The University of Southampton
University of Southampton Institutional Repository

Synergistic catalysis: merging amino catalysis and metal Lewis acid activation of azaarenes; Green chemistry: first organophotocatalytic approach to the synthesis of phosphoramidates

Synergistic catalysis: merging amino catalysis and metal Lewis acid activation of azaarenes; Green chemistry: first organophotocatalytic approach to the synthesis of phosphoramidates
Synergistic catalysis: merging amino catalysis and metal Lewis acid activation of azaarenes; Green chemistry: first organophotocatalytic approach to the synthesis of phosphoramidates
The art of building complex chemical scaffolds in a totally stereoselective manner is one of the cornerstones for Organic Chemists. The quest for new catalytic methodologies that fulfil the requirements of efficiency, green chemistry and predictable stereochemical outcome have become the Holy Grail for synthetic chemists.

In the present thesis we investigated new catalytic strategies for the enantioselective synthesis of azaarene scaffolds. Alkyl-azaarenes are common motifs in natural products and pharmaceutical compounds, however few methodologies are devoted to their functionalisation in an enantioselective manner. The major part of the approaches are based on the use of stoichiometric strategies and chiral auxiliaries due to the difficulty to activate the methylene position of alkylazaarenes. Our innovative approach relies on the use of a synergistic strategy where a Lewis acid activates the azaarene moiety making it a nucleophile while a Lewis base catalyst activates the electrophile. This dual activation presents several advantages such as an easy optimisation of each catalytic cycle and a greater decrease of the activation energy required for the reaction, allowing the use of low temperatures and soft conditions.

In Chapter 4 we demonstrate the proof of concept of this approach by joining transition metal catalysis (Lewis acid) and secondary amine catalysis (Lewis base, iminium activation) achieving the enantioselective addition of alkyl-benzoxazoles and related heterocycles to enals in good yields and reasonable stereoselectivity levels. In Chapter 5 we expanded this new concept in the application of cascade reactions. We designed a cascade reaction consisting in the Michael addition of chloromethylbenzoxazoles to enals followed by a 3-exo-trig cyclisation to furnish cyclopropanes in good yields and enantioselectivities.

The value of the present work is not only the development of these methodologies for the synthesis of chiral azaarenes (aldehyde derivatives and cyclopropanes) but also to demystify some misconceptions such as that metal Lewis acid could not coexist with secondary amine catalysis.

This pioneering work is an open gate to generate new methodologies using a synergistic approach that tries to take the best of two of the pillars of catalysis: the high activity and rich chemistry of transition metal catalysis with the affordable and easy stereochemical prediction of secondary amine catalysis, avoiding the use of extreme reaction conditions or the use of chiral ligands.
Meazza, Marta
c4665645-8c77-4cfd-aa02-6bcc3341c1aa
Meazza, Marta
c4665645-8c77-4cfd-aa02-6bcc3341c1aa
Rios Torres, Ramon
609bedf2-e886-4d62-a676-a32b6f8c1441

Meazza, Marta (2016) Synergistic catalysis: merging amino catalysis and metal Lewis acid activation of azaarenes; Green chemistry: first organophotocatalytic approach to the synthesis of phosphoramidates. University of Southampton, Department of Chemistry, Doctoral Thesis, 521pp.

Record type: Thesis (Doctoral)

Abstract

The art of building complex chemical scaffolds in a totally stereoselective manner is one of the cornerstones for Organic Chemists. The quest for new catalytic methodologies that fulfil the requirements of efficiency, green chemistry and predictable stereochemical outcome have become the Holy Grail for synthetic chemists.

In the present thesis we investigated new catalytic strategies for the enantioselective synthesis of azaarene scaffolds. Alkyl-azaarenes are common motifs in natural products and pharmaceutical compounds, however few methodologies are devoted to their functionalisation in an enantioselective manner. The major part of the approaches are based on the use of stoichiometric strategies and chiral auxiliaries due to the difficulty to activate the methylene position of alkylazaarenes. Our innovative approach relies on the use of a synergistic strategy where a Lewis acid activates the azaarene moiety making it a nucleophile while a Lewis base catalyst activates the electrophile. This dual activation presents several advantages such as an easy optimisation of each catalytic cycle and a greater decrease of the activation energy required for the reaction, allowing the use of low temperatures and soft conditions.

In Chapter 4 we demonstrate the proof of concept of this approach by joining transition metal catalysis (Lewis acid) and secondary amine catalysis (Lewis base, iminium activation) achieving the enantioselective addition of alkyl-benzoxazoles and related heterocycles to enals in good yields and reasonable stereoselectivity levels. In Chapter 5 we expanded this new concept in the application of cascade reactions. We designed a cascade reaction consisting in the Michael addition of chloromethylbenzoxazoles to enals followed by a 3-exo-trig cyclisation to furnish cyclopropanes in good yields and enantioselectivities.

The value of the present work is not only the development of these methodologies for the synthesis of chiral azaarenes (aldehyde derivatives and cyclopropanes) but also to demystify some misconceptions such as that metal Lewis acid could not coexist with secondary amine catalysis.

This pioneering work is an open gate to generate new methodologies using a synergistic approach that tries to take the best of two of the pillars of catalysis: the high activity and rich chemistry of transition metal catalysis with the affordable and easy stereochemical prediction of secondary amine catalysis, avoiding the use of extreme reaction conditions or the use of chiral ligands.

Text
finalthesis.pdf - Other
Download (35MB)

More information

Published date: 14 March 2016
Organisations: University of Southampton, Chemistry

Identifiers

Local EPrints ID: 393069
URI: http://eprints.soton.ac.uk/id/eprint/393069
PURE UUID: ee0fd30a-fa19-4227-91d0-b32f95d135a1
ORCID for Marta Meazza: ORCID iD orcid.org/0000-0003-4382-0626
ORCID for Ramon Rios Torres: ORCID iD orcid.org/0000-0002-3843-8521

Catalogue record

Date deposited: 22 Apr 2016 14:15
Last modified: 14 Mar 2019 05:01

Export record

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×