Thesis advisor: James Morken / Asymmetric hydroformylation (AHF) is a metal-catalyzed reaction in which CO and H2 are added across an olefin to form a new carbon-carbon bond. AHF has perfect atom-economy and is an ideal way to form a chiral aldehyde. However, the utility of branch selective hydroformylation is limited due to a lack of readily available ligands and restrictions on a wide variety of terminal olefins. Herein, Rh-catalyzed asymmetric hydroformylation of 1-alkenes is reported using commercially available Ph-BPE ligand to generate α-chiral aldehydes. A wide range of terminal olefins were explored and all showed high enantioselectivity (up to 98:2 er) and good regioselectivity (up to 15:1 branched to linear ratio). / Thesis (MS) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The hydroformylation of unfunctionalised olefins (such as prop-1-ene and oct-1-ene) is an extremely valuable process and is practised on a massive scale industrially in the synthesis of commodity chemicals. In fact, it represents the worlds largest scale application of homogeneous catalysis. As a result, the majority of research carried out on this reaction has been in the study of catalytic systems which provide high rates and selectivity for the production of linear aldehydes from terminal unfunctionalised olefins, with the products finding use in the production of plasticizers and detergents. Asymmetric hydroformylation, the enantioselective variant of this reaction is extremely attractive, as low cost or easily accessible olefins are transformed into highly versatile value-added enantioenriched aldehydes in a single step. However synthetic organic chemists interested in the synthesis of fine chemicals, both in academia and industry, have been slow to adopt this attractive protocol for the production of chiral aldehydes. This is mainly due to the fact that in the past catalysts for this reaction exhibited low activity and/or selectivity in this process. However, the last two decades have seen major advances, mainly in the development of highly effective chiral ligands, and with these developments the time has come to tackle the vastly under-explored area of asymmetric hydroformylation of more functionalised olefins. To set the scene for the research carried out during this project a brief introduction will be given which highlights the historical development of highly efficient catalysts for the hydroformylation of olefins. This will be accompanied by some examples of the use of this methodology in the synthesis of pharmaceutically relevant compounds. It should become apparent from the introduction that the asymmetric hydroformylation of functionalised olefins and in particular nitrogen containing olefins, has received very little attention despite the fact that over half of all medicinal compounds contain at least one nitrogen containing functional group. Firstly we describe hydroformylation as a useful alternative to the classical synthesis of a delicate chiral building block, namely α-formyl amides. These compounds, traditionally only available through multi-step synthetic procedures from enantiopure starting materials, have been accessed by asymmetric hydroformylation of readily accessible and in some cases commercially available acrylamides. By judicious choice of reaction conditions and selection of the appropriately active chiral ligand enantioenriched α-formyl amides (e.e. up to 82%) were produced in high yield. A comparison is made between the classical route and the hydroformylation route to illustrate the potential of this efficient transformation. We have studied the hydroformylation of enamides, a much under-studied substrate class in hydroformylation and developed knowledge of how some more functionalised 1,1- and 1-2-subtituted olefinic amides react under hydroformylation conditions. This research illustrates the work still to be done in terms of development of more active and selective catalysts for this reaction but despite limitations we developed a potential route to gamma amino aldehyde derivatives which could be used in turn in the synthesis of physiologically important gamma amino butyric acid (GABA) derivatives. We provide an example of the highly efficient and selective asymmetric hydroformylation of a bicyclic olefinic lactam, which is of industrial importance in the synthesis of carbocyclic nucleosides. We demonstrate the efficiency of this synthetic methodology by synthesising the central pharmacophore of a potent anti- HSV-1 (herpes simplex virus) carbocyclic nucleoside via a hydroformylationreduction protocol. The classical synthesis of this pharmacophore involves nine synthetic transformations to produce racemic material, whereas the hydroformylationreduction protocol produces highly enantioenriched material in just two steps. We also demonstrate some downstream chemistry of the aldehyde products showcasing the synthetic versatility of the aldehyde functionality in the production of a variety of functionalised cyclopentanes. Finally the synthesis and catalytic testing of a group of novel phosphine-phosphite ligands for use in asymmetric hydroformylation is described, one of which produces unprecedented regioselectivity and state of the art enantioselectivity in the asymmetric hydroformylation of styrene. Highly selective asymmetric hydroformylation of the other two ‘model substrates' in this reaction namely, vinyl acetate and allyl cyanide is also achieved. Having shown high activity and selectivity over these ‘model substrates' this ligand takes its place among the small group of highly active and selective ligands available for asymmetric hydroformylation and may also help to broaden the substrate scope of this efficient and atom-economic transformation.

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Ce mémoire de thèse est consacré au développement de nouveaux systèmes catalytiques dérivés de métallocyclodextrines. Les travaux qui y sont décrits ont trait à la mise au point de méthodes de fonctionnalisation régiosélective de la face primaire des cyclodextrines donnant accès à des ligands hétérodentés de type P,P’ à chiralité inhérente. Ces derniers forment quantitativement des complexes chélate de géométrie cis, dont les versions rhodiées ont été testées en hydrogénation eten hydroformylation asymétriques d’oléfines prochirales. L’étude des propriétés complexantes et catalytiques de deux phosphines confinantes dérivées d’α- et de β-cyclodextrine a également étér éalisée. L’ancrage rigide de l’atome de phosphore (III) au sein de la matrice cyclodextrine permet de confiner le centre métallique au coeur du macrocycle, ce qui se traduit par la formation exclusive de complexes mono-ligandés en phosphore. Les complexes monophosphine de rhodium (I) catalysent l’hydroformylation asymétrique du styrène avec une très forte sélectivité en produit branché et une énantiosélectivité très élevée. Le pontage de diaminocyclodextrines par l'acénaphtènequinone permet d’obtenir des ligands potentiellement confinants dans lesquels l’anse azotée de type N-(2-N’-alkylaminoacenaphthenyl)alkylimine est dissymétrique. L’oxydation du pont par voie chimique ou électrochimique conduit à une anse imidazole 1,2-disubstitué très courte qui provoque une forte déformation du squelette cyclodextrine. / This manuscript is concerned with the design of novel catalytic systems derived from metallocyclodextrins. The first part describes new ways of functionalising the cyclodextrin primary face regioselectively for accessing inherently chiral P,P’ chelators. These heterodentate ligands gavequantitatively cis-chelate complexes with various d8 cations. Their rhodium(I) complexes were assessed in the asymmetric hydrogenation and hydroformylation of prochiral olefins. Thecoordination and catalytic properties of two phosphines derived from a- and b-cyclodextrin are also reported. With their phosphorus lone pair pointing toward the CD core, these confining ligands force the coordinated metal centre to stay within the CD hollow and promote the formation of singly phosphorus-ligated complexes. Rhodium (I) monophosphine complexes of this type catalyse the asymmetric hydroformylation of styrene with both very high isoselectivity and enantioselectivity. Capping of diaminocyclodextrins with acenaphthenequinone resulted in the formation of a nonsymmetricN-(2-N’-alkylaminoacenaphthenyl)alkylimine handle with two intra-annular nitrogen atoms. A strong deformation of the cyclodextrin scaffold was shown to take place upon chemical or electrochemical oxidation of the bridging unit into the very short 1,2-disubstituted imidazole moiety.