Tesis sobre el tema "Ring opening of azirine and aziridines"

This thesis deals with the design and synthesis of chiralenantiopure nitrogencontaining ligands and the use of theseligands in asymmetric catalysis. A modular synthetic approachto enantiopure nitrogen-containing ligands was developed. Thesynthetic method is based on the ring-opening of activatedchiral aziridines by nitrogen nucleophiles. The aziridines areconveniently prepared from amino alcohols. The structure oftheaziridine and of the nucleophile can be extensively varied andlibraries of ligands are easily prepared. The use of primaryamines affords C₂-symmetric bis(sulfonamides), whereas the use ofammonia affords C₃-symmetric tris(sulfonamides) that can beelaborated into the corresponding tetra-amines.

The C₂- and C₃-symmetric ligands were used in the asymmetrictitaniummediated addition of diethylzinc to benzaldehyderesulting in modest enantioselection, 76% ee. A thoroughinvestigation of the reaction conditions revealed that theamount of Ti(OiPr)₄has a decisive effect on the reaction rate and thestereochemical outcome of the reaction. The reaction timedecreased from about 90 hours to 15 minutes and theenantioselectivity changed from 26% of the (R)- enantiomer to72% of the (S)-enantiomer when the Ti(OiPr)₄:benzaldehyde ratio was increased from 0.125:1 to1.48:1. Moreover, the titanium-mediated addition of diethylzincto benzaldehyde was studied in the presence of chiraladditives. The bis(sulfonamides) were also used in thecyclopropanation of cinnamyl alcohol. However, only lowenantioselection was observed, 27% ee.

The C₃-symmetric tetra-amines were reacted to formazaphosphatranes. These weak acids were only partiallydeprotonated by the strong base KOtBu to form the correspondingproazaphosphatranes. The unexpectedly strong basicity of theproazaphosphatranes was believed to be due to steric effects assuggested by DFT calculations. The tetra-amines and thesulfonamides were used for the preparation of metal complexesof Lewis acidic metals such as titanium(IV) andzirconium(IV).

Keywords:asymmetric catalysis, aziridine, benzaldehyde,diethylzinc, enantioselective, ligand, proazaphosphatrane,ring-opening, sulfonamide, symmetry, titanium, zirconium

Dans un premier chapitre, nous avons présenté un historique succinct de la chimiothérapie antivirale et l'utilisation d'analogues nucléos(t)idiques. Nous nous sommes focalisés en particulier sur les nucléosides phosphonates acycliques (ANP) en tant qu'antiviraux potentiels. Dans un second chapitre, nous avons décrit la synthèse de β-céto, β-hydroxylamino et β-O-(benzyl)hydroxylamino ANP dérivés de l'adénine et de la cytosine. Les isomèrs (R) et (S)-β-hydroxy-ANP ont été préparés par dédoublement du racémique correspondant avec le (S)-MPA et l'attribution des configurations absolues a été effectuée par RMN et calculs de modélisation moléculaire. Nous avons aussi développé une méthodologie de synthèse de β-azido-ANP, ces derniers étant utilisés pour la préparation de β-amino-ANP par hydrogénation catalytique. Dans un troisième chapitre, nous avons présenté la synthèse des 2H-azirine et cis-aziridne-ANP et examiné lʹ ouverture de cycle comme voie d'accès à des ANP α,β-fonctionnalisés. Les propriétés biologiques de ces nouveaux ANP ont été évaluées en culture cellulaire sur un certain nombre de virus à ADN et ARN
In the first chapter, we presented a brief history of antiviral chemotherapy and use of nucleos(t)ide analogues, especially acyclic nucleoside phosphonates as potential antiviral agents. In the chapter-II we have successfully synthesized ¦Â-keto, ¦Â-hydroxylamino and ¦Â-O-(benzyl)hydroxylamino ANPs of adenine and cytosine derivatives. Then (R) and (S)-¦Â-hydroxy-ANPs were prepared via chiral resolution of racemic ¦Â-hydroxy-ANPs with (S)-MPA and assignment of absolute configuration was achieved using NMR and molecular modeling studies. We also developed a methodology for the synthesis of ¦Â-azido-ANPs and those were used for the preparation of ¦Â-amino-ANPs by catalytic hydrogenation. In third chapter, we synthesized 2H-azirine and cis-aziridine-ANPs and explored their ring opening to functionalized ¦Á,¦Â-ANPs. The novel ANPs obtained during this study were evaluated for their inhibitory effect on a number of DNA and RNA viruses in cell culture experiments

1: The ring-opening of aziridine-2-carboxylates dominates their reactivity, providing diverse, biologically relevant compounds. Less is known about the chemistry of NH-aziridine-2-carboxylates, owing to multi-step preparation, and lack of N-functionality to aid ring-opening. Building on the recent disclosure of an NH-aziridination methodology applicable to enones, the substrate scope was expanded to include enoates. Aziridination provided access to NH-aziridine-2-carboxylates in a single step from readily available starting materials. Treatment of the resulting aziridine-2-carboxylates with nucleophiles proceeded with high regio- and stereoselectivity, providing access to natural and unnatural amino acid derivatives (Scheme 1).[Molecular structure diagrams appear here. To view, please open pdf attachment] Scheme 1: The synthesis and ring-opening of aziridine-2-carboxylates 2: Identification of kinase protein-substrate sets is crucial to further understand cellular processes, but is challenging with known methodology. Previous study had proposed a new methodology, incorporating two known strategies, bump-hole inhibition and photo-affinity labelling. Novel C3-aryl pyrazolo[3,4-d]pyrimidines were designed for the purpose (Fig. 1), although preparation of the compounds had proved challenging, with several key steps in the synthesis of analogues low-yielding and lengthy. A new synthetic route was developed, using hydrazone allylation to establish the α-tertamine functionality of the pyrazolo[3,4-d]pyrimidines. A late-stage oxidative cleavage was used to re-connect with the original synthetic strategy, to provide access to the C3-hydro analogues. Application of the revised route to the synthesis of the target compounds, using an alternative enol ether for C3-aromatic installation, provided access to two novel pyrazolo[3,4-d]pyrimidines for testing. [Molecular structure diagrams appear here. To view, please open pdf attachment] Fig. 1: C3-aryl pyrazolo[3,4-d]pyrimidines

Résumé Cette thèse consiste en trois thèmes résumés dans les paragraphes ci-dessous. L’influence de différents groupements protecteurs du groupe hydroxyle lors des réactions d’ouverture des cis- et trans- 3-hydroxy-1,2-époxycycloalcanes a été étudiée. Il a été montré que Yb(OTf)3 constituait un catalyseur doux pour l’ouverture régiosélective de cycles afin d’obtenir les -anilino cycloalcanols correspondants avec de bons rendements. Le chauffage du milieu réactionnel dans le toluène comme solvant a permis d’augmenter la cinétique de la réaction, au dépend du rendement. La partie aniline a été régiosélectivement introduite en position vicinale du groupe hydroxyle ou éther afin d’obtenir un unique régioisomère. La même tendance a été observée avec les époxydes du 3-azidocyclohex-1-ène et du 3-carbamate correspondant. Le temps de réaction a été réduit lorsque Yb(OTf)3 a été dissous dans l’acétonitrile. Le triflate d’ytterbium (III) a également été utilisé comme catalyseur pour l’ouverture de cycle régiosélective d’aziridines non-activées sur des cyclohexanes portant des substituants azotures ou éthers de benzyle. L’ion azoture ou l’aniline forment les produits trans correspondants, donnant alors accès à des diamines vicinales avec de bons rendements. Un éther ω-alcoxy p-méthoxybenzylique racémique, inhibiteur de HDAC, a été ainsi préparé en huit étapes synthétiques (rendement total de 26%) à partir du 1-((tert-butyldiphénylsilyl)oxy)hept-6-èn-2-ol. Ceci représente un progrès par rapport à la précédente méthode (9 étapes, rendement total de 16%). La métathèse croisée se montre particulièrement efficace et pratique dans cette stratégie et l’alkylation par le trichloroacétimidate de p-méthoxybenzyle en présence de Sc(OTf)3 améliore le rendement global de la synthèse. Un aminoalcool présent dans la pactamycine et contenant le squelette carboné, les groupements fonctionnels et la stéréochimie requise a été synthétisé en 27 étapes à partir de la L-thréonine. La méthodologie décrite dans cette thèse permet la synthèse de cet intermédiaire clé à l’échelle multigramme.
Abstract Ring-opening reactions of epoxides and aziridines have been extensively studied. The influence of different protecting groups on the hydroxyl group in the ring-opening reactions of cis- and trans- 3-hydroxy-1,2-cycloalkane epoxides with aromatic amines was studied. It was shown that Yb(OTf)3 in toluene was a mild catalyst for regioselective ring-opening, to give -anilino cycloalkanols in good yields. Heating the reaction mixture accelerated the rate of the reaction, albeit at the expense of yield. The aniline moiety was regioselectively added at the carbon furthest from the hydroxyl or ether group to yield a single regioisomer. The same trend was also observed with 3-azidocyclohex-1-ene epoxides and the corresponding 3-carbamates. The reaction time became shorter when acetonitrile was used as solvent, possibly due to the homogeneous medium. Ytterbium(III) triflate has also been used as the catalyst for the regioselective ring-opening of unactivated aziridines in cyclohexanes having an azide or benzyl ether substituent. Azide ion or aniline forms the corresponding trans-products giving access to vicinal diamines in good yields. A racemic ω-alkoxy p-methoxy benzyl ether HDAC inhibitor has been prepared in 8 synthetic steps (26% overall yield) from 1-((tert-butyldiphenylsilyl)oxy)hept-6-en-2-ol. This is an improvement over the published method (9 steps, 16% overall yield). The cross-metathesis method proved to be efficient and practical in this strategy, and alkylation using p-methoxybenzyl trichloroacetimidate in the presence of Sc(OTf)3 improved the overall yield of the synthesis. An amino alcohol that contains all the core carbons, functional groups and the required stereochemistry present in pactamycin was obtained starting from L-threonine over 27 steps. The methodology described in this thesis allows for a synthesis of this key intermediate on a multigram scale.

Aziridines, a class of organic compounds containing a three membered heterocycle with a nitrogen atom, are extremely valuable molecules in organic and medicinal chemistry. They are frequently used as versatile precursors in the synthesis of natural products, and many biologically active molecules possess the aziridine moiety. The reactivity of aziridines has been studied, for example, in ring-opening reactions with thiols. However, not much interest seems to be given to reactions of aziridines in aqueous media, despite the numberless advantages of using water as solvent in organic chemistry. The nucleophilic ring-opening reaction of aziridines in aqueous media was here explored. Following the Kaplan aziridine synthetic methodology, in which pyridinium salts undergo a photochemical transformation to give bicyclic vinyl aziridines, new aziridines were synthetized. Their nucleophilic ring-opening reaction in water under physiological conditions was investigated and a range of sulphur, nitrogen, carbon and oxygen nucleophiles tested. Thiols, anilines and azide proved to be good nucleophiles to react with the aziridines, giving the ring-opening product in moderate to good yields. The best results were obtained with thiols, more specifically with cysteine-derived nucleophiles. Preliminary results show that these bicyclic vinyl aziridines can modify calcitonin, a peptide containing two cysteine amino acids residues, grating them the potential to be used in bioconjugation as ligands to cysteine-containing proteins, or even as enzyme inhibitors of, for example, cysteine proteases. Additionally, exploratory investigations suggest that the separation of both enantiomers of the bicyclic vinyl aziridine can be performed by taking advantage of an enzymatic methodology for the resolution of racemic secondary alcohols. Both enantiomers would be highly valuable as precursors in the synthesis of enantiomerically pure molecules, as no other method is currently reported for their separation.

The thesis entitled “Chemistry of Tetrathiomolybdate and Tetraselenotungstate: Studies on Aziridine and Epoxide Ring Opening Reactions” is divided into five chapters. (For Formulas and Equations Refer PDF File) Chapter 1: Part 1: Synthesis of β-Sulfonamidodisulfides and β-Sulfonamidosulfides using Benzyltriethylammonium Tetrathiomolybdate In this chapter, a comprehensive study of general and effective one step procedure for the synthesis of β-sulfonamidodisulfides directly from optically pure N-tosyl aziridines using benzyltriethylammonium tetrathiomolybdate [BnEt3N]2MoS4 as sulfur transfer reagent in a regio manner under neutral conditions without the use of any Lewis acid or base has been reported. Additionally, we have demonstrated regio- and stereospecific ring opening of di- and trisubstituted aziridines using [BnEt3N]2MoS4 to synthesize substituted β-sulfonamidodisulfides in good yields. This methodology is extended to the synthesis of an optically pure unnatural amino acid with the disulfide bridge and a cyclic seven membered disulfide. Synthesis of a variety of β-sulfonamidosulfides involving cleavage of disulfide bonds assisted by tetrathiomolybdate and the use of masked thiolate for the synthesis of β-sulfonamidosulfides involving multi-step reactions in a one pot is also demonstrated. Chapter 1: Part 2: Synthesis of β-Sulfonamidodiselenides using Tetraethylammonium Tetraselenotungstate In this chapter, we report the results of regio- and stereospecific, nucleophilic ring opening of chirally pure N-tosyl aziridines with tetraethylammonium tetraselenotungstate [Et4N]2WSe4 as selenium transfer reagent to afford a number of β- sulfonamidodiselenides in good yields. Using this methodology, carbohydrate derived β- sulfonamidodiselenides from the corresponding carbohydrate derived aziridines have been synthesized. These enantiopure diselenide derivatives have the potential to be used as chiral ligands in diethyl zinc addition to aldehydes. Chapter 2: Ring Opening of Aziridine/Epoxide, Disulfide Formation, Reduction of Disulfide Bond and Michael Reaction In this chapter, we report a systematic study of tetrathiomolybdate mediated tandem regio- and stereospecific ring opening of aziridines, disulfide formation, in situ reduction of disulfide bond followed by Michael reaction in an one pot operation to give a variety of β-sulfonamidosulfides in good yields. The main advantage of this methodology is that four reactions involving three components take place in a one-pot operation. Chapter 3: Part 1: New Thia-aza Payne type Rearrangement Mediated by Benzyltriethylammonium Tetrathiomolybdate In this chapter, reaction of aziridinemethanol sulfonate esters with tetrathiomolybdate to give thiirane derivatives as the major product and cyclic disulfides as minor product under mild reaction conditions via an unprecedented thia-aza-Payne type rearrangement have been presented. Interestingly, when the reaction of tetrathiomolybdate was carried out with 2-aziridino-cyclohexanol derivatives it resulted in the formation of thia-bicyclo[3.1.1]heptane or dithia-bicyclo[3.2.1]octane derivatives. Chapter 3: Part 2: New selena-aza Payne Type Rearrangement Mediated by Tetraethylammonium Tetraselenotungstate In this chapter, reaction of tetraselenotungstate with simple N-tosyl aziridinemethanol tosylates to give allyl amine derivatives as the only product via an unprecedented selena-aza-Payne type rearrangement is discussed. When the methodology is extended to disubstituted N-tosyl aziridinemethanol tosylates, regio- and stereospecific ring opening of aziridines occurs to afford allyl amine derivatives as the major products and cyclic five membered diselenides as the minor products in good yields. Chapter 3: Part 3: Synthesis of Sulfur and Selenium Heterocycles by Azirdine Ring Opening followed by Cyclization In this chapter, studies on the synthesis of sulfur and selenium-heterocycles by aziridine ring opening followed by cyclization of N-tosyl aziridino-ethanol tosylates using tetrathiomolybdate as a sulfur transfer reagent and tetraselenotungstate as a selenium transfer reagent respectively are presented. Chapter 4: Tetrathiomolybdate Mediated Ring Opening of bis-Aziridines, bis-Epoxides and Aziridino-epoxides In this chapter, studies on the synthesis and ring opening of bis-aziridines, bis-epoxides and aziridino-epoxides with tetrathiomolybdate as the sulfur transfer reagent are presented. This has resulted in the synthesis of optically active sulfur heterocycles ranging from three membered to eight membered ring systems with excellent stereo and regio- control in good yields. Chapter 5: Part 1: Synthesis of Conformationally Locked, Bridged, Bicyclic Mono and Disulfides In this chapter, work related to the synthesis of conformationally locked bridged bicyclic disulfides and sulfides from cis-aziridino-epoxides by ring opening of both aziridines and epoxides in a tandem fashion using tetrathiomolybdate as a sulfur transfer reagent has been discussed. Comparative studies on the behavior of conformationally locked disulfides which has the dihedral angle close to zero (φ = 0) with disulfides having larger dihedral angles (φ>90) have been presented in this chapter. Some correlations have been made on the physicochemical characteristics of the disulfides with change in the dihedral angles. Chapter 5: Part 2: Synthesis of Conformationally Locked, Bridged, Bicyclic Diselenides In this chapter, work related to the development of a general synthetic methodology for the synthesis of conformationally locked, bridged diselena-bicyclo[3.2.1]octane skeleton by regio- and stereospecific, tandem nucleophilic ring opening of cis-1,4-aziridino-epoxides with tetraselenotungstate in one-pot are presented. To compare the behavior of conformationally locked diselenides which has the dihedral angle close to zero (φ = 0) with diselenides having larger dihedral angles (φ > 90), we have synthesized the acyclic diselenide (see chapter 1.2) and cyclic diselenide by regio- and stereospecific ring opening of simple aziridine and bis-aziridine respectively with tetraselenotungstate. Some correlations have been made on the physicochemical characteristics of the diselenides with change in the dihedral angles.

Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2009.
Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3516. Adviser: David Y. Gin. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.

Ce mémoire a comme sujet principal les réactions d’ouvertures d’aziridines et leur application synthétique. Notre groupe de recherche a récemment mis au point une méthode d’aziridination énantiosélective catalysée au cuivre à partir de N-tosyloxycarbamates qui permet d’obtenir une grande variété d’arylaziridines protégées avec un groupement carbamate. Or, même si le motif aziridine se retrouve dans certains produits naturels, l’intérêt de sa synthèse provient en partie de l’accès facile à différents composés contenant une fonction amine protégée qui peuvent être obtenus suite à l’ouverture d’aziridines par différents nucléophiles. L’ouverture nucléophile des aziridines fut largement explorée pour une variété de nucléophiles et d’aziridines. Toutefois, puisque les arylaziridines protégées par un groupement carbamate n’étaient auparavant pas disponibles, leur régio- et stéréosélectivité est encore méconnue. Nous présentons ici dans un premier temps, les résultats obtenus lors de l’ouverture de la p-nitrophénylaziridine protégée par un groupement Troc avec différents nucléophiles. Puis, suite à l’obtention de bonnes diastéréosélectivités lors de la synthèse d’aziridines avec le dérivé chiral PhTrocNHOTs, des réactions d’ouvertures ont été tentées avec la p-nitrophénylaziridine protégée avec un groupement PhTroc. Les conditions optimisées d’ouverture impliquent l’acide de Lewis BF3∙OEt2 (10 mol%) à 23 °C avec une variété de nucléophiles. Ces conditions ont été appliquées à l’ouverture d’une gamme d’aziridines protégées par le groupement PhTroc dont les résultats sont décrits dans cet ouvrage. Finalement, le dernier chapitre de ce mémoire rapporte l’utilisation de ces conditions dans la synthèse du (R)-Nifenalol, un agent beta-bloquant qui a démontré une activité en tant qu’antiangineux et antiarythmique.
The main subject of this Master thesis is the ring-opening reactions of azirdines and their synthetic applications. Our group has recently developed a copper-catalyzed enantioselective aziridination reaction from N-tosyloxycarbamates which leads to a variety of carbamate-protected arylaziridines. Although the aziridine motif appears in some natural products, interest in these models comes from the easy access to amine-protected derivatives obtained via the nucleophilic ring-opening of aziridines. Nucleophilic ring-opening of aziridines has been thoroughly studied for a variety of nucleophiles and aziridines. However, as carbamate-protected arylaziridines were not previously available, little is known on either their reactivity or regio- or stereoselectivity. We present herein the results of the ring-opening of Troc-protected p-nitrophenylaziridines with a variety of nucleophiles. Furthermore, following the discovery that excellent diastereoselectivities could be achieved by using the chiral derivative PhTrocNHOTs, ring-opening reactions were attempted on PhTroc-protected p-nitrophenylaziridine. Optimized conditions were found to be 10 mol% of BF3∙OEt2 at room temperature with a variety of nucleophiles. These conditions were also used in the ring-opening of various PhTroc-protected aziridines and the results are disclosed herein. Finally, these conditions were applied to the synthesis of (R)-Nifenalol, a beta-blocking agent that has shown antianginal and antiarrhythmic properties as described in the third chapter.

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019
O grupo funcional aziridina apresenta-se como uma das estruturas cíclicas mais pequenas com maior potencial como meio de síntese para novas moléculas de interesse químico. Devido à sua alta reatividade e tensão anelar, apresenta características que permitem a aplicação numa ampla gama de reações. Neste projeto, particularmente, retratamos as aziridinas bicíclicas. Estas moléculas foram já previamente estudadas no que diz respeito à abertura da estrutura recorrendo a nucleófilos baseados em heteroátomos. Neste contexto, durante este projeto quisemos estender o estudo no âmbito da abertura do ciclo das aziridinas bicíclicas com uso de nucleófilos baseados em ligação carbono-carbono e envolvendo catálise com paládio. Para tal, usando um sistema inovador de “flow”, sintetizamos inicialmente a aziridina bicíclica com o grupo hidroxilo [(1R,2R,5R)-6-butil-6-azabiciclo[3.1.0]hex-3-en-2-ol] em grande escala ( 8 gramas com 96% de rendimento). De seguida, a aziridina bicíclica com o grupo acetil [(1R,2R,5R)-6-butil-6-azabiciclo[3.1.0]hex-3-en-2-ol] também foi sintetizada. Posteriormente, a catálise com paládio foi testada com sucesso, na aziridina bicíclica hidroxilo e acetilo, com nucleófilos baseados em ligação carbono-carbono tais como: ácido de meldrum originando rendimentos isolados de 44% e 71%, respectivamente; ácido dimetil barbitúrico com rendimentos de 42% e 83%, respectivamente; acetoacetato de metilo com rendimento isolado de 60% para a aziridina bicíclica hidroxilo; e nitroacetato de etilo com rendimento isolado de apenas 24% para a aziridina bicíclica acetilo. Todos os produtos foram caracterizados por RMN (1H, 13C NMR e análise 2D), HRMS e por análise raio-X (para produtos obtidos com o ácido dimetil barbitúrico) que confirmou a regio e estéreo-seletividade desta reação. Outros nucleófilos como o malononitrilo, bis(fenilsulfonil)metano e metil 2-tosilacetato foram também testados, mas sem sucesso. De modo geral, alcançámos a síntese e caracterização de diversos novos compostos com abertura regio e estéreo-seletivamente controlada da aziridina bicíclica, demonstrando a importância desta química.
The functional group aziridine is one of the smallest cyclic structures having a great potential for synthesis of new molecules of chemical interest. Due to its high reactivity and ring tension, it has characteristics that allow its application in a wide range of reactions and, therefore, applications in the construction of new and bigger molecules. In previous reports by our group, the potential of bicyclic aziridines in chemistry was studied, and specially the opening of the structure in the presence of heteroatom-based nucleophiles. In this context, during this project, we wanted to extend this study concerning the ring opening of bicyclic aziridines, to the use of carbon-based nucleophiles by involving palladium catalysis. For that, using an innovative continuous flow system, first of all we synthetized the bicyclic aziridine bearing a free hydroxyl group [(1R,2R,5R)-6-butyl-6-azabicyclo[3.1.0]hex-3-en-2-ol] in large scale (8 grams in total with 96% yield). Then, the corresponding acetylated bicyclic aziridine [(1R,2R,5R)-6-butyl-6-azabicyclo[3.1.0]hex-3-en-2-ol] was also synthetized by an acylation reaction. Thereafter, the Pd catalysis was successfully tested on the unprotected and the acetylated bicyclic aziridines, with some carbon-based-nucleophiles, such as: Meldrum’s acid leading to 44% and 71% isolated yields, respectively; dimethyl barbituric acid given 42% and 83% isolated yields, respectively; methyl acetoacetate leading to 60% only with the unprotected bicyclic aziridine; and ethyl nitroacetate furnishing only 24% yield with the acylated bicyclic aziridine. All the products were characterized by NMR (1H, 13C NMR and 2D analysis), HRMS and by X-ray analysis (for products obtained with barbituric acid) that confirmed the regioselectivity of this reaction. Other nucleophiles like malononitrile, dimedone, bis(phenylsulfonyl)methane and methyl 2-tosylacetate, were also tested, but without successful results. Overall, we were able to synthetize and characterized a variety of new compounds, with both controlled stereo and regioselectivity cleavage of the bicyclic aziridine, showing the high value of this particular chemistry.
Instituto de Investigação do Medicamento, Faculdade de Farmácia da Universidade de Lisboa; Institut Parisien de Chimie Moléculaire, Sorbonne Université

碩士
臺北醫學大學
藥學系
94
Coumarin is important structure of organic chemistry and belongs to the benzopyrones. Coumarins are widely distributed in plants and have a variety of bioactivities including anticoagulation, estrogenic, dermal photosensitizing, antimicrobial, antioxidation, vasodilation, antithelmintic, sedative and hypnotic, analgesic and hypothermic activities. Aziridine is a class of compound important both in chemical synthesis and in chemotherapy of cancer. Ring opening of 2-methyl-N-acylaziridine by various nucleophiles has been reported. Nucleophilic attack at the unsubstituted carbon atom of the aziridine ring is called ” normal“ ring cleavage (in the SN2). Nucleophilic attack at tertiary or secondary carbon atom of aziridine ring is called “Abnormal” ring cleavage. We used the regioselectivity of ring opening of aziridines to synthesize a series of Coumarin-3- carboxamides. Four series of coumarin derivatives were synthesized from N-(coumarin-3-carboxyl) aziridines in this study. First, we used coumarin-3-carboxyl chloride (20) and a series of azirides with 4N NaOH to synthesize a class of N-(coumarin-3-caboxyl) aziridines (21, 22). Reactions of N-acylazirides with the radical anion of naphthalene had previusly been studied by Stamm, Mall, Falkenstein, Werry and Pen-Yuan Lin. Second, we used N-(coumarin-3-carboxyl) aziridines (21, 22) and activated thiols with the radical anion of naphthalene to synthesize Coumarin-3- carboxamide derivatives (27-40). Third, we used N-(coumarin-3- carboxyl) aziridines and 4-hydroxycoumarins to synthesize coumarin dimmer (41-50). Fourth, we used N-(coumarin-3-carboxyl) aziridines and 7-hydroxycoumarins to synthesize coumarin dimmer (51-54). The physical and chemical characteristics of the synthesized compound 1-35 were measured by 1H-NMR, IR, HRMS, and melting point determination. The cytotoxicities of all synthesized compounds to cancer cell lines (Colon 205, K-562, MCF7) are also examined in this study.

This work improved the radiosynthesis of a known M2 muscarinic receptor imaging agent, [18F]FP-TZTP, and subsequent syntheses and in vitro evaluation of several novel TZTP derivatives highlighted a lead compound which exhibited M4 potency and selectivity, the thioether fluoro-polyethyleneglycol, which was then adapted for radiolabelling (23% radiochemical yield (uncorrected), >99% radiochemical purity, reaction time of 37 minutes). The present study also seeked to utilize aziridines as intermediates in [18F]-radiolabelling chemistry for the facile radiosynthesis of [18F]-labelled beta-blockers. Novel [18F]-labelled amines were synthesized via ring-opening and deprotection to yield the [18F]-1-fluoro-2-propanamine moiety (85%) favourably over the regioisomer [18F]-2-fluoro-1-propanamine (15%). Subsequent attempts to use these amine synthons in the synthesis of the beta-blocker [18F]Exaprolol resulted in poor radiochemical yields (1-3%). The chemistry of aziridine ring-opening with 19F-fluoride sources was thoroughly explored in order to understand the fundamentals of this chemistry, and the 1-fluoro-2-propanamine moiety was characterized by X-ray crystallography and NMR spectroscopy.