PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (69)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
author:("guze, Ilia A.")
1.  1,4-Diazaspiro[2.2]pentanes as a Flexible Platform for the Synthesis of Diamine-Bearing Stereotriads 
The Journal of organic chemistry  2012;77(5):2446-2455.
Nitrogen-containing stereotriads occur in a number of biologically active compounds, but general and flexible methods to access these compounds are limited mainly to the manipulation of chiral olefins. An alternative approach is to employ a highly chemo-, regio-, and stereocontrolled allene oxidation that can install a new carbon–heteroatom bond at each of the three original allene carbons. In this paper, an intramolecular/intermolecular allene bis-aziridination is described that offers the potential to serve as a key step for the construction of stereotriads containing vicinal diaminated motifs. The resultant 1,4-diazaspiro[2.2]pentane (DASP) scaffolds contain two electronically differentiated aziridines that undergo highly regioselective ring-openings at C1 with a variety of heteroatom nucleophiles to give chiral N,N-aminals. Alternatively, the same DASP intermediate can be induced to undergo a double ring opening reaction at both C1 and C3 to yield vicinal diaminated products corresponding to formal ring opening at C3. The chirality of a propargyl alcohol is easily transferred to the DASP with good fidelity, providing a new paradigm for the construction of enantioenriched nitrogen-containing stereotriads.
doi:10.1021/jo3000282
PMCID: PMC4500119  PMID: 22304460
2.  Modular Functionalization of Allenes to Aminated Stereotriads 
Journal of the American Chemical Society  2012;134(26):10807-10810.
Nitrogen-containing stereotriads- compounds with three adjacent stereodefined carbons- are commonly found in biologically important molecules. However, the preparation of molecules bearing these motifs can be challenging. Herein, we describe a modular oxidation protocol which converts a substituted allene to a triply functionalized amine of the form C-X/C-N/CY. The key step employs a Rh-catalyzed intramolecular conversion of the allene to a strained bicyclic methylene aziridine. This reactive intermediate is further elaborated to the target products, often in one reaction vessel and with effective transfer of the axial chirality of the allene to point chirality in the stereotriad.
doi:10.1021/ja304859w
PMCID: PMC4476975  PMID: 22708990
3.  Aminodiols via Stereocontrolled Oxidation of Methyleneaziridines 
Organic Letters  2014;16(6):1696-1699.
A highly diastereoselective Ru-catalyzed oxidation/reduction sequence of bicyclic methyleneaziridines provides a facile route to complex 1-amino-2,3-diol motifs. The relative anti stereochemistry between the amine and the vicinal alcohol are proposed to result from 1,3-bischelation in the transition state by the C1 and C3 heteroatoms.
doi:10.1021/ol5003576
PMCID: PMC3993784  PMID: 24617556
4.  Phosphinogold(I) Dithiocarbamate Complexes: Effect of the Nature of Phosphine Ligand on Anticancer Properties 
Inorganic Chemistry  2014;53(4):2058-2067.
The reactions of potassium salts of the dithiocarbamates L {where L = pyrazolyldithiocarbamate (L1), 3,5-dimethylpyrazolyldithiocarbamate (L2), or indazolyldithiocarbamate (L3)} with the gold precursors [AuCl(PPh3)], [Au2Cl2(dppe)], [Au2Cl2(dppp)], or [Au2Cl2(dpph)] lead to the new gold(I) complexes [AuL(PPh3)] (1–3), [Au2L2(dppe)] (4–6), [(Au2L2)(dppp)] (7–9), and [Au2(L)2(dpph)] (10–12) {where dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, and dpph = 1,6-bis(diphenylphosphino)hexane}. These gold compounds were characterized by a combination of NMR and infrared spectroscopy, microanalysis, and mass spectrometry; and in selected cases by single-crystal X-ray crystallography. Compounds 4–6, which have dppe ligands, are unstable in solution for prolonged periods, with 4 readily transforming to the Au18 cluster [Au18S8(dppe)6]Cl2 (4a) in dichloromethane. Compounds 1–3 and 7–12 are all active against human cervical epithelioid carcinoma (HeLa) cells, but the most active compounds are 10 and 11, with IC50 values of 0.51 μM and 0.14 μM, respectively. Compounds 10 and 11 are more selective toward HeLa cells than they are toward normal cells, with selectivities of 25.0 and 70.5, respectively. Further tests, utilizing the 60-cell-line Developmental Therapeutics Program at the National Cancer Institute (U.S.A.), showed 10 and 11 to be active against nine other types of cancers.
Phosphinogold(I) complexes, featuring heterocycle dithiocarbamate ligands, have been synthesized and characterized. These complexes are active against several cancer cells, with the most active compound able to act against ten cancer cells in vitro and with GI50 as low as 0.03 μM against leukemia SR cell line.
doi:10.1021/ic4025926
PMCID: PMC3993921  PMID: 24476103
5.  Evaluation of a Cyclopentane-Based γ-Amino Acid for the Ability to Promote α/γ-Peptide Secondary Structure† 
The Journal of organic chemistry  2013;78(24):12351-12361.
We report the asymmetric synthesis of the y-amino acid (1R,2R)-2-aminomethyl-1-cyclopentane carboxylic acid (AMCP) and an evaluation of this residue's potential to promote secondary structure in α/γ-peptides. Simulated annealing calculations using NMR-derived distance restraints obtained for α/γ-peptides in chloroform reveal that AMCP-containing oligomers are conformationally flexible. However, additional evidence that suggests an internally hydrogen-bonded helical conformation is partially populated in solution. From these data, we propose characteristic NOE patterns for formation of the α/γ-peptide 12/10-helix and present discussion of the apparent conformational frustration of AMCP-containing oligomers.
doi:10.1021/jo401501g
PMCID: PMC4109159  PMID: 24303945
6.  Transfer of Chirality in Rhodium-Catalyzed Intramolecular (5+2) Cycloaddition of 3-Acyloxy-1,4-enyne (ACE) and Alkyne: Enantioselective Synthesis of Bicyclo[5.3.0]decatrienes 
Angewandte Chemie (International ed. in English)  2013;52(51):10.1002/anie.201306919.
Chiral Bicyclic
Bicyclo[5.3.0]decatrienes were prepared enantioselectively for the first time from readily available chiral 3-acyloxy-1,4-enynes (ACEs). The chirality of the allylic/propargylic esters in ACEs could be transferred with high efficiency to the bicyclic products in most cases. The experimentally observed overall inversion of stereochemistry confirmed the prediction from previous computational studies.
doi:10.1002/anie.201306919
PMCID: PMC3867534  PMID: 24150975
stereospecific; cycloaddition; rhodium; enyne; polycyclic; catalysis
7.  Crystal structure of nitrido[5,10,15,20-tetra­kis(4-methylphenyl)­porphyrinato]­manganese(V) 
In the title compound the Mn Nnitride distance is 1.516 (4) Å. The Mn atom is displaced from the plane defined by the four equatorial nitro­gen atoms toward the nitride ligand by 0.3162 (6) Å.
The title compound, [Mn(C48H36N4)(N)], is a manganese(V) complex with the transition metal in a square-pyramidal coordination geometry and a nitride as the axial ligand. The complex resides on a crystallographic inversion center and only one half of it is symmetry independent. The MnV atom and the nitride N atom are equally disordered across the inversion center. The Mn N distance is 1.516 (4) Å. The MnV atom is displaced from the plane defined by the four equatorial nitro­gen atoms toward the nitride ligand by 0.3162 (6) Å.
doi:10.1107/S1600536814020558
PMCID: PMC4257217  PMID: 25484663
porphyrin; nitride; crystal structure; manganese(V) complex
8.  Structure-activity studies of divin: an inhibitor of bacterial cell division 
ACS medicinal chemistry letters  2013;4(9):880-885.
We describe the synthesis and SAR studies of divin—a small molecule that blocks bacterial division by perturbing the assembly of proteins at the site of cell septation. The bacteriostatic mechanism of action of divin is distinct from other reported inhibitors of bacterial cell division and provides an opportunity for assessing the therapeutic value of a new class of antimicrobial agents. We demonstrate a convenient synthetic route to divin and its analogs, and describe compounds with a 10-fold increase in solubility and a 4-fold improvement in potency. Divin analogs produce a phenotype that is identical to divin, suggesting that their biological activity comes from a similar mechanism of action. Our studies indicate that the 2-hydroxynaphthalenyl hydrazide portion of divin is essential for its activity and that alterations and substitution to the benzimidazole ring can increase its potency. The SAR study provides a critical opportunity to isolate drug resistant mutants and synthesize photoaffinity probes to determine the cellular target and biomolecular mechanism of divin.
doi:10.1021/ml400234x
PMCID: PMC3773082  PMID: 24044050
divin; antimicrobial; synthesis; SAR
9.  Structure–Activity Studies of Divin: An Inhibitor of Bacterial Cell Division 
ACS Medicinal Chemistry Letters  2013;4(9):880-885.
We describe the synthesis and structure–activity relationship (SAR) studies of divin, a small molecule that blocks bacterial division by perturbing the assembly of proteins at the site of cell septation. The bacteriostatic mechanism of action of divin is distinct from other reported inhibitors of bacterial cell division and provides an opportunity for assessing the therapeutic value of a new class of antimicrobial agents. We demonstrate a convenient synthetic route to divin and its analogues, and describe compounds with a 10-fold increase in solubility and a 4-fold improvement in potency. Divin analogues produce a phenotype that is identical to divin, suggesting that their biological activity comes from a similar mechanism of action. Our studies indicate that the 2-hydroxynaphthalenyl hydrazide portion of divin is essential for its activity and that alterations and substitution to the benzimidazole ring can increase its potency. The SAR study provides a critical opportunity to isolate drug resistant mutants and synthesize photoaffinity probes to determine the cellular target and biomolecular mechanism of divin.
doi:10.1021/ml400234x
PMCID: PMC3773082  PMID: 24044050
Divin; antimicrobial; synthesis; SAR
10.  Structural, Spectroscopic, and Computational Characterization of the Azide Adduct of FeIII(2,6-diacetylpyridinebis(semioxamazide)), a Functional Analogue of Iron Superoxide Dismutase 
Inorganic chemistry  2013;52(15):8909-8918.
We have prepared and thoroughly characterized, using X-ray crystallographic, spectroscopic, and computational methods, the diazide adduct of [FeIII(dapsox)(H2O)2]1+ [dapsox=2,6-diacetylpyridinebis(semioxamazide)] (1), alow-molecular weight, functional analogue of iron superoxide dismutase (FeSOD). The X-ray crystal structure of the dimeric form of 1, (Na[FeIII(dapsox)(N3)2] DMF)2 (2) shows two axially coordinated, symmetry inequivalent azides with differing Fe–N3 bond lengths and Fe–N–N2 bond angles. This inequivalence of the azide ligands likely reflects the presence of an inter-dimer H-bonding interaction between a dapsox NH group and the coordinated nitrogen of one of the two azide ligands. Resonance Raman (rR) data obtained for frozen aqueous solution and solid-state samples of 2 indicate that the azides remain inequivalent in solution, suggesting that one of the azide ligands of 1 engages in an intermolecular hydrogen bonding interaction with a water molecule. Density functional theory (DFT) and time-dependent DFT calculations have been used to study two different computational models of 1, one using coordinates taken from the X-ray crystal structure of 2, and the other generated via DFT geometry optimization. An evaluation of these models on the basis of electronic absorption, magnetic circular dichroism, and rR data indicates that the crystal structure based model provides a more accurate electronic structure description of 1, providing further support for the proposed intermolecular hydrogen bonding of 1 in the solid state and in solution. An analysis of the experimentally validated DFT results for this model reveals that the azides have both σ- and π-bonding interactions with the FeIII center and that more negative charge is located on the Fe-bound, rather than on the terminal, nitrogen atom of each azide. These observations are reminiscent of the results previously reported for the azide adduct of FeSOD and provide clues regarding the origin the high catalytic activity of Fe-dapsox for superoxide disproportionation.
doi:10.1021/ic401098x
PMCID: PMC3974274  PMID: 23875582
11.  Generation of Rhodium(I) Carbenes from Ynamides and Their Reactions with Alkynes and Alkenes 
Rh(I) carbenes were conveniently generated from readily available ynamides. These metal carbene intermediates could undergo metathesis with electron-rich or neutral alkynes to afford 2-oxo-pyrrolidines or be trapped by tethered alkenes to yield 3-azabicyclo[3.1.0]hexanes, a common skeleton in numerous bioactive pharmaceuticals. Although the scope of the former is limited, the latter reaction tolerates various substituted alkenes.
doi:10.1021/ja4047069
PMCID: PMC3884031  PMID: 23701315
12.  n→π* Interactions of Amides and Thioamides: Implications for Protein Stability 
Carbonyl–carbonyl interactions between adjacent backbone amides have been implicated in the conformational stability of proteins. By combining experimental and computational approaches, we show that relevant amidic carbonyl groups associate through an n→π* donor–acceptor interaction with an energy of at least 0.27 kcal/mol. The n→π* interaction between two thioamides is 3-fold stronger than between two oxoamides due to increased overlap and reduced energy difference between the donor and acceptor orbitals. This result suggests that backbone thioamide incorporation could stabilize protein structures. Finally, we demonstrate that intimate carbonyl interactions are described more completely as donor–acceptor orbital interactions rather than dipole–dipole interactions.
doi:10.1021/ja4033583
PMCID: PMC3742804  PMID: 23663100
13.  n→π* Interactions of Amides and Thioamides: Implications for Protein Stability 
Carbonyl–carbonyl interactions between adjacent backbone amides have been implicated in the conformational stability of proteins. By combining experimental and computational approaches, we show that relevant amidic carbonyl groups associate through an n→π* donor–acceptor interaction with an energy of at least 0.27 kcal/mol. The n→π* interaction between two thioamides is 3-fold stronger than between two oxoamides due to increased overlap and reduced energy difference between the donor and acceptor orbitals. This result suggests that backbone thioamide incorporation could stabilize protein structures. Finally, we demonstrate that intimate carbonyl interactions are described more completely as donor–acceptor orbital interactions rather than dipole–dipole interactions.
doi:10.1021/ja4033583
PMCID: PMC3742804  PMID: 23663100
14.  A Peptoid Ribbon Secondary Structure** 
doi:10.1002/anie.201208630
PMCID: PMC3756557  PMID: 23576308
foldamers; peptidomimetics; peptoids; ribbon; secondary structure
15.  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.
doi:10.1021/ol3008815
PMCID: PMC3445736  PMID: 22568480
16.  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.
doi:10.1021/ic301799p
PMCID: PMC3494491  PMID: 23092381
17.  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.
doi:10.1021/jo300973r
PMCID: PMC3420071  PMID: 22793991
18.  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.
doi:10.1107/S1600536813011112
PMCID: PMC3648325  PMID: 23723945
19.  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.
doi:10.1021/ol300045c
PMCID: PMC3326344  PMID: 22394273
20.  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.
doi:10.1039/c2cc17406e
PMCID: PMC3334501  PMID: 22252254
21.  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.
doi:10.1021/ja210045s
PMCID: PMC3351109  PMID: 22280019
Racemic Protein Crystallization; Quasiracemic Proteins; Unnatural Amino Acids; Pentafluorophenylalanine; Villin Headpiece Subdomain
23.  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.
doi:10.1021/ja204755p
PMCID: PMC3186054  PMID: 21861531
24.  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
25.  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.
doi:10.1002/anie.201101301
PMCID: PMC3429132  PMID: 21567680
γ-peptides; 14-helix; H-bond; backbone; NOE

Results 1-25 (69)