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Synthesis of Optically Active Bicyclo[2.2.2]octane Derivatives - A Study Towards Novel Taxol Mimics and Development of New Chiral Ligands for Asymmetric Catalysis

Almqvist, Fredrik (1996)
Abstract
This thesis is a summary of six papers which concern synthesis of optically active bicyclo[2.2.2]octane derivatives. The derivatives prepared are important building blocks in a study towards a possible replacement of the diterpenoidic part of taxol, (baccatin III), so as to construct a taxol mimic. Some of the derivatives have also been developed into new bidentate ligands. TitaniumIV complexes of some of these have been shown to induce high enantioselectivity in a catecholborane reduction of prochiral ketones. An improved procedure for the synthesis of bicyclo[2.2.2]octane-2,6-dione via an intramolecular cyclization is presented. This prochiral diketone can be enantioselectively reduced by means of baker's yeast to the hydroxyketone... (More)
This thesis is a summary of six papers which concern synthesis of optically active bicyclo[2.2.2]octane derivatives. The derivatives prepared are important building blocks in a study towards a possible replacement of the diterpenoidic part of taxol, (baccatin III), so as to construct a taxol mimic. Some of the derivatives have also been developed into new bidentate ligands. TitaniumIV complexes of some of these have been shown to induce high enantioselectivity in a catecholborane reduction of prochiral ketones. An improved procedure for the synthesis of bicyclo[2.2.2]octane-2,6-dione via an intramolecular cyclization is presented. This prochiral diketone can be enantioselectively reduced by means of baker's yeast to the hydroxyketone (-)-(1R,4S,6S)-bicyclo[2.2.2]octane-6-ol-2-one. The antipode to that hydroxyketone was prepared in six steps from its enantiomer using orthogonal protecting groups and red-ox chemistry. A 1,2-carbonyl transposition of the optically active TBDMS-protected 2,6-hydroxyketone was employed as a key step to give access to the C2-symmetric (1S,4S)-bicyclo[2.2.2]octane-2,5-dione, (1S,2S,4S,5S)-bicyclo[2.2.2]octane-2,5-diol and several selectively protected derivatives with high enantiomeric purity. In the attempts to acetylate the TBDMS-protected 2,6-hydroxyketone, a regio- and stereoselective chlorination was found. A tentative mechanism involving neighboring group participation of an acetate group is presented, together with the appropriate conditions to either synthesise a chloroenone or a 1,3-diketone. A spirobicyclo[2.2.2]octane-cyclohexylidene derivative was prepared in a study towards a taxol mimic. The derivative displayed no activity in a microtubule assay, but has a potential of being developed further to more complex mimics. Various 2-aryl-substituted-bicyclo[2.2.2]octane-2,6-diols were synthesised. Their use as optically active ligands to titaniumIV was investigated, and two of those complexes were proven to be good catalysts in asymmetric reduction of ketones. The reduction of acetophenone gave in the best case 97 % ee, but perhaps more notable are the relatively high ee:s found for straight chain methylketones, (79 % ee for 2-octanone). (Less)
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author
opponent
  • Prof Moberg, Christina, Inst. for Chemistry, KTH
publishing date
type
Thesis
publication status
published
subject
keywords
Lewis acids, Asymmetric reduction, Asymmetric catalysis, Bidentate ligands, Enantioenriched, Optically active, Spiro, Taxol mimic, Bicyclo[2.2.2]octane derivatives, Ti(IV) complexes, Organic chemistry, Organisk kemi
pages
85 pages
publisher
Organic Chemistry, Lund University
defense location
Hörsal C, Kemicentrum
defense date
1996-10-04 10:15
external identifiers
  • Other:ISRN: LUNKDL/NKOK -- 1033 -- SE
language
English
LU publication?
no
id
0533eb0b-97d2-4214-8d37-236fbb7ea599 (old id 28647)
date added to LUP
2007-06-11 17:25:59
date last changed
2016-09-19 08:45:07
@phdthesis{0533eb0b-97d2-4214-8d37-236fbb7ea599,
  abstract     = {This thesis is a summary of six papers which concern synthesis of optically active bicyclo[2.2.2]octane derivatives. The derivatives prepared are important building blocks in a study towards a possible replacement of the diterpenoidic part of taxol, (baccatin III), so as to construct a taxol mimic. Some of the derivatives have also been developed into new bidentate ligands. TitaniumIV complexes of some of these have been shown to induce high enantioselectivity in a catecholborane reduction of prochiral ketones. An improved procedure for the synthesis of bicyclo[2.2.2]octane-2,6-dione via an intramolecular cyclization is presented. This prochiral diketone can be enantioselectively reduced by means of baker's yeast to the hydroxyketone (-)-(1R,4S,6S)-bicyclo[2.2.2]octane-6-ol-2-one. The antipode to that hydroxyketone was prepared in six steps from its enantiomer using orthogonal protecting groups and red-ox chemistry. A 1,2-carbonyl transposition of the optically active TBDMS-protected 2,6-hydroxyketone was employed as a key step to give access to the C2-symmetric (1S,4S)-bicyclo[2.2.2]octane-2,5-dione, (1S,2S,4S,5S)-bicyclo[2.2.2]octane-2,5-diol and several selectively protected derivatives with high enantiomeric purity. In the attempts to acetylate the TBDMS-protected 2,6-hydroxyketone, a regio- and stereoselective chlorination was found. A tentative mechanism involving neighboring group participation of an acetate group is presented, together with the appropriate conditions to either synthesise a chloroenone or a 1,3-diketone. A spirobicyclo[2.2.2]octane-cyclohexylidene derivative was prepared in a study towards a taxol mimic. The derivative displayed no activity in a microtubule assay, but has a potential of being developed further to more complex mimics. Various 2-aryl-substituted-bicyclo[2.2.2]octane-2,6-diols were synthesised. Their use as optically active ligands to titaniumIV was investigated, and two of those complexes were proven to be good catalysts in asymmetric reduction of ketones. The reduction of acetophenone gave in the best case 97 % ee, but perhaps more notable are the relatively high ee:s found for straight chain methylketones, (79 % ee for 2-octanone).},
  author       = {Almqvist, Fredrik},
  keyword      = {Lewis acids,Asymmetric reduction,Asymmetric catalysis,Bidentate ligands,Enantioenriched,Optically active,Spiro,Taxol mimic,Bicyclo[2.2.2]octane derivatives,Ti(IV) complexes,Organic chemistry,Organisk kemi},
  language     = {eng},
  pages        = {85},
  publisher    = {Organic Chemistry, Lund University},
  title        = {Synthesis of Optically Active Bicyclo[2.2.2]octane Derivatives - A Study Towards Novel Taxol Mimics and Development of New Chiral Ligands for Asymmetric Catalysis},
  year         = {1996},
}