No description available.

Various α,β-unsaturated carbonyl compounds and derivatives were explored in order to expand the range of substrates for the 1,4-addition of alkenylboronates using 3,3′-disubstituted binaphthols. Enones 2.60 were examined and found to be suitable for conjugate addition under our proposed reaction conditions. The asymmetric 1,4-additions of alkenylboronates to enones 2.60 using catalytic amounts of 3,3′-disubstituted binaphthols was shown to occur with moderate to good yields and high enantioselectivities. The chiral products could serve as enantioenriched substrates for further transformation such as asymmetric reduction, which was performed with good yield and selectivity. The absolute configuration for the alkenylation of enones was also confirmed to be the (R) enantiomer using (S)-3,3′-disubstituted binaphthols via X-ray crystallographic analysis. Investigations into selective Baeyer-Villiger oxidation of 1,4-addition products of enones was also examined. Although the desire ester products were not obtained, intriguing informative findings were still obtained from the investigation.

Various α,β-unsaturated carbonyl compounds and derivatives were explored in order to expand the range of substrates for the 1,4-addition of alkenylboronates using 3,3′-disubstituted binaphthols. Enones 2.60 were examined and found to be suitable for conjugate addition under our proposed reaction conditions. The asymmetric 1,4-additions of alkenylboronates to enones 2.60 using catalytic amounts of 3,3′-disubstituted binaphthols was shown to occur with moderate to good yields and high enantioselectivities. The chiral products could serve as enantioenriched substrates for further transformation such as asymmetric reduction, which was performed with good yield and selectivity. The absolute configuration for the alkenylation of enones was also confirmed to be the (R) enantiomer using (S)-3,3′-disubstituted binaphthols via X-ray crystallographic analysis. Investigations into selective Baeyer-Villiger oxidation of 1,4-addition products of enones was also examined. Although the desire ester products were not obtained, intriguing informative findings were still obtained from the investigation.

No description available.

The mechanism of a conjugate addition of an alcohol to an alkynic acid ester using a phosphine catalyst was investigated using pressurized sample infusion electrospray ionization mass spectrometry (PSI-ESI-MS) and proton and phosphorus nuclear magnetic resonance (NMR) experiments. Since ESI-MS only detects charged species, and only the phosphonium intermediates and by-products were visible by ESI-MS, 1H NMR was used to track the disappearance of the starting alkyne and the appearance of the conjugate addition product over time. 31P NMR was used to quantify the ESI-MS results. By-product formation was shown to out-compete product formation upon fast addition of alkyne, but with dropwise addition of alkyne, product was shown to dominate. A detailed numerical model was developed using PowerSim software to test mechanistic hypotheses. The experimental results were shown to be consistent with the mechanism proposed by Inanaga, and the cycle was elaborated to account for by-product formation. Piers’catalyst, a ruthenium complex with a phosphonium-functionalized carbene ligand, is a fast-initiating living catalyst for a number of olefin metathesis reactions, including ring-opening metathesis polymerization (ROMP) and cross metathesis (CM). Catalyst speciation was monitored in real-time for the ROMP of norbornene and the CM of 1-hexene using PSI-ESI-MS. The expected mass distribution of charged polymer-catalyst species were not observed, but merely catalyst and decomposition species were visible by ESI-MS. NMR and gel permeation chromatography (GPC) were used to determine quantitatively the presence of polymer and the polydispersity index, respectively. The results suggest that while Piers’ catalyst is indeed fast-initiating, the propagation rate greatly outstrips the initiation rate. In a foray into the area of chemical education, a well-known pH-induced colour change exhibited by the anthocyanins in red cabbage was developed into a simple – and ingestible – classroom demonstration. / Graduate / 0485

xx, 214 p. : ill. (some col.) / Intramolecular cascading Michael additions have the ability to transform simple, symmetric substrates into densely functionalized compounds containing new ring structures and chiral centers. The Rauhut-Currier (RC) reaction, also known as the vinylogous Morita-Baylis-Hillman reaction, utilizes this type of reactivity by cyclizing tethered, activated alkenes using phosphine or thiolate catalysis. This dissertation describes the expansion of the scope of the RC reaction, the introduction and importance of co-catalysts to cascading Michael additions, the development of the first amine-catalyzed RC reaction, and the transformation of cyclization products into fused, polycyclic aromatic compounds. Chapter I reviews the development and applications of the Rauhut-Currier reaction. Chapter II describes the regioselective synthesis of di-substituted indenes and introduces phenol as a rate- and selectivity-enhancing co-catalyst. Although tertiary amine nucleophiles were found to be inferior to phosphines as cyclization catalysts, chapter III discusses the ability of unhindered primary and secondary amines to undergo a diastereoselective, cascading aza-Michael-Michael addition to yield a wide variety of amino-indanes in the presence of an acid catalyst. Recognizing the importance of protic environments and small nucleophiles, the development of the first amine-catalyzed intramolecular RC is introduced in chapter IV. Chapter V describes the conversion of methyl ketone-substituted indenes to fluorene derivatives via an intramolecular aldol reaction. Chapter VI describes the serendipitous discovery and synthesis of indenopyrylium salts. Chapter VII details the novel production of indenopyridines from di-substituted indenes. Lastly, chapter VIII provides a summary and suggests future directions for this research. This dissertation includes previously published and unpublished co-authored material. / Committee in charge: Shih-Yuan Liu, Chairperson; Kenneth Doxsee, Advisor; David Tyler, Member; Michael Haley, Member; A. Dana Johnston, Outside Member

Polyketide secondary metabolites constitute a structurally-diverse and clinically-important family of natural products. The wide range of biological activities represented by these substrates have contributed to therapeutic agents with annual sales exceeding $20B USD. Large multi-domain proteins called polyketide synthases (PKSs) use simple building blocks to generate highly-oxygenated and stereochemically-rich frameworks with astonishing selectivity. These substrates often feature rigidifying biases imposed by macrocyclic lactones and substituted heterocycles, which can impact their bioactive conformation. The work of this dissertation combines synthetic chemistry and biochemistry to investigate chemoenzymatic production of macrocyclic polyketide natural products. Research focused on validating a transannular oxa-conjugate addition strategy to assembly 2,6-cis-tetrahydropyran (THP) ring systems, as demonstrated by synthesis of the macrocyclic core to neopeltolide. Ultimately, we wish to apply this chemistry to de novo PKS pathways for rapid, reliable, and sustainable production of THP-bearing products like neopeltolide, and toward building SAR libraries. Additionally, a second study probed the specificity of the macrolactonizing thioesterase (TE) domain from the 6-deoxyerythronolide B (DEBS) biosynthetic pathway. This pathway is the paradigm for type-I PKS systems, and is responsible for producing the macrolide core of erythromycin. Our on-going research evaluates the limits of promiscuity within this specific catalytic domain, to characterize the structural elements required to accurately predict macrolactonization. The long-term goal of this study is to assess the potential applicability of DEBS TE as a generalized cyclization biocatalyst for combinatorial biochemistry and chemoenzymatic research.

The Streptomyces metabolite 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone (COTC), the antheminones and the carvotacetone derivatives are all bioactive natural products, whose structure is based on the α oxymethyl-a,β-cyclohexenone moiety. Both COTC and antheminone A have been shown to exhibit cytotoxic and cancerostatic activity with low toxicity. The potent biological activity of these natural products has instigated numerous investigations into the synthesis of novel analogues in an attempt to determine the key structural features necessary for optimum bioactivity. The synthesis of a small library of novel anti-tumour agents which are structurally related to the natural products COTC and antheminone A is described, using the chiral pool material (-)-quinic acid as a starting material. At the outset, the aim of this project was to develop and optimise copper-mediated conjugate addition reactions and rhodium catalysed conjugate addition reactions of organoboron reagents to functionalised cyclic enones and subsequently, to apply the methodologies to the synthesis of the novel analogues. A range of novel mono-hydroxylated analogues bearing aryl side chains were prepared and their antiproliferative activity was assessed towards the A549 non-small cell cancer cell line. The biological assays revealed important structure-activity relationships and the most bioactive compound of this series had an IC50 value of 1.2 µM. In addition, the design and synthesis of a new class of GSH-activated prodrugs is described. These novel compounds are activated by GSH leading to intracellular release of an NQO1 inhibitor. The most potent compound of this new class of compounds had an IC50 value of 710 nm.

京都大学 / 新制・課程博士 / 博士(理学) / 甲第23036号 / 理博第4713号 / 新制||理||1675(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)准教授 加納 太一, 教授 時任 宣博, 教授 依光 英樹 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

This doctoral thesis focuses on applying different organocatalysts in several enantioselective reactions and aerobic photooxidations using visible light. Chapter 1 describes using a chiral primary amine-salicylamide derived from (1R,2R)-cyclohexane-1,2-diamine as chiral organocatalyst in the asymmetric conjugate Michael addition of aldehydes and ketones to maleimides, giving the corresponding enantioenriched succinimides. The same organocatalyst is used in the enantioselective Michael addition of aldehydes to nitroalkenes, yielding enantiopure γ-nitroaldehydes. Furthermore, these Michael additions of aldehydes to maleimides and nitroalkenes are carried out employing sustainable and environmentally friendly deep eutectic solvents (DES), being able to reuse the catalytic system for several cycles. Chapter 2 describes using a chiral primary-amine monocarbamate derived from (1R,2R)-cyclohexane-1,2-diamine as chiral organocatalyst in the enantioselective α-amination of aldehydes with azodicarboxylates, obtaining the corresponding α,α-disubstituted aldehydes with the absence of solvent under mild conditions. This simple orgacatalytic system’s applicability is demonstrated by preparing a chiral oxazolidinone precursor of amino acids. The reaction is also successfully scaled-up. In addition, theoretical calculations were performed to demonstrate how the absolute configuration of the final adducts is produced. Chapter 3 shows how riboflavin tetraacetate, a cheap vitamin B2 derivative, is an appropriate metal-free photocatalyst in the aerobic photooxidation of xanthenes, thioxanthenes and dihydroacridines under visible light irradiation. / This research work has been possible thanks to funding from the Spanish Ministerio de Economía y Competitividad (PGC2018-096616-B-100, CTQ201788171-P), the Generalitat Valenciana (AICO 2021/013) and the University of Alicante (VIGROB-173). The author wishes to express his gratitude to the Institute of Organic Synthesis for a research contract (I-PI/21-20) and to the University of Alicante-Banco Santander consortium for a grant to spend a three-months research period in the Chemistry Interdisciplinary Project research center (ChIP) of the University of Camerino (Italy) under the supervision of Dr. Matteo Tiecco.