Rhodium-catalysed allylic substitution with unstabilised carbon nucleophiles: asymmetric construction of carbon-carbon bonds

O'Connor, Ryan
Rhodium-catalysed allylic substitution with unstabilised carbon nucleophiles: asymmetric construction of carbon-carbon bonds. Doctor of Philosophy thesis, University of Liverpool.

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The controlled formation of carbon-carbon bonds is the bedrock of organic chemistry, with the asymmetric construction of stereogenic carbon-carbon bonds remaining a key motivation for the development of novel synthetic methodologies. Transition metal catalysis provides an important strategy in the arsenal of the modern synthetic chemist. While there is a plethora of transition metal-catalysed cross-couplings for the formation of sp2-sp2 and achiral sp2-sp3 carbon bonds, there are relatively few methodologies for the selective formation of stereogenic sp-sp3, sp2-sp3 and sp3-sp3 carbon-carbon bonds, the number of which that involve highly reactive organometallic reagents are fewer still. Two methodologies that can enable this asymmetric coupling are copper-catalysed SN2’ allylic alkylation and transition metal-catalysed allylic substitution. The overall utility of both these methods is described in the introductory review, which seeks to compare and contrast the relative advantages and disadvantage of both approaches. The asymmetric formation of carbon-carbon bonds utilising unstabilised carbon nucleophiles is generally dominated by the copper-catalysed SN2’ allylic alkylation. However, the copper-catalysed reaction suffers from poor substrate scope, in which electronically biased or symmetrical substrates are required in order to ensure favourable regioselectivities. Another restriction is that, for the formation of a stereocenter, the reaction is mechanistically limited to disubstituted allylic substrates. These linear substrates often require a multistep synthesis which involves a selective olefination, as an isomeric mixture of alkenes would result in the erosion of asymmetric induction. In contrast, there has been very little development of the analogous transition metal-catalysed allylic substitution utilising unstabilised carbon nucleophiles, especially in comparison to the analogous methodologies utilising stabilised carbon and heteroatom nucleophiles. Despite the numerous potential advantages that are afforded by this approach, a general method for the regio- and stereoselective transition-metal catalysed allylic substitution utilising unstabilised carbon nucleophiles has yet to be reported. Chapter 2 describes the development of a novel regio- and stereoselective rhodium-catalysed allylic substitution reaction, which utilises benzyl magnesium bromide as an unstabilised carbon nucleophile. Following a brief introduction to the rhodium-catalysed allylic substitution reaction, this chapter is organised into four distinct sections. The first of these outlines the identification of a suitable nucleophile, and the subsequent development of reaction conditions for the regioselective alkylation of secondary allylic carbonates with a range of benzyl magnesium bromides transmetallated with zinc iodide. Then the next section will deal with studies toward the development of the stereospecific variant, these studies will highlight the main challenges of deploying a sp3-hybridised carbon nucleophile. This section will also determine the absolute stereochemical outcome of the reaction, thus confirming the inner sphere mechanism of the reaction. The third section will demonstrate that how the limitation of the stereospecific reaction, namely the fluxionality of the rhodium-enyl, can be utilised to develop a regio- and diastereoselective alkylation for the formation of 1,2-stereoarrays containing tertiary and quaternary carbon stereocenters. Finally, preliminary studies towards the expansion of this methodology to include an sp2-hybridised vinylic nucleophiles for the preparation of 1,4-skipped dienes will be detailed. Overall, we have developed a novel, highly regioselective rhodium-catalysed allylic substitution of secondary allylic carbonates utilising highly unstabilised carbon nucleophiles. We also have developed a highly diastereoselective allylic substitution for the construction of both tertiary and quaternary carbon stereocenters, which to best of our knowledge, has yet to be described in the context of rhodium-catalysed allylic substitution utilising an unstabilised carbon nucleophile. We have successfully carried out preliminary studies towards the development of a rhodium-catalysed allylic substitution utilising a vinyl organometallic reagent as nucleophile, as well.

Item Type: Thesis (Doctor of Philosophy)
Additional Information: Date: 2013-09 (completed)
Subjects: ?? QD ??
Divisions: Faculty of Science and Engineering > School of Physical Sciences
Depositing User: Symplectic Admin
Date Deposited: 31 Jul 2014 11:10
Last Modified: 17 Dec 2022 01:37
DOI: 10.17638/00017253
  • Evans, P Andrew
  • Aissa, Christophe
URI: https://livrepository.liverpool.ac.uk/id/eprint/17253