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
Fritz S
(2012)
(2-Bromoethyl)sulfonium Trifluoromethanesulfonates in Stereoselective Annulation Reactions for the Formation of Fused Bicyclic Epoxides and Aziridines
in Helvetica Chimica Acta
Aggarwal V
(2010)
A Novel Asymmetric Azaspirocyclisation Using a Morita-Baylis-Hillman-Type Reaction
in Synlett
Robiette R
(2016)
Activation of the SN2 Reaction by Adjacent p Systems: The Critical Role of Electrostatic Interactions and of Dissociative Character.
in Journal of the American Chemical Society
Aggarwal V
(2012)
An Efficient Synthesis of Azetidines with (2-Bromoethyl)sulfonium Triflate
in Synthesis
McGarrigle EM
(2011)
An efficient synthesis of imidazolinium salts using vinyl sulfonium salts.
in Organic letters
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
Watson C
(2013)
Asymmetric Synthesis of 1-Heteroaryl-1-arylalkyl Tertiary Alcohols and 1-Pyridyl-1-arylethanes by Lithiation-Borylation Methodology
in Organic Letters
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)
Aggarwal VK
(2011)
Asymmetric synthesis of tertiary and quaternary allyl- and crotylsilanes via the borylation of lithiated carbamates.
in Organic letters
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
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
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)
T. Chinnusamy, K. Feeney, C. Watson, D. Leonori, V. K. Aggarwal
(2014)
Comprehensive Organic Synthesis II
Arena G
(2013)
Concise synthesis of (+)-allo-kainic acid via MgI2-mediated tandem aziridine ring opening-formal [3 + 2] cycloaddition.
in Organic letters
Hesse MJ
(2012)
Diastereodivergent synthesis of trisubstituted alkenes through protodeboronation of allylic boronic esters: application to the synthesis of the Californian red scale beetle pheromone.
in Angewandte Chemie (International ed. in English)
Fritz SP
(2012)
Diastereoselective synthesis of CF3-substituted, epoxide-fused heterocycles with ß-(trifluoromethyl)vinylsulfonium salts.
in Organic letters
Fritz SP
(2013)
Efficient synthesis of cyclopropane-fused heterocycles with bromoethylsulfonium salt.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Partridge B
(2011)
Enantioenriched synthesis of Escitalopram using lithiation-borylation methodology
in Tetrahedron
Sonawane RP
(2011)
Enantioselective construction of quaternary stereogenic centers from tertiary boronic esters: methodology and applications.
in Angewandte Chemie (International ed. in English)
Roesner S
(2011)
Enantioselective syntheses of (+)-sertraline and (+)-indatraline using lithiation/borylation-protodeboronation methodology.
in Organic letters
Partridge BM
(2012)
Enantioselective synthesis and cross-coupling of tertiary propargylic boronic esters using lithiation-borylation of propargylic carbamates.
in Angewandte Chemie (International ed. in English)
Roesner S
(2012)
Enantioselective synthesis of (R)-tolterodine using lithiation/borylation-protodeboronation methodology.
in Canadian journal of chemistry
Chausset-Boissarie L
(2013)
Enantiospecific, regioselective cross-coupling reactions of secondary allylic boronic esters.
in Chemistry (Weinheim an der Bergstrasse, Germany)
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)