Vinigrol was isolated in 1987 from the fungal strain Virgaria nigra F-5408 by Hashimoto and co-workers. This compound was identified as having antihypertensive and platelet aggregation properties as well as being recognized as a tumor necrosis factor inhibitor. Aside from its interesting biological activities, vinigrol also possesses a unique structural motif consisting in a decahydro-1,5-butanonaphthalene core decorated with 8 contiguous stereocenters. Despite synthetic efforts by many research groups since its isolation, it wasn’t until 2009 that the first total synthesis of vinigrol was reported by Baran and co-workers. Herein is presented a formal synthesis of this highly compact molecule which relies upon a highly diastereoselective ketal Claisen rearrangement as the stereodefining step and an intramolecular Diels-Alder reaction to access the tricyclic structure of the molecule. (+)-Digitoxigenin is a cardiac glycoside used in the treatment of many ailments such as congestive heart failure. It is a member of the cardenolides, a sub-type of steroid containing certain structural differences such as cis A/B and C/D ring junctions, a tertiary hydroxyl group at C14 and a butenolide substituent at C17. Although a few syntheses of this class of compounds have been reported, general strategies to access their framework is scarce. Herein we report our studies towards the total synthesis of digitoxigenin which rely upon a cascading gold-catalyzed cycloisomerization (or enyne metathesis)/Diels-Alder reaction.

The increasing emergence of multi-drug-resistant microorganisms has led the World Health Organisation to plead for action to be taken against antimicrobial resistance. The fungal secondary metabolite (+)-pleuromutilin displays antibacterial activity with a novel mode of action: pleuromutilin derivatives bind to functionally important nucleotides within the peptidyl transfer centre of the prokaryotic ribosome and inhibit bacterial protein synthesis. The first non-racemic total synthesis of the antibiotic natural product pleuromutilin has been developed. A chiral pool strategy has been employed to gain access to the cyclisation substrate, which underwent a SmI2-mediated cyclisation cascade to give the 5,6,8 tricyclic core in a single step. The reaction proceeded with excellent diastereocontrol at the four contiguous stereocentres generated during the cascade. Elaboration of the cyclisation product to (+)-pleuromutilin was achieved by electron transfer reduction of the hindered ester at C5, stereoselective introduction of the hydroxyl at C11 and installation of the quaternary stereocentre at C12. Finally the first efficient conversion of (+)-mutilin to the target was developed. This strategy is now being used for the synthesis of simplified novel analogues of pleuromutilin: access to a range of simplified cores has been demonstrated in 5 steps.

Orientador: Luiz Carlos Dias / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-26T10:31:22Z (GMT). No. of bitstreams: 1 Kuroishi_PaulaKishi_M.pdf: 5417860 bytes, checksum: ee15eb079e97f744325e1ec5d6c13315 (MD5) Previous issue date: 2014 / Resumo: Os criptocarióis A-H foram isolados em 2011 por Gustafson e colaboradores. Esses compostos apresentaram uma promissora atividade contra o câncer por serem capazes de estabilizar Pdcd4, uma proteína supressora de tumor. Neste trabalho, foi concluída a síntese total do enantiômero do criptocariol A em 17 etapas e 0,1% de rendimento (rota linear mais longa) a partir do (R)-penten-2-ol. As etapas chave dessa rota foram reações aldólicas mediadas por boro, assim como reduções estereosseletivas que permitiram a instalação de todos os seis estereocentros presentes na molécula. Além disso, realizamos a reação de Horner-Wadsworth-Emmons utilizando o protocolo de Ando para obter a olefina Z presente no anel a-pirona. Nas etapas finais da síntese, foram observados baixos rendimentos. Sendo assim, foram realizados estudos de modo a tentar otimizar essas condições reacionais utilizando substratos modelo. Embora as condições otimizadas tivessem sido apropriadas para os compostos modelos, elas não se mostraram efetivas para o substrato real / Abstract: Cryptocaryols A-H were isolated in 2011 by Gustafson and coworkers. These compounds have notable anticancer activity because of their ability to stabilize tumor suppressor protein Pdcd4. In this work, the total synthesis of the enantiomer of cryptocaryol A was completed in 17 steps and 0.1% yield (longest linear sequence) starting from (R)-penten-2-ol. The key steps are comprised of boron-mediated aldol reactions and stereoselective reductions allowing the installation of all six stereocenters present in the molecule. In addition, we performed a Horner-Wadsworth-Emmons reaction using Ando's protocol to obtain the Z-alkene present in the a-pyrone ring. The final steps of the synthesis were low yielding; thus, we attempted to optimize the reaction conditions with model substrates. Although the optimized conditions worked well for the model compounds, they were ineffective for the actual substrate. / Mestrado / Quimica Organica / Mestra em Química

The terpene and terpenoid family of compounds is considered to be the largest group of natural products. These compounds not only display great diversity in their structural features but are also known to have a multitude of biological activities including but not limited to anti-bacterial, anti-cancer, anti-inflammatory, and anti-HIV properties. Remarkably, all the terpenoids formed in nature come from two molecules viz. isopentenyl pyrophosphate and its isomer, dimethylallyl pyrophosphate both consisting of just five carbons but assembled in many ways. Nature utilizes highly efficient, enzyme-mediated cascade reactions to transform simple linear molecules to more complex cyclic scaffolds. Cascade or domino reactions are organic chemistry’s most powerful tools that, if executed correctly, mimic the extreme complexity of reactions occurring in nature. Our group has successfully utilized cationic cascade cyclization reactions, to prepare a large library of natural products along with their analogues. It was during the synthesis of one such natural product that it was discovered that a methoxymethyl (MOM) “protecting group” had been transferred within the same molecule. The optimization of this process not only allowed the synthesis of the desired tricyclic framework but also resulted in the liberated MOM group doing an EAS reaction which gave a new C-C bond. This transferred MOM group was further elaborated to different functional groups. Use of the tandem reaction sequence in an attempt to prepare radulanin E has been described. Total syntheses of two chalcone-based analogous meroterpenoids have been successfully completed using the aforementioned sequence. An advanced intermediate for an entire new class of acridine-based schweinfurthins has been elaborated. The results will be discussed in detail.

Pleiomaltinine is an alkaloid-pyrone natural product that was the first of its kind to be isolated in nature. Synthesis of this compound from pleiocarpamine and a reactive quinone methide-like pyrone is described. Furthermore, model compounds have been made that will allow for full testing of this new heterocycle’s biological properties. This process has also been rendered enantioselective using asymmetric organocatalysis with thioureas. Additionally, work has been conducted towards the total synthesis of vinylallene-derived natural products. Progress towards the syntheses of chloropupukeananin, chloropestolide A, pestalofone C, iso-A82775c, and maldoxin isolated from Pestalotiopsis fici are described. All of these compounds are complex and possess biological activities including anti-cancer and anti-HIV. The strategies applied to develop a selective synthesis of reactive vinylallenes are discussed and plans designed to overcome this synthetic challenge are shown in detail. New methodologies are presented along with literature precedent in these areas of research.

Le manuscrit de thèse traite de la synthèse totale de molécules naturelles de structures particulièrement intrigantes. Deux familles de molécules naturelles issues du monde marin ont été ciblées dans ce travail : les halichonadines et les araiosamines.- La famille des halichonadines nous plongent dans le domaine des terpènes d’origine marine. Isolées d’éponges du genre Halichondria, deux structures ont particulièrement retenues notre attention : les halichonadines K et L. En effet, non seulement, ces deux molécules complexes contiennent une partie terpénique de type eudesmane (halichonadine C, un isonitrile naturel) mais aussi un cœur central de nature peptidique constitué, notamment, d’une pipéridine disubstituées par des fonctions acide carboxylique. Une partie est dédiée à comprendre comment dans la nature, des molécules de type isonitrile sont produites et peuvent réagir dans des voies de biosynthèse. Par ailleurs, le travail expérimental s’est organisé de la façon suivante :1- Concevoir une synthèse efficace de l’halichonadine C. Une stratégie au départ de la santonine est développée. La présence d’un groupement isopropyle sur la structure finale s’est avérée poser un nombre important de problèmes. Cependant, un composé très avancé a été obtenu figurant tout le squelette et l’atome d’azote nécessaire à la finalisation de la synthèse de l’halichonadine C.2- Concevoir une synthèse du cœur central permettant de contrôler la stéréochimie relative des deux fonctions carboxyliques en alpha de l’atome d’azote. Plusieurs stratégies ont été étudiées faisant appel notamment à une double addition de Michael ou à des réactions inspirées de la synthèse de la tropinone. Le cœur central est ainsi accessible en un nombre très limité d’étapes.Les résultats sont très encourageants et la quasi-totalité des pièces du puzzle sont là pour entrevoir rapidement la synthèse totale des halichonadines K et L.- La partie consacrée aux araisoamines (A-D, extraites d’éponges du genre Clathria) est exploratoire et permet de proposer des pistes synthétiques prometteuses pour l’accès bio-inspiré à ces molécules naturelles constituants un défi pour le chimiste. Un des défis relevés dans le travail est de concevoir des analogues synthétiques d’intermédiaires biosynthétiques très réactifs tels que des indoles aldéhydiques très instables. Une méthode pour générer in situ de telles entités a été étudiée. Les premières expériences ont été appliquées à la synthèse des « pyridiniums de Discodermia » et apparaissent prometteurs.Les travaux menés s’inscrivent dans « l’art de la synthèse totale » mais sont aussi toujours en lien avec le souci de mieux comprendre « chimiquement » comment des architectures moléculaires complexes s’assemblent au cours des voies de biosynthèse des substances naturelles. / The work described in this PhD dissertation is dedicated to the total synthesis of intriguing natural product structures. Two distinct families of natural substances of marine origin have been targeted in this work: the halichonadins and the araiosamines.- With the halichonadins, we plunge into the marine terpene chemistry. Isolated from sponges of the genus Halichondria, two structures have particularly drawn our attention: halichonadins K and L. Indeed, besides two subunits of terpene origin (namely halichonadin C, a natural isonitrile) with an eudesmane skeleton, a central core of peptidic origin is also original (especially a carboxylic acid disubstituted piperidine ring). A part of the work is dedicated to understanding how, in nature, isonitrile natural products may be formed and may react. The experimental part is organized according to the two following topics:1- Devise an efficient and straightforward total synthesis of halichonadin C. A strategy starting from santonin has been studied and developed. The presence of an isopropyl pending group has attracted many synthetic problems. Anyhow, an advanced intermediate comprising the whole skeleton and the crucial nitrogen atom of the target has been reached and provides good hopes for the access to halichonadin C.2- Conceiving a strategy of the stereocontroled access to the central piperidine ring of halichonadins K and L. Several strategies have been evaluated including the recourse to double Michael additions and reactions inspired by Robinson’s tropinone synthesis. The peptidic central core is now accessible in a limited number of steps.Most of the pieces of the puzzle are in our hands at the end of this PhD to secure a rapid access to the complex targets that constitutes halichonadins K and L.- The chapter dedicated to araiosamines (A-D, isolated from sponges of the genus Clathria) is exploratory and allows to propose promising strategies for a bio-inspired synthesis that constitutes true challenges for the organic chemists. One of the challenges to take up is to prepare highly reactive indole aldehyde units that could be foreseen as chemical equivalents of postulated biosynthetic intermediates. A method to generate in situ such units is studied. The first applications have been directed to the synthesis of “Discodermia pyridiniums” and appear to be promising towards the total synthesis of these molecules.The work conducted during this PhD take place in the framework of the “art of total synthesis”. But, in our strategies, the chemical understanding of biosynthetic pathways is never far away.

Total Synthesis of 4'-ester Resveratrol Analogs and 8, 9-amido Geldanamycin Analog and toward the Total Synthesis of (-)-Englerin A Yong Wang Department of Chemistry and Biochemistry, BYU Doctor of Philosophy The phytoalexin resveratrol and its 4'-ester analogs have been prepared with a decarbonylative Heck reaction. The deprotecting step has been modified and improved to increase yield and avoid chromatography. A set of resveratrol analogs and resveratrol have been tested with melanoma and pancreatic cell assays. The 8, 9-amido Geldanamycin analog has been synthesized with a convergent route, involving 28 simplified steps in its longest linear sequence. Synthetic methodologies, such as Andrus auxiliary controlled asymmetric anti-glycolate Aldol and selective p-Quinone formation, were employed. The total synthesis of Englerin A starts from (R)-carvone, passed through the modified Farvoskii ring-contraction and ring closing metathesis to get the ring skeleton. Other routes involving isopropyl group installation before closure of the seven-member ring failed. Although there are still problems to build the isopropyl moiety and the bridged ether, several reasonable alternative routes to address the problems have been designed.

<p>  </p> <p>A concise and scalable total synthesis of the therapeutically relevant methyl ester of the prostaglandin D₂ metabolite, tricyclic-PGDM, was accomplished in 8 steps from a known and easily accessed cyclopentene-diol derivative. The route features three key transition metal catalyzed steps. These steps include: a nickel catalyzed Ueno-Stork type dicarbofunctionalization which generates two consecutive stereocenters on the central cyclopentane core, a late-stage palladium-catalyzed carbonylative oxaspirolactonization, and a <em>Z</em>-selective cross metathesis to introduce the <em>Z</em>-butenoate side chain- a motif difficult to introduce through traditional protocols and which caused significant issues in the previous total syntheses of tricyclic-PGDM. Through this route, we have accumulated 75 mg of material for an ¹⁸O tricyclic-PGDM clinical assay which previously suffered from a material shortage. In addition to completing the synthesis, we generalized the <em>Z</em>-selective cross metathesis and nickel catalyzed Ueno-Stork protocols to numerous other substrates further demonstrating the utility of these transformations. </p> <p><br></p> <p>Protein arginine methyltransferases (PRMTs) catalyze the transfer of methyl groups from the cofactor SAM to arginine residues on various cytosolic and nuclear proteins. Of the nine members of the PRMT family, PRMT5 has been the most extensively studied and has been shown to regulate processes such as the DNA damage response, cell proliferation, and mRNA translation. Although numerous pathways have been identified that regulate PRMT5 activity, the cytosolic protein MEP50 has been identified as a key regulator in many diseases. PRMT5 and MEP50 interact to form a hetero-octameric complex, which can modulate the activity of PRMT5 for many cellular processes. Two new generations of PRMT5:MEP50 inhibitors were strategically designed and synthesized, which do not suffer from chemical instability like our previously most potent analogues. Our best compounds have IC₅₀ values ranging from 512 to 2.5 nM in LNCaP cells, and were confirmed to target the PRMT5:MEP50 interaction through BiFC analysis.</p>

Yes / We describe a concise and straightforward approach to the total syntheses of (+)-Strictifolione and Cryptofolione in the longest linear sequences of four steps and six steps from 3-phenyl propanal and trans-cinnamaldehyde, respectively. The route utilized a titanium tetraisopropoxide/(R)-[1,1'-binaphthalene]-2,2'-diol catalyzed Mukaiyama aldol reaction, indium(0)-promoted Barbier reaction, and olefin cross-metathesis as the key reactions. / National Science Foundation of China [21062088, 21562020, and 21462004], the Science and Technology Plan Project of Jiangxi Province [No. 20151BBG70028, 20142BBE50006] and State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources [CMEMR2014-A04] for the funding support.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第22751号 / 薬科博第125号 / 新制||薬科||14(附属図書館) / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 掛谷 秀昭, 教授 大野 浩章, 教授 高須 清誠 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM