Triple Diels-Alder Cascades: Development and Application to Daphnezomine Synthesis
Lead Research Organisation:
University of York
Department Name: Chemistry
Abstract
We have recently shown that 1,2,4-triazines and ketones can be employed in a tandem cascade sequence producing complex polycyclic diamines. This remarkable transformation proceeds via initial enamine formation and then a triple Diels-Alder cascade (inverse electron demand, retro and intramolecular) transforming flat starting materials into complex polycyclic products with the formation of 2 new rings. 4 new bonds and 5 new stereogenic centres! Based on these encouraging preliminary results, we now seek funds to appoint a postdoctoral researcher who will optimise, extend and apply this new technology as follows:(i) To optimise the triple Diels-Alder cascade sequence and fully establish its scope,(ii) To investigate the use of alternative aza-dienes and dienophiles in these triple Diels-Alder sequences leading to a range of novel polycyclic amines,(iii) To develop enantioselective variants of the above processes using enantiopure Lewis acids, enantiopure enamines or chiral auxiliaries,(iv) To apply the triple Diels-Alder methodology to prepare the anti-cancer natural products, the Daphnezomines, along with novel aza-analogues for biological screening..
Organisations
People |
ORCID iD |
Richard Taylor (Principal Investigator) |
Publications
J. K. Taylor R
(2012)
Alkyne-Acetal Cyclisation Reactions Mediated by Formic Acid; 3-Acylated-2,5-dihydrofurans and Related Oxygen and Nitrogen Heterocycles
in HETEROCYCLES
Kitsiou C
(2014)
Substrate scope in the direct imine acylation of ortho-substituted benzoic acid derivatives: the total synthesis (±)-cavidine
in Tetrahedron
Osler JD
(2013)
The Cope rearrangement of gem-dimethyl substituted divinylcyclopropanes.
in Organic & biomolecular chemistry
Unsworth W
(2013)
An Expedient Protecting-Group-Free Total Synthesis of (±)-Dievodiamine
in Organic Letters
Unsworth WP
(2014)
Direct imine acylation for molecular diversity in heterocyclic synthesis.
in The Journal of organic chemistry
Unsworth WP
(2013)
Direct imine acylation: synthesis of the proposed structures of 'upenamide.
in Organic letters
Unsworth WP
(2013)
'Upenamide: trials and tribulations.
in Organic & biomolecular chemistry
Unsworth WP
(2013)
Total synthesis of spirobacillene A.
in Organic letters
Unsworth WP
(2013)
Direct imine acylation: rapid access to diverse heterocyclic scaffolds.
in Organic letters
Description | 1. Further studies of the triple Diels-Alder cascade were carried out. 2. Simple cyclisation reactions were developed to prepare a range of heterocyclic systems (invited paper in Heterocycles). 3. Direct imine acylation (DIA) was developed and applied to prepare a range of heterocycles and the bioactive natural product Evodiamine (paper in Organic Letters). 4. Direct imine acylation (DIA) was applied to complete the first synthesis of the bioactive natural product 'Upenamide and cast doubt on its published structure Evodiamine (paper in Organic Letters). 5. The first synthesis of the bioactive natural product Dievodiamine was developed using an unprecedented organometallic addition process (paper in Organic Letters). 6. The first synthesis of the bioactive extremophile-derived natural product Spriobacillene A was developed using an unprecedented alkyne spirocyclisation process (paper in Organic Letters). 7. The scope of Direct imine acylation (DIA) was dramatically extended and applied to prepare a range of heterocyclic scaffolds (paper submitted). 8. The above advances were widely disseminated to academic and industrial audiences in conference presentations, invited lectures and posters. 9. The PDRA (Dr Will Unsworth) was subsequently employed as a Teaching / Research Fellow at the University of York. |
Exploitation Route | The methods are widely applicable in research labs in both industry and academia (and the high level of citation indicates widespread interest). |
Sectors | Chemicals Pharmaceuticals and Medical Biotechnology |
Description | The methodology has been widely cited in scientific papers indicating wide use in academia and industry. |
First Year Of Impact | 2011 |
Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |