General and Convergent Strategy for Asymmetric Synthesis
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
Many important molecules required for life exist in two forms that are mirror images of each other. They are related like our left and right hands, but they are not the same. This property is called chirality, from the Greek word for hand, and the two forms are called enantiomers, from the Greek word for opposite. Perhaps surprisingly, Nature mainly uses only one of the two enantiomers available. Many drugs consist of chiral molecules and in the past a mixture of the two enantiomers was routinely employed since it is much easier to produce than the single more effective enantiomer. Since the catastrophic case of thalidomide, this scenario has changed and now two enantiomers of a chiral compound have to be treated as different products and are required to be tested separately. Consequently, it is vital to be able to produce the two chiral forms separately, particularly because they cannot easily be separated from a mixture. Thus, there is a strong industrial need fuelled by the pharma and agrochemical industries to be able to produce single enantiomers for testing and ultimately marketing. These large industries clearly impact on our every day lives: we need to eat, and need help to fight off disease. But chirality also has a major impact in biology. Anyone studying biological processes needs to make small molecules with the correct chirality to interact appropriately with the natural host. Chirality is also important in materials. The properties of polymers and liquid crystals are directly related to how they align (conformation) and stereogenic centres along the polymer chain can force the chain to turn right/left or go straight on (depending on whether it is a right or left handed centre). Thus, from medicine to materials, chirality is important. It spans all the scientific disciplines because it is a fundamental property of matter. Clearly, chemical processes that create chirality are extremely important. Chemical processes (synthesis) that create new C-C bonds from simpler molecules are also hugely important as this is how chemical complexity is built up. In a synthesis starting molecules are used to build new molecules by means of various chemical reactions. Organic synthesis generally involves the reaction between two molecules a nucleophile and an electrophile. These are attracted to each other rather like opposite poles of a magnet and a chemical bond is created between them. One class of useful nucleophiles are organometallic reagents as they readily react with electrophiles to make new bonds. However, chiral organometallic reagents are very rare, but clearly if they could be easily prepared they would be extremely useful as they would provide a direct synthesis of a broad range of chiral molecules. We propose a unique method for generating configurationally stable chiral organometallics and then we will explore what classes of electrophiles they react with. With this information we will then apply the new chemistry in the synthesis of biologically important molecules that are otherwise difficult to make. This will particularly highlight the power of the new methodology.A range of methodologies and their applications in synthesis are proposed in this proposal with common themes of synthesis and chirality. They are all linked together in that each methodology involves a nucleophile bearing a group that makes it behave as a nucleophiles but also leaves during the course of the reaction. We believe that reactions of this class of nucleophiles with conventional and non- conventional electrophiles will open up a whole new area of synthesis and provide a step change in asymmetric synthesis that could have far reaching consequences.
Organisations
People |
ORCID iD |
Varinder Aggarwal (Principal Investigator) |
Publications
Robinson A
(2010)
Asymmetric Total Synthesis of Solandelactone E: Stereocontrolled Synthesis of the 2-ene-1,4-diol Core through a Lithiation-Borylation-Allylation Sequence
in Angewandte Chemie
Riches SL
(2010)
On the mechanism of ylide-mediated cyclopropanations: evidence for a proton-transfer step and its effect on stereoselectivity.
in Journal of the American Chemical Society
Binanzer M
(2010)
Asymmetric synthesis of allylsilanes by the borylation of lithiated carbamates: formal total synthesis of (-)-decarestrictine D.
in Angewandte Chemie (International ed. in English)
Arshad M
(2010)
Synthesis of quinine and quinidine using sulfur ylide-mediated asymmetric epoxidation as a key step
in Tetrahedron: Asymmetry
Ros A
(2010)
Benzylic boron reagents behaving as allylic boron reagents towards aldehydes: a new asymmetric reaction leading to homoallylic alcohols with concomitant dearomatisation.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Aggarwal V
(2010)
A Novel Asymmetric Azaspirocyclisation Using a Morita-Baylis-Hillman-Type Reaction
in Synlett
Nave S
(2010)
Protodeboronation of tertiary boronic esters: asymmetric synthesis of tertiary alkyl stereogenic centers.
in Journal of the American Chemical Society
Kitulagoda J
(2010)
Synthesis of highly functionalized 2,5-disubstituted pyrrolidines via an aza-Morita-Baylis-Hillman-type reaction
in Tetrahedron
Althaus M
(2010)
Application of the lithiation-borylation reaction to the preparation of enantioenriched allylic boron reagents and subsequent in situ conversion into 1,2,4-trisubstituted homoallylic alcohols with complete control over all elements of stereochemistry.
in Journal of the American Chemical Society
Illa O
(2010)
Practical and highly selective sulfur ylide mediated asymmetric epoxidations and aziridinations using an inexpensive, readily available chiral sulfide. Applications to the synthesis of quinine and quinidine.
in Journal of the American Chemical Society
Bagutski V
(2010)
Full chirality transfer in the conversion of secondary alcohols into tertiary boronic esters and alcohols using lithiation-borylation reactions.
in Angewandte Chemie (International ed. in English)
Fontana F
(2010)
Stereoselective synthesis of trans-beta-lactams by palladium-catalysed carbonylation of vinyl aziridines.
in Chemical communications (Cambridge, England)
Fontana F
(2011)
Palladium-Catalyzed Insertion of CO 2 into Vinylaziridines: New Route to 5-Vinyloxazolidinones
in Organic Letters
Bagutski V
(2011)
Synthesis of highly enantioenriched C-tertiary amines from boronic esters: application to the synthesis of igmesine.
in Angewandte Chemie (International ed. in English)
Scott H
(2011)
Highly Enantioselective Synthesis of Tertiary Boronic Esters and their Stereospecific Conversion to other Functional Groups and Quaternary Stereocentres
in Chemistry - A European Journal
Yar M
(2011)
Remote chiral induction in vinyl sulfonium salt-mediated ring expansion of hemiaminals into epoxide-fused azepines.
in Chemistry, an Asian journal
Yar M
(2011)
Synthesis of N -Vinyloxazolidinones and Morpholines from Amino Alcohols and Vinylsulfonium Salts: Analysis of the Outcome's Dependence on the N-Protecting Group by Nanospray Mass Spectrometry
in European Journal of Organic Chemistry
Larouche-Gauthier R
(2011)
Use of alkyl 2,4,6-triisopropylbenzoates in the asymmetric homologation of challenging boronic esters.
in Chemical communications (Cambridge, England)
Fritz S
(2011)
Sulfinamides as Highly Effective Amine Protecting Groups and Their Use in the Conversion of Amino Alcohols into Morpholines
in European Journal of Organic Chemistry
Larouche-Gauthier R
(2011)
Ate complexes of secondary boronic esters as chiral organometallic-type nucleophiles for asymmetric synthesis.
in Journal of the American Chemical Society
Elford TG
(2011)
Total synthesis of (+)-erogorgiaene using lithiation-borylation methodology, and stereoselective synthesis of each of its diastereoisomers.
in Journal of the American Chemical Society
Partridge B
(2011)
Enantioenriched synthesis of Escitalopram using lithiation-borylation methodology
in Tetrahedron
Aggarwal VK
(2011)
Asymmetric synthesis of tertiary and quaternary allyl- and crotylsilanes via the borylation of lithiated carbamates.
in Organic letters
McGarrigle EM
(2011)
An efficient synthesis of imidazolinium salts using vinyl sulfonium salts.
in Organic letters