Browsing by Subject "Cyclopropane"
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Item Design and synthesis of conformationally constrained Src SH2 ligands for protein–ligand thermodynamic evaluation(2016-08) Gravenstreter, Alicia Nicole; Martin, Stephen F.; Keatinge-Clay, Adrian TPredicting how small structural changes will impact the thermodynamics of binding a small molecule to a protein represents a major challenge in the fields of drug design and biological recognition. The tetrapeptide, pYEEI, binds to the sarcoma (Src) SH2 domain in both hot spot and non-hot spot locations, presenting an opportunity to examine how ligand preorganization at a non-hot spot region will affect the thermodynamics of binding. Incorporation of a cyclopropane to constrain both the backbone and side-chain of the isoleucine residue of the native pYEEI ligand will allow us to preorganize the ligand in its binding conformation for thermodynamic evaluation. Several attempts towards the preparation of the constrained ligand will be discussed as well as preparation of a flexible control ligand for direct comparison.Item Mutant peptides and proteins : a molecular inquiry into biological form and function(1995-12) Spaller, Mark Robert; Not availableItem New chemistry of donor-acceptor cyclopropanes(2004) Yu, Ming; Pagenkopf, Brian L.Donor-Acceptor (DA) cyclopropanes are considered to be well-understood compounds with predictable chemistry. This dissertation focuses on our recent advances and synthetic applications of DA cyclopropanes principally involving 1,3-dipole intermediates revealed by reactions with Lewis acids. Particular emphasis is placed on reactions involving sugar-derived substrates. Chapter one is an overview of the literature preparations and synthetic applications of DA cyclopropanes. It begins with general DA cyclopropanes but is mostly focused on carbohydrate-derived cyclopropanes. Chapter two describes our intramolecular glucal cyclopropanation approach toward lactonized cyclopropanes 2.5a-c, their transformations under mild conditions, and their application to the quasi formal synthesis of the natural product xylobovide 2.34a. Chapter three investigates the different chemical behaviors of glucal-derived lactonized cyclopropane 2.5a under the influence of a variety of different Lewis acids. Use of boron trifluoride etherate (BF3•OEt2) leads to regioselective mono-desilylation of the di-tert-butylsilylene ether to 2.27; trimethylsilyl trifluoromethanesulfonate (TMSOTf) results in anhydro-sugar 3.8 formation; and titanium tetrachloride (TiC4) facilitates stereoselective allylation and glycosidation. Chapter four discuses our recently discovered formal [3+2] dipolar cycloaddition reactions of DA cyclopropanes with a wide variety of dipolarophiles including silyl enol ethers, imines, aldehydes and nitriles. The extension of nitrile cyclization to general noncarbohydrate derived DA cyclopropanes leads to the discovery of a novel synthetic methodology toward pyrroles, bipyrroles and thienylpyrroles. Finally, the [3+2] cycloaddition has also been extended to heterocycles including pyridines, quinolines and indoles. Chapter five summarizes the investigation of regio-selective mono-desilylation of di-tert-butylsilylene ethers as a new protocol for selective hydroxy protection. Under optimized conditions, the reaction demonstrates high regioselectivity as well as strong functional group compatibility, and proves promising as a new protocol for selectively manipulating 1,3-diols. Chapter six provides the experimental procedures and characterization of all the new compounds.Item Studies on the Daphniphyllum alkaloids : strategies towards the synthesis of daphnicyclidin alkaloids(2008-05) Harrington, Ryan Matthew, 1980-; Magnus, Philip D.Herein describes our approaches to the Daphniphyllum alkaloids. Specifically targeted are the recently isolated daphnicyclidins. The first chapter describes the structural diversity and biological properties of this class of alkaloids. Chapter 2 discusses some exploratory chemistry towards the daphnicyclidin fused tricycle. Chapter 3 describes the use of cyclopropanes in synthesis and their use in our ring expansion strategy. Preliminary results on the key cyclopropane ring expansion and the stereoselective quaternary center formation are also discussed. The chemistry concerning the diasteroselective cyclopropanation of a key intermediate and further details concerning the cyclopropane ring expansion are delineated. Chapter 4 contains the experimental details and characterization data for all new reported compounds.Item Studies on the viability of cyclopropane-containing peptidomimetics and application of the vinylogous Mannich reaction to the syntheses of indolizidine natural products(2003) Reichelt, Andreas; Martin, Stephen F.1,2,3-Trisubstituted cyclopropanes have been previously incorporated into inhibitors of matrix metalloproteases, in order to mimic extended conformations of the peptide backbones and orient the amino acid side chains. Two reduced dipeptides, which are flexible analogues of these cyclopropane-containing peptidomimetics, were synthesized. Biological evaluation of the flexible compounds, the conformationally restricted peptidomimetics, and the parent inhibitor provided a deeper insight into the scope and limitation of cyclopropanecontaining replacements as mimics for peptide secondary structures. A concise enantiospecific synthesis of the angiotensin-converting enzyme inhibitor A58365A has been achieved. In the key step, a sequence involving a vinylogous Mannich reaction followed by a base-induced lactone–lactam rearrangement was applied to establish the indolizidine core of the molecule. A conceptually novel approach to the potent immunosuppressant FR901483 has been proposed. It has been demonstrated that an addition– vinylogous Mannich reaction sequence can be employed to obtain unsymmetrical α,α-disubstituted amines from carbamate-protected lactams. This sequence could be applied to the diastereoselective generation of one of the bridgehead centers in FR901483.Item Synthesis and evaluation of conformationally constrained peptide replacements and studies toward the total synthesis of kidamycin(2004) Plake, Hilary Ruth; Martin, Stephen F.A series of conformationally constrained pseudopeptides derivative of the tripeptide pYVN were designed and synthesized. The conformationally restricted compounds contained either trans- or cis-cyclopropanes as replacements to enforce locally extended and reverse turn peptide conformations, respectively. In addition, the proper flexible control molecules were prepared. All compounds were evaluated for the ability to bind to the Grb2-SH2 domain in order to determine the energetic consequences of introducing a conformational constraint into peptide ligands. No difference in the ∆Gbinding between the trans-cyclopropane and its control partner was observed. Surprisingly, there was an entropic disadvantage when comparing the binding energetics of the constrained and flexible pseudopeptides. Therefore, the introduction of the cyclopropane constraint was associated with an entropic disadvantage in the system, which is the opposite of conventional wisdom. An X-ray crystal structure of the trans- cyclopropane containing ligand bound to the Grb2-SH2 domain was obtained and vii discussed. On the other hand, cis-cyclopropane containing pseudopeptides do not seem to enforce the desired turn conformation of the ligand. A method to allow access to unsymmetrical C-aryl glycoside natural products was developed through employing a disposal tether to enforce the desired regioselectivity in a [4+2] cycloaddition between benzyne and glycosyl-substituted furan. Application of this novel strategy toward the synthesis of kidamycin is discussed. Additional synthetic routes, including utilizing Suzuki’s O → C glycoside rearrangement are also provided. Studies toward the synthesis of sugar ring E and F are illustrated.