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New synthetic routes to azaspiro alkaloids: Applications to the synthesis perhydrohistrionicotoxin
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry.
1998 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Perhydrohistrionicotoxin, 1, is related to a family of alkaloids which display pharmacologically interesting properties. The thesis deals with development of new methods for the chemical synthesis of such alkaloids, and is divided into three parts according to the different approaches.

The first part describes a modification of a previously developed synthesis in which the azaspiro system was formed via an intramolecular ring opening of either an epoxide or an iodonium ion by a nitrogen nucleophile. The alkene precursor of the iodonium ion was synthesised in good overall yield but cyclisation was not accomplished. The epoxide was prepared in good yields but low diastereoselectivity in the epoxidation step rendered this route as a poor alternative.

The second approach describes the use of a [2,3] sigmatropic rearrangement in combination with a ruthenium-catalysed ring-closing metathesis (RCM) for the synthesis of the azaspiro ring systems. The [2,3] rearrangement of an allylic selenide was completely stereospecific and both azaspiro-[4.5] and [5.5] systems were synthesised by RCM. This methodology was utilised in a formal total synthesis of 1 where a known key intermediate was prepared in 10 steps and 20% overall yield starting from 2,3- epoxycyclohexan-1-one. The synthesis is potentially enantioselective as both enantiomers of the starting material are available in high enantiomeric purity. A possible route to 6-epi-1 was identified by the addition of an allyl boron reagent to an oxime.

In the third approach a convergent enantioselective total synthesis of 1 is described. The key step was a Lewis acid-promoted, diastereoselective, intramolecular imino ene-type reaction. A highly efficient one-pot, three-component coupling involving two chiral building blocks was used to synthesise the cyclisation precursor. The configurations of the stereogenic centres in the two building blocks originated from kinetic resolutions via Sharpless asymmetric epoxidation of an allylic alcohol. Thesynthesis proceeded in a total yield of 11% involving 10 laboratory operations starting from 1-bromo-3-((tert-butyldimethylsilyl)oxy)-propane.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1998. , 49 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 387
Keyword [en]
Keyword [sv]
National Category
Chemical Sciences
Research subject
Organic Chemistry
URN: urn:nbn:se:uu:diva-907ISBN: 91-554-4279-XOAI: oai:DiVA.org:uu-907DiVA: diva2:172303
Public defence
1998-10-17, Svedberg lecture hall at the Institute of Chemistry, Uppsala University, Uppsala, 10:15
Available from: 1998-09-26 Created: 1998-09-26Bibliographically approved

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