京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21784号 / 工博第4601号 / 新制||工||1717(附属図書館) / 京都大学大学院工学研究科物質エネルギー化学専攻 / (主査)教授 中村 正治, 教授 近藤 輝幸, 教授 村田 靖次郎 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

As malaria, caused by Plasmodium spp., continues to afflict millions of people worldwide, there is a dire need for the discovery of novel, inexpensive antimalarial drugs. Although there are effective drugs on the market, the consistent development of drug resistant species has decreased their efficacy, further emphasizing that novel therapeutic measures are urgently needed. Natural products provide the most diverse reservoir for the discovery of unique chemical scaffolds with the potential to effectively combat malarial infections, but, due to their complex structures, they often pose extreme challenges to medicinal chemists during pharmacokinetic optimization. In our laboratory we have performed unbiased, cell-based assays of numerous synthetic compounds from chemical libraries enriched with nature-like elements. This screening has led to the discovery of many original chemical scaffolds with promising antimalarial properties. In an attempt to further characterize these scaffolds, the most promising compounds were assayed in order to determine their cytotoxic effects on mammalian cells. In addition, the development of a drug resistant parasite line of Plasmodium falciparum to the most promising compound was done in order to determine the relative probability for parasite resistance development.

Thesis advisor: Amir H. Hoveyda / Chapter One: Stereoretentive Cross-Metathesis of Trisubstituted Olefins The development of stereoretentive olefin metathesis catalysts has solved a long-standing problem in the field, allowing for trisubstituted alkenes to be synthesized in high stereochemical purity and under kinetic control. E- as well as Z-isomers of trisubstituted alkenyl halides, nitriles, and allylic alcohols can be accessed through cross-metathesis of commercially available and easily accessible alkenes. Through the use of the same strategy, macrocyclic trisubstituted alkenes have been accessed in either isomeric form through stereoretentive ring-closing metathesis of the corresponding diene starting materials. Thus, for the first time, a wide range of E- and Z-trisubstituted alkenes can be obtained selectively through olefin metathesis, regardless of the underlying thermodynamic preferences. Chapter Two: Development of Catalytic Stereoretentive Cross-Metathesis of Trisubstituted Alkenyl Bromides We have introduced a general and widely applicable strategy for the synthesis of E- and Z-trisubstituted alkenyl bromides through cross-metathesis. The reaction is applicable to terminal, disubstituted, and trisubstituted olefins bearing a variety of functional groups including alkenes with α-, or β-branches. The requisite stereodefined cross-partners, E- and Z-2-bromo-2-butene are commercially available and can be synthesized with ease in one step from abundant starting materials. This represents a notable improvement over our previous approach, where the non-halogenated alkene starting material had to be prepared through cross-coupling in high stereochemical purity to ensure high stereoretention in the subsequent cross-metathesis. Catalysts derived from Mo monoaryloxide pyrrolide complexes, some of which are commercially available, are optimal for this transformation. The applicability of the approach is underscored through the formal synthesis of phomactin A with improved overall yield and step count. Chapter Three: Total Synthesis of Ambrein We have completed a total synthesis of ambrein, a terpenoid isolated from whale secretion, a much sought perfume ingredient. The approach involved joining two fragments through formation of the central trisubstituted alkene. Our route entailed a sequence of cross-metathesis of alkenyl bromides and cross-coupling, providing access to a previously difficult-to-access trisubstituted olefin with high efficiency and selectivity. One fragment was generated from a readily accessible enantiomerically enriched compound, sclareolide, and the other from inexpensive methylcyclohexenone. The stereogenic center of the latter was established through a NHC-Cu-catalyzed enantioselective allylic substitution, which was followed by differentiation of these alkenes through site-selective epoxidation. The total synthesis is more efficient and offers a more practical route to ambrein. Chapter Four: Stereoretentive Cross-Metathesis of Trisubstituted α,β-Unsaturated Carbonyl Compounds We have developed a strategy for the synthesis of Z- and E-Trisubstituted α,β-unsaturated carbonyl compounds through stereoretentive CM involving commercially available or easily accessible alkene substrates. The method is applicable to a variety of α,β-unsaturated esters, thioesters, and acyl fluorides. Furthermore, mono-, di-, and trisubstituted alkenes can be used as starting materials. Transformations may be carried out on gram scale and, in some cases, with commercially available Mo catalysts. The utility of the catalytic approach was highlighted through synthesis of previously accessed intermediates more directly and with improved efficiency. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The work disclosed in this dissertation outlines a newly discovered acidic alumina-mediated orthoallylation of unprotected phenols and the application of this method to the synthesis of prenylated phenolic natural products including dorsmanin A and hyperbeanol Q. Chapter 1 consists of a literature review of prenylated phenolic compounds and includes a discussion of their biological significance followed by an extensive review of the various synthetic strategies that have been used to prepare them. It is our intention to publish the content of this chapter as a review article for the synthetic chemistry community. Showcased in Chapter 2 is the optimization of a novel prenylation method via acidic alumina as the promoter. Phenols and allyl alcohols are combined with acidic alumina in 1,2-dichloroethane or acetonitrile to induce a proposed coordination of the substrates to the alumina surface via hydrogen bonding which facilitates the regioselective ortho-prenylation of phenols. The extensive substrate scope of this chemistry is discussed. In Chapter 3, this alumina-mediated prenylation is applied to the syntheses of several acylphloroglucinol natural products and unnatural structural analogues which are evaluated for their antimicrobial and anthelmintic (anti-parasitic) activity. Some of these compounds exhibited antimicrobial activity and some exhibited anthelmintic potential. In Chapter 4, this prenylation strategy is further extended to the syntheses of additional prenylated phenolic natural products: (±)-sanjuanolide and dorsmanin A. Investigations towards the synthesis of HP1 are also reported. Development of the syntheses of these natural product targets provides a useful venue to investigate the scope of our alumina-mediated phenol prenylation chemistry and to identify its scope and limitations. / Thesis / Doctor of Philosophy (PhD)

No description available.

No description available.

No description available.

No description available.

No description available.

<p>The glycopeptide antibiotic vancomycin is used as front line treatment for serious Gram-positive infections and resistance to this drug is widespread. Three genes are essential for resistance, <em>vanHAX</em>, which are controlled by a two-component regulatory system VanR and VanS. Here, glycopeptide resistance is found to be ancient and diverse in the environment. A <em>vanA</em> open reading frame from 30 000 yr old DNA was identified and the enzyme was shown to be as functional as comparable to modern day VanA homologs. In the environment resistance is found to be diverse and widespread. For example, the organism <em>Desulfitobacterium hafniense</em> Y51 VanH was shown as non-essential in conferring inducible resistance. Furthermore in the glycopeptide producer <em>Amycolatopsis balhimycina</em> harboring the classic <em>vanHAX,</em> a functional VanA homolog is described as an orphan gene outside of any recognizable gene cassette .</p> <p>Glycopeptides are natural products made by members of the Actinomycete family and are modified by different types of tailoring enzymes. Of particular interest is the glycopeptide A47934, which is ‘aglyco’, and sulfated. The sulfotransferase StaL will transfer not only a sulfate group to A47934, but a sulfamide and fluorosulfonate group. Focusing on additional tailoring enzymes, the biosynthetic cluster of the sulfated glycopeptide UK68597 was sequenced. This cluster has provided a resource for glycopeptide tailoring enzymes for use to modify the A47934 backbone. Sulfation was the first focus and the substrate promiscuity of StaL was explored to expand the chemical diversity A47934 and vancomycin. This work has led to the discovery that glycopeptide sulfation will antagonize the activation and expression of <em>vanHAX</em>. A new sulfated vancomycin derivative was created with this antagonizing activity in the clinical pathogen <em>Enterococcus faecium</em> of the VanB phenotype. Implications of these results and the further use of tailoring enzymes to modify glycopeptides to antagonize resistance will be discussed.</p> / Doctor of Philosophy (PhD)