Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2009. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3511. Adviser: Paul J. Hergenrother. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.

Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2009. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3515. Adviser: Scott E. Denmark. Includes bibliographical references (leaves 342-373) Available on microfilm from Pro Quest Information and Learning.

Glycosyl iodides have proven to be highly efficient and stereospecific glycosyl donors. Unfortunately with such high reactivity, they possess short shelf lives. Glycosyl bromides, on the other hand, are more robust than their iodo-counterparts. But, glycosylations using glycosyl bromides in the absence of Lewis acid catalysts are slow. Recently, we have demonstrated conditions augmenting glycosylations involving glycosyl bromides to levels matching the efficiency and stereospecificity of glycosyl iodides. Results of our studies will be discussed.

Amide linked carbohydrates represent a tremendously different type of compound. Sugars have traditionally been linked together as either N or O linked via the anomeric carbon to make larger compounds, i.e. Sialyl Lewis X. This linkage leads to great instability under acidic and biological conditions. N-Acetyl neuraminic acid is a naturally occurring delta peptide. Colominic acid is the naturally occurring O linked polymer of N-acetyl neuraminic acid. This polymer has been found to possess a helical structure starting at the hexamer length. Changing from an O linkage to an amide linkage provides much greater stability under various conditions, including acidic and biological. Various derivatives of N-acetyl neuraminic acid have been synthesized and linked together via an amide linkage. Experiments including NH/ND exchange and circular dichroism has given strong evidence indicating there is some type of ordered secondary structure. Proving the existence of secondary structure is extremely difficult. Techniques traditionally used in the area of peptide chemistry to elucidate secondary structure cannot be directly applied to this system. Various techniques will be used and evidence presented to support the formation of secondary structure.

An unprecedented anionic condensation, fragmentation, and elimination sequence from the coupling of bicyclo[2.2.1]heptenones with aldehydes is described. This reaction leads to the stereoselective formation of disubstituted five-membered rings which are present in a wide array of bioactive molecules. Oxabicyclo[2.2.1]heptenone 106 also undergoes two-carbon ring expansions when subjected to anionic conditions and Michael acceptors. As an outgrowth of this interesting chemistry, we have been able to access the carbon skeleton of oxygenated cembranoids by subjecting bis-activated ene-yne to the enolate from oxabicyclo[2.2.1]heptenone 106. In order to demonstrate the synthetic utility of the anionic condensation, fragmentation, and elimination reaction, we have applied it to the synthesis of nortetillapyrone.

We have designed and synthesized several small libraries of chiral nitrogen-based ligands and tested their ability to provide stereoselectivity in selected transition metal-catalyzed reactions. Chapter 1 provides background for asymmetric catalysis and summarizes applications of trans-2,5-disubstituted pyrrolidine moieties as chiral auxiliaries and as building blocks for chiral ligands. Although these moieties have found many successful applications as chiral auxiliaries in different asymmetric reactions, application of chiral ligands derived from these moieties has been rare. Chapter 2 summarizes the synthesis of several small libraries of chiral ligands derived from trans-2,5-dimethylpyrrolidine and trans-2,5-diarylpyrrolidines. A modular synthetic strategy has been followed to ensure ease in constructing these libraries with diversity. Small libraries of pyridine-pyrrolidine ligands, bidentate N-O and N-S type ligands, bidentate and tridentate Schiff-base ligands, aminoalcohol ligands, tridentate N-N-O type ligands, C2-symmetric diamine ligands, and a cyclopalladated complex have been prepared. Chapter 3 summarizes the results of using these ligands in several transition metal-catalyzed asymmetric processes, including allylic alkylation, cyclopropanation and diethylzinc addition to benzaldehyde. The pyridine-pyrrolidine ligands are effective catalyst precursors for the palladium-catalyzed allylic alkylation and provided moderate to good stereoselectivities. The stereoselectivity of this reaction catalyzed by palladium complexes of the pyridine-pyrrolidine ligands could be adjusted by changing the substituents on the 6-position of the pyridine ring as well as the chelation size of the complexes. Evidence from these experimental results, 1H NMR studies and MM3* calculations suggested that nucleophilic attack to the 1,3-diphenylallyl moiety in the transition state mainly occurred trans to the pyridine ring of the less stable conformation of the palladium complexes. Combinatorial screening has been applied to accelerate the discovery of new catalysts. Although we did not identify effective catalysts for allylic alkylation, results from the combinatorial screening suggested that the chiral Schiff-base ligands were effective catalyst precursors for copper-catalyzed cyclopropanation. The chiral aminoalcohol ligands were found to be active catalysts for the asymmetric diethylzinc addition to benzaldehyde. The substituents at the alpha position of the hydroxy group played an important role in determining the stereoselectivity of the diethylzinc addition to benzaldehyde.

A highly efficient and flexible approach to fused polycyclic ethers that couples the synthesis of C-glycosides with enol ether-olefin ring closing metathesis (RCM) and/or acid mediated cyclizations has been presented. We have developed a single flask, enol ether oxidation, carbon-carbon bond forming approach to the generation of C-glycosides. We have been successful in the formation of both alpha- (Table 1.11) and beta- (Table 1.10) C-glycosides from a single glycosyl donor (glycal anhydride). Both Schrock's Mo catalyst 123 and the 2nd generation Grubbs' Ru catalyst 124 have been used in enol ether-olefin RCM reactions to generate alpha-substituted enol ethers. PPTS, pyridine, and heat have been effective in generating alpha-unsubstituted enol ethers. Our ability to couple the formation of C-glycosides with RCM or acid mediated cyclizations directed our attention to the use of this strategy in the synthesis of fused polycyclic ether natural products. We initially targeted the synthesis of hemibrevetoxin B (2). We have completed a formal total synthesis of ±-hemibrevetoxin B to Mori intermediate 167 in 21 overall steps and in 3.9% yield from the Danishefsky-Kitahara diene 74. Our success in the formal total synthesis of hemibrevetoxin B gave us great confidence to pursue the synthesis of gambierol 6. We have synthesized the A-D ring system 283 in 20 steps and in 4.2% overall yield. The FG ring system 302 was synthesized in 9 steps and in 13% overall yield. We have been successful in the generation of C-glycosides and have been able to apply them in the formation of fused polycyclic ether natural products.

The recent upsurge of interest in the peptide-based drug molecules has been accompanied by a great deal of attention to the design of stereochemically defined non-proteinogenic amino acids. As a continuous effort to develop efficient syntheses of χ-constrained amino acids in our group, we recently have developed a practical methodology for the asymmetric synthesis of substituted pyroglutamic acid, glutamic acid and proline analogues, which are of important use in examining the relationships between conformation and bioactivities of biologically important peptides (e.g. DPDPE, α-MSH). The key step in this method is an asymmetric Michael addition reaction between a chiral Ni(II)-complex of the glycine Schiff base (S)-NiGlyBPB, and derivatives of α,β-unsaturated carboxylic acids. This new method is the first highly diastereoselective, room temperature, organic base-catalyzed, asymmetric Michael addition reaction. Excellent chemical yields and diastereoselectivity, along with the simplicity of experimental procedure, renders the present method of immediate use for preparation of various novel beta-substituted pyroglutamic acids, glutamic acids and prolines. Decomposing the resulting addition products in acidic medium, followed by neutralizing with ammonia, gave optically pure substituted pyroglutamic; acids in good yields (>80%). The substituted pyroglutamic acids were converted to the corresponding substituted glutamic acids by hydrolysis in 6N HCl, or to substituted proline analogues by selective reduction of amide carbonyl group to a methylene group. Both novel substituted glutamic acids and prolines are being incorporated into biologically important peptide MT-II analogues for structure-activity studies.

A highly efficient and general approach to fused ether ring systems has been presented. The approach couples stereoselective C-glycoside forming reactions with subsequent annulations. C-glycosides were formed from glycals through an oxidation and carbon-carbon bond forming sequence. Annulations involving a two step methylenation/enol ether-olefin ring closing metathesis or a single flask, acid mediated cyclization/elimination proved to be efficient tribenzyl- D-glucal (95), [4.4.0] and [4.5.0] bicyclic enol ethers (194, 200, 204) were stereoselectively generated in 2-4 steps in good overall yields (53%, 57%, and 39% respectively). Iteration resulted in the stereoselective formation of tricylic enol ethers (240, 241). In addition, our C-glycoside approach was applied to the synthesis of fused ether containing natural products. A formal synthesis of (±)-hemibrevetoxin B (2) was achieved by intercepting Mori's intermediate ( 278) in 21 steps and 3.8% overall yield. The C-glycoside approach to fused ethers was also demonstrated in the synthesis of halichondrin B's model compounds, bicycle 374 and tricycle 383. Subsequent fragmentation of 383 resulted in bicyclic alcohol 384 which correlates to the C,23-C,38 subunit of halichondrin B (8).

Non-covalent interactions influence supramolecular organization in the solid, solution and gaseous state. While intermolecular forces are well understood individually, it is difficult to predict how their interplay will lead to a highly symmetric and low energy crystalline solid. Analysis, design, and prediction of crystalline architecture is a recently popularized sub-field of supramolecular chemistry referred to as 'crystal engineering'. Crystal engineering seeks to fully understand non-bonding intermolecular forces in order to build crystalline solids that serve some designed purpose. Hydrogen bonds are strong and directional intermolecular forces used to build crystalline solids with desirable supramolecular topography. Much focus has been placed on cyclic diamides, such as diureas and dioxamides, as robust structural motifs due to their propensity to form highly rigid hydrogen bonded structures. The diketopiperazine is an exceptional cyclic diamide synthon due to its planar, inflexible, ring structure and predictable solid state organization. Professor E. A. Mash has studied the indane diketopiperazine designed such that hydrogen bonding occurs along one principal axis, while two orthogonal and linearly independent non-covalent interactions occur 90° offset from each other. Substitution changes to the indane ring system can explore a range of non-bonding interactions influencing self-recognition. Several different 1,4-alkyloxy indane 2,5-diketopiperazines were synthesized and studied. The 1,4-dodecyloxy and 1,4-octadecyloxy diketopiperazines are liquid crystalline as observed by differential scanning calorimetry and optical microscopy. The 1,4-dodecyloxy diketopiperazine crystal structure, while exhibiting much alkyl chain disorder, indicated the supramolecular construct remained constant throughout the 1,4-alkyloxy indane diketopiperazine series. In order to better understand non-bonding associations of the indane diketopiperazines in the solid, solution and gas phase, an N-methylated 1,4-methyloxy 2,5-diketopiperazine was synthesized and studied by X-ray crystallography, ESI mass spectrometry, and by UV-VIS and NMR spectroscopy. While the solid state N-Me diketopiperazine is polymorphic, existing as hydrogen bonded dimer and polymer, the gas and solution phase experiments indicated predominant dimeric associations. 1,4-Dialkyloxy indane bis-diketopiperazines were envisioned as the next generation of robust indane targets, and their synthesis required construction of novel unnatural bis-amino esters. All of the bis-diketopiperazines exhibited extremely high melting points and low solubilities. Microcrystalline bis-diketopiperazine material was analyzed by X-ray powder diffraction.