Synthesis of the Brasilinolides
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
The polyketides represent a diverse array of structurally complex natural products having a wide range of biological activity, typically antibiotic, antitumour, antifungal or immunosuppressive action, with many members having important therapeutic utility in human medicine. This project falls within the general theme of complex polyketide synthesis and focuses on the total synthesis of the brasilinolides, which are a novel family of potent immunosuppressive and antifungal 32-membered macrolides with unprecedented structural and stereochemical complexity. The planned synthesis of the brasilinolides draws on and extends contemporary methods of acyclic stereocontrol to efficiently set up the required stereochemistry, with particular emphasis on the use of new methodology recently developed in the Cambridge group. Our approach aims to incorporate maximum flexibility in terms of segment coupling, enabling the synthesis of other stereoisomers if necessary as well as novel analogues, and relies on a versatile combination of reagent and substrate-based control. Altogether, the pronounced biological activities of the brasilinolides, along with their lack of acute toxicity, makes further evaluation as new immunotherapeutic and/or antifungal agents of interest, with potential applications inter alia to autoimmune diseases and in counteracting tissue rejection in organ transplantation. These considerations, along with the significant intellectual challenge and high quality training provided by tackling such complex molecule synthesis, make the brasilinolides an attractive and platform for developing new methodology and strategies, which is also expected to become an exciting arena for further chemical and biological studies. Significantly, this project will build on the considerable expertise that we have developed over the years on the stereocontrolled synthesis of bioactive natural products and their analogues.
Organisations
People |
ORCID iD |
| Ian Paterson (Principal Investigator) |
Publications
Paterson I
(2008)
Total synthesis of the marine macrolide (+)-neopeltolide
in Chemical Communications
Paterson I
(2008)
Total synthesis of (-)-spirangien A and its methyl ester.
in Chemical communications (Cambridge, England)
Paterson I
(2015)
Synthetic studies toward the brasilinolides: controlled assembly of a protected C1-C38 polyol based on fragment union by complex aldol reactions.
in Organic & biomolecular chemistry
Paterson I
(2009)
Total synthesis of (-)-spirangien A, an antimitotic polyketide isolated from the myxobacterium Sorangium cellulosum.
in Chemistry, an Asian journal
Paterson I
(2010)
Synthesis of the C1-C13 tetraenoate subunit of the chivosazoles.
in Organic letters
Paterson I
(2010)
Synthesis of the C15-C35 northern hemisphere subunit of the chivosazoles.
in Organic letters
Paterson I
(2010)
Total synthesis and configurational validation of (+)-phorbaside A.
in Organic letters
Paterson I
(2009)
Toward the total synthesis of the brasilinolides: construction of a differentially protected C20-C38 segment.
in Organic letters
Paterson I
(2011)
Leiodermatolide, a potent antimitotic macrolide from the marine sponge Leiodermatium sp.
in Angewandte Chemie (International ed. in English)
| Description | The polyketides represent a diverse array of structurally complex natural products having a wide range of biological activity, typically antibiotic, antitumour, antifungal or immunosuppressive action, with many members having important therapeutic utility in human medicine. This project falls within the general theme of complex polyketide synthesis and focuses on the total synthesis of the brasilinolides, which are a novel family of potent immunosuppressive and antifungal 32-membered macrolides with unprecedented structural and stereochemical complexity. The planned synthesis of the brasilinolides draws on and extends contemporary methods of acyclic stereocontrol to efficiently set up the required stereochemistry, with particular emphasis on the use of new methodology recently developed in the Cambridge group. Our approach aims to incorporate maximum flexibility in terms of segment coupling, enabling the synthesis of other stereoisomers if necessary as well as novel analogues, and relies on a versatile combination of reagent and substrate-based control. Altogether, the pronounced biological activities of the brasilinolides, along with their lack of acute toxicity, makes further evaluation as new immunotherapeutic and/or antifungal agents of interest, with potential applications inter alia to autoimmune diseases and in counteracting tissue rejection in organ transplantation. These considerations, along with the significant intellectual challenge and high quality training provided by tackling such complex molecule synthesis, make the brasilinolides an attractive and platform for developing new methodology and strategies, which is also expected to become an exciting arena for further chemical and biological studies. Significantly, this project builds on the considerable expertise that we have developed over the years on the stereocontrolled synthesis of bioactive natural products and their analogues. As a sideline to the main project, contributions to the synthesis and structure determination of some other important bioactive polyketides were achieved. To date, this project has resulted in 10 publications in peer-reviewed journals. |
| Exploitation Route | the findings are relevant to other work on the stereocontrolled construction of biologically important polyketides |
| Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | The research results have facilitated ongoing projects in my group and other groups based on the published outcomes. |
| First Year Of Impact | 2010 |
| Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Societal |