Dissertationen zum Thema „Regioselective reduction“

New methods were developed for the regioselective synthesis of new classes of cellulose derivatives with properties that could help improve the delivery of pharmaceutical drugs within the human body. The specific synthetic targets of this research were regioselectively carboxylated and regioselectively aminated cellulose derivatives. While different avenues to the carboxylated cellulose were ultimately explored without success, a new method for the synthesis of selectively O-acylated 6-amino-6-deoxy-cellulose esters was devised. A key reaction that enabled the synthesis of the new cellulose derivatives described in this dissertation was the one-pot conversion of microcrystalline cellulose to 6-bromo-6-deoxy-cellulose esters. This reaction resulted in the highly selective displacement of the primary hydroxyl groups attached to the 6-carbon (C-6) on each anhydroglucose unit (AGU) in cellulose with bromide, with little or no bromination occurring at carbons 2 and 3 (C-2 and C-3). The brominated cellulose was then completely esterified by adding acetic, propionoic, or butyric acid anhydride to the reaction solution. The reaction products were readily soluble in many common organic solvents, including acetone, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and chloroform. It was shown that the bromides could be converted to iodides under Finkelstein reaction conditions. The presence of halides at C-6 allows a variety of new functional groups to be regioselectively introduced to cellulose via nucleophilic substitution. In one case, the 6-bromo-6-deoxy-cellulose esters were reacted with sodium cyanide to produce regioselectively synthesized cellulose nitriles. These compounds were synthesized with the idea that they could be converted to regioselectively carboxylated cellulose derivatives as an alternative pathway to the rhodium-catalyzed carbonyl insertion reactions also attempted in this research. However, the cellulose nitriles were highly susceptible to alkaline degradation, and conversion to the carboxylated cellulose was not achieved. The 6-bromo-6-deoxy-cellulose esters were also reacted with sodium azide to successfully produce 6-azido-6-deoxy-cellulose esters. The azide groups were then reduced to amines using the Staudinger reaction. This very mild and selective reaction allowed the conversion of the azides to amines in the presence of the ester groups still attached to the cellulose backbone. Such derivatives could have properties useful for a range of biomedical applications, including the delivery of anionic drugs.
Ph. D.

The synthetic progress towards yaku'amide A is described. The study leads to development of new synthetic methodologies. Base-free regioselective aminohydroxylation is convenient to deliver β-tert-hydroxyamino acids. A sequence consisting of alkylative esterification, Martin sulfurane mediated anti dehydration, a tandem azide reduction-O→N acyl transfer allows the rapid access of E- and Z-dehydroisoleucine-containing peptides from β-tert-hydroxyisoleucine derivatives. Those methods are effective in constructing complicated peptides and advanced subunits of yaku'amide A.

Ce travail presente les differents resultats obtenus dans l'etude de la reduction purement electrochimique ou electroenzymatique de molecules presentant une ou plusieurs insaturations. Ainsi, differentes 2-aroyl et 2-acetylchromones ont ete etudiees en vue de leur reduction regioselective. Il a ete montre que dans le cas des 2-aroylchromones, la fonction carbonyle du substituant en position 2 du cycle chromone a ete reduite regioselectivement tandis que pour la 2-acetylchromone, c'est la double liaison du cycle qui est reduite. Les produits obtenus conduisent apres une nouvelle electroreduction a des dimeres extremement instables. Un phenomene d'autoprotonation a ete observe avec les chromones substituees par des fonctions phenol ou chlorhydrate d'amine. La reduction enzymatique d'-ceto-carboxylates par proteus mirabilis avec regeneration electrochimique du systeme enzyme-cofacteur par un mediateur (viologene) a conduit a des -hydroxyacides de configuration (r) avec d'excellents exces enantiomeriques. Le choix de la solution tampon et l'influence d'additions de tensioactifs ont ete discutes. Dans le cas d'un cetocarboxylate racemique, l'electrochimie a permis de mettre en evidence une enantioselectivite des reductases vis-a-vis du substrat par le suivi de l'intensite du courant d'electrolyse. L'etude electrochimique d'-dicetones a mis en evidence une certaine regioselectivite dans la reduction de diones dissymetriques en particulier dans le cas de la 1-phenylpropane-1,2-dione pour laquelle seule la fonction carbonyle en du groupement phenyle est reduite. La reduction microbiologique de ces diones toujours par proteus mirabilis a conduit a un unique cetol de configuration (2s) avec une tres bonne purete optique pour les 2,3-diones et la 1-phenylpropane-1,2-dione. La reduction electroenzymatique de ces composes n'a pas donne de bons resultats, les differentes molecules etudiees se reduisant a un potentiel trop proche de celui des mediateurs utilises. Differentes techniques d'analyses (rmn, point de fusion, microanalyses, pouvoir rotatoire, chromatographie en phase vapeur sur colonne chirale ou non chirale, rpe, ir), ont permis d'identifier et de caracteriser les produits obtenus

La present tesi doctoral té com a objectiu el desenvolupament de sistemes per aconseguir una regioselectivitat no convencional en l’hidroformilació d'alquens terminals. Degut a que nombroses substàncies naturals perfumades contenen un grup aldehid. Els processos d’hidroformilació, on es fan reaccionar monòxid de carboni i hidrogen amb olefines, han esdevenit mètodes inestimables per a les empreses de fragàncies per a la producció d’aquests derivats. La regioselectividad del procés, per a l’obtenció del producte lineal o ramificat, és extremadament dependent del substrat. Com a tendència general en l’hidroformilació catalitzada per Rh, els alquens terminals, com l’1-octè, reaccionen per a la producció d’aldehids lineals, mentre que els alquens vinílic, com l’estirè, proporcionen els productes ramificats corresponents. No obstant, per a la síntesis de noves substàncies perfumades, l’accés als aldehids oposats seria sens dubte beneficiós. Al Capítol 3 es descriu la síntesis de nous lligands bidentats centrats en fòsfor i nitrogen i la seva aplicació en l’hidroformilació de 1-hexè catalitzada per rodi, obtenint el producte ramificat. Al Capítol 4 s’aporta la síntesi d’una nova família de lligands fosfina-fosfit i fosfina-fosforamidit i la seva aplicació en l’hidroformilación de l’1-octè cap a l’aldehid ramificat, catalitzada per rodi. El Capítol 5 es centra en la hidroformilació d’estirè catalitzada per rodi amb lligands bis (dipirrolil-fosforamidit), cap a la producció del producte lineal. El Capítol 6 ofereix el desenvolupament d'un procés sense precedents anomenat "carbonilació reductora catalitzada per rodi" de l'acetat al·lílic, per a la producció de l'aldehid corresponent. A més d’un estudi de la reactivitat del sistema catalític mitjançant RMN d'alta pressió. Finalment, al Capítol 7 es presenten els resultats obtinguts en l’hidroformilació d’estirè catalitzada per pal·ladi, utilitzant formaldehid com a substitut de gas de síntesi.
La presente tesis doctoral tiene como objetivo el desarrollo de sistemas para la obtención de regioselectividad no convencional en la hidroformilación de alquenos terminales. Debido a que numerosas sustancias naturales perfumadas contienen un grupo aldehído. Los procesos de hidroformilación, en los cuales monóxido de carbono e hidrógeno son añadidos a las olefinas, se han convertido en métodos invaluables para la producción de estos derivados en empresas de fragancias. La regioselectividad del proceso, en el cual se obtiene el producto lineal o ramificado, depende en gran medida del sustrato. Como tendencia general en la hidroformilación catalizada por Rh, los alquenos terminales, como por ejemplo el 1-octeno, reaccionan para producir aldehídos lineales mientras que los alquenos vinílicos, como el estireno, forman los correspondientes productos ramificados como productos favorecidos. Sin embargo, para la síntesis de nuevas sustancias perfumadas sería beneficioso el acceso a los aldehídos contrarios. En el Capítulo 3 se describe la síntesis de nuevos ligandos bidentados centrados en nitrógeno y fósforo y su aplicación en la hidroformilación catalizada por rodio de 1-hexeno hacia el producto ramificado. En el Capítulo 4 se aporta la síntesis de una nueva familia de ligandos fosfina-fosfito y fosfina-fosforamidita y su aplicación en la hidroformilación de 1-octeno catalizada por rodio, formando el aldehído ramificado. El Capítulo 5 se centra en la hidroformilación de estireno catalizada por rodio con ligandos de bis (dipirrolilfosforamidita), en este caso, hacia la obtención del producto lineal. El Capítulo 6 presenta el desarrollo de un proceso sin precedentes denominado “carbonilación reductora catalizada por rodio” del acetato alílico, para la producción del aldehído correspondiente. Además de un estudio de la reactividad del sistema catalítico mediante RMN de alta presión. Finalmente, el Capítulo 7 ofrece los resultados obtenidos en la hidroformilación de estireno catalizada por paladio, utilizando en este caso formaldehído como sustituto del gas de síntesis.
The current Ph.D. Thesis deals with the development of systems for achieving unconventional regioselectivity in the hydrofomylation of terminal alkenes. Numerous scented natural substances contain an aldehyde group. As such, hydroformylation processes, where carbon monoxide and hydrogen are added onto olefins, have become invaluable methods for the fragrance companies to produce these derivatives. The regioselectivity between linear and branched product of the process is extremely substrate dependent. As a general trend, terminal alkenes, such as 1-octene, react to yield linear aldehydes while vinyl arenes, such as styrene, afford the corresponding branched products, as favoured products in Rh-catalysed hydroformylation. However, to synthetise new scented substances, accessing the opposite aldehydes would be undoubtedly beneficial. In Chapter 3 the application of newly synthetised bidentate phosphorus-nitrogen-centred ligands in the rhodium catalysed hydroformylation of 1-hexene towards the branched product, is described. In Chapter 4 is reported a novel family of phosphine-phosphite and phosphine-phosphoramidite ligands and their application in the rhodium catalysed hydroformylation of 1-octene, towards the branched aldehyde. Chapter 5 is focused on the rhodium catalysed hydroformylation of styrene with bis(dipyrrolyl-phosphoramidite) ligands, towards the production of linear product. Chapter 6 deals with the development of an unprecedent process so called “rhodium catalysed reductive carbonylation” of allylic acetate to produce the corresponding aldehyde. Furthermore, the results obtained via high pressure NMR in the study of the reactivity of the catalytic system are described. Finally, Chapter 7 presents the results obtained in the palladium catalysed hydroformylation of styrene, using formaldehyde as syngas surrogates.

Ces travaux décrivent l’utilisation d’ynamides et de N-allènamides comme intermédiaires clés pour la synthèse d’hétérocycles azotés et fluorés inédits. Une réaction de cyclisation intramoléculaire de mésyl N-allènamides trifluorométhylés promue par le TBAF a permis la synthèse de y-sultames trifluorométhylés alors que, l’utilisation d’un mélange TBAF/acide acétique, a permis l’obtention de y-sultames gem-difluorés. La formation de diènes trifluorométhylés substitués par une fonction amide, obtenue par une réaction de métathèse d’ène-ynamides avec un aldéhyde, a permis la synthèse de plateformes moléculaires hautement fonctionnalisées. Le traitement de ces diènes par des amines primaires, a permis l’obtention stéréosélective de y-lactames trifluorométhylés à l’aide d’un processus domino d’hydroamination/isomérisation/transamidation. Enfin, la réduction régio- et stéréosélective de chaque double liaison des N-allènamides trifluorométhylés a été explorée. Des allylamides ont été obtenus par réduction de la partie énamide des N-allènamides, alors que des énamides ont été formés par isomérisation, en milieu basique des allylamides
This work describes the use of ynamides and N-allenamides as key intermediates for the synthesis of novel nitrogen and fluorine containing heterocycles. A TBAF-promoted intramolecular cyclization reaction of trifluoromethylated mesyl N-allenamides led to the synthesis of trifluoromethylated y-sultams, while the use of a TBAF/acetic acid mixture afforded gem-difluorinated y-sultams. The formation of amide-substituted trifluoromethylated dienes, obtained through metathesis of ene-ynamides with an aldehyde, enabled the synthesis of highly functionalized molecular platforms. Treatment of these dienes with primary amines enabled the stereoselective production of trifluoromethylated y-lactams via a domino hydroamination/isomerization/transamidation process. Finally, the regio- and stereoselective reduction of each double bond of trifluoromethylated N-allenamides was explored. Allylamides were obtained by reduction of the enamide part of N-allenamides, while enamides were formed by isomerization, in basic medium of allylamides

Parmi les composes naturels ou synthetiques possedant des activites biologiques interessantes, les alcaloides tiennent une part importante. Recemment une nouvelle famille d'alcaloides bicycliques et oligocycliques, nommee myrmicarine, a ete isolee de glandes a poisons de fourmis d'afrique de type mirmicinae. La plupart de ces composes possedent en totalite ou en partie un motif hexahydropyrroloindolizine contenant un centre stereogene dont la configuration absolue n'est pas connue. Nous avons entrepris la synthese de ces alcaloides sous forme enantiopure. Dans un premier temps, suivant une strategie divergente basee sur des reactions de substitution electrophile regioselective sur un noyau pyrrolique nous avons synthetise un motif hexahydropyrroloindolizinone sous forme enantiopure, et par la suite les myrmicarines 217 et 215 (a et b). Dans un deuxieme temps, nous avons etudie la regioselectivite des reactions d'acylation de type vilsmeier-haack sur le tricycle quasi-symetrique hexahydropyrroloindolizine. Des conditions ideales ont ete mises au point permettant une substitution electrophile regiospecifique. Cette etude a ouvert une deuxieme voie d'acces aux myrmicarines 217 et 215 (a et b). Enfin nous avons propose deux voies d'acces a la myrmicarine 430 dont une est basee sur l'auto condensation des myrmicarines 215 (a et b) et pourrait etre assimilee a une synthese biomimetique de cet alcaloide.

L’accès par voie chimique à des oligosaccharides nécessite souvent le recours à de nombreuses étapes de protection-déprotection. Au cours de ce projet de thèse, une méthodologie pour la protection régiosélective et orthogonale des fonctions alcool de disaccharides dérivant de la biomasse a tout d’abord été développée. Les glycopyranosides protégés ont été préparés par catalyse tandem au FeCl3∙6H2O en réalisant dans le même pot des réactions d’acétalation, d’éthérification réductrice, d’acétylation et/ou d’ouverture réductrice régiosélective d’acétals. Dans un second temps, une stratégie de synthèse flexible, rapide et performante pour accéder à des sulfoglycolipides diacylés et tétraacylés comportant un cœur tréhalose a été mise au point. Ces molécules sont produites par Mycobacterium tuberculosis, l’agent pathogène responsable de la tuberculose, et les sulfoglycolipides diacylés pourraient permettre l’élaboration d’un nouveau vaccin contre cette maladie. Des sulfoglycolipides diacylés et tétraacylés comportant des chaînes monométhylées chirales ont été obtenus. Les précurseurs des acides gras chiraux utilisés au cours de la synthèse ont été analysés par spectroscopie RMN du deutérium en abondance naturelle dans des cristaux liquides chiraux
The synthesis of oligosaccharides often requires long sequences of protection-deprotection steps. For a rapid access to suitably protected glycopyranosides, we have developed a one-pot regioselective protection strategy based on FeCl3∙6H2O-tandem catalyzed reactions (acetalation, acetylation, reductive etherification, regioselective ring opening of acetal). This procedure was applied to persilylated disaccharides derived from biomass. This methodology allowed the development of a fast, efficient and flexible access to diacylated and tetraacylated sulfoglycolipids based on a trehalose core. These molecules are found in the cell wall of Mycobacterium tuberculosis and the diacylated sulfoglycolipids appear to be promising candidates for the development of a new tuberculosis vaccine. Synthetics diacylated and tetraacylated sulfoglycolipids bearing chiral monomethylated fatty chains were produced. The chiral fatty-acid precursors, used in the procedure, were synthetized and analyzed by NMR spectroscopy of natural abundance deuterium in chiral liquid crystals

碩士
國立中央大學
化學研究所
97
The method for regioselective palladium-catalyzed formate reduction of allylic acetates formed by ring closing metathesis was developed. We used ((E)-2,5,6,7-tetrahydro-7-methyl-7-phenyloxepin-3-yl)methyl acetate 4 as the model compound, and found an optimized condition for the formate reduction by screening several ligand. In order to apply this methodology to organic synthesis , We planned to synthesize compound C5 , that was the key synthetic intermediate in Cossy’s synthesis to product Zoapatanol . Zoapatanol contains a seven membered oxygen-heterocycle with two chiral centers. The first chiral center was prepared utilizing the Sharpless asymmetric oxidation, and the second chiral center was built by Grignard reaction whose stereochemistry assume to follow the Felkin-Anh model.

碩士
國立中山大學
化學系研究所
89
In this report, we described a general method which could regioselectively reduce the carbonyl group on 3-sulfonyl glutarimides and lead to the corresponding hydroxy piperidones (hydroxy lactams) and further converted to 3,4-dihydro-5-tosylpyridin-2-ones .

博士
國立中央大學
化學研究所
99
There are two topics in the thesis. The first is formal syntheses of zoapatanols by ring-closing metathesis/regioselective formate reduction. The combination of ring-closing metathesis and regioselective formate reduction is an effective strategy for the synthesis of cyclic compounds with exo olefins. Reduction of allylic acetates, formed by ring-closing metathesis, using allylpalladium chloride dimer, di-tert-butyl 2-biphenyl-phosphine, and formic acid/ triethylamine in DMF gives the exo-cyclic olefins with excellent regioselectivity and high yields under a mild condition. Synthetic application to prepare zoapatanols is accomplishing. The key vicinal stereocenters in zoapatanol were constructed from the L-malic acid dericed lactone by the nucleophilic acyl addition with excellent diastereoselectivities. Then the oxidation, Olefination, subtle allylation, RCM and Pd-formate reduction to get the key intermediums。 The second is asymmetric synthesis of (‒)-isooncinotine. The asymmetric total synthesis of the macrocyclic spermidine alkaloid isooncinotine, was completed by efficient RCM from resolution of 2-piperidineethanol as a starting material. Michael addition, amidations, and aluminum hydride reduction were applied to form the moiety of spermidine. Retro-Michael addition was observed when β-amido- and β-amino-propionitriles were reduced by LAH. The effects of LAH versus AlH3 were discussed.

博士
國立中山大學
化學系研究所
91
A formal [3+3] cycloaddition strategy to substituted glutarimides was studied. N-Alkyl-sulfonylacetamides and various a,b-unsaturated esters were used as starting materials. Regioselective reduction of N-alkyl-3-sulfonyl glutarimides and the applications in pharmaceuticals and natural product synthesis

碩士
國立臺灣師範大學
化學系
105
I. Catalyst-controlled regioselective (3+2) cycloaddition of azomethine ylide and indandionebenzylidines for synthesis of highly enantioselective chromanopyrrolidines. II. Synthesis of functionalized furans via chemoselective reduction/Wittig reaction using catalytic triethylamine and phosphine Part I. A novel and highly enantioselective (3+2) cycloaddition/esterification cascade for the synthesis of chromano[3,4-b]pyrrolidine derivatives is reported. Quinine-derived base, hydroquinine squaramide, affects this cascade reaction efficiently providing the products in good yields and stereoselectivities. Furthermore we found out the interesting phenomenon while the basicity change the reioselectivity of (3+2) cycloaddition could be controlled. The mechanism of how the regioselectivity could be controlled is also revealed in this work. Part II. An efficient protocol for the synthesis of highly functionalized furans via intramolecular Wittig reaction has been developed using catalytic amounts of phosphine and triethylamine. Silyl chloride served as the initial promoter to activate the phosphine oxide. Reduction of the activated phosphine oxide by hydrosilane resulted in the generation of phosphine, while the decomposition of triethylamonium chloride resulted in the regeneration of base, both of which mediated the formation of phosphorus ylide. Remarkably, the in situ generated by-product, triethylammonium chloride, is also found to catalyze the reduction of phosphine oxide.

碩士
國立清華大學
化學系
91
A systematic study of various metal trifluoromethanesulfonates as efficient catalysts including the effects of solvents, reducing reagents, and temperature in the regioselective silane-reductive ring opening of 4,6-O-benzylidene acetals at O4 is described. The corresponding secondary alcohols were obtained in excellent yields under an optimized combination of 1 mol% Cu(OTf)2 and 2 equiv Me2EtSiH in CH3CN.

碩士
國立中興大學
化學系所
107
Aryl imidazolium ionic liquids successfully catalyzed Friedel−Crafts acylation, thioesterification, per-O-acetylation, and regioselective reductive ring opening of benzylidene acetals in the sealed tubes. These reactions can form a C−C bond, a C−S bond, a C−O bond, and C−H bond with high atom economy. Two ionic liquids exhibited high activity and catalyzed essential reactions with good to excellent yields.

The advent of transition metal catalysis has greatly expanded the scope of viable cycloaddition reactions, allowing for the direct synthesis of highly functionalized and complex biologically active compounds. By manipulating various aspects of catalyst structure, including the supporting ligands and the central metal, the function of a catalyst can be modified. In this context, the catalytic properties of dinuclear complexes have not been greatly explored in cycloaddition reactions. Our research has focused on studying the catalytic properties of dinuclear complexes in cycloaddition reactions. Comparative studies between dinuclear and mononuclear Ni-complexes led us to discover and develop an efficient route to synthesize 1,2,4-trisubstituted benzene derivatives from terminal alkynes. The key organometallic intermediates in this process were isolated, and computational studies were performed to unravel a novel bimetallic mechanism for alkyne cyclotrimerizations. As an extension of this study, we have found that the dinuclear catalyst is capable of catalyzing the methylenecyclopropanation of olefins. The reaction uses 1,1-dichloroalkene as a vinylidene precursor along with Zn as a stoichiometric reductant. A wide range of monosubstituted terminal alkenes and relatively unhindered internal alkenes are viable substrates. Furthermore, to understand the mechanism of vinylidene transfer, various stoichiometric and stereochemical experiments were performed. Furthermore, we discovered that mononuclear and dinuclear Ni-complexes are highly efficient in achieving vinylidene insertions into Si–H bonds to synthesize Si-containing heterocyclic molecules. Ongoing efforts are directed toward optimizing the reaction conditions and elucidating the substrate scope of the reaction.