Dissertations / Theses on the topic 'Lactonization'

Rh(III) and Ir(III) dimeric complexes with tunable cyclopentadienyl (Cp) rings have proven versatile for both catalysis and as synthetic precursors. An efficient microwave method to synthesize Rh(III) and Ir(III) dimeric complexes [(η5-ring)MCl]2(μ2-Cl)2, (where (η5-ring)MCl = (η5-Me4C5R)Rh(III)Cl or (η5-Me4C5R)Ir(III)Cl) was developed. A modular design for the substituted cyclopentadienes HC5Me4R was based on Grignard reactions of 2,3,4,5-tetramethylcyclopent-2-en-1-one (R = alkyl, 12 examples; R = aryl, 3 examples) or by SNAr reactions of potassium tetramethylcyclopentadienide with perfluoroarenes (R = perfluoroaryl, 3 examples). Reaction of the Me4CpHR ligands with [M(COD)](μ2-Cl)2 (M = Rh, Ir; COD = 1,5-cyclooctadiene) produced the dimeric complexes [Cp*RMCl]2(μ2-Cl)2 in moderate to excellent yield. The resulting dimers were characterized by nuclear magnetic resonance (NMR) spectroscopy, single-crystal X-ray diffraction (XRD), high-resolution mass spectrometry (HRMS), elemental analysis, and examined as catalysts for oxidative lactonization of 1,4- and 1,5-diols. Oxidative lactonization of 1,4-butanediol to afford γ-butyrolactone proceeded selectively and efficiently using [(η5-Me4C5R)IrCl]2(μ2-Cl)2 as the catalyst. Several R substituents were tested to assess electronic substituent effects. The most active complex contained an electron donating group, R = CHMe2 and successfully catalyzed the formation of diols to lactones across a range of 1,4- and 1,5-diols, generally in high yield. Computational analysis of the rate-determining b-hydrogen elimination reactions provided an atomistic account of observed trends in reaction yield and selectivity as a function of substrate structure, while accounting neatly for the observed selective formation of lactones (vs. succinaldehyde) in the transfer dehydrogenation of 1,4-butyrolactone.
Doctor of Philosophy
Rhodium(III) and iridium(III) complexes are useful synthetic precursors, catalysts, and biologically active compounds. This dissertation explores a rapid synthesis of these metal complexes and their subsequent catalytic applications with 1,4- and 1,5-diols. The oxidative lactonization of diols with rhodium and iridium complexes is an attractive one-pot synthesis, opening a variety of lactones to be produced. Structural studies involving novel fluorinated rhodium and iridium chloro-bridged dimers are discussed in detail.

In this work, an highly enantioselective vinylogous aldol-lactonization cascade reaction of 3-alkylidene oxindole to α,β-unsaturated trifluoromethyl ketone, promoted by bifunctional organocatalysts, is presented. The reaction proceed through 1,2-addition followed by cascade lactonization to afford an unsaturated lactone bearing a chiral trifluoromethylated tetrasubstituted carbon stereocenter with high enantioselectivity and moderate yield. Nevertheless, also the two E/Z isomers of the correspondent 1,2-addition product are obtained.

Chemistry
Ph.D.
Hypervalent iodine (HVI) reagents are easily accessed, highly tunable, mild, selective oxidants that are less toxic and more environmentally benign compared to their heavy metal counterparts. λ3-Iodanes, which possess an iodine center bound to one aryl substituent and two heteroatom ligands, have been the subject of recent interest due to their electrophilicity and hypernucleofugality. A central focus of the Wengryniuk laboratory has been the further development and application of a class of electrostatically activated (bis)cationic nitrogen-ligated HVI (N-HVI) reagents. N-HVIs feature datively bound heterocyclic ligands which results in dramatically enhanced electrophilicity and redox potentials. Despite being a highly tunable platform for reagent development, N-HVIs remain a relatively underexplored class of λ3-iodanes. This dissertation focuses on demonstrating N-HVI’s synthetic potential and developing novel variants to enhance their synthetic utility. Chapter 1 of this dissertation serves as a general background and introduction to nitrogen-ligated HVI reagents. Chapter 2 outlines our efforts in N-HVI library expansion, novel syntheses, and characterization. With a library of 33 novel N-HVIs in hand, ligand effects on N-HVI reactivity were analyzed via qualitative and quantitative methods. Chapter 3 describes our first synthetic application of N-HVIs in the development of novel oxidative rearrangements of simple and complex cyclic alcohols. This chapter describes the chemoselective ring expansion of 2° and 3° cyclic alcohols accessing medium-sized cyclic acetal products in good to excellent yields with applicability to Complexity-to-Diversity (CTD) efforts. Chapter 4 demonstrates our initial efforts toward the development of another synthetic method where the functionalized N-heterocyclic ligands of the N-HVIs can be regioselectivity incorporated into a molecule following N-HVI activation of an olefin. The pyridinium lactone salts formed from olefinic acids were isolated in excellent yields via simple trituration, supplying a synthetically useful functional handle that was easily derivatized via known methods. These four chapters summarize the current state of the research with nitrogen-ligated HVI salts, expand upon our initial publications to highlight the development of novel heterocyclic syntheses, and provide a useful guide to further explore the reactivity of these tunable reagents.
Temple University--Theses

The intramolecular nucleophile catalyzed aldol-lactonization (NCAL) process was optimized successfully. A variety of C9-acylated cinchona alkaloids were synthesized and used for NCAL reactions with non-activated aldehydes. New pyridinium salts, derivatives of Mukaiyama’s reagent, led to marked improvements in efficiency for the catalytic, asymmetric NCAL process while maintaining high enantioselectivity. Larger scale versions of the catalytic, asymmetric NCAL reaction were also developed allowing practical access to chiral bicyclic b-lactones. As an extension of the intramolecular NCAL process, pyrrolidine and piperidine fused blactones were synthesized. Simple g-lactam fused b-lactones were synthesized as a model study for omuralide, salinosporamide A, and derivative synthesis. Synthesis of asubstituted aldehyde acids was extensively studied but steric effects from both acid and amine moieties led to great difficulties in this approach.

Le développement de méthodes de synthèse asymétrique est très important pour l’accès à des molécules à visées thérapeutiques. Dans ce contexte, nous nous sommes intéressés à l’utilisation d’organocatalyseurs chiraux pour la synthèse de molécules cycliques énantioenrichies. Dans une première partie sont présentées des réactions de cycloadditions formelles (3+2), (4+2) et (4+3) à partir d’ènecarbamates ou de diènecarbamates catalysées par des acides phosphoriques chiraux. Ces derniers étant bifonctionnel, ils permettent l’activation des deux partenaires de cycloaddition menant à la synthèse d’indolines, de 2,3-dihydrobenzofuranes, de benzoquinones carbonannulées, de cyclohepta[b]indoles et de tétrahydroquinolines de façon hautement stéréosélective. Dans une seconde partie, nous nous sommes intéressés à l’utilisation de composés d’iode hypervalent chiraux comme organocatalyseurs. En effet, ces composés présentent une réactivité intéressante tout en étant stable et faiblement toxique. Ainsi, leur utilisation dans une réaction de lactonisation à partir de substrats flexibles a permis l’obtention de divers hétérocycles avec de bons résultats
The development of new enantioselective methodologies is essential for the synthesis of bioactive compounds. In this context, we were interested in using organocatalysts for the synthesis of enantioenriched cyclic molecules. In a first part will be describe chiral phosphoric acid catalyzed (3+2), (4+2) and (4+3) formal cycloadditions using enecarbamate or dienecarbamate. These catalysts are bifunctional and can interact with both cycloaddition partners leading to the synthesis of 2,3-dihydrobenzofuranes, carboannulated benzoquinones, cyclohepta[b]indoles and tetrahydroquinolines with high stereocontrol. In a second phase, we were interested in using chiral hypervalent iodine as organocatalyst. Theses compounds present interesting reactivity while being stable and not very toxic. Their use permits us to develop a lactonisation starting from flexible substrate and led to the synthesis of various heterocycles with good results

Les abiétanes diterpénoïdes aromatiques sont une famille de composés naturels qui sont suspectés d'avoir de nombreuses vertus thérapeutiques. C'est pourquoi, les chimistes organiciens ont cherché à développer différentes stratégies pour atteindre leurs squelettes. L'une d'entre elles implique la polycyclisation de polyènes par oxydation de β-céto-ester avec du manganèse triacétate en quantité surstoechiométrique dans l'acide acétique. Or, ces dernières années, l'électrosynthèse est apparue comme un outil puissant permettant le développement d'oxydation en utilisant des quantités catalytiques de réactifs. C'est ainsi que de nombreuses équipes ont décrit des méthodologies permettant l'oxydation anodique de composés 1,3-dicarbonylés. Nous avons donc envisagé de développer une version électrochimique de ces polycyclisations de Snider. Dans un premier temps, l'oxydation anodique de malonates en utilisant le ferrocène comme médiateur redox a permis la synthèse diastéréosélective de composés tricycliques ayant un squelette trans-décaline mais également de lactones bicycliques comme produits secondaires. Jusqu'à aujourd'hui ce type de structures polycycliques restaient inaccessibles par oxydation au manganèse triacétate. Notre méthodologie a été étendue aux groupements électro-attracteurs cyanoester, dinitrile et β-céto-esters mais également à une variété de cœurs aromatiques. Les cyclisations avec des hétéroaryles comme terminaison ont également été explorées. Ensuite des lactonisations intermoléculaires ont été effectuées, en effet il a été observé que le radical-malonate peut réagir avec des dérivés de styrène, puis cyclise par la suite, ce qui permet de former une variété de γ-lactones. Dans un second temps, il a été essayé de développer une version énantiosélective de la polycyclisation des abiétanes diterpénoïdes aromatiques. Tout d'abord en utilisant des 2-acétyles-imidazoles et 2-acétyles-thiazoles comme groupement initiateur de la cyclisation. En effet, en présence d'un catalyseur chiral, il est possible de réduire le potentiel redox de ces énols. Une fois le radical formé, une addition énantiosélective sur une double liaison pourrait avoir lieu. Cependant dans notre cas, seule la synthèse d'un produit non-désiré a été observée au lieu de la structure tricyclique. In fine, l'utilisation de la fonction β-céto-ester comme groupement électro-attracteur en présence d'une diamine a été essayée. L'objectif était de développer une version électrochimique de la catalyse SOMO développée par MacMillan, une fois que l'énamine correspondante est formée. Les recherches continuent aujourd'hui concernant ce type d'activation
Aromatic abietane diterpenoids are a family of natural compounds that are suspected to have numerous therapeutic effects. That is why organic chemist developed a lot of different strategies to reach their cores. One of them involve the polycyclizaton of polyenes initiated by the oxidation of β-keto-ester by manganese triacetate in substoichiometric amount in acetic acid. On the other hand, electrochemistry emerged as a powerful sustainable synthetic tool in organic chemistry, which avoids the use of external stoichiometric oxidant. Lately, number of research teams described methods for the anodic oxidation of 1,3-dicarbonyls. Therefore, we investigated the development of an electrochemical version of these Snider-type polycyclizations. In the first part of the thesis, conditions involving ferrocene-mediated oxidation of malonate were developed, which enable the diastereoselective formation of tricyclic structures with a trans-decalin core alongside bicyclic lactone by-products. Until nowadays these kinds of polycyclic structures remained inaccessible by manganese triacetate oxidation. This methodology was extended to cyanoester, dinitrile and β-keto-ester electron withdrawing groups alongside different aromatic cores. Cyclization with heteroaryle terminaison was also explored. Then intermolecular lactonizations were performed, indeed it was observed that malonate-radical could react with by styrene derivatives, followed by cyclization, which allow the formation of the desired γ-lactones. In the second part of the thesis, development of an enantioselective polycyclization of the aromatic abietane diterpenoids was attempted. First, by using 2-acetyl-imidiazole and 2-acetyl-thiazole as initiator of the cyclization. Indeed, in presence of the adequate chiral catalyst it is possible to reduce the redox potential of these enols. Then enantioselective addition on a double bond could occur. However, production of an undesired product was observed in our case instead of the polycyclic compound. In fine, use of β-keto-ester electron-withdrawing group in presence of diamine was attempted. The objective was to develop an enantioselective version of the SOMO catalysis described by MacMillan on the formed enamine. This activation mode is still studied

The development of new, potent and selective bacterial, viral and human sialidase (neuraminidase) inhibitors is an important issue to be pursued in order to achieve both useful therapeutical and biochemical tools. In fact, these hydrolytic enzymes can represent a good target since they play key roles in some physio-pathological processes by regulating the levels of sialic acid (such as the N-acetyl neuraminic acid; Neu5Ac) presents in glycoconjugates. In addition, in the design of inhibitors against a specific member of this class of enzymes is critical to take into account that these proteins share some common features such as the tridimensional structure of their catalytic domain, but, on the other hand, they show a very low sequence identity. Indeed, the only conserved residues are some active site amino acids essential for the catalytic mechanism. This thesis work was focused on the synthesis of hemagglutinin-neuraminidase (HN) inhibitors against the Newcastle virus (NDV), a member of the Paramyxoviridae family and strictly related to human parainfluenza viruses (hPIVs). NDV is a single-stranded RNA virus which could affect most species of both domestic and wild birds, causing significant and substantial economic losses in the poultry industry. To date, vaccination is the preferential instrument to border the infection, but when this procedure is not applicable, an efficient antiviral therapy could be the only useful way to control NDV outbreaks. At this purpose, the HN glycoproteins of paramyxoviruses represent an excellent target to be hit because they have some key roles in viral lifecycle: a) allowing viral attachment to the target cell; b) promoting the fusion process and, finally c) ensuring the release of the neo-synthesized virions. Over the past years, while some 2,3-unsaturated Neu5Ac derivatives (DANA derivatives) have been marketed as inhibitors against influenza virus neuraminidases (belonging to Orthomyxoviridae family), no compounds reach the clinical phase for paramyxoviruses treatment. In particular, few molecules have been developed for NDV-HN, and the N-trifluoroacetyl derivative of DANA (FANA) was still the best inhibitor until my thesis work. So, the necessity to find new, potent and possibly selective inhibitors against paramyxoviruses-HNs remain a key issue. At this purpose, the successful strategy, resulted fundamental to develop new NDV-HN inhibitors, was based on a multidisciplinary approach that combined the use of a) the chemical synthetic procedures, b) the computational docking studies and c) some biochemical activity assays. More in detail, the attention was directed to the study of two classes of inhibitors:  Some C5 or C4/C5 modified 2,3-unsaturated DANA derivatives, as reversible inhibitors.  Some scarcely investigated C2 modified 3,4-unsaturated Neu5Ac analogues, as irreversible ones. We finally reached satisfying results, regarding both classes of inhibitors: a) The understanding of the influence of the C5 N-perfluorinated substituents on the inhibitory activity of some 2,3-unsaturated DANA analogues, as potent and reversible NDV-HN inhibitors. b) The discovery of a new C5 N-perfluorinated inhibitor against NDV-HN as potent as FANA (the best NDV-HN inhibitor previously published) but more selective for NDV-HN towards human NEU3. c) The significant achievements of five new, potent and selective C4 and C5 modified 2,3-unsaturated DANA derivatives. All these compounds, combining the C4 azido or C4 p-toluensolfonamido group with the C5 N-perfluorinated chains, showed IC50 values in the nanomolar range; thus, they are up to 15-fold more potent than FANA. d) The set-up of more efficient synthetic procedures to achieve the 3,4-unsaturated Neu5Ac derivatives in high yields and β-anomeric stereoselectivity. e) The set-up of a smart and rapid method to unequivocally attribute the C2 configuration of the 3,4-unsaturated Neu5Ac inhibitors, via a 1,7-lactonization reaction. f) The mechanism elucidation of an unreported and unexpected chemical scrambling between the C4 and the C5 position of Neu5Ac derivatives (through a previously uncharacterized reaction intermediate). In addition, the rigid and induced fit docking simulation results permitted me to speculate on the interactions of the synthesized inhibitors with some active site amino acids, such as Lys236, a well know key residue involved in NDV-NH catalytic site activation mechanism and in fusion promotion activity. The comprehension of ligand/receptor interactions could lead to the development of molecules able to block, not only the neuraminidase activity of NDV-HN or other paramyxoviruses-HN, but also other viral functions mediated by these enzymes. Some of the obtained results allowed the publication of two scientific articles:  Rota, P., La Rocca, P., Piccoli, M., Montefiori, M., Cirillo, F., Olsen, L., Orioli, M., Allevi, P., and Anastasia, L. (2018) Potent Inhibitors against Newcastle Disease Virus Hemagglutinin-Neuraminidase, ChemMedChem 13, 236-240.  Rota, P., Papini, N., La Rocca, P., Montefiori, M., Cirillo, F., Piccoli, M., Scurati, R., Olsen, L., Allevi, P., and Anastasia, L. (2017) Synthesis and chemical characterization of several perfluorinated sialic acid glycals and evaluation of their in vitro antiviral activity against Newcastle disease virus, MedChemComm 8, 1505-1513.

博士
國立清華大學
化學系
96
硫酸乙醯肝素(heparan sulfate, HS)與肝素(heparin, HP)是屬於葡胺聚醣(glycosaminoglycan, GAG)的生物分子。兩者皆是具有負電荷性質的多醣體，主要的結構是由��1��4方式連接D式葡萄胺醣(GlcNH2)衍生物及��1��4方式連接D式葡萄醣酸(GlcA)或是L式艾杜醣酸(IdoA)。硫酸乙醯肝素廣佈於細胞表面及胞外纖維組織裡，另一方面肝素則是只由巨細胞(mast cell)分泌而得的。到目前為止已經被發現有許多生理反應或病毒的感染皆是透過和硫酸乙醯肝素的鍵結，然而由於硫酸乙醯肝素在自然界中不容易取得，所以很多的生物學家都採用由牛肺與豬腸提煉而得的肝素，來作為研究硫酸乙醯肝素與其他生物分子(例如:病毒、細菌、或生物體重要的蛋白質)間作用的機制，但是，硫酸乙醯肝素與肝素畢竟還是屬於兩種不同的個體，各自有屬於自己的結構特色，並不適合混為一談。因此，本論文將著重於如何使用化學合成來製備結構確定且成份均勻的硫酸乙醯肝素的寡醣體。 這篇論文大致上可分成十個章節，第一章主要是在描述細胞表面的醣類種類，並將重點著重在描述硫酸乙醯肝素與肝素兩者的結構與生物活性。第二章則是簡介目前幾位重量級醣類化學家對於合成硫酸乙醯肝素與肝素寡醣的工作。第三章則是提出關於在這個領域中我們想要解決的幾個問題及我們想要合成的目標分子，並試著將目標分子進行反合成分析。 第四章描述了我們對於構成硫酸乙醯肝素與肝素的單醣體建構單元的合成工作，我們經由七個步驟可以將D式葡萄糖轉變成我們所需要的糖予體。第五章則有系統的探討各種三氟甲磺酸金屬鹽催化苯亞甲基縮醛還原開環反應的位向選擇性，並且在氘取代還原劑的作用下進行了一系列的氘取代標幟實驗，並試著提出合理的反應機構。 第六章描述了我們如何由還原端來建構寡醣體的骨架，在遇到了一些問題以後，我們將合成策略改由非還原端來建立寡醣體的骨架，八醣體是本篇論文中所合成最長的寡醣單元。第七章是描述將連結單元接上寡醣體骨架以後，經由八個步驟就可以得到硫酸乙醯肝素的雙醣體、四醣體以及六醣體。最後，第八章提出了關於硫酸乙醯肝素內酯化反應的概念，並用硫酸乙醯肝素三醣體為例，證明了三醣體及其內酯化產物可以互換的想法。 第九章結論中，我們統整了第四到第八章的合成工作。第十章則是提供了在合成工作中所需要的實驗步驟與新產生化合物的詳細物理性質與光譜資料。

博士
國防醫學院
生命科學研究所
91
Sialic acids are monosaccharides possessing a unique 9-carbon skeleton with a carboxylate group at the 1-carbon position. Since they are usually found in the outmost part of oligosaccharide chains of glycoproteins and glycolipids, sialic acids involve in many important biological events. At present, more than 40 members of this sugar family have been found in nature. The structural diversity of sialic acids is due to various subsititutions at the 4, 5, 7, 8, and 9-carbon positions. Capillary electrophoresis (CE) is a modern analytical technique, which allows rapid and efficient separations of charged components present in minute quantity. CE can simultaneously analyze sialic acids derivatives with different linkages and degree of polymerization, as well as free acids and their various lactonized species. Synthetic sialic acid derivatives, Neu5Ac-α2→5-Oglycolyl-Neu5Gc-OBn, Neu5Gc-α2→5-Oglycolyl-Neu5Gc-OBn, Neu5Ac-α2→9-Neu5Ac-OBn, Neu5Ac-α2→9-Neu5Ac, and their sulfated dimers could be separated and identified by sialidase hydrolysis following CE analysis. The internal sialic acid residues inα2→8-linked-tetra-/penta-Neu5Ac are prone to lactonization in glacial acetic acid. Furthermore, the reducing-end lactones are formed faster than the corresponding nonreducing-end lactones in a-2→8-linked tri-/tetra-/penta-sialic acids. Twelve products are detected by CE for the lactonization study of α2→8-penta-sialic acid in glacial acetic acid. They can be classified into five groups based on the number of lactones: free, mono-lactones, di-lactones, tri-lactones and fully lactonized species. Among them, nine products are identified with sialidase hydrolysis and subsequent CE analysis. Based on the results obtained, the elution order of the lactonized isomers in the same group (with the same number of charge) could be predicted according to the pKa values of each carboxylic groups in penta-sialic acid (pKa1＜pKa2＜pKa3＜pKa4). The rate of lactonization also depends on the type of glycosidic linkages in the following order: α2→8＞α2→9＞α2→3. For oligosialic acids containingα2→5-Oglycolyl-linkage, no lactonization was detected. In the cases of α2→8 andα2→9 dimers, their corresponding C’-9 sulfated derivatives display no rate enhancement in the lactonization. It was observed that lactonization and hydrolysis ofα2→8-linked-oligosialic acids are competitive under acidic conditions and lactonization is faster than hydrolysis. The glycosidic bonds in α2→8-linked oligosialic acids are resistant to acidic hydrolysis if the bonds are part of the lactone ring. In a 0.1 N acetic acid aqueous solution, oligosialic acids are slowly hydrolyzed into free sialic acid. Depending on their linkage type, the rate of hydrolysis is in the following order: α2→5-Oglycolyl＞α2→9＞α2→8. This observation could be explained by the competition of hydrolysis and lactonization under acidic conditions. Under these conditions,α2→8-linked-oligosialic acids undergo lactonization and reduce the hydrolytic rate. The Vmax/KM value for Neu5Gc-α2→5-Oglycolyl-Neu5Gc (0.049 min-1) was greater than other substrates, indicating that Neu5Gc-α2→5-Oglycolyl-Neu5Gc is the best substrate of the sialidase from A. ureafaciens.

碩士
國立中正大學
化學暨生物化學研究所
100
A steroselectivity synthesis of fully subsititude decahydro-1H- pentaleno [2,1-c]pyran derivatives have been achieved with alkylidene malonates and aldehydes. By a sequential oganocatalyzed anti-selective Michael reaction－reduction－lactonization－Pauson-Khand reaction, varios additives effected different results of steroselectivity.

Natural products are essential tools for basic cellular studies leading to the identification of medically relevant protein targets and the discovery of potential therapeutic agents. We have developed a set of second generation diazo reagents with small steric footprints, namely an alpha-trifluoroethyl (HTFB) diazo reagent, for simultaneous arming and SAR studies of bioactive natural products. The Rh(II)-catalyzed O-H insertions of several alcohol-containing natural products, including the potent translation inhibitor lactimidomycin, are investigated and useful reactivity and both chemo- and site- (chemosite) selectivities are observed. The alpha-trifluoroethyl diazo reagents (HTFB) shows clear differences in the IL-2 reporter assay with FK506 derivatives and provides greater retention of biological activity in a hMetAP2 proliferation assay of fumagillol derivatives compared to the first generation pbromophenyl diazo reagent (HBPA). The synthetic utilities of the new alpha-trifluoroethyl diazo reagent (HTFB) provide a great new tool for basic cellular studies facilitating the discovery of new drug candidates for human disease. Furthermore, we are interested in methodologies for beta-lactone synthesis and transformations. In this study, we demonstrated synthetic versatilities of beta-lactones for the synthesis of beta-lactam congeners of orlistat as fatty acid synthase inhibitors via SnCl4- promoted tandem Mukaiyama aldol-lactonization (TMAL) reaction and a one-pot, mild conversion of beta-lactones to beta-lactams. The inhibitory activities of the derived beta-lactam derivatives are determined in a biochemical fluorogenic assay using recombinant FASTE, and the micro-molar range FAS-TE inhibitory activities were observed. Additionally, we pursued synthetic studies toward the total synthesis of spongiolactone, which is a unique beta-lactone-containing marine diterpenoid, isolated from the marine sponge Spongionella gracilis. This natural product bears a unique tricyclic beta-lactone core possessing four contiguous stereogenic centers and an additional stereogenic quaternary carbon on a cyclohexyl appendage. We completed the total synthesis of 6,15-bis-epi-spongiolactone by employing an intramolecular nucleophilecatalyzed aldol-lactonization (NCAL) process as the key step to construct the fused tricyclic beta-lactone core. Importantly, we developed a double diastereoselective and, for the first time, a kinetic resolution via the NCAL process that enables an enantioselective strategy to the tricyclic beta-lactone core of (+)-spongiolactone.

An original palladium-catalyzed ring opening carbonylative lactonization of synthetic available hydroxycyclopropanols was reported to efficiently synthesize tetrahydrofuran (THF) and tetrahydropyran (THP)-fused bicyclic γ-lactones, two unique scaffolds often found in quite a few natural products. This new developed reaction features mild reaction conditions, good functional group tolerability, and the scale-up abilities. The synthetic application was demonstrated in a short total synthesis of (±)-Paeonilide. The THF-fused bicyclic γ-lactone products can be readily diversified into some medicinally important structures, which further broadens the application of this new carbonylation approach.

The first total synthesis of Phleghenrine A was reported. This synthesis features an unprecedented inverse electron-demand Diels-Alder reaction and Tiffeneau-Demjanov ring expansion to rapidly construct bicyclo[3,2,2]-nonane core structure of Phleghenrine alkaloids. Two Diels-Alder adducts were synthesized, which were the synthetic precursors for divergent synthesis of Phleghenrine A and B, respectively.

The development of methods for site-selective derivatization of natural products to enable simultaneous arming and structure activity relationship (SAR) studies has shown great potential for the synthesis of pharmaceutical drug leads and cellular probes for mechanism of action studies. Herein, we describe a strategy to functionalize carboxylic acid and phenol containing natural products. This methodology relies on the in situ generation of diazoalkanes to form the corresponding carbonyl esters and phenolic ethers derived from natural products. We applied this process to several natural products, to begin demonstrating the utility of this methodology for the simultaneous arming and SAR studies of natural products. To expand our group’s nucleophile catalyzed aldol lactonization (NCAL) reaction for synthesizing highly substituted cyclopentane fused beta-lactones, we developed a nucleophile catalyzed, tandem Michael aldol lactonization (NCMAL) reaction. Herein, we show the synthetic utility of this reaction in varying the Michael donors and acceptors, developing a catalytic, enantioselective NCMAL, and synthesizing tricyclic-!-lactones. Furthermore, we initiated studies toward applying this new methodology to the synthesis of a lipase inhibitor, vibralactone.

Natural products continue to inspire synthetic chemists to develop novel methodologies to provide efficient and expedient syntheses of the target molecules. Haterumalide NA aroused our interest and prompted development of four differing methodologies. Three of the strategies pursued involved use of B-lactone scaffolds as intermediates. Extensions of the nucleophile catalyzed, aldol-lactonization (NCAL) reaction were also pursued and targeted toward alternative natural product targets. The reactivity of the unexpectedly stable strained spirocycle, spiroepoxy-B- lactone, was explored. Spiroepoxy-B-lactones exhibited a wide range of reactivity, but largely rearranged to tetronic acids. The desired reaction manifold remained inaccessible and led to application of the NCAL process to tetrahydrofuran-fused B-lactones. Several tetrahydrofuran-fused B-lactones were prepared, which displayed low diastereoselectivity. The diastereoselectivity could be somewhat improved in a double diastereoselective NCAL process with varied solvent systems, yet the carbocyclic analogues gave much more promising results. The use of carbocycle-fused !-lactones ultimately culminated in a double diastereoselective NCAL process, and overall led to improvements in diastereoselectivities from 1:1-2 up to >19:1. Further expansion of the substrate scope for the NCAL process was studied for application to bridged tricyclic B- lactones, access to carbocycle-fused y-lactones, and towards development of a dynamic kinetic resolution NCAL process. With our interest aimed at haterumalide NA, a modified Negishi cross coupling between zincates and dichloroolefins was also revisited. The stringent anhydrous reaction conditions led to reexamination of initial leads, which provided user-friendly anhydrous conditions by utilizing commercially available anhydrous solvent. However, application was implemented solely to a simplified model system.

The potential of human 20S proteasome inhibitors continues to be of interest for anticancer chemotherapy and the recent FDA approval of bortezomib (Velcade) validates the proteasome as a target for cancer chemotherapy. Salinosporamide A, a marine unique bicycle [3.2.0] Beta-lactone-containing natural product, is not only a potent nanomolar inhibitor of the human proteasome but also active against bortezomibresistant multiple myeloma cells. The racemic and asymmetric syntheses of salinosporamide A and derivatives were targeted. In this dissertation, we successfully accomplished the shortest route to date with only a 9-step total synthesis of (–)-salinosporamide A. The conciseness of this strategy arises from the key bis-cyclization of a Beta-keto tertiary amide, amenable to gram scale, constructs both the Gamma-lactam and the fused-Beta-lactone in one operation with high enantiopurity, which was enabled by A^1,3-strain. Several derivatives were synthesized and their inhibition activity toward chymotripsin-like, caspase-like, and trypsin-like of the human 20S proteasome was evaluated. This dissertation also included a successfully optimized Organic Syntheses procedure for asymmetric synthesis of (1S,5R)-6-oxaspiro[bicyclo[3.2.0]heptane-3,2'- [1,3]dioxolan]-7-one via the nucleophile-catalyzed aldol-lactonization.

Les matériaux utilisés pour les applications biomédicales doivent être biocompatibles, et idéalement biodégradables. Les acides biliaires proviennent de sources naturelles et sont présents dans le corps humain. De plus, les polyetsers composés en partie de ces molécules possèdent des liens hydrolysables, une mémoire de forme thermique, et leur flexibilité peut être variée. Jusqu’à présent, la synthèse de ces matériaux exigeait l’utilisation de catalyseurs contenant des métaux de transition lourds pour l’étape de macrocyclisation. Puisque la polymérisation par ouverture de cycle nécessite des précurseurs cycliques, l’étape de lactonisation fut réalisée par voie enzymatique, au lieu d’utiliser des catalyseurs à plus grande toxicité. De plus, une seule étape enzymatique a pu remplacer deux étapes de synthèse organique, avec un rendement de 58 % et l’obtention d’un matériel transparent. Ces macrocycles nouvellement obtenus ont par la suite été polymérisés par ouverture de cycle, de façon similaire à la technique élaborée par notre groupe en 2013, tout en optimisant la durée de réaction. En 15 heures, une masse molaire relativement grande de 40 000 g/mol fut obtenue, tout en maintenant la dispersité sous 1.4 et la température de transition vitreuse à 12 °C. Pour valider le principe de cyclisation et de polymérisation enzymatique, les conditions optimales pour combiner l’acide thapsique et le 1,10-decanediol furent préalablement déterminées. Entre autres, la durée de réaction et la quantité d’enzyme nécessaire furent analysées. Les polymères semi-crystallins obtenus possèdent aussi de grandes masses molaires et de basses dispersités. Or, il est possible d’utiliser un enzyme à la fois pour la fermeture et pour l’ouverture de cycle de molécules rigides à cœur stéroïdal, telles que les acides biliaires. Cette synthèse permet la production de matériaux plus biocompatibles, tout en favorisant plusieurs principes de chimie verte.
Materials used in biomedical applications need to be biocompatible and ideally biodegradable. Bile acids are natural occurring compounds found in humans, and their polyesters possess hydrolyzable bonds, thermal shape memory and tunable flexibility. Until now, the synthetic pathway to obtain such materials required transition metal catalysts for the macrocyclization step, which is necessary to perform ring-opening polymerization (ROP). To circumvent the need for such catalysts, enzymatic ring closing was performed using lipases. Conveniently, two synthetic steps were replaced with a single step, using a renewable and reusable catalyst, with 58 % yield and a colorless product. The bile acid-containing macrocycles were then enzymatically polymerized as described in our previous work, while optimizing the reaction time. In 15 hours, relatively high Mw of 40 000 g/mol were obtained, while maintaining the dispersity ≤ 1.4 and a glass transition temperature of about 12 °C. As a proof-of-concept, conditions for the enzymatic ring closure of thapsic acid with 1,10-decanediol were determined beforehand. While optimizing for enzyme amount and reaction time, enzymatic ROP conditions to obtain di- and tetralactones from these monomers were established. The resulting semi-crystalline polymers also possess relatively high molecular weight and low dispersity. Hence, the use of lipases for both ring-closing and ring-opening reactions now shows potential for large, rigid moieties in addition to more mobile structures, using the same enzyme. This is a step towards the production of more biocompatible polymers, with a synthetic pathway that follows many green chemistry principles.