Chiral synthesis on catalysts immobilized in microporous and mesoporous materials

This paper reviews the recent progress made in the asymmetric synthesis on chiral catalysts in porous materials and discusses the effects of surface and pores on enantio-selectivity (confinement effect). This paper also summarizes various approaches of immobilization of the chiral catalysts onto surfaces and into pores of solid inorganic supports such as microporous and mesoporous materials. The most important reactions surveyed for the chiral synthesis in porous materials include epoxidation. hydrogenation, hydroformylation, Aldol and Diels-Alder reactions, etc. The confinement effect originated from the surfaces and the pores turns out to be a general phenomenon. which may make the enantioselectivity increase (positive effect) or decrease (negative effect). The confinement effect becomes more pronounced particularly when the bonding between the catalyst and the surface is more rigid and the pore size is tuned to a suitable range. It is proposed that the confinement in chiral synthesis is essentially a consequence of subtle change in transition states induced by weak-interaction in pores or on surfaces. It is also anticipated that the enantioselectivity could be improved by tuning the confinement effect based on the molecular designing of the pore/surface and the immobilized catalysts according to the requirements of chiral reactions.

Highly efficient and recoverable dendritic organocatalyst from click chemistry for the asymmetric michael addition of ketones to nitroolefins without the use of organic solvent

A series Of pyrrolidine-triazole based dendritic catalysts have been synthesized and applied directly in the asymmetric Michael addition of ketones to nitroolefins without the use of an organic solvent. Good yields (up to 99%), and high diastereoselectivities (up to syn/anti = 45:1) and enantioselectivities (up to 95% ee) have been obtained. Furthermore. the third generation catalyst can be reused at least five times without significant loss of catalytic activity. (C) 2008 Elsevier Ltd. All rights reserved.

Immobilization of dipyridyl complex to magnetic nanoparticle via click chemistry as a recyclable catalyst for Suzuki cross-coupling reactions

A magnetic nanoparticle (MNP)-supported di(2-pyridyl)methanol palladium dichloride complex was prepared via click chemistry. The MNP-supported catalyst was evaluated in Suzuki coupling reaction in term of activity and recyclability in DMF. It was found to be highly efficient for Suzuki coupling reaction using aryl bromides as substrates and could be easily separated by an external magnet and reused in five consecutive runs without obvious loss of activity.

[4+2] Annulation - Convenient Synthesis of Substituted Dihydropyranones in Aqueous Media

A facile and convenient synthesis of dihydropyranones has been developed by a formal [4+2] annulation of readily available alpha-acetyl ketene S,S-acetals with various aldehydes, involving a tandem aldol reaction and conjugate addition-elimination reaction, in the presence of NaOH in water.

Efficient synthesis of highly substituted pyrrolin-4-ones via PIFA-mediated cyclization reactions of enaminones

A convenient and efficient synthesis of highly substituted pyrrolin-4-ones is developed via the PIFA-mediated cyclization reactions of readily available enaminones, and a mechanism involving sequential cleavage of N-C bond, formation of new N-C bond, intramolecular addition reaction, and benzilic acid type rearrangement is proposed.

Synthesis of new bis-BINOLs linked by a 2,2 '-bipyridine bridge

A series of new G-symmetric chiral ligands 8, 9, 11 and 12, consisting of two binaphthyl units linked by a 2,2'-bipyridine bridge, has been synthesized via Suzuki cross-coupling reactions.

Optimisation of chemoenzymatic processes in asymmetric synthesis

This thesis describes the optimisation of chemoenzymatic methods in asymmetric synthesis. Modern synthetic organic chemistry has experienced an enormous growth in biocatalytic methodologies; enzymatic transformations and whole cell bioconversions have become generally accepted synthetic tools for asymmetric synthesis. Biocatalysts are exceptional catalysts, combining broad substrate scope with high regio-, enantio- and chemoselectivities enabling the resolution of organic substrates with superb efficiency and selectivity. In this study three biocatalytic applications in enantioselective synthesis were explored and perhaps the most significant outcome of this work is the excellent enantioselectivity achieved through optimisation of reaction conditions improving the synthetic utility of the biotransformations. In the first chapter a summary of literature discussing the stereochemical control of baker’s yeast (Saccharomyces Cerevisae) mediated reduction of ketones by the introduction of sulfur moieties is presented, and sets the work of Chapter 2 in context. The focus of the second chapter was the synthesis and biocatalytic resolution of (±)-trans-2-benzenesulfonyl-3-n-butylcyclopentanone. For the first time the practical limitations of this resolution have been addressed providing synthetically useful quantities of enantiopure synthons for application in the total synthesis of both enantiomers of 4-methyloctanoic acid, the aggregation pheromone of the rhinoceros beetles of the genus Oryctes. The unique aspect of this enantioselective synthesis was the overall regio- and enantioselective introduction of the methyl group to the octanoic acid chain. This work is part of an ongoing research programme in our group focussed on baker’s yeast mediated kinetic resolution of 2-keto sulfones. The third chapter describes hydrolase-catalysed kinetic resolutions leading to a series of 3-aryl alkanoic acids. Hydrolysis of the ethyl esters with a series of hydrolases was undertaken to identify biocatalysts that yield the corresponding acids in highly enantioenriched form. Contrary to literature reports where a complete disappearance of efficiency and, accordingly enantioselection, was described upon kinetic resolution of sterically demanding 3-arylalkanoic acids, the highest reported enantiopurities of these acids was achieved (up to >98% ee) in this study through optimisation of reaction conditions. Steric and electronic effects on the efficiency and enantioselectivity of the biocatalytic transformation were also explored. Furthermore, a novel approach to determine the absolute stereochemistry of the enantiopure 3-aryl alkanoic acids was investigated through combination of co-crystallisation and X-ray diffraction linked with chiral HPLC analysis. The fourth chapter was focused on the development of a biocatalytic protocol for the asymmetric Henry reaction. Efficient kinetic resolution in hydrolase-mediated transesterification of cis- and trans- β-nitrocyclohexanol derivatives was achieved. Combination of a base-catalysed intramolecular Henry reaction coupled with the hydrolase-mediated kinetic resolution with the view to selective acetylation of a single stereoisomer was investigated. While dynamic kinetic resolution in the intramolecular Henry was not achieved, significant progress in each of the individual elements was made and significantly the feasibility of this process has been demonstrated. The final chapter contains the full experimental details, including spectroscopic and analytical data of all compounds synthesised in this project, while details of chiral HPLC analysis are included in the appendix. The data for the crystal structures are contained in the attached CD.

A concise and convergent (formal) total synthesis of huperzine A

The first convergent synthesis of the tricyclic skeleton of huperzine A is described and includes, as the key step, an efficient regioselective intramolecular Heck reaction of 2-(tert-butyldimethylsillyoxymethyl)-6-(2-methoxy-5-bromopyridin-6-yl)methylcyclohex-2-enol.

Assembly intermediates in polyketide biosynthesis; enantioselective syntheses of beta-hydroxycarbonyl compounds

A versatile approach for the enantioselective synthesis of functionalised beta-hydroxy N-acetylcysteamine thiol esters has been developed which allows the facile incorporation of isotopic labels. It has been shown that a remarkable reversal of selectivity occurs in the titanium mediated aldol reaction of the acyloxazolidone intermediate using either (S)- or (R)-tert-butyldimethylsilyloxybutanal. The aldol products are valuable intermediates in the synthesis of 4-hydroxy-6-substituted gamma-lactones.

Asymmetric Carbon-Carbon Bond Forming Reactions Catalysed by Metal(II) Bis(oxazoline) Complexes Immobilized using Supported Ionic Liquids

A series of bis(oxazoline) metal(II) complexes has been supported on silica and carbon supports by non-covalent immobilisation using an ionic liquid. The catalytic performance of these solids was compared for the enantioselective Diels-Alder reaction between N-acryloyloxazolidinone and cyclopentadiene and the Mukaiyama-aldol reaction between methyl pyruvate and 1-methoxy-1-trimethylsilyloxy-propene. In both reactions the enantioselectivity was strongly influenced by the choice of support displaying enantioselectivies (ee values) up to 40% higher than those conducted under homogeneous reaction conditions.

Synthesis of the putative structures of homopumiliotoxins 235C and 233F

A novel approach to diene based quinolizidines, using an intramolecular Heck reaction in which the vinyl bromide double bond undergoes inversion of configuration, is reported. These quinolizidines have previously been proposed as tentative structures for homopumiliotoxin alkaloids 233F and 235C. The mass spectral data of the synthetic materials were different to those of the natural products confirming that the original structures need to be revised. (C) 2004 Elsevier Ltd. All rights reserved.

An efficient Cu(II)-bis(oxazoline)-based polymer immobilised ionic liquid phase catalyst for asymmetric carbon–carbon bond formation

The asymmetric Diels-Alder reaction between N-acryloyloxazolidinone and cyclopentadiene and the Mukaiyama-aldol reaction between methylpyruvate and 1-phenyl-1-trimethylsilyloxyethene have been catalysed by heterogeneous copper(II)-bis(oxazoline)-based polymer immobilised ionic liquid phase (PIILP) systems generated from a range of linear and cross linked ionic polymers. In both reactions selectivity and ee were strongly influenced by the choice of polymer. A comparison of the performance of a range of Cu(II)-bis(oxazoline)-PIILP catalyst systems against analogous supported ionic liquid phase (SILP) heterogeneous catalysts as well as their homogeneous counterparts has been undertaken and their relative merits evaluated.

Enantiodivergent chemoenzymatic synthesis of Balanol and approaches to the synthesis of (+)-Codine

The present thesis reviews the development of a formal enantiodivergent synthesis of the (+)- and (-)-isomers of balanol. This approach commences from a cis-dihydrodiol derived from the enzymatic dihydroxylation of bromobenzene. The stereochemistry of the diol is used to direct the synthesis of two different aziridines, each used in the formal synthesis of one enantiomer of balanol. Also described are several enantioselective approaches to (+ )-codeine. Each strategy begins with the enzymatic dihydroxylation of p-bromoethylbenzene and involves a Mitsunobu inversion and intramolecular Heck reaction as key steps.

Synthesis and utilization of guanidine catalysts for applications directed towards the preparation of butenolide and modified amino acid derivatives

Development of guanidine catalysts is explored through direct iminium chloride and amine coupling, alongside a 2-chloro-l,3-dimethyl-IH-imidazol-:-3-ium chloride (DMC) induced thiourea cyclization. Synthesized achiral catalyst N-(5Hdibenzo[ d,t][1,3]diazepin-6(7H)-ylidene)-3,5-bis(trifluoromethyl) aniline proved unsuccessful towards O-acyl migrations, however successfully catalyzed the vinylogous aldol reaction between dicbloro furanone and benzaldehyde. Incorporating chirality into the guanidine catalyst utilizing a (R)-phenylalaninol auxiliary, generating (R)-2-((5Hdibenzo[ d,t] [1,3 ]diazepin-6(7H)-ylidene ) amino )-3 -phenylpropan-l-ol, demonstrated enantioselectivity for a variety of adducts. Highest enantiomeric excess (ee) was afforded between dibromofuranone and p-chlorobenzaldehyde, affording the syn conformation in 96% ee and the anti in 54% ee, with an overall yield of30%. Attempts to increase asymmetric induction were focused on incorporation of axial chirality to the (R)phenylalaninol catalyst using binaphthyl diamine. Incorporation of (S)-binaphthyl exhibited destructive selectivity, whereas incorporation of (R)-binaphthyl demonstrated no effects on enantioselectivity. Current studies are being directed towards identifying the catalytic properties of asymmetric induction with further studies are being aimed towards increasing enantioselectivity by increasing backbone steric bulk.

Synthèse stéréosélective de motifs polypropionates via la chimie des radicaux : application à l'élaboration de l'hémisphère ouest de la narasine

Cet ouvrage traite principalement de la synthèse de motifs polypropionates de type stéréopentade ainsi qu’une application à la synthèse d’une molécule naturelle possèdant des propriétés biologiques. La stratégie envisagée pour l’élaboration de ces motifs récurrents dans plusieurs structures d’origine naturelle fait appel à la chimie des radicaux. Cette thèse se divise en différents chapitres dans lesquels la versatilité de la méthodologie développée sera démontrée. En premier lieu, il sera question de présenter l’importance de la synthèse de motifs polypropionates. Le domaine couvert par la chimie de ces molécules complexes hautement fonctionnalisées a contribué énormément à l’avancement de nos connaissances en synthèse organique, particulièrement dans le contexte des réactions impliquant des molécules acyliques. Une brève description des méthodes connues est présentée afin de saisir l’étendue des défis restants pour construire efficacement tous les isomères possibles des polypropionates de type stéréopentade. La stratégie proposée est basée sur une approche contrôlée entièrement par le substrat. Ce contrôle s’appuie sur le choix judicieux de l’acide de Lewis activant les deux réactions impliquées, soit la réaction de Mukaiyama et le transfert d’hydrogène. La seconde section de cette thèse concerne principalement le développement d’une réaction de Mukaiyama impliquant un éther d’énol silylé portant un lien pouvant être homolytiquement brisé dans la réaction suivante et un aldéhyde de type propionate. Le contrôle de l’aldolisation provient de la nature de l’acide de Lewis. Une espèce monodentate (BF3·OEt2) génère une relation 3,4-syn selon le modèle dit Felkin-Anh tandis que les acides de Lewis bidentates mènent à la relation 3,4-anti via un état de transition définit comme Cram-chélate. Une optimisation des conditions réactionnelles en variant l’acidité et la stoechiométrie de l’acide de Lewis de titane a permis de construire diastéréosélectivement le produit de Mukaiyama ayant une relation 3,4-anti. En outre, la nature des complexes impliqués dans ces réactions a été élucidée par des études RMN 13C à basse température. Une fois les précurseurs radicalaires synthétisés, notre méthodologie de réduction par transfert d’hydrogène contrôlée également par les acides de Lewis s’avère très efficace. Les acides de Lewis dérivés d’aluminium mènent sélectivement à la relation 2,3-syn selon un contrôle endocyclique tandis que les acides de Lewis de bore permettent la création des relations 2,3-anti en se basant sur une stabilisation par les divers facteurs de contrôle de molécules acycliques. Cette stratégie novatrice nous a ainsi permis de construire efficacement les 16 diastéréoisomères possibles. Le chapitre suivant concerne l’application de cette méthodologie à la synthèse de l’hémisphère ouest de la salinomycine et de la narasine. Plusieurs défis synthétiques ont été relevés à cette occasion par la présence de nombreux centres stéréogènes contigus. Nous avons réalisé que la relation stéréochimique 2,3-anti de la salinomycine n’est pas accessible sélectivement par la chimie des radicaux via l’effet exocyclique. Des études ont été entreprises afin de comprendre cette perte de sélectivité. Les conclusions suggèrent que les substituants sur le cycle imposent un biais conformationnel conduisant à des faibles sélectivités. Une alternative utilisant un réactif de crotylsilane chiral a été développée pour arriver à la molécule cible. Cette situation est différente dans le cas de la narasine où la présence du méthyle sur le carbone en position β du radical bloque efficacement l’approche d’une des faces d’attaque par l’hydrure. Des sélectivités impressionnantes nous ont permis de construire le fragment C1-C9 de la narasine de manière expéditive et efficace. Finalement, l’élongation sélective utilisant à nouveau la séquence d’aldolisation de Mukaiyama/réduction radicalaire suivie d’un couplage de type aldol stéréosélectif conduit au fragment C1-C17 de la narasine (hémisphère ouest)en 19 étapes avec un rendement global de l’ordre de 7 %. En dernier lieu, nous nous sommes penchés sur la réactivité des α-bromo-β- alkoxycétones lors de transfert d’hydrogène. Nous avons découvert que la chimie de ces derniers pourrait s’avérer utile dans le contexte de la synthèse de motifs complexes polypropionates. La présence d’un centre stéréogène de l’autre coté de la cétone semble avoir un impact sur la sélectivité.