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Title: The development of new, direct and asymmetric Ni(II) catalysed carbon-carbon bond forming reactions and their application to total synthesis
Author: Kennington, Stuart C. D.
Director/Tutor: Urpí Tubella, Fèlix
Romea, Pedro
Keywords: Química orgànica
Organic chemistry
Issue Date: 21-Dec-2020
Publisher: Universitat de Barcelona
Abstract: [eng] This thesis focuses on the search for new methodologies for the direct, stereoselective and catalytic formation of carbon-carbon bonds through the formation of chiral nickel(II) enolate species and the application of such methods to the synthesis of natural products. The project starts with the stereocontrol coming from chiral auxiliaries, developed first by Evans and then later by Crimmins and Nagao, following the previous experience and expertise of the research group. These auxiliaries have proved to be a reliable and high yielding option to afford excellent levels of stereocontrol in various reactions. Furthermore, they can be removed after such processes to leave enantiopure synthons. However, they do have their drawbacks, one being the inability of synthesising all of the available stereoisomers from one starting material. To combat this issue, the second part of the thesis is centred around the development of a new methodology based on achiral starting materials (scaffolds) with chiral nickel(II) complexes, which both enable the reaction and control its stereochemical outcome. In the first Chapter, methods previously developed in the group were applied to the synthesis of a fragment of the marine sponge macrolide Peloruside A, which has shown to have anticancer activity, especially against leukaemia. Three key steps involve reactions based on the use of chiral auxiliaries that had been developed in the group: a nickel catalysed reaction with trimethyl orthoformate, a titanium-mediated acetate aldol reaction, and a titanium-mediated addition of an acetate enolate to an acetal. The overall yield of the synthesis of the target fragment C9-C19 was 24% over 14 steps. Chapter 2 presents a new reaction based on the addition of enolates, generated from chiral N-acyl thiazolidinethiones with an achiral nickel(II) complex, to stable carbocationic salts. This alkylation reaction was first thoroughgoingly optimised and later applied to a large range of substrates with wide success. Moreover, it was applied to a highly challenging electrophile successfully which lead to the discovery of a reversible alkylation process. The products were also transformed via the removal of the auxiliary to leave a variety of functional groups. In Chapter 3 the stereocontrol is passed from the starting material to the catalyst in an ambitious advancement of the group’s chemistry. After an extensive study of potential achiral scaffolds to provide the platform for the reactions and chiral diphosphine ligands to provide the enantiocontrol, we observed the best scaffold was the 6-memberd thiazinanethione structure and the best ligand DTBM-SEGPHOS®. We were able to apply this methodology to the reaction of: trimethyl orthoformate (an oxocarbenium precursor), tropylium tetrafluoroborate (a cationic salt), a diaryl methyl ether (a carbenium precursor), and also a more complex diaryl ketal electrophile with high yields and exceptional control over the one stereocentre formed. Furthermore, using a dimethyl acetal we were able to exert some control over the relative configuration of two stereocentres whilst maintaining exceptional enantioselectivity. Calculations and elucidation of the configuration of the new stereocentre formed support our hypothesis for the mechanism for such a process. We also demonstrated the ease with which the scaffold can be removed and were able to synthesise a wide variety of synthons with differing functional groups. Finally, we were able to scale up and apply the methodology to the synthesis of Peperomin D, a five membered lactone containing two stereocentres. Finally, in the last Chapter we present a new methodology for the asymmetric aldol reaction of N-acyl thiazinanethiones with aromatic aldehydes catalysed by a chiral nickel (II) complex, which involves the simultaneous silyl protection of the adducts. This new reaction proceeds through an open transition state and leads to the anti-aldol products. We were able to optimise the reaction to achieve a high diastereoselectivity, exceptional enantioselectivity, and excellent yield. Furthermore, we were able to apply the conditions to various aromatic aldehydes and N-acyl thiazinanethiones. Finally, the scope of the reaction was expanded to three different electrophiles, opening new lines of investigation.
[cat] La present Tesi Doctoral està adreçada a la cerca de noves metodologies per a la formació directa, estereoselectiva i catalítica d’enllaços carboni–carboni a partir de derivats carboxílics i la seva aplicació a la síntesi de productes naturals. Inicialment, s’avalua el control estereoquímic que proporcionen auxiliars quirals com les oxazoldininones d’Evans o les seves versions sulfurades degudes a Crimmins i Nagao. Tots aquests auxiliars han resultat ser una excel·lent plataforma per a nombrosos processos estereoselectius. No obstant això, tenen las seves limitacions, sobretot la falta de accés a tots els isòmers d’un determinat material de partida. En aquest sentit, la segona part de la Tesi s’ha centrat en el desenvolupament de metodologies paral·leles a partir d’auxiliars aquirals (scaffolds) i carregant el control estereoquímica sobre catalitzadors de níquel(II) quiral. El primer capítol descriu la síntesi del fragment C9-C19 de la pelorusida A amb un rendiment del 24% en catorze etapes. La construcció estereoselectiva dels enllaços C–C estratègics s’ha aconseguit mitjançant sengles metodologies desenvolupades pel grup basades en l’ús d’auxiliars quirals. En el segon capítol presentem una nova reacció d’alquilació d’N-acil tioimides quirals amb sals carbocatiòniques estables catalitzada per complexos de níquel(II). Després d’una exhaustiva optimització, la reacció s’ha aplicat a diferents substrats amb molt bons resultats. Al tercer capítol el control estereoquímic es trasllada al catalitzador. Després d’un estudi molt detallat es va descobrir que els millors resultats en un ampli ventall de processos d’alquilació s’assolien amb N-acil tiazinantiones que incorporen un scaffold aquiral de sis baules en presencia d’un complex quiral de níquel(II). Aquesta metodologia ha estat aplicada a la síntesi de la peperomina D. Finalment, en el quart capítol es desenvolupa una nova reacció aldòlica. Partint dels resultats obtinguts als capítols anteriors s’han trobat unes condicions per a la síntesi d’aldols sililats d’estereoquímica anti amb rendiments elevats i una extraordinària enantioselectivitat. A més s’han obert tres línies de investigació basades en l’ús de diferents electròfils.
Appears in Collections:Tesis Doctorals - Departament - Química Inorgànica i Orgànica

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