AcOH-d4 and toluene-d8, resulting in PdII/DMSO adducts with < 2:1 DMSO:PdII stoichiometry. Collectively, these results provide useful insights into the coordination properties of DMSO to PdII under catalytically relevant conditions.
PMCID: PMC3494491  PMID: 23092381
3.  Rhodium-Catalyzed Carbonylation of Cyclopropyl Substituted Propargyl Esters: A Tandem 1,3-Acyloxy Migration [5+1] Cycloaddition 
The Journal of organic chemistry  2012;77(15):6463-6472.
We have developed two different types of tandem reactions for the synthesis of highly functionalized cyclohexenones from cyclopropyl substituted propargyl esters. Both reactions were initiated by rhodium-catalyzed Saucy-Marbet 1,3-acyloxy migration. The resulting cyclopropyl substituted allenes derived from acyloxy migration then underwent [5+1] cycloaddition with CO. The acyloxy group not only eased the access to allene intermediates but also provided a handle for further selective functionalizations.
PMCID: PMC3420071  PMID: 22793991
4.  Pyramidalization of a carbonyl C atom in (2S)-N-(seleno­acet­yl)proline methyl ester 
The title compound, C8H13NO2Se, crystallizes as a non-merohedral twin with an approximate 9:1 component ratio with two symmetry-independent mol­ecules in the asymmetric unit. Our density-functional theory (DFT) computations indicate that the carb­oxy C atom is expected to be slightly pyramidal due to an n→ π* inter­action, wherein the lone pair (n) of the Se atom overlap with the anti­bonding orbital (π*) of the carbonyl group. Such pyramidalization is observed in one mol­ecule of the title compound but not the other.
PMCID: PMC3648325  PMID: 23723945
5.  An Asymmetric Synthesis of L-Pyrrolysine 
Organic Letters  2012;14(6):1378-1381.
An efficient asymmetric synthesis of the 22nd amino acid L-pyrrolysine has been accomplished. The key stereogenic centers were installed by an asymmetric conjugate addition reaction. A Staudinger/aza-Wittig cyclization was used to form the acid-sensitive pyrroline ring. Pyrrolysine was synthesized in thirteen steps in 20% overall yield.
PMCID: PMC3326344  PMID: 22394273
6.  Rhodium-catalyzed 1,3-acyloxy migration and subsequent intramolecular [4 + 2] cycloaddition of vinylallene and unactivated alkyne† 
A Rh-catalyzed 1,3-acyloxy migration of propargyl ester followed by intramolecular [4 + 2] cycloaddition of vinylallene and unactivated alkyne was developed. This tandem reaction provides access to bicyclic compounds containing a highly functionalized isotoluene or cyclohexenone structural motif, while only aromatic compounds were observed in related transition metal-catalyzed cycloadditions.
PMCID: PMC3334501  PMID: 22252254
7.  Quasiracemic Crystallization as a Tool to Assess the Accommodation of Non-canonical Residues in Native-Like Protein Conformations 
Quasiracemic crystallization has been used to obtain high-resolution structures of two variants of the villin headpiece subdomain (VHP) that contain a pentafluorophenylalanine (F5Phe) residue in the hydrophobic core. In each case, the crystal contained the variant constructed from L-amino acids and the native sequence constructed from D-amino acids. We were motivated to undertake these studies by reports that racemic proteins crystallize more readily than homochiral forms, and the prospect that quasiracemic crystallization would enable us to determine whether a polypeptide containing a non-canonical residue can closely mimic the tertiary structure of the native sequence. The results suggest that quasiracemic crystallization may prove to be generally useful for assessing mimicry of naturally evolved protein folding patterns by polypeptides that contain unnatural side chain or backbone subunits.
PMCID: PMC3351109  PMID: 22280019
Racemic Protein Crystallization; Quasiracemic Proteins; Unnatural Amino Acids; Pentafluorophenylalanine; Villin Headpiece Subdomain
9.  Extraordinarily Robust Polyproline Type I Peptoid Helices Generated via the Incorporation of α-Chiral Aromatic N-1-Naphthylethyl Side Chains 
Journal of the American Chemical Society  2011;133(39):15559-15567.
Peptoids, or oligomers of N-substituted glycines, are a class of foldamers that have shown extraordinary functional potential since their inception nearly two decades ago. However, the generation of well-defined peptoid secondary structures remains a difficult task. This challenge is due, in part, to the lack of a thorough understanding of peptoid sequence-structure relationships and consequently, an incomplete understanding of the peptoid folding process. We seek to delineate sequence-structure relationships through the systematic study of noncovalent interactions in peptoids and the design of novel amide side chains capable of such interactions. Herein, we report the synthesis and detailed structural analysis of a series of (S)-N-(1-naphthylethyl)glycine (Ns1npe) peptoid homooligomers by X-ray crystallography, NMR and circular dichroism (CD) spectroscopy. Four of these peptoids were found to adopt well-defined structures in the solid state, with dihedral angles similar to those observed in polyproline type I (PPI) peptide helices and in peptoids with α-chiral side chains. The X-ray crystal structure of a representative Ns1npe tetramer revealed an all cis-amide helix, with approximately three residues per turn, and a helical pitch of approximately 6.0 Å. 2D-NMR analysis of the length-dependent Ns1npe series showed that these peptoids have very high overall backbone amide Kcis/trans values in acetonitrile, indicative of conformationally homogeneous structures in solution. Additionally, CD spectroscopy studies of the Ns1npe homooligomers in acetonitrile and methanol revealed a striking length-dependent increase in ellipticity per amide. These Ns1npe helices represent the most robust peptoid helices to be reported, and the incorporation of (S)-N-(1-naphthylethyl)glycines provides a new approach for the generation of stable helical structure in this important class of foldamers.
PMCID: PMC3186054  PMID: 21861531
10.  Design and Conformational Analysis of Peptoids Containing N-Hydroxy Amides Reveals a Unique Sheet-Like Secondary Structure 
Biopolymers  2011;96(5):604-616.
N-hydroxy amides can be found in many naturally occurring and synthetic compounds and are known to act as both strong proton donors and chelators of metal cations. We have initiated studies of peptoids, or N-substituted glycines, that contain N-hydroxy amide side chains to investigate the potential effects of these functional groups on peptoid backbone amide rotamer equilibria and local conformations. We reasoned that the propensity of these functional groups to participate in hydrogen bonding could be exploited to enforce intramolecular or intermolecular interactions that yield new peptoid structures. Here, we report the design, synthesis, and detailed conformational analysis of a series of model N-hydroxy peptoids. These peptoids were readily synthesized, and their structures were analyzed in solution by 1D and 2D NMR and in the solid-state by X-ray crystallography. The N-hydroxy amides were found to strongly favor trans conformations with respect to the peptoid backbone in chloroform. More notably, unique sheet-like structures held together via intermolecular hydrogen bonds were observed in the X-ray crystal structures of an N-hydroxy amide peptoid dimer, which to our knowledge represent the first structure of this type reported for peptoids. These results suggest that the N-hydroxy amide can be utilized to control both local backbone geometries and longer-range intermolecular interactions in peptoids, and represents a new functional group in the peptoid design toolbox.
PMCID: PMC3448284  PMID: 22180908
11.  Characteristic Structural Parameters for the γ-Peptide 14-Helix:Importance of Subunit Preorganization 
We report crystallographic data for a set of homologous γ-peptides that contain a Boc-protected residue derived from the flexible gabapentin monomer at the N-terminus and cyclically constrained γ-residues at all other positions. The crystallized γ-peptides range in length from 3 to 7 residues. Previously only one atomic-resolution structure had been available for a short γ-peptide 14-helix. The new data provided here allow derivation of characteristic parameters for the γ-peptide 14-helix, and establish guidelines for characterizing 14-helical folding in solution via 2D NMR. In addition, the results suggest that the substitution pattern of a γ-residue has a profound effect on the propensity for 14-helical folding.
PMCID: PMC3429132  PMID: 21567680
γ-peptides; 14-helix; H-bond; backbone; NOE
12.  1,2-Bis[(3,5-diphenyl-1H-pyrazol-1-yl)meth­yl]benzene 
The title compound, C38H30N4, a potentially mono- and bidentate ligand, does not seem to form palladium complexes similar to other poly(pyrazol-1-ylmeth­yl)benzenes due to the large steric size of the phenyl substituents on the pyrazole rings. The pyrazole rings have a 21.09 (5)° angle between their mean planes and exhibit a trans-like geometry in which the in-plane lone pairs of electrons on the 2-N nitrogen atoms point in opposite directions.
PMCID: PMC3415022  PMID: 22905009
13.  (3,5-Di-tert-butyl-2-eth­oxy­benzyl­idene)[2-(3,5-di-tert-butyl-1H-pyrazol-1-yl)eth­yl]amine 
The angles within the benzene ring in the title compound, C30H49N3O, ranging from 116.34 (16) to 124.18 (16)°, reflect the presence of electron-donating and electron-withdrawing substituents. The angles at the two electron-donating tert-butyl substituents are smaller than 120°, at the electron-withdrawing eth­oxy substituent larger than 120°, and at the imine substituent equal to 119.59 (16)°. The latter does not reflect the electron-donating nature of the imine group due to the presence of other substituents.
PMCID: PMC3414966  PMID: 22904953
14.  2-[(3,5-Diphenyl-1H-pyrazol-1-yl)meth­yl]pyridine 
The title compound, C21H17N3, crystallizes with the phenyl ring in the 3-position coplanar with the pyrazole ring within 4.04 (5)°, whereas the phenyl ring in the 5-position forms a dihedral angle of 50.22 (3)° with the pyrazole ring. There is no ambiguity regarding the position of pyridine N atom, which could have exhibited disorder between the ortho positions of the ring.
PMCID: PMC3344127  PMID: 22606130
15.  Photocatalytic Reductive Cyclizations of Enones: Divergent Reactivity of Photogenerated Radical and Radical Anion Intermediates 
Photocatalytic reactions of enones using metal polypyridyl complexes proceed by very different reaction manifolds in the presence of either Lewis or Brønsted acid additives. Previous work from our lab demonstrated that photocatalytic [2+2] cycloadditions of enones required the presence of a Lewis acidic co-catalyst, presumably to activate the enone and stabilize the key radical anion intermediate. On the other hand, Brønsted acid activators alter this reactivity and instead promote reductive cyclization reactions of a variety of aryl and aliphatic enones via a neutral radical intermediate. These two distinct reactive intermediates give rise to transformations differing in the connectivity, stereochemistry, and oxidation state of their products. In addition, this reductive coupling method introduces a novel approach to the tin-free generation of β-ketoradicals that react with high diastereoselectivity and with the high functional group compatibility typical of radical cyclization reactions.
PMCID: PMC3222952  PMID: 22121471
16.  Ethyl 3-ferrocenyl-1-(pyridin-2-ylmeth­yl)-1H-pyrazole-5-carboxyl­ate 
The title compound, [Fe(C5H5)(C17H16N3O2)], crystallizes with an essentially eclipsed conformation of the cyclo­penta­dienyl (Cp) rings. The unsubstituted ring is disordered over two positions with the major component being present 90 (1)% of the time. The substituted Cp ring, the pyrazole ring and three atoms of the eth­oxy­carbonyl group form a conjugated π-system. These 13 atoms are coplanar within 0.09 Å.
PMCID: PMC3254307  PMID: 22259337
17.  5′,11′-Dihydro­dispiro­[cyclo­hexane-1,6′-indolo[3,2-b]carbazole-12′,1′′-cyclo­hexa­ne] 
The title compound, C28H30N2, is a symmetrical 2:2 product from the condensation of indole and cyclo­hexa­none. It is the only reported 5,11-dihydro­indolo[3,2-b]carbazole compound in which the spiro atoms are quaternary C atoms. Crystals were grown by vapor diffusion in a three-zone electric furnace. The mol­ecule resides on a crystallographic inversion center. The cyclo­hexyl rings are in a slightly distorted chair conformation, whereas the indole units and the spiro-carbons are coplanar within 0.014 Å.
PMCID: PMC3254282  PMID: 22259386
18.  Oxaziridine-Mediated Oxyamination of Indoles: An Approach to 3-Aminoindoles and Enantioenriched 3-Aminopyrroloindolines 
PMCID: PMC3047499  PMID: 20967810
aminohydroxylation; chiral auxiliaries; copper; indoles; oxaziridines
19.  Synthesis and Magnetic Properties of Gd Doped EuS Nanocrystals with Enhanced Curie Temperatures 
Journal of the American Chemical Society  2010;132(45):15997-16005.
EuS nanocrystals (NCs) were doped with Gd resulting in an enhancement of their magnetic properties. New EuS and GdS single source precursors (SSPs) were synthesized, characterized, and employed to synthesize Eu1-xGdxS NCs by decomposition in oleylamine and trioctylphosphine at 290 °C. The doped NCs were characterized using X-ray diffraction, transmission electron miscroscopy and scanning transmission electron microscopy, which supports the uniform distribution of Gd dopants through electron energy loss spectroscopy (EELS) mapping. X-ray absorption spectroscopy (XAS) revealed the dopant ions in Eu1-xGdxS NCs to be predominantly Gd3+. NCs with a variety of doping ratios of Gd (0 ≤ x < 1) were systematically studied using vibrating sample magnetometry and the observed magnetic properties were correlated with the Gd doping levels (x) as quantified with ICP-AES. Enhancement of the Curie temperature (TC) was observed for samples with low Gd concentrations (x ≤ 10 %) with a maximum TC of 29.4 K observed for NCs containing 5.3 % Gd. Overall, the observed TC, Weiss temperature (θ), and hysteretic behavior correspond directly to the doping level in Eu1-xGdxS NCs and the trends qualitatively follow those previously reported for bulk and thin film samples.
PMCID: PMC2978792  PMID: 20964293
EuS; nanocrystals; magnetism; magnetic semiconductor; spintronics; doping
20.  {1,2-Bis[(3,5-dimethyl-1H-pyrazol-1-yl-κN 2)meth­yl]benzene}­dichloridozinc(II) 
The title zinc complex, [ZnCl2(C18H22N4)], contains a bidentate 1,2-bis(3,5-dimethyl-1H-pyrazol-1-ylmeth­yl)benz­ene ligand that binds to the zinc atom, forming a nine-membered metallocyclic ring. The geometry about the Zn atom is distorted tetra­hedral, with the largest deviation observed in the magnitude of the Cl—Zn—Cl angle. Similar distortions are observed in the cobalt analogue and related zinc compounds containing metallocyclic rings with more than six members. The copper analogue exhibits a more severe distortion of the metal coordination sphere than is observed in the title compound.
PMCID: PMC3238634  PMID: 22199525
21.  Allylic C–H Acetoxylation with a 4,5-Diazafluorenone-Ligated Palladium Catalyst: A Ligand-Based Strategy to Achieve Aerobic Catalytic Turnover 
Journal of the American Chemical Society  2010;132(43):15116-15119.
Pd-catalyzed C–H oxidation reactions often require the use of oxidants other than O2. Here, we demonstrate a ligand-based strategy to replace benzoquinone with O2 as the stoichiometric oxidant in Pd-catalyzed allylic C–H acetoxylation. Use of 4,5-diazafluorenone (1) as an ancillary ligand for Pd(OAc)2 enables terminal alkenes to be converted to linear allylic acetoxylation products in good yields and selectivity under 1 atm O2. Mechanistic studies reveal that 1 facilitates C–O reductive elimination from a π-allyl-PdII intermediate, thereby eliminating the requirement for benzoquinone in this key catalytic step.
PMCID: PMC2971663  PMID: 20929224
22.  (μ-Piperazine-1,4-dicarbodithio­ato-κ4 S 1,S 1′:S 4,S 4′)bis­[bis­(triphenyl­phos­phane-κP)gold(I)] chloro­form disolvate 
In the title compound, [Au2(C6H8N2S4)(C18H15P)4]·2CHCl3, the digold complex resides on a crystallographic inversion center and co-crystallizes with two mol­ecules of chloro­form solvent. The piperazine-1,4-dicarbodithio­ate linker has an almost ideal chair conformation. The geometry about the gold atoms is severely distorted tetra­hedral punctuated by a very acute S—Au—S bite angle.
PMCID: PMC3247547  PMID: 22219852
23.  Dichlorido[2-(3,5-dimethyl-1H-pyrazol-1-yl-κN 2)ethanamine-κN]zinc(II) 
The amine title complex, [ZnCl2(C7H13N3)], resulted from imine hydrolysis in a Schiff base compound. The Zn metal atom has a distorted tetra­hedral geometry with the most significant deviation identified in the magnitude of the N—Zn—N angle. This deviation stems from the participation of the Zn and N atoms in a six-membered metallocyclic ring. The latter is in an approximate screw-boat conformation. Two strong N—H⋯Cl hydrogen bonds link the mol­ecules into ribbons propagating along the b-axis direction. The ribbons contain two second-order hydrogen-bonded motifs: a chain and a ring. The chain described by the graph set notation C 2 2(6) is formed by one hydrogen bond going in the forward direction (donor to acceptor) and the other in the backward direction (acceptor to donor). In the ring motif R 2 2(8), both hydrogen bonds propagate in the forward direction.
PMCID: PMC3253618  PMID: 22247716
24.  Crystallographic Characterization of 12-Helical Secondary Structure in β-Peptides Containing Side Chain Groups 
Journal of the American Chemical Society  2010;132(39):13879-13885.
Helices are the most extensively studied secondary structures formed by β-peptide foldamers. Among the five known β-peptide helices, the 12-helix is particularly interesting because the internal hydrogen bond orientation and macrodipole are analogous to those of α-peptide helices (α-helix and 310-helix). The β-peptide 12-helix is defined by i, i+3 C=O…H-N backbone hydrogen bonds and promoted by β-residues with a five-membered ring constraint. The 12-helical scaffold has been used to generate β-peptides with specific biological functions, for which diverse side chains must be properly placed along the backbone and, upon folding, properly arranged in space. Only two crystal structures of 12-helical β-peptides have previously been reported, both for homooligomers of trans-2-aminocyclopentanecarboxylic acid (ACPC). Here we report five additional crystal structures of 12-helical β-peptides, all containing residues that bear side chains. Four of the crystallized β-peptides include trans-4,4-dimethyl-2-aminocyclopentanecarboxylic acid (dm-ACPC) residues, and the fifth contains a β3-hPhe residue. These five β-peptides adopt fully folded 12-helical conformations in the solid state. The new crystal structures, along with previously reported data, allow a detailed characterization of the 12-helical conformation; average backbone torsion angles of β-residues and helical parameters are derived. These structural parameters are found to be similar to those for i, i+3 C=O…H-N hydrogen-bonded helices formed by other peptide backbones generated from α- and/or βamino acids. The similarity between the conformational behavior of dm-ACPC and ACPC is consistent with previous NMR-based conclusions that 4,4-disubstituted ACPC derivatives are compatible with 12-helical folding. In addition, our data show how a β3-residue is accommodated in the 12-helix, thus enhancing understanding of the diverse conformational behavior of this flexible class of β-amino acids.
PMCID: PMC2976582  PMID: 20828159
25.  Construction of Peptoids with All Trans-Amide Backbones and Peptoid Reverse Turns via the Tactical Incorporation of N-Aryl Side Chains Capable of Hydrogen Bonding 
The Journal of organic chemistry  2010;75(18):6068-6078.
The ability to design foldamers that mimic the defined structural motifs of natural biopolymers is critical for the continued development of functional biomimetic molecules. Peptoids, or oligomers of N-substituted glycine, represent a versatile class of foldamers capable of folding into defined secondary and tertiary structures. However, the rational design of discretely folded polypeptoids remains a challenging task, due in part to an incomplete understanding of the covalent and noncovalent interactions that direct local peptoid folding. We have found that simple, peptoid monomer model systems allow for the effective isolation of individual interactions within the peptoid backbone and side chains, and can facilitate the study of the role of these interactions in restricting local peptoid conformation. Herein, we present an analysis of a set of peptoid monomers and an oligomer containing N-aryl side chains capable of hydrogen bonding with the peptoid backbone. These model peptoids were found to exhibit well-defined local conformational preferences, allowing for control of the ω, φ, and ψ dihedral angles adopted by the systems. Fundamental studies of the peptoid monomers enabled the design and synthesis of an acyclic peptoid reverse-turn structure, in which N-aryl side chains outfitted with ortho-hydrogen bond donors were hypothesized to play a critical role in the stabilization of the turn. This trimeric peptoid was characterized by X-ray crystallography and 2D NMR spectroscopy, and was shown to adopt a unique acyclic peptoid reverse-turn conformation. Further analysis of this turn revealed an n→π*C=O interaction within the peptoid backbone, which represents the first reported example of this type of stereoelectronic interaction occurring exclusively within a polypeptoid backbone. The installation of N-aryl side chains capable of hydrogen bonding into peptoids is straightforward and entirely compatible with current solid-phase peptoid synthesis methodologies. As such, we anticipate that the strategic incorporation of these N-aryl side chains should facilitate the construction of peptoids capable of adopting discrete structural motifs, both turn-like and beyond, and will facilitate the continued development of well-folded peptoids.
PMCID: PMC3175427  PMID: 20722367

Results 1-25 (56)