(+)-Neopeltolide is a highly potent marine polyketide natural product with activity against multiple cancer cell lines in vitro. The nanomolar range of antifungal and anticancer cytotoxicity in this tetrahydropyran (THP)-containing polyketide, combined with its limited natural supply, has led to several syntheses. In this study, the feasibility of an oxa-Michael conjugate addition route to cis-2,6-THP rings is examined through the efforts toward a total synthesis of the macrocyclic core of (+)-neopeltolide using a highly convergent route. This study is based on the successful preliminary results with a simple 14-member ring model system and the synthesis of the key aldehyde intermediate shown below. The highlighted transformation of this synthesis will be a transannular oxa-conjugate addition to generate the cis-2,6-tetrahydropyran ring system. This route also highlights a highly convergent Wittig coupling to generate the full carbon framework of (+)-neopeltolide. One of the key goals of this project is to compare this synthesis with a chemo-enzymatic total synthesis that relies on chemistry catalyzed by polyketide synthase enzymes in the late stage of the synthesis.

<p>Histone deacetylases (HDACs) have been shown to play key roles in tumorigenesis, and</p><p>have been validated as effective enzyme target for cancer treatment. Largazole, a marine natural</p><p>product isolated from the cyanobacterium Symploca, is an extremely potent HDAC inhibitor that</p><p>has been shown to possess high differential cytotoxicity towards cancer cells along with excellent</p><p>HDAC class-selectivity. However, improvements can be made in the isoform-selectivity and</p><p>pharmacokinetic properties of largazole.</p><p>In attempts to make these improvements and furnish a more efficient biochemical probe</p><p>as well as a potential therapeutic, several largazole analogues have been designed, synthesized,</p><p>and tested for their biological activity. Three different types of analogues were prepared. First,</p><p>different chemical functionalities were introduced at the C2 position to probe the class Iselectivity profile of largazole. Additionally, docking studies led to the design of a potential</p><p>HDAC8-selective analogue. Secondly, the thiol moiety in largazole was replaced with a wide</p><p>variety of othe zinc-binding group in order to probe the effect of Zn2+ affinity on HDAC</p><p>inhibition. Lastly, three disulfide analogues of largazole were prepared in order to utilize a</p><p>different prodrug strategy to modulate the pharmacokinetic properties of largazole.</p><p>Through these analogues it was shown that C2 position can be modified significantly</p><p>without a major loss in activity while also eliciting minimal changes in isoform-selectivity. While</p><p>the Zn2+-binding group plays a major role in HDAC inhibition, it was also shown that the thiol</p><p>can be replaced by other functionalities while still retaining inhibitory activity. Lastly, the use of</p><p>a disulfide prodrug strategy was shown to affect pharmacokinetic properties resulting in varying</p><p>functional responses in vitro and in vivo.</p><p>v</p><p>Largazole is already an impressive HDAC inhibitor that shows incredible promise.</p><p>However, in order to further develop this natural product into an anti-cancer therapeutic as well as</p><p>a chemical probe, improvements in the areas of pharmacokinetics as well as isoform-selectivity</p><p>are required. Through these studies we plan on building upon existing structure–activity</p><p>relationships to further our understanding of largazole’s mechanism of inhibition so that we may</p><p>improve these properties and ultimately develop largazole into an efficient HDAC inhibitor that</p><p>may be used as an anti-cancer therapeutic as well as a chemical probe for the studying of</p><p>biochemical systems.</p> / Dissertation

The benefits of fish oil supplementation for inflammation based disorders has been well-documented,[1] prompting investigations into the pathways through which these benefits are achieved. This led Serhan et al. to the discovery of a new class of pro-resolution lipid mediators, termed resolvins .[2][3] There has subsequently been much research into their being a potential treatment for chronic inflammatory diseases such as asthma,[4] diabetes,[5] and arthritis.[6] The aim of this research was to study the bioactivity of resolvin E1 (RvE1) and its analogues; to do this a flexible and versatile route towards the chemical synthesis of RvE1 had to be developed, which would allow for easy modification of the stereochemistry of the C-C double bonds and hydroxyl groups, as well as producing fragments containing key functional groups. The first proposed route synthesised RvE1 from two key fragments termed the lactone and epoxide fragments. RvE1 contains three stereogenic hydroxyl groups, one with S configuration and two with R configuration. The epoxide fragment was to be converted into two adjacent sections of the RvE1 chain. The S-stereocentre was introduced via hydrolytic kinetic resolution using a Jacobsen s catalyst.[7] The two R-stereocentres were introduced via the chiral pool originating from 1,2:5,6-di-O-isopropylidene-D-mannitol. Unfortunately, problems were encountered late on in the synthesis of both fragments and therefore a new synthetic route had to be devised. The second proposed route synthesised RvE1 from two key fragments termed the alkyne and halide fragments. The S-stereocentre and one R-stereocentre were proposed to be introduced via asymmetric reduction of a ketone group. The other R-stereocentre was proposed to be synthesised with the use of chiral additives during an indium-mediated coupling reaction.[8] As work progressed on the halide fragment, the Lewis acid catalysed thermodynamic conversion of a branched chain homoallylic alcohol to its linear counterpart was trialled in order to obtain one of the conjugated diene system in RvE1. Using literature conditions for a similar system[9] this reaction was unsuccessful. The reaction mechanism was studied and a hypothesis was put forward that adding a catalytic amount of the aldehyde that the branched chain homoallylic alcohol was synthesised from to the reaction mixture would promote the thermodynamic conversion to the linear chain. These conditions were trialled on a number of different starting materials, leading to either an improvement in yield for the thermodynamic conversion, or the success of a previously unsuccessful conversion.

Structure-activity relationships (SARs) in the disorazole family have been revealed through the biological testing of natural disorazoles and their synthetic analogues, but little is known about the contribution of the oxazole to the anti-tubulin activity of disorazole C1 I. The development of a novel Evans-Tishchenko/alkyne metathesis (ET-AM) route towards the synthesis of disorazole C1 will provide straightforward access to disorazole C1 and its heterocyclic analogues, thus allowing the contribution of the oxazole to the natural product's bioactivity to be elucidated. Our ET-AM approach offers a highly diastereoselective and convergent means of constructing heterocyclic analogues of the disorazole C1 scaffold Het-II. It is envisaged that ET coupling of C(1)-C(9) aldehydes Het-IV to the C(10)-C(19) β-hydroxyketone V will give the key, requisite, 1,3-anti diol monoester bis-alkynes Het-III for dimerisation via an alkyne cross-metathesis/ring-closing alkyne metathesis (ACM-RCAM) reaction. Further diversification may be achieved through the synthesis of C(6)-heteroatom analogues of the C(1)-C(9) fragment Het-IV. Chapter 2 outlines efforts towards the synthesis of C(6)-amino analogues Het-VI of the C(1)-C(9) fragment IV. Elaboration of Garner's aldehyde VIII allowed the synthesis of the N-protected C(5)-C(9) mesylate VII; an analogue of an advanced C(1)-C(9) fragment intermediate. A scalable route towards the synthesis of the C(10)-C(19) fragment V and investigations into its reactivity under ET coupling conditions are critical to the success of our ET-AM approach. Chapter 3 details convergent approaches towards the synthesis of the C(10)-C(19) β-hydroxyketone V, which centred around: (i) an olefin cross-metathesis reaction [C(11)-C(12) disconnection]; (ii) an epoxide ringopening reaction [C(12)-C(13) disconnection]; and (iii) a Mukaiyama aldol reaction [C(14)-C(15) disconnection]. Chapter 4 describes our successful linear synthesis of the β-hydroxyketone V. Gram-scale preparation of the C(10)-C(19) fragment V permitted investigation into the viability of the ET reaction as a fragment coupling strategy, the results of which are reported in Chapter 5. Although many (hetero)aryl aldehydes failed to react, the successful coupling of electron-deficient substrates allowed a contingency strategy to be explored through preparation of the mono-protected diol IX. Esterification of IX with the carboxylic acid derivative of the C(1)-C(9) oxazole has allowed generation of the C(1)-C(9)/C(10')-C(19') bis-alkyne X required for future AM investigations.

(+)-Neopeltolide is a highly potent marine polyketide natural product with activity against multiple cancer cell lines in vitro. The nanomolar range of antifungal and anticancer cytotoxicity in this tetrahydropyran (THP)-containing polyketide, combined with its limited natural supply, has led to several syntheses. In this study, the feasibility of an oxa-Michael conjugate addition route to cis-2,6-THP rings is examined through the efforts toward a total synthesis of the macrocyclic core of (+)-neopeltolide using a highly convergent route. This study is based on the successful preliminary results with a simple 14-member ring model system and the synthesis of the key aldehyde intermediate shown below. The highlighted transformation of this synthesis will be a transannular oxa-conjugate addition to generate the cis-2,6-tetrahydropyran ring system. This route also highlights a highly convergent Wittig coupling to generate the full carbon framework of (+)-neopeltolide. One of the key goals of this project is to compare this synthesis with a chemo-enzymatic total synthesis that relies on chemistry catalyzed by polyketide synthase enzymes in the late stage of the synthesis.

Since the isolation of azinomycins A and B in 1954 from the soil bacterium, Streptomyces sahachiroi, these natural products have been synthetic targets. Both compounds exhibit in vitro cytotoxic activity at submicromolar levels and demonstrate anti-tumor activities comparable to that of mitomycin C in vivo. Unique to this class of natural products is the presence of an aziridine [1,2-a] pyrrolidine ring system. Coupled with an epoxide moiety, these structural functionalities impart the ability to form interstrand cross-links with DNA via the electrophilic C10 and C21 carbons of azinomycin and the N7 positions of suitably disposed purine bases. This dissertation investigates the global impact of azinomycin B treatment in a yeast model with special emphasis on DNA damage response, the resulting cell cycle effects, and cellular localization of the compound. The results provide the first demonstration of the in vivo actions of azinomycin B and are consistent with the proposed role of the drug as a DNA crosslinking agent. Biosynthesis of azinomycin B was investigated and appears to have polyketide, non-ribosomal peptide synthetase and alkaloid origins. In pursuit of elucidating the biosynthetic origin we developed both a cell culturing system and a cell-free extract procedure capable of supporting azinomycin synthesis; we used these. These were employed with labeled metabolites to probe the biosynthetic origins of the molecule. Investigations with this enzyme preparation imparted important information regarding the substrate and cofactor requirements of the pathway. These results supported the premise of a mixed origin for the biosynthesis of the molecule and paved the way for expansive stable isotope labeling studies, which largely revealed the biosynthetic precursors and probable construction of the azinomycins. Some of these studies corroborate while other results conflict with initial proposed biosynthetic routes based upon the azinomycin biosynthetic gene cluster sequence. Future azinomycin biosynthetic gene cluster enzyme characterization, mechanistic investigations, and genetic modifications will ultimately provide definitive proof for the intermediacy of proposed biosynthetic precursors and the involvement of specific cofactors. Better understanding of how nature constructs unique molecule may provide insight into eventual chemoenzymatic/gene thearapy based approaches toward cancer therapy.

This dissertation mainly discussed the investigation of five different soft corals collected in Green Island and one soft coral collected in Kenting. They were identified as Clavularia viridis, Xenia florida, Cespitularia taeniata, Cespitularia hypotentaculata, and Sarcophyton stolidotum. In the isolation of these corals, there were sixty natural products discovered, including twenty night new compounds and three new derivatives. The research of soft coral Clavularia viridis has result in the isolation of six new prostanoids, designated as 4-deacetoxyl-12-O-deacetylclavulone I (1), 4-deacetoxyl-12-O-deacetylclavulone II (2), bromovulone II (3), iodovulone II (4), 4-deacetoxyl-12-O-deacetylclavuloneIII (5), and bromovulone III (6), together with seven known prostanoids, identified as clavulone I (33), clavulone II (34), chlorovulone II (35), 4-deacetoxylclavulone II (36), clavulone III (37), chlorovulone III (38), and 7-acetoxy-7,8-dihydroiodovulone I (39). In the investigation of the soft coral Xenia florida, three new compounds called florxenilides A-C (7-9), has been purified. The research also obtained seven xenicane-type diterpenes, xeniafaraunol A (40), xeniafaraunol B (41), florlide A (42), florlide C (43), florlide D (44), 9-deoxyxeniolide A (45), and 9-deoxyxeniolide B (46) in addition to two cadinene-type sesquiterpenes, xenitorins A (47) and B (48). Florxenilides A and C also treated with some chemical reagents to afford three new derivatives, 10-benzoylflorxenilide A (10), Florxenilide C monoacetate (11), and 10-dehydroflorxenilide A (12). Otherwise, the study in Cespitularia taeniata has afforded ten new nitrogen-containing compounds, cespitulactams D-K (13-20) and taenialactams A-B (21-22), in addition to four known compounds, atractylenolactam (49), cespitulactam A (50), cespitulactam B (51), and cespitularin F (52). Moreover, there were three new compounds, namely cespihypotins E, F, and H (23, 24, 25) have been discovered from another soft coral Cespitularia hypotentaculata. The study of this coral also observed seven known components called cespihypotin G (53), cespitulactone A (54), cespitularin F (52), cespitularin D (56), cespihypotins A-C (55, 57, 58). Investigation of the non-polar extract of the soft coral Sarcophyton stolidotum collected in Kenting resulted in the isolation of seven new 14-membered carbocyclic cembranes, sarcostolides A-G (26-32), together with two known cembranes isosarcophytoxide (59) and isosarcophine (60). All the structures of above metabolites were elucidated by physical and spectroscopic analyses including IR, Mass, UV, NMR, and optical rotation, and by compared with published data in many previous papers. The stereochemistry of these compounds as determined by NOESY experiments, CD spectroscopic data, and Mosher¡¦s methods. Cytotoxicity tests were measured by Dr. Kuo Yao-Haur and Dr. Guh Jih-Hwa. Isolated marine prostanoids showed potent activities against human prostate carcinoma (PC-3) and colon adenocarcinoma (HT-29) cells. Among them bromovulone III (6) had the most potent cytotoxicity against both cell lines at IC50 0.5

1. We have explored a formal [3+2] strategy that is synthetically useful for constructing 3,4-disubstituted succinimides with ethyl bromoacetate derivatives or methyl glyoxylate in one step. 2. We reported a new approach to (E)-£]-aryl-£\,£]-unsaturated amides. Instead of using aldehydes, phosphorus, silicon containing compounds and metal catalysts for the synthesis of double bonds, £\-sulfonyl acetamide and various benzyl bromides were used as starting materials

No description available.

Transition metal-catalyzed olefin hydroacylation represents an atom-economical approach for the synthesis of valuable ketone products. To date, the intermolecular variant of this reaction suffers from several drawbacks, which include limited substrate scope, poor reactivity and/or regioselectivity for non-activated, non-chelating alkene substrates, and competitive reductive decarbonylation pathways that lead to catalyst decomposition. Herein, we report the linear-selective intermolecular hydroacylation of a wide range of electronically diverse olefins with salicylaldehydes employing catalyst loadings as low as 2 mol%. A unique reactivity profile is observed for the chiral C2-symmetric phosphoramidite ligand employed in our catalyst system, and thus, we outline progress made towards the synthesis of new phosphoramidite ligands. We have applied our methodology in the total synthesis of nine octaketide natural products belonging to the dothiorelone, cytosporone, and phomopsin families. Due to recent reports demonstrating the anticancer activity of cytosporone B (Csn-B), we will also discuss progress towards the synthesis of Csn-B analogues.