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On molecular butterflies and eagles: improved synthesis of 5,11-R2dxCOTs

Romano de Gea, Jan LU (2018) KEMP31 20181
Department of Chemistry
Abstract
Enantioselective synthesis is an important research topic with applications in drug development. Asymmetrical catalysis is one of the available ways of producing enantioenriched products.
C2-Symmetric dibenzo[a,e]cyclooctenes or dbCOTs are a family of versatile chiral ligands for transition metals. They display great efficiency and enantioselectivity in 1,2- and 1,4- additions reactions.
In this work, a two-step synthesis to 5,11-R2dbCOT, initially reported in 1962 and improved by the Strand group, is presented. Methods and chemicals not widely available at that time have been used, aiming for better yields in an already efficient synthesis. It also offers a simpler, faster, milder, safer, cheaper and scalable pathway to the ligands,... (More)
Enantioselective synthesis is an important research topic with applications in drug development. Asymmetrical catalysis is one of the available ways of producing enantioenriched products.
C2-Symmetric dibenzo[a,e]cyclooctenes or dbCOTs are a family of versatile chiral ligands for transition metals. They display great efficiency and enantioselectivity in 1,2- and 1,4- additions reactions.
In this work, a two-step synthesis to 5,11-R2dbCOT, initially reported in 1962 and improved by the Strand group, is presented. Methods and chemicals not widely available at that time have been used, aiming for better yields in an already efficient synthesis. It also offers a simpler, faster, milder, safer, cheaper and scalable pathway to the ligands, with minor drawbacks compared to the state of the art synthesis.
Four dbCOT analogues have been synthesised and three of them have been evaluated, following the reactions by quantitative 1H NMR (qNMR). Several factors: thermal/photochemical conditions, fluoride sources, reagents, stoichiometries, concentrations and reaction temperatures have been tested and optimised. Optimal conditions have been identified for 5,6-Ph2dbCOT and 5,6-Ph2dnCOT.
5,6-Ph2dbCOT was isolated by crystallisation from warm heptane yielding 48%, which represents an important increase of 65% compared to the originally reported yield (29%) and 35% from unpublished work previously performed in the group (38%). This paves the way to an important cost reduction, a more sustainable pathway to the desired ligand, and the production capacity of covering the ligand necessity. (Less)
Popular Abstract
Like your hands, some molecules exist as non-superimposable mirror-images, called enantiomers. These two enantiomers will have different properties and behave differently in chiral environments of the body. One famous example of a molecule whose two enantiomers exhibited different properties is thalidomide. It was used in the late 50’s to alleviate morning sickness in pregnant women (one enantiomer had pharmaceutical applications) but caused malformations to the foetus (the other one was teratogenic).
The compounds in this research also have two enantiomers. They have a special ability: when one enantiomer of the compound reacts with another molecules, it produces one enantiomer of the product. As you can imagine, this is of great... (More)
Like your hands, some molecules exist as non-superimposable mirror-images, called enantiomers. These two enantiomers will have different properties and behave differently in chiral environments of the body. One famous example of a molecule whose two enantiomers exhibited different properties is thalidomide. It was used in the late 50’s to alleviate morning sickness in pregnant women (one enantiomer had pharmaceutical applications) but caused malformations to the foetus (the other one was teratogenic).
The compounds in this research also have two enantiomers. They have a special ability: when one enantiomer of the compound reacts with another molecules, it produces one enantiomer of the product. As you can imagine, this is of great interest to scientists as, with our compounds, you can form selectively the enantiomer with useful properties.
In this study, we are optimising the way we prepare these compounds to make the process cheaper, faster, safer and more environmentally friendly. We try to produce them in big amounts, so other chemists can synthesise the active components in the drugs that will heal us in the future. (Less)
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author
Romano de Gea, Jan LU
supervisor
organization
course
KEMP31 20181
year
type
M2 - Bachelor Degree
subject
keywords
Organic Chemistry, Ligand Synthesis, Asymmetric Catalysis, Organisk kemi
language
English
id
8956910
date added to LUP
2018-11-06 13:22:02
date last changed
2018-11-06 13:22:10
@misc{8956910,
  abstract     = {Enantioselective synthesis is an important research topic with applications in drug development. Asymmetrical catalysis is one of the available ways of producing enantioenriched products. 
C2-Symmetric dibenzo[a,e]cyclooctenes or dbCOTs are a family of versatile chiral ligands for transition metals. They display great efficiency and enantioselectivity in 1,2- and 1,4- additions reactions. 
In this work, a two-step synthesis to 5,11-R2dbCOT, initially reported in 1962 and improved by the Strand group, is presented. Methods and chemicals not widely available at that time have been used, aiming for better yields in an already efficient synthesis. It also offers a simpler, faster, milder, safer, cheaper and scalable pathway to the ligands, with minor drawbacks compared to the state of the art synthesis.
Four dbCOT analogues have been synthesised and three of them have been evaluated, following the reactions by quantitative 1H NMR (qNMR). Several factors: thermal/photochemical conditions, fluoride sources, reagents, stoichiometries, concentrations and reaction temperatures have been tested and optimised. Optimal conditions have been identified for 5,6-Ph2dbCOT and 5,6-Ph2dnCOT.
5,6-Ph2dbCOT was isolated by crystallisation from warm heptane yielding 48%, which represents an important increase of 65% compared to the originally reported yield (29%) and 35% from unpublished work previously performed in the group (38%). This paves the way to an important cost reduction, a more sustainable pathway to the desired ligand, and the production capacity of covering the ligand necessity.},
  author       = {Romano de Gea, Jan},
  keyword      = {Organic Chemistry,Ligand Synthesis,Asymmetric Catalysis,Organisk kemi},
  language     = {eng},
  note         = {Student Paper},
  title        = {On molecular butterflies and eagles: improved synthesis of 5,11-R2dxCOTs},
  year         = {2018},
}