Biologically many disease states lead to changes in expressed proteins. Therefore, "system changes" that occur must be considered in any treatment for the disease. This new approach to drug design and discovery would be particularly applicable to the diseases that involve adaptive changes in the central nervous system, such as neuropathic pain. There is growing evidence that drugs behave differently in pathological states than in normal states, thus preventing their effectiveness in pathological disease states. Therefore, a new paradigm for drug design is needed. In recent years, the melanocortin-4 receptor (MC4R) found in the spinal cord and CNS has received growing attention as a therapeutic target. MC4R based agonist ligands produce anti-opioid effects, and researchers have shown that an antagonist of the MC4R can produce pronounced anti-allodynic effect. Opioid receptors have been the central and most efficacious targets sought after for relieving neuropathic pain. In our new approach, single peptide molecules are designed to interact with opioid receptors as an agonist, and as an antagonist at the MC4 receptor. For the treatment of pain, a series of linear and cyclic peptides based on the overlapping pharmacophores of endogenous melanocyte stimulating hormone and opioid ligands are designed through computational aided molecular modeling and synthesized. Throughout the studies the opioid pharmacophore is maintained towards the N-terminal while melanocortin pharmacophore is maintained towards the C-terminal. Cyclization of peptides has been the central synthetic feature in designing the bifunctional ligands. The use of microwave has been shown to be very efficient in cyclizing the peptides. Solvent, reagent, power and temperature conditions are established for the microwave application in aiding the macromolecules for cyclizing their side chain termini.

This thesis describes the development of new thermal and oxidative radical cyclization methodologies and their application to the total syntheses of alkaloids, particularly to bridged diketopiperazine (DKP) alkaloids. A practical solvent free approach to diverse DKPs and quinazolines is described. The methodology proceeds by thermal silica gel mediated deprotection of the Boc protecting group and intramolecular condensation of the resulting free dipeptides and tripeptides. It was applied to the total syntheses of alkaloids glyantrypine and ardeemin. A major part of the thesis concerns with the discovery and applications of novel diketopiperazine derived alkoxyamines. Their propensity to undergo facile thermal C-O bond homolysis to generate captodative DKP radicals and persistent TEMPO radical allowed using them as radical surrogates. The methodology takes advantage of the persistent radical effect (PRE). The methodology based on PRE was applied in an asymmetric approach to the alkaloid asperparaline C. An asymmetric synthesis of a very advanced precursor to asperparaline C, 8- oxoasperparaline C, was accomplished in 11 steps and 15% overall yield. The key steps of the synthesis include a direct oxidative cyclization of DKPs, regioselective furan dearomatization with singlet oxygen and a reductive...

Thesis advisor: Jianmin Gao / Thesis advisor: Eranthie Weerapana / Cyclic peptides provide a privileged scaffold when optimizing interactions with various biological targets. Their rigidified structure decreases the entropic cost of binding by preorganizing residues in a fixed conformation, which may enhance binding affinity. These molecules occupy a larger chemical space than typical small molecule drugs and may provide good candidates for inhibiting protein-protein interactions or being able to interact with previously undruggable targets. Given the benefits of these structures we aim to develop a one-bead-one-compound peptide library for screening against relevant biological targets. Herein we describe several routes to achieving cyclic peptides through side chain interactions and head-to tail amide bond linkages. Additional considerations for the development of the on resin library such as linker strategies and sequencing methods will be discussed. / Thesis (MS) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Natural products are a rich source of lead compounds for treatment of cancer as well as other diseases. Researchers at the National Cancer Institute, as part of their continuing effort to discover anticancer agents from natural sources, created the 60 human tumor cell-line anticancer screen to test natural products for their potential against various types of cancer. Through this screening process a family of natural products called schweinfurthins was discovered to possess potent and differential activity. Of potentially great significance, the pattern of activity that the schweinfurthins displayed in the screen does not correlate with any currently used anticancer drug, indicating that the schweinfurthins likely act via a previously unknown mechanism or on a novel target. Our group has synthesized many of the natural schweinfurthins as well as numerous analogues in an effort to probe the pharmacophore and gain understanding of the key features that are important for potency as well as differential activity. During the course of these studies, it was discovered that the right-half of the molecule is most amenable for modifications. One potential modification to the schweinfurthins is to replace the resorcinol substructure seen in the right-half of the natural product with a heteroaromatic moiety such as a benzofuran or indole system. This change may produce analogues that are potentially more active, that contain motifs that are seen in many therapeutic drugs, and that have improved chemical stability relative to the natural products. With this goal in mind benzofuran and indole containing schweinfurthin analogues were synthesized. Once these compounds were prepared, it was found that such modifications were welltolerated, and in the case of the indole analogues activity in the 60 cell-line screen was equivalent to the corresponding natural product. In an effort to improve that activity, prenyl and geranyl side chains were added to the indole system, at both the C-2 and C-3 positions, to better match the structure of the natural schweinfurthins. In addition, analogues methylated selectively on the indole nitrogen or phenol were synthesized to improve stability. The impact of those modifications on the activity was tested, and potent compounds were found. The left-half of the schweinfurthins is prepared via a Lewis acid mediated cascade of a geranyl epoxide. The protecting group that is typically employed on the terminating phenol, a methoxymethyl ether or MOM group, is cleaved during the reaction. In the past preparation of an analogue that lacked a substituent at the C-5 position, it was found that the MOM cation released during the cyclization would participate in an electrophilic aromatic substitution reaction at the neighbouring position which resulted in the formation of a benzyl methyl ether. In order to probe the scope of this reaction and its potential utility in the synthesis of natural products, several geranyl epoxides with various "protecting groups" on the phenol were prepared and subjected to the cyclization conditions. These investigations have established that stabilization of the liberated cation determines the likelihood and regioselectivity of a tandem electrophilic aromatic substitution reaction.

A set of studies centered around the reactions of the active methine compound 1-carbomethoxy-5-dicyanomethyl-1,3-cyclohexadiene (the "ring-opened adduct"), obtained by base-induced ring-opening of the Diels-Alder adduct of 5,5-dicyanocyclopentadiene and methyl acrylate, has been carried out. A plan was devised for the anionic (at the dicyanomethyl carbon) ring-opened adduct whereby its reaction with electrophiles, for example Michael reactions with double-bond acceptors, would generate reactive intermediates that would undergo cyclization by tandem conjugate addition to the a,ß,?,d-unsaturated ring p-system to generate bicyclic compounds. In practice, reaction with di-<i>tert</i>-butyl methylidenemalonate, methyl vinyl ketone, and cyclopentenone generated intermediates that exhibited greater tandem reactivity than was anticipated: the bicyclic enolates were found to cyclize further by Thorpe-Ziegler-like reaction with the proximal nitrile to generate, after facile acid hydrolysis, substituted known tricyclic skeleta termed homobrendanes, specifically, tricyclo[5. 2. 1. 0^4,8]decenes. An attempt was made to generalize the reaction to other substrates, among them singly-activated Michael acceptors and 1,2-heteroatom electrophiles, but the generalization of the homobrendane forming reaction did not meet with success. Attempted functional group manipulations to probe the conversion of the homobrendane derived from di-<i>tert</i>-butyl methylidenemalonate to the homobrendane natural product 2-isocyanoallopupukeanane revealed the unreactivity of the skeletal double-bond toward electrophiles and the high reactivity of the ring ketone toward nucleophiles, among them mCPBA which brought about Baeyer-Villiger reaction, and chloride and hydroxide, which brought about addition/elimination reactions to cleave the last-formed homobrendane ring. <br /> The ring-opened adduct was also envisaged as a potential substrate in intramolecular Heck reactions. To this end, Heck substrates were generated from the ring-opened adduct anion and iodo- and bromo-benzyl halides. A key observation at this stage pertained to the unexpected acidity of the ring-opened adduct C5 proton, which could be deprotonated by DBU to bring about allylic isomerization, a finding that would provide a key insight to the pattern of reactivity later evidenced with alkyl propiolates. Optimization of the Heck substrate-generating reaction was followed by Heck reactions under Jeffery's conditions, which generated angular tricycles as intended, accompanied by aromatic compounds generated by base-induced HCN elimination/rearrangement and dehydrogenation. The Jeffery's conditions were optimized to limit the production of aromatics. <br /> The possibility of ring-opened adduct-derived vinyl silane intermediates undergoing cationic cyclizations led to a minor study based upon the bromination of allylsilanes and the elimination of TMSBr from 1,2-dibromo-3-trimethylsilyl compounds, accessible compounds unaccounted for in the review literature. It was determined that the combination of HBr and Br₂ (perhaps as HBr₃) was required to eliminate TMSBr, in contravention of the textbook account of electrophilic substitutions being the inherent reactions of allylsilanes and Br₂. <br /> Unexpected tandem reactivity was observed in the reactions of the anionic ring-opened adduct and alkyl propiolates under catalytic DBU conditions. Rather than tandem cyclization or simple adduct formation, the allenolate intermediates were determined to undergo extremely facile formal allenolate Cope rearrangements involving the ?,d-double-bond of the parent ring. Excess base intercepted the allenolate by deprotonating ring C5 and effecting 1,2-vinyl transfer by 3-<i>exo</i>-trig addition-elimination. The chemistry of the highly delocalized side-chain carbanion in the Cope product was studied in detail.

A set of studies centered around the reactions of the active methine compound 1-carbomethoxy-5-dicyanomethyl-1,3-cyclohexadiene (the "ring-opened adduct"), obtained by base-induced ring-opening of the Diels-Alder adduct of 5,5-dicyanocyclopentadiene and methyl acrylate, has been carried out. A plan was devised for the anionic (at the dicyanomethyl carbon) ring-opened adduct whereby its reaction with electrophiles, for example Michael reactions with double-bond acceptors, would generate reactive intermediates that would undergo cyclization by tandem conjugate addition to the a,ß,?,d-unsaturated ring p-system to generate bicyclic compounds. In practice, reaction with di-<i>tert</i>-butyl methylidenemalonate, methyl vinyl ketone, and cyclopentenone generated intermediates that exhibited greater tandem reactivity than was anticipated: the bicyclic enolates were found to cyclize further by Thorpe-Ziegler-like reaction with the proximal nitrile to generate, after facile acid hydrolysis, substituted known tricyclic skeleta termed homobrendanes, specifically, tricyclo[5. 2. 1. 0^4,8]decenes. An attempt was made to generalize the reaction to other substrates, among them singly-activated Michael acceptors and 1,2-heteroatom electrophiles, but the generalization of the homobrendane forming reaction did not meet with success. Attempted functional group manipulations to probe the conversion of the homobrendane derived from di-<i>tert</i>-butyl methylidenemalonate to the homobrendane natural product 2-isocyanoallopupukeanane revealed the unreactivity of the skeletal double-bond toward electrophiles and the high reactivity of the ring ketone toward nucleophiles, among them mCPBA which brought about Baeyer-Villiger reaction, and chloride and hydroxide, which brought about addition/elimination reactions to cleave the last-formed homobrendane ring. <br /> The ring-opened adduct was also envisaged as a potential substrate in intramolecular Heck reactions. To this end, Heck substrates were generated from the ring-opened adduct anion and iodo- and bromo-benzyl halides. A key observation at this stage pertained to the unexpected acidity of the ring-opened adduct C5 proton, which could be deprotonated by DBU to bring about allylic isomerization, a finding that would provide a key insight to the pattern of reactivity later evidenced with alkyl propiolates. Optimization of the Heck substrate-generating reaction was followed by Heck reactions under Jeffery's conditions, which generated angular tricycles as intended, accompanied by aromatic compounds generated by base-induced HCN elimination/rearrangement and dehydrogenation. The Jeffery's conditions were optimized to limit the production of aromatics. <br /> The possibility of ring-opened adduct-derived vinyl silane intermediates undergoing cationic cyclizations led to a minor study based upon the bromination of allylsilanes and the elimination of TMSBr from 1,2-dibromo-3-trimethylsilyl compounds, accessible compounds unaccounted for in the review literature. It was determined that the combination of HBr and Br₂ (perhaps as HBr₃) was required to eliminate TMSBr, in contravention of the textbook account of electrophilic substitutions being the inherent reactions of allylsilanes and Br₂. <br /> Unexpected tandem reactivity was observed in the reactions of the anionic ring-opened adduct and alkyl propiolates under catalytic DBU conditions. Rather than tandem cyclization or simple adduct formation, the allenolate intermediates were determined to undergo extremely facile formal allenolate Cope rearrangements involving the ?,d-double-bond of the parent ring. Excess base intercepted the allenolate by deprotonating ring C5 and effecting 1,2-vinyl transfer by 3-<i>exo</i>-trig addition-elimination. The chemistry of the highly delocalized side-chain carbanion in the Cope product was studied in detail.

Treatment of 1-(methylsulfinyl)-2-(phenylethynyl)benzene with 10 mol % of mercury dichloride and 1 equivalent of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in refluxing benzene gave benzo[b]thiophene in good yields. This method tolerated various functional groups in phenylethynyl moiety, including electron donating groups and electron withdrawing groups. Useing 1-(benzylsulfinyl)-2-(phenylethynyl)benzene as reaction substrate increased the yields of benzo[b]thiophene derivatives. Isotope effect showed that this cyclization reaction belong to Pummerer type cyclization reaction.

Pyrazoles have been focus of a large number of investigations in the design and synthesis of novel biologically active agents that show remarkable medicinal activities. Although pyrazoles have been studied for over a century as an important class of heterocyclic compounds, they still continue to attract considerable attention due to the wide range of medicinal activities they possess. Recent studies have shown that combination of a ferrocenyl unit with structural features of pyrazoles can lead to products with enhanced or/and unexpected biological activity since several ferrocene derivatives have already been shown to be active against a number of tumors. As a result, we have investigated the reaction of 3-ferrocenylpropynal with hydrazinium salts. As anticipated, these reactions afforded two kinds of pyrazoles, namely 1-alkyl/aryl-5-ferrocenylpyrazoles (1,5-isomer) and 1-alkyl/aryl-3- ferrocenylpyrazoles (1,3-isomer). In most cases, 1,5-pyrazole isomers have resulted from these reactions as the single or the major product of the reactions. The structures of 1-benzyl-5-ferrocenylpyrazole, 1-phenyl-5-ferrocenyl-pyrazole and 1- (2-hydroxy-ethyl)-3-ferrocenylpyrazole were identified by X-ray single crystal analysis. The analogous reactions between 3-phenylpropynal and hydrazinium salts were also studied, which afforded 1-alkyl/aryl-5-phenylpyrazoles (1,5-isomer) and/or v 1-alkyl/aryl-3-phenylpyrazoles (1,3-isomer). The regioselectivity of the reactions is mainly governed by the nature of the substituents in hydrazine derivative.

Pyrazoles have been intensely studied in the design and synthesis of biologically active agents because they display considerable medicinal activities. Recent studies have shown that integration of a ferrocenyl unit with structural features of pyrazoles can result in the formation of the new products with enhanced or/and unexpected biological activity since several ferrocene derivatives have already been illustrated to be active against a number of tumors. Therefore, we have investigated the electrophilic cyclizations of the hydrazones to afford 5-ferrocenyl-4-((4-nitrophenyl)sulfenyl)-substituted pyrazole derivatives. First, the requisite hydrazone derivatives were synthesized by the reactions of ferrocenyl propargyl aldehydes or ketones with a series of hydrazines. Then electrophilic cyclizations of these hydrazones were investigated by treating with 4-(nitrophenyl)sulfenyl chloride as electrophile. By employing these electrophilic cyclizations, a series of 5-ferrocenyl-4-((4-nitrophenyl)sulfenyl)-1H-pyrazoles, 5-ferrocenyl-4-((4-nitrophenyl) sulfenyl)-3-methyl-1H-pyrazoles and 5-ferrocenyl-4-((4-nitrophenyl)sulfenyl)-3-phenyl-1H-pyrazoles have been synthesized in moderate to good yields.

Part I: Pyrrolidine derivatives were attached a methoxy group on a-C position of pyrrolidine-ring via anodic oxidation. Followed with alkylation and series of transformation under Lewis acids to obtain tropane alkaloids. Part II: Application of intramolecular radical cyclization toward the synthesis of aporphine alkaloids. Tributyltinhydride and AIBN were used to generate aryl radicals. Trapping of aryl radicals with unsaturated alkenes led to products.