2-Pyridinyl-2-pyrazinylmethanone (L4) is able to exist in the neat ketone form and gem-diol form (2-C5H4N)C(OH) 2(2-C4H3N2) (L4a) in its Ag(I) and Cu(II) complexes. Two isostructural Cu(II) complexes [Cu(L4 a)2X2·2H2O, X = C lO4-, BF4-] with the L4a ligand taking the chelating mode are formed, in which the different linkage modes of lattice water molecules between the Cu(L4 a)22+ units lead to different space groups in crystallization. Through versatile anion-pi(pyrazinyl ring) and hydrogen-bonding interactions, the Cu(L4a)22+ units are assembled into distinct 3-D metal-organic hybrid frameworks in these two complexes. Different ligation modes of L4 in its neat ketone and gem-diol forms are found in its silver(I) complexes that exhibit diverse network structures. / By tuning the counter anion, mu2-bridging 2,6-pyridinediylbis(4-pyridinyl)methanone (L2) via two terminal 4-pyridyl N atoms links Ag(I) ions into two distinct structural motifs in its silver(I) complexes, namely infinite helical chain and metallacyclophane, which are further assembled into higher-dimensional metal-organic frameworks through Ag···Ag, pi···pi, hydrogen-bonding, Ag···O=C, carbonyl···carbonyl, as well as unconventional anion-pi(pyridyl ring) interactions. Intermolecular dipolar carbonyl···carbonyl interaction of three principal types serves as a common dominant non-covalent interaction in the supramolecular conglomeration of these complexes. / Di-2-pyrazinylmethanone (L3) readily undergoes metal-assisted hydration reaction in its Ag(I), Cu(II), Co(II) and Cd(II) complexes, and is potentially useful for the construction of extended coordination networks with its gem-diol (2-C4H3N2)2C(OH) 2 (L3a) or anionic (2-C4H3N 2)2C(OH)CO- (L3b) form as an architectural moiety. A sheet-like net, an alpha-polonium topology of the NaCl-type and a rare 1-D nanotubular coordination architecture has been generated in its Ag(I) complexes through the tuning of counter-anions. Three isostructural complexes Cu(L3a)2X2· nH2O (n = 4.5; X = ClO 4-, BF4-, PF 6-) have been obtained and characterized. The 3-D host frameworks of these complexes are constructed from the linkage of mononuclear Cu(L3a)22+ metallotectons through a combination of hydrogen-bonding and anion-pi interactions, leading to honeycomb-like channels that accommodate guest water molecules. A cubane-like Co(II) cluster stabilized by L3b and the topological structure of Cd(II) complexes with L3a have also been obtained. / Di-2-pyridinylmethanone (di-2-pyridyl ketone) is a well-known versatile ligand among the basic building blocks for the construction of metal-organic hybrid materials. It can exist in its neat form, or in the hydrated gem-diol and alcoholated hemiketal forms. In this thesis, through modification of the heterocyclic ring and the bridging functional group, we have systematically synthesized a series of transition metal complexes of five carbonyl-bridged heterocycles (L1-L5) (see P. xi) and two structural analogs with sulfinyl and sulfonyl bridging groups (L6-L7), which are expected to provide flexible coordination bonding and additional non-covalent interactions in the generation of metal-organic hybrid frameworks. / In the two mononuclear Cu(II) complexes of 2,6-pyridinediylbis(3-pyridinyl)methanone (L1) with the ligand taking a chelating mode, four distinct types of unconventional intermolecular C=O···pi interactions between the carbonyl and pyridyl rings were identified. Moreover, the mu2-bridging L1 via two 3-pyridyl N atoms proves to be an excellent building block for the construction of disilver(I) metallacyclophanes with a [Ag2(L1) 2]2+ skeleton in a series silver(I) complexes. The [Ag 2(L1)2]2+ metallacycle functions as a secondary building unit to form infinite chains through Ag···O=C or argentophilic interactions, which are further assembled into a 3-D supramolecular structure via collective weak interactions including the anion-pi interaction. The employment of different Cd(II) and Hg(II) salts to react with the flexible L1 ligand has resulted in infinite chain, mononuclear, and 3-D network structures, in which L1 takes eta1-terminal, N,N-chelating, and mu2- and mu3-bridging modes. In these complexes, C--H···O, C--H···Cl--M hydrogen bonding, pi···pi, carbonyl···carbonyl, O(perchlorate)···C=O, as well as unconventional anion···pi(pyridyl ring) interactions, play important roles in consolidation of the supramolecular frameworks. / Sulfinyldipyrazine (L7) is capable of forming intriguing architectures in various sivler(I) salts, including a series of coordination polymers exhibiting (4,4) net, infinite chain and 3-D framework structures. A remarkable characteristic of L7 is that the electron-deficient pyrazinyl ring and the sulfonyl group provide potential bonding sites for lone-pair-aromatic interactions in the supramolecular assemblies, such as anion-pi and S=O···pi(pyrazinyl ring) interactions. The S=O moiety of the sulfonyl group exhibits an affinity for the pyrazinyl ring, which is evidenced by the existence of two types of such interaction in the silver(I) complexes of L7. (Abstract shortened by UMI.) / by Wan, Chongqing. / Adviser: Thomas C. W. Mak. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3504. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 172-190). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

This thesis describes expansion of the ability of isothioureas to act as organocatalysts in formal [2+2]-, [3+2]- and [4+2]-cycloadditions between carboxylic acids and various acceptors via Type I ammonium enolate intermediates. Chapter 2 describes the optimisation and investigation of [2+2]-cycloadditions from ammonium enolates and N-sulfonylimines as the two components. The development of this methodology allows successful access to highly stereodefined β-lactams and, following in situ ring-opening, β-aminoesters. The products are obtained from either preformed homoanhydrides or directly from carboxylic acids, using open flask conditions, from simple, bench-stable starting materials and is scalable. A variety of anti-β-lactams (21 examples, 46-68% yield, up to >95:5 dr, 21->99% ee) and β-aminoesters (9 examples, 44-74% yield, up to >95:5 dr, 68-92% ee) were accessed in moderate yield, excellent diastereo- and good enantioselectivity. This represents an improved route to anti-β-lactams over previously described ketene and N-triflyl imine based methods. Chapter 3 subsequently describes studies focussed on the use of ester surrogates in the formal [4+2]-cycloaddition reactions of isothiourea generated Type I ammonium enolates. Iso-propylphosphonate 163 proved highly effective as the four-component in this process, which following the in situ ring-opening of the initial dihydropyranone product allowed isolation of a range of novel diester products which were previously unobtainable using this methodology. The products were accessed in moderate to excellent yields, excellent diastereo- and enantiocontrol (9 examples, 12-63% yield, up to >95:5 dr, 67-99% ee) with this process also amenable to a large scale. Furthermore, selective reduction and acid-catalysed cyclisation allowed access to δ-lactone products in good yield with retention of stereocontrol. Finally, Chapter 4 describes work on isothiourea-catalysed formal [3+2]-cycloadditions of oxaziridines and acetic anhydrides gave access to stereodefined five-membered oxazolidin-4-one heterocycles. In this case, the use of preformed homoanhydrides and an inorganic base was imperitive to avoid reduction of the oxaziridine starting material. The oxazolidin-4-one products could be accessed in excellent yield and ee however poor dr (13 examples, 63-96% yield, up to 59:41 dr anti:syn, up to >99% ee for both diastereoisomers). Following isolation, reduction of these heterocycles allowed access to enantioenriched diols with little loss in stereocontrol. Mechanistic analysis has shown that an improvement in diasterocontrol can be obtained by the use of an enantioenriched oxaziridine, demonstrating the stereospecificity of this process.

Wu, Kwun Wang. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 76-79). / Abstracts in English and Chinese. / Acknowledgment --- p.i / Table of Contents --- p.ii / Abstract --- p.iii / Abstract (Chinese Version) --- p.v / Abbreviation --- p.vi / Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- Organocatalysis --- p.1 / Chapter 1.2 --- Diels-Alder reaction --- p.3 / Chapter 1.3 --- Intramolecular Diels-Alder (IMDA) reaction --- p.4 / Chapter 1.4 --- Methods for obtaining optical active product --- p.5 / Chapter 2. --- Results and Discussion - Synthetic Studies of Carbocycles from Carbohydrates --- p.15 / Chapter 2.1 --- Organocatalyst dervied from D-arabinose --- p.15 / Chapter 2.2 --- Synthesis of Intramolecular Diels-Alder reaction substrates --- p.28 / Chapter 2.3 --- Organocatalytic enantioselective IMDA reaction --- p.36 / Chapter 4. --- Conclusion --- p.43 / Chapter 5. --- Experimental --- p.45 / Chapter 6. --- References --- p.76 / Appendix --- p.80 / HPLC chromatogram --- p.1-1 - 1-2 / NMR spectra --- p.II-1 - II-36

基於本課題組以前的工作，通過以廉價易得的D-阿拉伯糖為起始原料，我們進一步探討和優化了一條快速有效地合成手性胺類催化劑的有效路線（81-84）。在第一代催化劑的基礎上，我們設計合成了含有雙環碳酸酯結構的新型胺類催化劑（98）。 / 通過製備叁烯醛類底物，我們探討研究了一系類分子內DA反應的不對稱催化條件，如溶劑、共酸和水等。我們發現水的存在基本上不會影響反應的對映體選擇性，但對反應的非對映體選擇性卻具有極其重要的影響。同時我們也研究了各催化劑的手性誘導能力。 / 通過以催化劑（81）的高氯酸鹽和肉桂醛反應製備了反應中間體亞胺鹽，并經NOE試驗確認了其幾何構型。製備的胺類催化劑对空气和水不敏感，同時也能穩定存在於過量酸（1.2 eq）的環境中。 / 此外，我們也初步探討了由糖衍生的胺類催化劑催化的分子間DA反應。這些不成功的嘗試表明胺類催化的分子間DA反應需要更高的活化能，因此可能需要活性更強的催化劑。 / Based on our previous work, we further explored and optimized an efficient route to prepare chiral amine catalysts from inexpensive and commercially available D-arabinose with good yield (81-84). On the basis of our 1st generation catalysts, a novel amine catalyst with bicyclic carbonate structure was obtained (98). / By preparing trienal substrates, a series of asymmetric catalysis conditions for Intramolecular Diels-Alder (IMDA) reactions were investigated, such as solvent, co-acid, water, et.al. Water was found to have a significant effect to the diastereoselectivity and without losing the enantioselectivity. The chiral induction capability of the synthesized catalysts was also assessed. / The reactive intermediate of iminium salt was prepared from perchlorate salt of catalyst 81 with cinnamaldehyde, and the geometry of the iminium ion was proved by NOE experiment. The prepared catalysts were insensitive to moisture and oxygen and also stable even with excess amount of perchloric acid (1.2 eq). / A preliminary investigation to the amine catalyzed Intermolecular Diels-Alder reaction was also tried. The unsuccessful trials demonstrated that amine catalyzed Intermolecular Diels-Alder reaction requires higher activation energy. Some more reactive catalysts may be needed for this type of reaction. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Xiao, Qicai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 76-82). / Abstracts also in Chinese. / Acknowledgment --- p.i / Table of Contents --- p.ii / Abstract --- p.iv / Abstract (Chinese Version) --- p.v / Abbreviation --- p.vi / Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- General background --- p.1 / Chapter 1.2 --- Chiral amine catalyzed organic reactions --- p.3 / Chapter 1.2.1 --- LUMO-Lowing activation (Iminium Catalysis) --- p.4 / Chapter 1.2.2 --- HOMO-Raising activation (Enamine Catalysis) --- p.6 / Chapter 1.2.3 --- SOMO activation (SOMO Catalysis) --- p.8 / Chapter 1.3 --- Diels-Alder reaction --- p.10 / Chapter 1.4 --- Chiral amine catalysts --- p.13 / Chapter 1.5 --- Objective of this study --- p.14 / Chapter 2. --- Results and Discussion --- p.16 / Chapter 2.1 --- Optimization and synthesis of amine catalysts from D-arabinose --- p.16 / Chapter 2.2 --- Synthesis of substrates for intramolecular Diels-Alder reactions --- p.23 / Chapter 2.3 --- Enantioselective organocatalytic intramolecular Diels-Alder (IMDA) reactions --- p.28 / Chapter 2.4 --- Determination the geometry of the iminium ion --- p.38 / Chapter 2.5 --- Determination the stereochemistry of the major and minor product for the organocatalyzed IMDA reaction --- p.41 / Chapter 2.6 --- Exploring the epimerization effect --- p.43 / Chapter 2.7 --- Amine catalyzed intermolecular Diels-Alder reactions --- p.46 / Chapter 3. --- Conclusion --- p.50 / Chapter 4. --- Experimental Section --- p.53 / Chapter 5. --- References --- p.76 / Chapter 6. --- Appendix --- p.83 / Chapter 6.1 --- HPLC spectra and data --- p.84 / Chapter 6.2 --- NMR spectra --- p.87 / Chapter 6.3 --- X-ray crystallographic structure and data --- p.126

Orientador: Cintia Duarte de Freitas Milagre / Banca: Luciana Gonzaga de Oliveira / Banca: Leandro Helgueira Andrade / Resumo: Os biocatalisadores (enzimas e/ou micro-organismos) são amplamente utilizados na síntese de moléculas bioativas, em especial os fármacos, para gerar ou resolver centros quirais. O levetiracetam, comercialmente conhecido como Keppra®, é um composto quiral com propriedades anticonvulsivantes cuja atividade farmacológica está relacionada ao enantiômero (S). O aumento da opção pelo uso do levetiracetam em detrimento a outros fármacos anticonvulsivantes está intimamente associado à baixa ocorrência de efeitos colaterais provocados por este. Diversas rotas quimiossintéticas para sua produção são relatadas na literatura. A maioria delas envolve um elevado número de etapas, alto consumo energético, uso de catalisadores metálicos e baixos rendimentos globais. Em contrapartida, este projeto teve por objetivo empregar uma rota quimioenzimática, com menor número de etapas, condições mais brandas e ambientalmente amigáveis de reação para a síntese do levetiracetam e análogos (série alifática). A respectiva série aromática também foi sintetizada, uma vez que trata-se de blocos construtores quirais para a síntese de compostos com reconhecida atividade anti-malária. A primeira etapa consistiu na síntese das cianidrinas racêmicas seguida da substiuição da hidroxila destas por heterociclos nitrogenados. Uma coleção de enzimas do tipo nitrila hidratases (E.C. 4.2.1.84) foi empregada para catalisar a conversão das nitrilas α-substituidas por N-heterociclos nas respectivas amidas quirais. As enzimas foram utilizadas tanto na forma isolada (obtidas comercialmente) quanto em células íntegras de bactérias e leveduras da Coleção de Micro-organismos do Laboratório de Biocatálise do IQ-UNESP Araraquara. As reações enzimáticas foram conduzidas em meio aquoso tamponado e em sistemas binários líquido iônico : solução tampão (10, 20, 40 e 80%) a fim de avaliar a influência do... / Abstract: Biocatalysts (enzymes and/or microorganisms) are widely used in the synthesis of bioactive molecules, in particular pharmaceuticals, to generate or resolve chiral centers. Levetiracetam, commercially known as Keppra®, is a chiral compound with anticonvulsant properties whose pharmacological activity is related to the (S)-enantiomer. The increase in option for the use of levetiracetam over the others anticonvulsant drugs is closely associated with low incidence of side effects caused by this. Several chemosynthetic routes for its production are reported in the literature. Most of them involve numerous synthetic steps, high energy consumption, use of metal catalysts and low overall yields. On the other hand, this project aims to develop a chemoenzymatic route, with fewer steps, milder conditions and environmentally friendly reaction for the synthesis of levetiracetam and analogues (aliphatic series). The respective aromatic series was also synthesized, since it is chiral building blocks for the synthesis of compounds with known antimalarial activity. The first step was the synthesis of racemic cyanohydrin followed by substitution of the hydroxyl group by nitrogen heterocycles. Collections of nitrile hydratase enzymes type (EC 4.2.1.84) were used to catalyze the conversion of N-heterocycles α-substituted nitriles in the respective chiral amides. The enzymes were used both in isolated form (obtained commercially) as in whole cells bacteria and yeast Collection of Microorganisms of Biocatalysis Laboratory of IQ-UNESP Araraquara. The enzymatic reactions were performed in buffered aqueous medium and ionic liquid : buffer (10, 20, 40 and 80%) binary systems in order to evaluate the influence of the solvent on the enantioselectivity and yield of these reactions. The ionic liquids synthesized and used in this work were 1-butyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium... / Mestre

There are many diverse classes of biologically active natural products containing chiral 1,5- or 1,5,7-polyol moieties, including the novel fibrinogen receptor antagonist tetrafibricin, a potential antiplatelet therapeutic drug to treat various arterial thrombotic diseases. There have been some elegant synthetic strategies developed to synthesize these challenging 1,5-diol motifs; however, many of them suffer from a variety of inherent limitations. To overcome many of these challenges, our group has developed an iterative configuration-encoded strategy to access 1,5-polyols with unambiguous stereocontrol by exploiting Julia–Kocienski couplings of enantiopure α-siloxy-γ-sulfononitrile building blocks with alcohol stereocenters previously established via asymmetric catalysis. Our method is a strategy level innovation that allows for the efficient and rapid access to all stereoisomers of a 1,5-polyol family from cheap and easily accessible reagents, without the need to determine the configuration of each alcohol stereocenter in the growing polyol chain. We were able to modify our configuration-encoded 1,5-polyol methodology to access the anti,syn-1,5,7-triol within the C15–C25 fragment of tetrafibricin with excellent selectivity by incorporating differentiable protection and merging this approach with the tactic of diastereoselective intramolecular conjugate addition via benzylidene acetal construction to access the syn-1,3-diol functionality. We also applied our iterative configuration-encoded strategy to the synthesis of the 1,5-polyol-containing C26–C40 fragment of tetrafibricin with excellent stereoselectivity by modifying our previous route to the C27–C40 segment. By overcoming the challenges associated with the reduction of α-siloxynitriles and extending the carbon chain to alter the subsequent Mukaiyama aldol coupling location, we were able to furnish the C26–C40 fragment with the correct protection and functionality for further coupling to the C15–C25 segment. With the C15–C25 and C26–C40 fragments in hand, we joined these segments via asymmetric BF3⋅OEt2-mediated Mukaiyama aldol construction with high 1,3-anti stereoinduction. We determined the preceding stereoselectivity by first using the simplified model C26–C40 fragment and found that replacing the TBDPS with TBS protection of the β-siloxy aldehyde increased the level of 1,3-anti induction. To complete the C15–C40 fragment of tetrafibricin, we performed an intramolecular hydroxyl-directed anti-reduction to furnish the desired anti,anti,anti-1,3,5,7-tetraol moiety. We were able to establish the configurations of these chiral alcohols using a battery of 2D NMR experiments. Finally, to complete the total synthesis of tetrafibricin, we have proposed a route to couple our C15–C40 fragment with the C8–C14 segment via a precedented asymmetric aldol reaction, followed by coupling to the known C1–C7 polyene fragment. With minor functional group transformations and a global deprotection, access to the natural product tetrafibricin should be achievable.

The ortho metallation of some aromatic ring systems has been investigated in regard to the influence of several types of phosphorus-centred directing groups upon the reactivity, regioselectivity, and utility in later synthetic elaboration. The metallation step allows derivatisation in several useful ways, offering several routes to the synthesis of novel chiral ditertiary phosphines. Thus, an ortho lithiation of N,N,N',N'-tetramethyl-P-phenylphosphonic diamide (10) led to the interesting primary phosphine, 2-(diphenylphosphino)phenylphosphine (14), after elaboration of the phosphonic diamide directing group. This primary phosphine undergoes an unprecedented facile phenyl group exchange process between its two phosphorus atoms, upon di-lithiation of the primary phosphorus centre. The primary phosphorus centre of (14) has been elaborated in several ways to yield new ditertiary phosphines. The alkylation of this centre in the copper(I) chelate complex has been investigated in several directions. In another direction, (14) has been chemically elaborated to give a new hybrid chiral ditertiary phosphine ligand, &quotSemiPHOS&quot, containing both a chiral phospholane ring and an adjacent diphenylphosphino group. SemiPHOS has been obtained in optically pure forms by a stereoselective synthesis and, independently, by a resolution procedure on its racemate. The molecular design of SemiPHOS was devised such that, when chelated to a metal atom, a subtle steric interaction appears to allow the chirality of the phospholane ring to influence the neighbouring diphenylphosphino group to adopt a complementary chiral conformation. This idea was tested and evaluated by applying SemiPHOS in catalytic asymmetric hydrogenations of (Z)-a-(Nacylamino) acrylate substrates to produce the R-amino acid precursors. Aryl species lithiated ortho to phosphorus-centred directing groups were coupled oxidatively by a convenient in situ method, to yield biaryl species that could then be elaborated to give biaryl ditertiary phosphine ligands. This method was used to make several atropisomeric chiral ditertiary phosphines.

During the course of this work we have synthesized and evaluated a series of new enantiopure silyl triflmides as catalysts for asymmetric reactions. 3-Phenyl dialkylsilyl ketones, which were the key precursors to the target silyl triflmides were prepared by 1,4-addition of the corresponding silyl cuprate to enones, and resolved by chiral HPLC. Enantiopure trans silyl ketones were successfully reduced via the corresponding tosylhydrazones by the NaBH3CN/ZnCl2 system. However, due to an isomerization of the tosylhydrazone during the reaction, cis isomers (m = 0) were reduced via the corresponding dithioketals followed by desulfurization. The diastereoselective synthesis of enantiopure silyl triflimides from enantiomerically pure compounds has been also studied. The enantiopure trialkylsilyl triflimides were generated in situ by protodesilylation of the corresponding phenylsilanes with bis-(trifluoromethylsulfonyl)imide. The Diels-Alder reaction of methyl acrylate with cyclopentadiene was used as the model reaction for testing the new chiral catalysts : 1) Almost all silyl triflimides were efficient catalysts giving high yields and excellent diastereoselectivities in favour of the endo-isomer. 2) the best ee's (up to 56%) were obtained from catalysts carrying an aryl group directly attached to the cyclohexane ring (m = 0) which were much better than those obtained from catalysts carrying a benzyl-type group (m = 1). Interestingly catalysts of the same configuration carrying phenyl or naphthyl group gave cycloadducts of opposite configuration. 3) When m = 0, additional substituents at position-3 or 6 of the cyclohexyl ring had little influence on the ee. However, for m = 1, a methyl group at C2 increased the ee from 3% to 35%. 4) The replacement of the methyl groups connected to the silicon atom by bulkier ethyl groups decreased the ee (m = 0). 5) When m = 0, ee's for cycloaddition reactions of N,N-dimethyl acrylamide or acryloxazolidinone with cyclopentadiene were lower than those obtained with methyl acrylate.

Synthetic methods of phosphinic acids and bicyclic aza-beta and gamma-lactams has been described.

Synthetic methods of phosphinic acids and bicyclic aza-beta and gamma-lactams has been described.