Determining the Barrier to Inversion of Chiral Organometallics

Lead Research Organisation: University of Sheffield
Department Name: Chemistry

Abstract

The research outlined in this proposal is in the area of physical organic chemistry. In particular, it involves the study of organometallic species. We have determined the barrier to inversion of 2-lithiopyrrolidines and applied this knowledge to their highly enantioselective dynamic resolution, leading to the asymmetric preparation of 2-substituted pyrrolidines. The aim of this research is to build on this expertise and apply it to other organometallic species. We plan to use a combination of NMR spectroscopy and conventional electrophilic quench/chiral chromatographic analysis to determine the rate of interconversion of the mirror images of selected chiral organometallic species.This will allow comparison of different substituted derivatives and will therefore provide valuable information on the influence of these substituents on the enantiomerization process. This will include all different types of organometallic species, from non-stabilized to dipole stabilized (especially organometallics alpha to oxygen and nitrogen) to mesomerically stabilized (benzyl and allyl species).With quantitative rate data to hand for these enantiomerizations, we will study the effect of ligands on this process, including chiral ligands. This knowledge will then be used to explore dynamic resolution of the organometallics and the mechanism for this resolution.

Publications

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Cochrane EJ (2014) Synthesis and kinetic resolution of N-Boc-2-arylpiperidines. in Chemical communications (Cambridge, England)

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Coldham I (2009) The barrier to enantiomerization and dynamic resolution of N-Boc-2-lithiopiperidine and the effect of TMEDA. in Chemical communications (Cambridge, England)

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Coldham I (2008) Synthesis of 2-arylpiperidines by palladium couplings of aryl bromides with organozinc species derived from deprotonation of N-boc-piperidine. in Organic letters

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Coldham I (2010) Asymmetric substitutions of 2-lithiated N-boc-piperidine and N-Boc-azepine by dynamic resolution. in Chemistry (Weinheim an der Bergstrasse, Germany)

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Coldham I (2010) Regioselective and stereoselective copper(I)-promoted allylation and conjugate addition of N-Boc-2-lithiopyrrolidine and N-Boc-2-lithiopiperidine. in The Journal of organic chemistry

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Coldham I (2008) Dynamic resolution of N-Boc-2-lithiopiperidine. in Chemical communications (Cambridge, England)

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Leonori D (2009) Direct Preparation of 7-Allyl- and 7-Arylindolines in Advanced Synthesis & Catalysis

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Li X (2013) Synthesis of 1-substituted tetrahydroisoquinolines by lithiation and electrophilic quenching guided by in situ IR and NMR spectroscopy and application to the synthesis of salsolidine, carnegine and laudanosine. in Chemistry (Weinheim an der Bergstrasse, Germany)

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N/a Coldham (2010) Kinetics of inversion of chiral organolithiums

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Sheikh NS (2012) An experimental and in situ IR spectroscopic study of the lithiation-substitution of N-Boc-2-phenylpyrrolidine and -piperidine: controlling the formation of quaternary stereocenters. in Journal of the American Chemical Society

 
Description The research outlined in this proposal is in the area of physical organic chemistry. In particular, it involves the study of organometallic species. We have determined the barrier to inversion of 2-lithiopyrrolidines and applied this knowledge to their highly enantioselective dynamic resolution, leading to the asymmetric preparation of 2-substituted pyrrolidines. The aim of this research was to build on this expertise and apply it to other organometallic species.



We used conventional electrophilic quench/chiral chromatographic analysis to determine the rate of interconversion of the mirror images of selected chiral organometallic species. In particular, we were able to determine the barrier to inversion together with the enthalpy and entropy of activation of 2-lithiopiperidines in the presence or absence of the additive TMEDA. In addition, we were able, in collaboration with Professor Gawley, to determine the barrier not just for enantiomerization but also for dynamic resolution in the presence of a chiral ligand. This uncovered an interesting rate dependence on the achiral ligand TMEDA. Therefore this study has allowed a comparison of different conditions and has provided valuable information on the influence of these factors on the enantiomerization process.



With quantitative rate data to hand for these enantiomerizations, we studied the effect of ligands on this process, including chiral ligands. This knowledge was used to explore dynamic resolution of the organometallics and the mechanism for this resolution.



In addition, we studied the transmetallation from lithium to zinc-cuprates for allylation reactions and we carried out Negishi couplings of the organozinc species. We also applied some of this chemistry to 7-metallated-indolines.