Organocatalytic Asymmetric Bromination of Alkenes
Lead Research Organisation:
Imperial College London
Department Name: Chemistry
Abstract
The preparation of chemicals as single enantiomers is of vital importance in the fields of pharmaceutical chemistry, fine chemicals and academia. The use of a chiral catalyst in order to do so is widely recognised as the most efficient way of inducing asymmetry. Several excellent methods exist for catalytic asymmetric synthesis of eg epoxides, and these act as building blocks for the preparation of other enantiopure materials.To date the catalytic asymmetric bromination of alkenes has not been achieved. This is somewhat surprising given that bromination is a classic textbook reaction, and the potential utility of the obtained enantiomerically pure bromides by stereospecific nucleophilic displacement with a wide-range of nucleophiles.We propose herein to develop a general catalytic asymmetric bromination reaction of alkenes. The catalysts will be based on 2,6-disubstituted iodobenzenes where the de facto catalytic entity will have a hypervalent X-I-Br bond. The catalysts will be designed so that the electrophilic bromine is a region of high asymmetry.
Organisations
People |
ORCID iD |
| David Braddock (Principal Investigator) |
Publications
Armstrong A
(2013)
Catalytic asymmetric bromolactonization reactions using (DHQD)2PHAL-benzoic acid combinations
in Tetrahedron Letters
Braddock DC
(2011)
Enantiospecific bromonium ion generation and intramolecular capture: a model system for asymmetric bromonium ion-induced polyene cyclisations.
in Chemical communications (Cambridge, England)
Braddock DC
(2013)
An enantiospecific polyene cyclization initiated by an enantiomerically pure bromonium ion.
in Chirality
Braddock DC
(2009)
Clarification of the stereochemical course of nucleophilic substitution of arylsulfonate-based nucleophile assisting leaving groups.
in The Journal of organic chemistry
Braddock DC
(2009)
The generation and trapping of enantiopure bromonium ions.
in Chemical communications (Cambridge, England)
Braddock DC
(2009)
Bromonium ion induced transannular oxonium ion formation-fragmentation in model obtusallene systems and structural reassignment of obtusallenes V-VII.
in The Journal of organic chemistry
Christopher Braddock D
(2008)
The stereochemical course of bromoetherification of enynes.
in Chemical communications (Cambridge, England)
Christopher Braddock D
(2010)
The reaction of aromatic dialdehydes with enantiopure 1,2-diamines: an expeditious route to enantiopure tricyclic amidines
in Tetrahedron: Asymmetry
| Description | The preparation of chemicals as single enantiomers is of vital importance in the fields of pharmaceutical chemistry, fine chemicals and academia. The use of a chiral catalyst in order to do so is widely recognised as the most efficient way of inducing asymmetry. Several excellent methods exist for catalytic asymmetric synthesis of eg epoxides, and these act as building blocks for the preparation of other enantiopure materials. To date the catalytic asymmetric bromination of alkenes has not been achieved. This is somewhat surprising given that bromination is a classic textbook reaction, and the potential utility of the obtained enantiomerically pure bromides by stereospecific nucleophilic displacement with a wide-range of nucleophiles. Accordingly, we set out to solve this challenging problem. Our preliminary studies had previously shown that bromoiodinanes (hypervalent iodine-containing molecules with a Br-I-O bonding pattern; Br=bromine, I=iodine, O=oxygen) functioned as electrophilic bromine sources [Chem. Commun. 2006, 1442-1444], and further that fine-tuned hypervalent iodine molecules could be used catalytically by re-oxidation with an added electrophilc bromine source [Chem. Commun. 2006, 2483-2485]. Accordingly, we have now prepared a series (a 'library') of novel chiral (molecules which have unique spacial orientation related as non-superimposable mirror images, like your right and left hands) molecules to function as asymmetric catalysts for bromination. To synthesize these molecules required the refinement of an existing method which was otherwise not suitable for our purpose. During these investigations we also discovered an unexpected chemical pathway which led to the formation of novel chiral tricyclic molecules, and all these results have now been published [Adv. Synth. Catal. 2010, xx-xx]. Unfortunately, although the library molecules proved to highly effective catalysts, any asymmetric induction (the degree of 'handedness' induced in the process) proved only to be minimal. We considered that this could be due to the inherent propensity of the expected enantiopure bromonium intermediate to racemise (change from left to right hand and vice versa) under the reaction conditions. This required us to develop a method to produce single enantiomer bromonium ions so as to study their behaviour. We were successful in generating the first enantiopure bromonium ion and trapping it to give enantiomerically pure products [Chem. Commun. 2009, 1082-1084]. This proves that an catalytic asymmetric bromination of alkenes per se is not impossible. It also represents the first time that an enantiopure bromonium ion has been generated and is another milestone in the history of the bromonium ion. To generate the first enantiopure bromonium ion we successfully utilised a modified leaving group (a group of atoms specifically designed to break away from a given molecule to be then be replaced by another group) recently reported by a US chemistry team. Results from their laboratory suggested that this leaving group conferred a highly unusual stereochemical outcome. However, this was not the finding in our research to generate an enantiopure bromonium ion. Accordingly we became interested in the generality (or not) of this reported unusual stereochemical outcome. Our research has now categorically shown that the previous reports were highly substrate dependent (and not a function of the leaving group) as well as depending on the precise experimental conditions (solvent, temperature) employed. A UK team in Oxford came to the same conclusion (albeit with different substrates) and we published our work jointly in 2009 [J. Org. Chem. 2009, 74, 6042-6049]. We have also used our bromination methodology in the synthesis of some naturally occuring brominated metabolites originally isolated from sponges and seaweeds. These findings are published also [Chem. Commun. 2008, 1419-1421, J. Org. Chem. 2009, 74, 1835-1841] |
| Exploitation Route | These findings are useful to the academic chemistry community |
| Sectors | Chemicals |
| URL | http://www.ch.ic.ac.uk/braddock/index.html |
| Description | Catalytic Asymmetric Bromination of Alkenes |
| Amount | £50,000 (GBP) |
| Funding ID | DCB-SAH |
| Organisation | GlaxoSmithKline (GSK) |
| Department | Research and Development GSK |
| Sector | Private |
| Country | United Kingdom |
| Start | 10/2007 |
| End | 09/2010 |
| Description | New Catalytic methods for the production of Anti-Malarials |
| Amount | £51,000 (GBP) |
| Organisation | Commonwealth Scientific and Industrial Research Organisation |
| Sector | Public |
| Country | Australia |
| Start | 10/2013 |
| End | 09/2017 |
| Description | Triggering Polyene Cyclisations with enantiomerically Pure bromonium Ions |
| Amount | £26,000 (GBP) |
| Organisation | AstraZeneca |
| Department | Arrow Therapeutics |
| Sector | Private |
| Country | United Kingdom |
| Start | 10/2009 |
| End | 10/2012 |