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Synthesis of 10-epi-ABCDE ring fragment of pectenotoxin 2

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dc.contributor Aalto-yliopisto fi
dc.contributor Aalto University en
dc.contributor.author Aho, Jatta
dc.date.accessioned 2012-08-23T07:16:53Z
dc.date.available 2012-08-23T07:16:53Z
dc.date.issued 2009
dc.identifier.isbn 978-952-248-076-7
dc.identifier.isbn 978-952-248-075-0 (printed) #8195;
dc.identifier.issn 1795-4584
dc.identifier.uri https://aaltodoc.aalto.fi/handle/123456789/4653
dc.description.abstract The pectenotoxins (PTXs) are a family of marine macrolactones produced by Dinophysis dinoflagellates and found in coastal areas worldwide. The PTXs have drawn considerable attention not only because of their complex structure and toxicity but also because of their potential medical applications. Pectenotoxins have shown selective cytotoxicity against a variety cancer cell lines and they are known to interact with the actin cytoskeleton by unique mechanism. These properties could be of great clinical importance for the development of new cancer chemotherapy agents. The scarcity of the PTXs has hampered further studies into their biological activity, and as such access to synthetic PTXs would be immensely helpful. The exquisitely complex structure of the PTXs presents a considerable challenge for a synthetic chemist. One of the most challenging structural elements is the AB spiroketal ring fragment that is in the more unstable and less easily accessible nonanomeric configuration. Importantly, the PTX congeners that contain this nonanomeric spiroketal ring system, has been reported to be the most biologically active. In the literature part, a short discussion of the anomeric effect is presented. The previously published syntheses of the AB spiroketal ring fragment of PTXs are discussed. And finally, a brief insight into other natural products containing nonanomeric spiroketals and their recent syntheses are presented. In this work the objective was to synthesize the ABCDE ring fragment of PTX2 using a highly convergent strategy. Three advanced ring fragments corresponding to the A, C and DE ring systems were synthesized. The A ring lactone was also used for the synthesis of the AB spiroketal ring fragment of PTX2. During these studies we developed kinetic spiroketalization conditions that delivered for the first time the desired nonanomeric spiroketal isomer of the PTXs as the major product. For the C ring fragment an efficient synthesis was developed that delivered the key center peace with the right stereochemistry in excellent 46% total yield over nine steps. The connection of the C ring aldehyde with the DE ring fragment using Mukaiyama aldol reaction gave access to the CDE ring system in highly stereoselective manner. The CDE ring allylic alcohol was connected with the A ring fragment via cross-metathesis. As the final step, the kinetic spiroketalization delivered a 3:1 mixture of the nonanomeric and the anomeric spiroketal. Unfortunately, it was discovered that the final ABCDE ring product had the wrong stereochemistry at C10. Studies targeting the inversion of this stereocenter are under way, which would finally give access to the natural ABCDE ring fragment of PTX2. en
dc.format.extent Verkkokirja (1632 KB, 167 s.)
dc.format.mimetype application/pdf
dc.language.iso en en
dc.publisher Teknillinen korkeakoulu en
dc.relation.ispartofseries TKK dissertations, 180 en
dc.subject.other Biotechnology
dc.subject.other Chemistry
dc.title Synthesis of 10-epi-ABCDE ring fragment of pectenotoxin 2 en
dc.type G4 Monografiaväitöskirja fi
dc.contributor.department Kemian laitos fi
dc.subject.keyword pectenotoxin en
dc.subject.keyword total synthesis en
dc.subject.keyword spiroketal en
dc.subject.keyword nonanomeric en
dc.subject.keyword anomeric en
dc.identifier.urn URN:ISBN:978-952-248-076-7
dc.type.dcmitype text en
dc.type.ontasot Väitöskirja (monografia) fi
dc.type.ontasot Doctoral dissertation (monograph) en
local.aalto.digifolder Aalto_63946
local.aalto.digiauth ask

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