Base-induced coupling-cyclization stepwise [3+2] annulation of £\-sulfonylacetamide with (Z)-2-bromoacrylate yielded the polysubsti- tuted pyroglutamate with three contiguous chiral centers with trans- trans orientation in a one-pot synthesis. The pyrrolizidine skeleton and the core of stenine were obtained via the ring-closing metathesis (RCM) method.This facile strategy was used to synthesize (¡Ó)-trachelantha- midine, (¡Ó)-supinidine and the core of stenine.

Orientador: Ronaldo Aloise Pilli / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-10T13:11:39Z (GMT). No. of bitstreams: 1 Salvador_MayraBeloti_M.pdf: 2010457 bytes, checksum: 350e267c8a65621fe41d0da941852b62 (MD5) Previous issue date: 2007 / Resumo: Esta dissertação de mestrado trata da síntese da Criptomoscatona D2, uma lactona isolada pelo grupo de pesquisa dos Profs. Cavalheiro e Yoshida a partir da Cryptocarya moschata, planta encontrada em território brasileiro, cujas configurações relativa e absoluta ainda não foram determinadas. Além de auxiliar em sua elucidação estrutural a síntese desta molécula nos permitiria realizar estudos sobre sua atividade citotóxica, dando prosseguimento a estudos anteriores desenvolvidos em nosso laboratório com essa classe de compostos. Partindo-se do benziloxiacetaldeído obteve-se o álcool homoalílico quiral correspondente através de uma reação de alilação assimétrica com alilestanana e (S)-binaftol. Clivagem oxidativa da dupla ligação e reação de alilação mediada por InCl3 e estanho metálico na presença de brometo de alila forneceu uma mistura de álcoois homoalílicos sin/anti 1:1 cuja separação cromatográfica permitiu o prosseguimento da síntese racêmica com cada um dos diasteroisômeros. A reação de proteção das hidroxilas com o grupo TBS, seguida de clivagem oxidativa da dupla ligação e reação de alilação com BF3.Et2O e alilestanana forneceu o terceiro álcool homoalílico com mistura diastereoisomérica de cerca de 2:1 em ambas as rotas. Por fim, uma reação de esterificação do álcool remanescente na forma de acrilato seguida de reação de metátese de olefinas para formação do anel lactônico nos possibilitou o mapeamento de grande parte da rota sintética da Criptomoscatona D2 em sua forma racêmica / Abstract: This work describes the preliminary studies on the racemic and the asymmetric synthesis of Cryptomoscatone D2 based on sequential allylation reactions for the construction of its three stereogenic centers and ring-closing methatesis reaction to construct the lactone scaffold. Besides allowing the structure elucidation of the molecule isolated from a typical brazilian plant by the research groups of Profs. Cavalheiro and Yoshida, the synthesis of such a lactone would allow us to carry new cytotoxic studies which are being lately developed with this class of compound. The synthesis started with the allylation reaction of benzyloxyacetaldehyde under the conditions described by Keck and coworkers to furnish corresponding homoallylic alcohol. After an oxidative cleavage of the double bond, an InCl3 promoted allylation reaction allowed the preparation a 1:1 mixture of syn/anti homoallylic alcohols which were as the TBS ethers and submitted separately to double bond oxidative cleavages. These aldehydes were used as substrates for another allylation reaction with BF3.Et2O and allyltri-n-butyltin and the homolallylic alcohols (2:1 diatereoisomeric mixtures) were converted to the corresponding acrylates in order to carry out the planned RCM reaction. Several allylation reactions were tested and the homoallylic alcohols were prepared in 1:1 diasteroisomeric excesses. Efforts will be carried out in order to enhance the distereoselectivity of the allylation reactions for an efficient approach to Cryptomoscatone D2 (12) backbone / Mestrado / Quimica Organica / Mestre em Química

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Owing to its unique electronic properties, the CF₂ group has the potential to affect the conformation and polarity of molecules. The Introduction provides an overview of the conformational effects induced by the incorporation of fluorine into hydrocarbons, e.g. gauche effect, 1,3-C,F bond repulsion and angle deviation in organofluorine compounds. A summary of synthetic strategies for the introduction of the gem-difluoride motif into organic molecules is also presented. In order to explore the conformational impact of the CF₂ group in alicyclic hydrocarbon systems, cyclododecane was employed as the molecular framework. In 1,1,4,4- and 1,1,7,7- tetrafluorocyclododecanes, two CF₂ groups replaced CH₂ units within the square [3333] cyclododecane ring where the spacing enables the CF₂ groups to occupy adjacent or opposite corner locations. In the case of 1,1,6,6-tetrafluorocyclododecane, one of the CF₂ groups was forced to the edge position, which changes the ring conformation dramatically. Strategic incorporation of two CF₂ groups is shown to either stabilise or significantly alter the conformation of the cyclododecane framework, a revealing conformational preference of the CF₂ group to locate at the corner rather than the edge position of hydrocarbon rings. The study extends to larger cycloalkanes, rectangular [3434] cyclotetradecanes and square [4444] cyclohexadecanes. The target cycloalkanes bearing two CF₂ units were assembled through a novel synthetic route, employing ring-closing metathesis (RCM) as the key step. X-Ray structure analyses revealed that the CF₂ groups occupy exclusively corner locations of these rings too. The spacing between the CF₂ moieties dictates the overall ring conformations and offers a useful tool for controlling molecular arrangement. An accelerating role of the CF₂ group, relative to the CH₂ group, on the ring-closing metathesis of C5-substituted 1,8-nonadienes has also been studied. Remarkably, the CF₂ group exhibited a similar reaction rate to that observed for nonadienes bearing 1,3-dioxolane or dimethylmalonate groups. This effect was rationalised by the thermodynamic stability of the cycloheptene products, rather than a Thorpe-Ingold effect.

Student Number : 0002306V - MSc dissertation - School of Chemistry - Faculty of Science / The first part of the dissertation involves the use of ring closing metathesis (RCM) and ruthenium mediated isomerisation-RCM tandem reactions to form a wide range of nitrogencontaining benzo-fused heterocycles. Those synthesized include the 6-membered isoquinolines, the 7-membered benzazepines and the 8-membered benzazocines. In order to put these compounds into perspective, a review of selected naturally occurring nitrogencontaining benzo-fused heterocycles is included along with some of their synthetic approaches. Of major significance is our utilization of the Wits methodology allowing one to access the 6-, 7- and 8-membered ring systems from a common synthetic intermediate. The 1,2,3,6-tetrahydro-2-benzazocines were all obtained after RCM in excellent yields (82-99%). We were also able to show that some ofthe protecting groups used were easily removed and that the ring could be hydrogenated after RCM to yield the 1,2,3,4,5,6-hexahydro-2- benzazocines. The isoquinolines were synthesized in 78% and 27% yield for the Ac- and Tsprotected compounds respectively, with no product isolated for the Boc- or SO2Bn-protected compounds. These poor results, caused a change to our strategy and we then used a “combinatorial-type” approach for the synthesis of the 2,5-dihydro-1H-2-benzazepines and the 2,3-dihydro-1H-2-benzazepines with yield of 9, 47, 58 and 82% and 8, 26, 39 and 82% obtained respectively for the RCM reaction Futhermore, we attempted the synthesis of the substituted 4-phenyl isoquinolines and 5-phenyl benzazepines, but we found that the systems would not undergo RCM even at high temperatures and with large amounts of Grubbs II metathesis catalyst. A short review is given in the second part of the dissertation concerning the naturally occurring and pharmaceutically useful indenols, indenones and indanones. It further highlights how our methodology was extended to include the synthesis of 4-isopropoxy-5- methoxy-1H-inden-1-ol (X), 4-isopropoxy-5-methoxy-1H-inden-1-one (X) and 4-isopropoxy- 5-methoxy-1H-indanone (X) through the use of ruthenium-mediated isomerisation and RCM from a similar common intermediate. We have shown the synthesis of 3-substituted indenols, indenones and indanones using the same synthetic procedure, but by changing the reaction temperature during RCM. This dissertation also answers many of the questions posed during the post-doctoral work of Coyanis. Namely, we were able to support our proposed mechanism that the conversion of the unsubstituted indenol to the indenone was occurring via a dehydrogenative-oxidation, through the use of 1H NMR studies that were coupled with an ICP-MS analysis. To the best of our knowledge, this is the first reported use of the Grubbs II catalyst (or its degradation products) in a tandem RCM-oxidation procedure by our group recently.

Student Number : 0410864E - MSc dissertation - School of Chemistry - Faculty of Science / The aim of the project described in this dissertation is to explore the application of ring closing metathesis (RCM) to the synthesis of 6-, 7-, 8- and 9-membered N,N-, N,O- and O,O-benzo-fused heterocyclic compounds which are interesting structural motifs in medicinal chemistry. In recent times, their structures have been widely used as molecular scaffolds. Some of these heterocycles have been identified as antitumour agents, antibiotics and anti-HIV agents. In our laboratories, a variety of 6-, 7- and 8-membered nitrogen- and oxygen- containing benzo-fused rings have been synthesized through ruthenium-mediated isomerisation and RCM in moderate to good yields. The first step in the present project was N-protection of suitable 2-aminophenols or o-phenylenediamines followed by allylation. Rutheniummediated isomerisation followed by RCM was then used for the synthesis of the 6- membered ring system tert-butyl 4H-1,4-benzoxazine-4-carboxylate 91 and the 7- membered ring system tert-butyl 1,5-benzoxazepine-5(4H)-carboxylate 103 while only RCM was used for the 8-membered ring systems, di(tert-butyl) 2,3,4,5-tetrahydro-1,6- benzodiazocine-1,6-carboxylate 130, di(tert-butyl) 2,5-dihydro-1,6-benzodiazocine-1,6- dicarboxylate 129, 1,6-dibenzoyl-1,2,5,6-tetrahydro-1,6-benzodiazocine 132, 7-methoxy- 2,5-dihydro-1,6-benzodioxocine 137 and the 9-membered ring system 1,6-bis[(4- methylphenyl)sulfonyl]-2,5,6,7-tetrahydro-1H-1,6-benzodiazonine 159. In the synthesis of the 7-membered ring systems, based on established methodology, we encountered problems with the RCM from suitable benzylamine or benzyl alcohol precursors. The reasons for this are not clear but we suspect this could be as a result of electronic and kinetic factors. Nevertheless, we were able to synthesize a 7-membered ring system, tert-butyl 1,5-benzoxazepine-5(4H)-carboxylate 103, from a readily available precursor using a different methodology. Approaches to the synthesis of the 8-membered ring systems, di(tert-butyl) 2,3,4,5- tetrahydro-1,6-benzodiazocine-1,6-carboxylate 130, di(tert-butyl) 2,5-dihydro-1,6- benzodiazocine-1,6-dicarboxylate 129, 1,6-dibenzoyl-1,2,5,6-tetrahydro-1,6- benzodiazocine 132 and 7-methoxy-2,5-dihydro-1,6-benzodioxocine 137, as described in this dissertation, made extensive use of RCM in moderate to good yields, but the deprotection of the Boc group after hydrogenation proved to be a problem. The synthesis of the 9-membered nitrogen containing benzo-fused compounds, 1,6- bis[(4-methylphenyl)sulfonyl]-2,5,6,7-tetrahydro-1H-1,6-benzodiazonine 159 by RCM was successful but in the synthesis of the N,O-benzo-fused compound by RCM, we suspect that polymerization, which is a side reaction in RCM reactions that are slow, occurred. In the synthesis of the 9-membered O,O-benzo-fused compounds, we only isolated the starting material. The final approach in this dissertation involved the use of ruthenium-mediated isomerisation to afford internal isomerisation of the double bond within the heterocyclic rings of the 8-membered and 9-membered benzo-fused compounds previously prepared in our laboratory. This gave a mixture of regioisomers of 10-methoxy-2,3-dihydro-1,6- benzodioxocine 163 and 7-methoxy-2,3-dihydro-1,6-benzodiazocine 164, 1,6-bis[(4- Methylphenyl)sulfonyl]-1,2,3,6-tetrahydro-1,6-benzodiazocine 166, a regioisomeric mixture of 6-[(4-methylphenyl)sulfonyl]-3,6-dihydro-2H-1,6,-benzoxazocine 161 and 6-[(4-methylphenyl)sulfonyl]-5,6-dihydro-4H-1,6,-benzoxazocine 162, and the 9- membered benzo-fused ring system, 1,6-bis[(4-methylphenyl)sulfonyl]-2,3,6,7- tetrahydro-1H-1,6-benzodiazonine 170. The yields were good and the solid state structures of these isomerised compounds were examined by X-ray crystallography. Xray diffraction was also performed on the solid state 8- and 9-membered benzo-fused ring systems. We also compared the crystal structures of the 8- and 9-membered benzo-fused compounds with their isomerised compounds.

Thesis advisor: Amir H. Hoveyda / Chapter 1. The first examples of highly Z- and enantioselective ring-opening/cross-metathesis reactions are disclosed. Transformations involve meso cyclic olefin substrate and styrenes or enol ethers as olefin cross partners. A stereogenic-at-Mo monoaryloxide monopyrrolide (MAP) complex, prepared and used in situ, is discovered for the efficient formation of Z olefins. Such complex, bearing a relatively smaller adamantylimido and a larger chiral aryloxide ligand, leads to kinetic Z-selectivity due to the size differential. In most cases, the resulting disubstituted Z olefins are formed with excellent stereoselectivity (>95% Z). Chapter 2. The protocols for efficient Z-selective formation of macrocyclic disubstituted alkenes through catalytic ring-closing metathesis (RCM) is described. Stereoselective cyclizations are performed with either Mo- or W-based monoaryloxide monopyrrolide (MAP) complex at 22 oC. Synthetic utility of such broadly applicable transformation is demonstrated by synthesis of several macrocyclic natural products: relatively simpler molecules such as epilachnene (91% Z) and ambrettolide (91% Z), as well as advanced precursors to epothilones C and A (97% Z) and nakadomarin A (94% Z). Several principles of catalytic stereoselective olefin metathesis reactions are summarized based on the studies: 1) Mo-based catalysts are capable of delivering high activity but can be more prone to post-RCM isomerization. 2) W-based catalysts, though furnish lower activity, are less likely to cause the loss of kinetic Z selectivity by isomerization. 3) Reaction time is critical for retaining the stereoselectivity gained from kinetic, which not only applicable with MAP complexes but potentially with other complexes as well. 4) By using W-based catalyst, polycyclic alkenes can be accessed with sequential RCM reactions, without significant erosion of the existing Z olefins in the molecule. Chapter 3. An enantioselective total synthesis of anti-proliferative agent (+)-neopeltolide is presented. The total synthesis is accomplished in 11 steps for the longest linear sequence and 28 steps in total, including 8 catalytic reactions. Particularly, several Mo- or Ru-catalyzed stereoselective olefin metathesis reactions as well as N-hetereocyclic carbene (NHC)-catalyzed enantioselective boron conjugate addition to an acyclic enoate have proven to be effective for convergent construction of the molecule. The most important novelty of the study incorporates the explorations of feasibility of Z-selective cross-metathesis reactions to solve the challenge of installing two Z olefins with excellent selectivity. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Marc L. Snapper / Tandem processes can have several advantages over multiple single step processes. Non-metathesis transformations of ruthenium alkylidenes were studied and applied to tandem processes. Ruthenium catalyzed tandem RCM/hydroacylation that allows access to tricyclic ring systems from readily available substrates was developed. Mechanistic investigations indicated that this reaction may proceed through a mechanism involving [Ru]-H species. A Ru-catalyzed tandem RCM/olefin isomerization/C-H activation sequence that provides significant advantages in terms of rapid elaboration of simple reaction partners to more complex entities was developed. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1: Efficient Z-Selective Cross-Metathesis of Secondary Allylic Ethers Efficient Z-selective cross-metathesis of secondary allylic ethers were catalyzed by monoaryloxide monopyrrolide molybdenum complexes. Reactions involving both silyl and benzyl protected ethers were demonstrated, as well as ethers containing alkyl, aryl and alkynyl substituents. Mechanistic studies were performed, and the reactions were applied to the total synthesis of several ene-diyne natural products. Chapter 2. Stereoselective Total Synthesis of Disorazole C1 The stereoselective total synthesis of disorazole C1 is reported. The synthesis was completed in 12 longest linear steps. Our synthesis demonstrates the utility of Z-selective cross-metathesis to form both alkenyl borons and alkenyl halides. Another key transformation was a one-pot Suzuki-dimerization reaction to form a symmetric 30 membered ring in relatively high yield. Chapter 3. Stereoselective Cross-Metathesis to Form Trisubstituted Alkenes Initial studies into the stereoselective formation of trisubstituted olefins through molybdenum catalyzed cross-metathesis have been performed. Our mechanistic understanding of the reaction lead us to focus on the synthesis of alkenyl halides, which can be obtained in up 90% yield and 75:25 E:Z selectivity. Chapter 4: Ring-Closing Metathesis in the Synthesis of Natural Products Development of highly efficient and selective ring-closing metathesis reactions have enabled collaborators to successfully implement routes in total synthesis endeavors. A diastereoselective seven-membered ring-closing metathesis enabled the successful synthesis of (±)-tetrapetalone A methyl-aglycon. An enantioselective ring-closing metathesis to form a six membered ring has provided access to enantioenriched aspidosperma alkaloids. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.