No description available.

Cette thèse a été consacrée à la formation et l'utilisation de 4-amino- et 4-hydroxy-1-allénylmétaux. Deux méthodes de préparation stéréosélective et stéréospécifique des 4-sulfinamido- et 4-acétamido-1-allénylsilanes ont été développées. Ces deux voies reposent sur la réaction du tris(diméthylphényl)zincate de lithium avec les N-tert-butanesulfinylaziridines acétyléniques d'une part, et les acétates propargyliques de -acétamidoalkyle d'autre part. L'étendue et les limites de ces deux méthodes complémentaires ont été explorées. La fluorodésilylation électrophile des 4-acétamido-1-allénylsilanes avec le Selecfluor® a ensuite permis d'accéder de façon stéréosélective aux -fluoroacétates propargyliques correspondants. Un modèle d'état de transition a été proposé pour expliquer la différence de transfert de chiralité observée. Finalement, plusieurs voies d'accès aux 4-sulfinamido- et 4-sulfonylamido-1-allénylzincs par réarrangement métallate-1,2 de tris(diméthylphényl)zincates de lithium acétyléniques, obtenus à partir des N-tert-butanesulfinyl- et N-tert-butanesulfonylaziridines, se sont révélées infructueuses. En revanche, dans le cadre d'une collaboration franco-belge, l'étude de la borylation cupro-catalysée d'époxydes acétyléniques a donné des résultats prometteurs et a ouvert une nouvelle voie d'accès stéréosélective aux 4-hydroxy-1-allénylboranes. / During this research, the synthesis and use of 4-amino- and 4-hydroxy-1-allenylmetals have been studied.Two stereoselective and stereospecific syntheses of 4-sulfinamido- and 4-acetamido-1-allenylsilanes have been developed. These two synthetic routes rely on the reaction of lithium tris(dimethylphenylsilyl)zincate with acetylenic N-tert-butanesulfinylaziridines on one hand, and propargylic -acetamidoalkyl acetates on the other hand. The scope and limitations of these two complementary methods have been explored. The electrophilic fluorodesilylation reaction of 4-sulfinamido- and 4-acétamido-1-allenylsilanes with Selecfluor® gave access to propargylic -fluoroacetates in a stereoselective manner. A transition state model has also been postulated to explain the level of the chirality transfer observed. Finally, different synthetic routes towards 4-sulfinamido- and 4-sulfonylamido-1-allenylzincs through the 1,2-metalate rearrangement of acetylenic lithium tris(dimethylphenylsilyl)zincates, obtained from N-tert-butanesulfinyl- and N-tert-butanesulfonylaziridines, were proven to be unsuccessful. However, in the context of a French-Belgian collaboration, the study of the copper-catalyzed borylation of acetylenic epoxides led to promising results and paved the way for a new stereoselective synthesis of 4-hydroxy-1-allenylboranes.

Bisacetylenic cabamates/carbonates are most useful compounds in finger mark development, for the synthesis of polymeric gels and other material applications. Organochalogen derivatives are the organic compounds containing chalcogen (S, Se) atoms. They have been used as chiral ligands for enatioselective catalysis, glycosyl donors and in the synthesis of heterocyclic compounds etc. This thesis describes our efforts towards synthesis of bisacetylenic cabamates/carbonates and development new synthetic strategies using rongalite (Na+HOCH2SO2-) and benzyltriethyl ammonium tetrathiomolybate [BnEt3N]2MoS4 as a reducing agents led to obtain various organochalcogen derivatives. We developed a new reagent, hexa-2,4-diyne-1,6-bisoxycarbonyl chloride [Hbc Cl] for the synthesis of symmetrical diacetylenic biscarbamates/biscarbonates and further studied the solid state structures using X-ray crystallography. Later we described a stereoselective method for the hydrothiolation of buta-1,3-diynes derivatives using diaryldichalcogenides in the presence of rongalite and K2CO3. The buta-1,3-diynes underwent stereoselective addition reaction with in situ generated chalocgenate anion from diaryl dichalcogenides which afforded the corresponding (Z)-chalcogenynes. The reactivity of buta-1,3-diynes with diaryl dichalcogenides was further studied at higher temperature led to a mixture of mono chalcogenated and bischalcogenated products. Then an efficient method was developed for the synthesis of enatiopure β-amino sulfides/selenides via ring opening of sulfamidates using diarylchalcogenides with rongalite as reducing agent. Further we synthesized chalcogeno derivatives of sugars from glycosyl halides and diaryl dichalcogenides in the presence rongalite. In addition, the synthesis of mixed glycosyl dichalcogenides has been demonstrated using [BnEt3N]2MoS4 as sulfur transfer agent as well as reducing agent. Finally the reactivity of [BnEt3N]2MoS4 was studied in detail with various isatioc anhydrides which led to the formation of S-benzyl 2-aminobenzothioate derivatives. Further we synthesized S-alkyl/aryl 2-aminobenzothioate derivatives via ring opening of isatoic anhydrides and diaryl/dialkyl chalcogenides by mean of [BnEt3N]2MoS4 as a reducing agent. We extended this method in a one-pot, tandem fashion with various alkyl halides. In this thesis, details of all of the above studies have been described.

Pyrazoles have been studied for over a century as an important class of heterocyclic compounds and continue to attract considerable interest due to the broad range of biological activities they possess. The electrophilic cyclization of the acetylenic hydrazones initiated by molecular iodine could provide new ways of synthesizing biologically active 4-iodopyrazole derivatives, which are important precursors for the synthesis of highly substituted pyrazole derivatives. For this reason, we investigated the synthesis of 4-iodopyrazole derivatives, such as 1-aryl- 5-alkyl/aryl-4-iodopyrazoles, starting from phenylhydrazine and ,-acetylenic aldehyde derivatives. Initially, ,-acetylenic aldehydes were synthesized by formylation reaction of corresponding alkynes with DMF. Then, hydrazone derivatives of these aldehydes were prepared by heating them with phenylhydrazine in a neat manner at 55 &deg / C for 5 h. Finally, acetylenic phenyl hydrazone derivatives were subjected to electrophilic cyclization by treating with excess molecular iodine at 80 &deg / C for 3 h. Although electrophilic cyclization is commonly used in organic chemistry, it has not been employed for the cyclization of acetylenic phenyl hydrazones to pyrazole derivatives. Under optimized conditions, these reactions afforded 1-aryl-5-alkyl/aryl-4-iodopyrazole derivatives in moderate to good yields as the single or the major product of the reactions. In some cases, 1-aryl-5-alkyl/arylpyrazole derivatives resulted from these reactions as minor products. In conclusion, 4-iodopyrazole derivatives were synthesized for the first time directly from acyclic starting materials, ,-acetylenic phenylhydrazones and iodine, via electrophilic cyclization.

No description available.

Αντικείμενο της παρούσης διδακτορικής διατριβής αποτελεί ο υπολογισμός των ηλεκτρικών πολυπολικών ροπών (διπολική έως και δεκαεξαπολική) ακετυλενικών αλυσίδων οι οποίες υπάγονται στους γενικούς τύπους H-(C≡C)n-H, Χ-(C≡C)n-H και Χ-(C≡C)n-X, n=1–7, X=F, Cl, Br, I, CN, NC, η συστηματική μελέτη των (υπερ)πολωσιμοτήτων των μη υποκατεστημένων ακετυλενικών αλυσίδων Η-(C≡C)n- H, n=3–7 και τέλος ο υπολογισμός των ηλεκτρικών ιδιοτήτων αλληλεπίδρασης συστημάτων του τύπου Η-(C≡C)n-H…Ηe, n=1–7. Σε όλες τις περιπτώσεις χρησιμοποιήθηκαν οι ab initio μέθοδοι SCF και MP2 καθώς και οι ευρέως χρησιμοποιούμενες DFT μέθοδοι B3LYP, B3PW91 και mPW1PW91. Στους υπολογισμούς των ηλεκτρικών πολυπολικών ροπών χρησιμοποιήθηκε η βάση ccpVDZ σε όλες τις περιπτώσεις και ιδιαίτερη έμφαση δόθηκε στον τρόπο μεταβολής των υπό μελέτη ιδιοτήτων με την μεταβολή του υποκαταστάτη στα άκρα της αλυσίδας. Στους υπολογισμούς των ηλεκτρικών (υπερ)πολωσιμοτήτων των μη υποκατεστημένων ακετυλενικών αλυσίδων Η-(C≡C)n-H χρησιμοποιήθηκαν ελάχιστα πολωμένα σύνολα βάσης και πραγματοποιήθηκε σύγκριση με τα αποτελέσματα που προέκυψαν από την χρήση μεγαλύτερων συνόλων βάσης. Για τον υπολογισμό των εν λόγω ιδιοτήτων χρησιμοποιήθηκε η μέθοδος του πεπερασμένου πεδίου. Τέλος πραγματοποιήθηκαν υπολογισμοί των ηλεκτρικών ιδιοτήτων αλληλεπίδρασης συστημάτων Η-(C≡C)n-H…Ηe για δυο συγκεκριμένες διαμορφώσεις ενώ για την αποφυγή του σφάλματος υπέρθεσης συνόλου βάσης χρησιμοποιήθηκε η υπερμοριακή προσέγγιση των Boys-Bernardi. / The purpose of the present doctoral dissertation is the calculation of the electric multipole moments (dipole up to hexadecapole) of acetylenic chains under the general formulas H-(C≡C)n-H, Χ-(C≡C)n-H and Χ-(C≡C)n-X, n=1–7, X=F, Cl, Br, I, CN, NC, the systematic study of the (hyper)polarizabilities of the non substituted acetylenic chains Η-(C≡C)n-H, n=3–7 and finally the calculation of interaction induced electric properties of systems of the general formula Η-(C≡C)n-H…Ηe, n=1– 7. In all cases considered the ab initio SCF and MP2 methods have been used along with the very popular DFT methods B3LYP, B3PW91 and mPW1PW91. For the electric multipole moment calculations the cc-pVDZ basis set has been used in all cases and special attention has been paid in the way the properties of interest change by changing the substituent at the ends of the acetylenic chains. For the electric (hyper)polarizability calculations on the non substituted acetylenic chains H-(C≡C)n- H minimally polarized basis sets have been used and comparison was made with the results obtained by using larger basis sets. In order to calculate the above mentioned properties the finite field method was applied. Finally, calculations were performed in order to calculate the interaction induced electric properties of the systems Η-(C≡C)n- H…Ηe for two particular configurations while in order to avoid the basis set superposition error the Boys-Bernardi counterpoise method has been applied.

This thesis is focussed on the biosynthesis of three toxins: fluoroacetate, 4-fluoro-L-theronine and β-ethynyl-L-serine which are biosynthesised by the soil bacteria Streptomyces cattleya. The two fluorinated metabolites originate from a common biosynthetic pathway and the thesis describes studies carried out on an aldose-ketose isomerase enzyme of the pathway. The biosynthetic origin of β-ethynyl-L-serine is not known. A total synthesis of this acetylenic amino acid is descibed along with the development of a new analytical method for identifying the metabolite and for future isotope-labelling based biosynthetic studies. Chapter 1 presents the background of this research. It is focussed on the biosynthesis of fluoroacetate and 4-fluoro-L-threonine by S. cattleya and it also introduces alkyne-containing natural products and their biosynthesis. Chapter 2 describes the work carried out on crystallisation of the aldose-ketose isomerase of the fluorometabolite pathway in S. cattleya. Crystals of the isomerase were obtained and they were diffracted by X-ray, however a structure could not be solved. Chapter 3 contains site-directed mutagenesis studies of the isomerase from S. cattleya. Chapter 4 describes an enantioselective total synthesis of β-ethynyl-L-serine. A robust analytical technique based on derivatisation using 'Click' chemistry and LC-MS was developed for the detection of this amino acid directly from the fermentation broth. Chapter 5 details the experimental procedures for compounds synthesised in this thesis and the biological procedures for gene cloning and protein purification.

Ce manuscrit présente nos travaux de recherches réalisés sur : i) des éponges marines de Méditerranée (Phorbas tenacior) et des DOM-TOM (Niphates sp. et Clathria rugosa), sélectionnées sur la base des propriétés biologiques préliminaires réalisées sur les extraits bruts, de l’originalité des métabolites, et/ou de l’absence d’étude chimique antérieure de l’espèce ; ii) la synthèse et l’évaluation des propriétés biocides d’analogues de la viscosaline, molécule de type 3-alkylpyridinium aux propriétés antibactériennes et antisalissures faiblement valorisées. L’étude de l’éponge calédonienne Niphates sp. a conduit à l’isolement des népheliosynes A et B, deux polyacétylènes polyhydroxylés avec des cytotoxicités modérées. Les anchinopeptolides B-D, inhibiteurs sélectifs des kinases GSK-3 et PfGSK-3, ont été isolés de Phorbas tenacior, ainsi que la phorbasoïne, un alcaloïde nouveau avec un coeur hydantoïne. Enfin, la première étude chimique de Clathria rugosa a conduit à l’isolement d’un nouveau macrolide, le Clathriolide, un métabolite secondaire cytotoxique vis-à-vis de nombreuses lignées cellulaires tumorales. Chacun des métabolites isolés a fait l’objet d’une étude structurale et biologique poussée. Une stratégie de synthèse originale d’analogues structuraux de la viscosaline a été mise au point. Les dérivés obtenus possèdent d’excellentes activités antibactériennes et antisalissures ainsi que des activités antitumorales modérées. / This manuscript deals with : i) marine sponges from the Mediterranean Sea (Phorbas tenacior) and New Caledonia (Niphates sp. and Clathria rugosa), selected for their biological activities conduced on their crude extract, the originality of produced secondary metabolites and the absence of previous chemical studies ii) the synthesis and the antibacterial properties of analogues of viscosaline. Viscosaline is a 3-alkylpyridinium secondary metabolites which exhibited interesting antibacterial and antifouling properties. The study of the New Caledonian marine sponge Niphates sp. led to the isolation of nepheliosynes Aand B, two polyhydroxylated polyacetylenic acids which exhibited moderate cytotoxic properties. The anchinopeptolides B-D, selective inhibitors of GSK-3 and PfGSK-3 kinases, have been isolated from Phorbas tenacior along with the new alkaloid phorbasoïne. Finally, the first study of the New Caledonian sponge Clathria rugosa let to the isolation of new macrolide, clathriolide, which exhibited cytotoxic properties. The structures and biological properties of each metabolite have been extensively studied in this work. An original synthesis of analogues of viscosaline had been developed. All the derivatives showed excellent antibacterial and antifouling properties, and moderate antitumoral activities.

The homoaldol reaction is one of the most powerful methods for the construction of C–C bonds as well as 1,4-oxygenated compounds yet this reaction remains in challenging tasks due to the instability of homoenolates which spontaneously cyclize to the cyclopropanolate. A regioselective catalytic homoaldol equivalent reaction of 3-bromo vinyl acetate with aldehydes under Cr(III)-Mn(0) redox condition was developed. This homoaldol equivalent reaction allows access to the 1,4-oxygenated compounds that are not possible by a conventional aldol process. Mild hydrolysis of the vinyl acetate and reduction of the homoaldol adducts generated diols and lactols in high yield (99%). Further manipulation including stereoselective epoxidation and cyclopropanation was achieved in an efficient manner. Furans, found in many natural products and utilized in drug discovery, have been well studied but current synthetic methods toward furans have some limitations in functional group tolerance, substrate scope, and low product yield in many cases. A highly efficient and catalytic cycloisomerization reaction that transforms acetylenic α,β-epoxides to 2,3,5-tri-substituted furans under InCl3 catalysis was developed. This reaction sequence allows access to rapid construction of highly valuable, tri-substituted furan derivatives. Cross-coupling reactions utilizing transition metals and Lewis acids are important synthetic tools for the formation of C–C and C–N bonds and a number of cross-coupling reactions between α-bromo carbonyl compounds and metal reagents such as aryl metals, alkenyl metals, and alkyl metals have been reported. Transition metal-catalyzed cross-coupling reaction for the construction of α-alkynyl carbonyl compounds has reported in a limited case. The first approach to secondary α-alkynyl carbonyl compounds from secondary α-bromo esters and amides with tributyl(phenylethynyl)stannane under palladium-catalyzed cross-coupling reaction conditions was developed. This synthetic method allows access to secondary α-alkynyl carbonyl compounds which are valuable precursors in pharmaceuticals and agricultural applications.

ABSTRACT This thesis describes an investigation into the role of acetylenic and allenic precursors in the formation of the important aroma compound β-damascenone (1). Chapter 1 provides an introduction to the subject, beginning with a brief history of the Australian wine industry which began with the first fleet’s arrival in 1788. Many of the various volatile compounds found in wine are then discussed, with particular emphasis on β-damascenone (1). Some previous syntheses of 1 are summarised, as well as the in vivo generation of this compound, and also the role of glycoconjugation in nature. The chapter concludes with the aims of the present work. Chapter 2 covers the synthesis of the suspected acetylenic precursor 9-hydroxymegastigma-3,5-dien-7-yne (36), which was prepared by the addition of 3-butyn-2-ol to 2,6,6-trimethylcyclohex-2-en-1-one, followed by a conjugate dehydration reaction. The synthetic sample of 36 was shown to be identical to a compound previously observed in the hydrolysate of 3,5,9-trihydroxymegastigma-6,7-diene (31). Upon acid hydrolysis, 36 produced > 90% β-damascenone (1). Chapter 3 outlines the synthesis and hydrolysis of the C9 glycoside 43, which was prepared by a modified Koenigs-Knorr procedure on aglycone 36. Diastereomerically pure samples of each of the two possible glycosides were synthesised from corresponding enantiomerically pure samples of 36, which in turn were prepared by the use of either (R) or (S) 3-butyn-2-ol. Detailed hydrolytic studies (at 25 ºC) were conducted on both the aglycone and the two glycosides: the half lives of conversion of 36 into 1 were 40 hours and 65 hours at pH 3.0 and pH 3.2 respectively; the (9R) diastereomer of 43 had half-lives of 3 days and 6 days, respectively at the same pH values, whereas the (9S) diastereomer had half lives of 3.5 days and 6.5 days, respectively at the same pH values. The synthesis of the other suspected precursor, megastigma-4,6,7-triene-3,9-diol (35) is covered in Chapter 4. This allene was prepared by addition of 3-butyn-2-ol to phorenol, with the allene function generated by reaction with lithium aluminium hydride. By using (3S)-phorenol and both (R) and (S) 3-butyn-2-ol, four different diastereomers of 35 were prepared and characterised. The (3S, 6R, 9S)-isomer of 35 was also found to be identical to a compound previously observed in the hydrolysate of (31). A detailed hydrolytic study of the four synthetic isomers of 35 is contained within Chapter 5. This study revealed that each of the four isomers underwent rapid epimerisation at 25 ºC and pH 3.0. Careful analysis of the four product mixtures by chiral GC-MS revealed that this epimerisation was occurring exclusively at C3. The complete absence of 3-hydroxydamascone (2) from any of the hydrolysates required a re-appraisal of the mechanism of in vivo formation of β-damascenone (1), which forms the focus of the second half of this chapter. The experimental procedures (materials and methods) for all work covered in chapters 2-5 are located in Chapter 6.