Rabiller, Delphine S.
Formation of 2,5-trans-tetrahydrofuran-3-one
application towards the synthesis of natural products.
PhD thesis, University of Glasgow.
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The tetrahydrofuran backbone is one of the most common heterocyclic units found in natural products. Among them structurally complex substituted tetrahydrofuran rings which present a 2,5-trans stereochemistry have been of particular interest to many groups as polyether antibiotics and highly biologically active compounds, such as the potent anti cancer Amphidinolide, possess this kind of backbone.
Different methodologies to synthesise this kind of structure have been developped starting in the late 70’s. The first efficient methodology was published by Fukuyama in Tetrahedron Letters in 1978. It involves the stereospecific epoxidation of bishomoallylic alcohol using VO(acac)2. Treatment of the epoxide with acetic acid led to the desired 2,5-trans-tetrahydrofuran in up to 20:1 ratio.
In 1990, Inoki developed an efficient method for the synthesis of trans-tetrahydrofurans. Using this methodology, 5-hydroxy-1-alkenes can be converted to the desired cyclisation product via oxidative cyclisation with molecular oxygen using cobalt complex as a catalyst. The 5-hydroxy-1-alkene react with the Co complex and the oxygen. The radical complex thus formed could be converted to the cyclised intermediate. The cyclisation occurs in reasonable yields (up to 79 %) and exellent trans selectivity (99 %).
More recently Panek published a methodology involving the chelation controlled formation of trans tetrahydrofuran. A Lewis acid such as SnCl4 is able to form chelate with a α-benzyloxy group of an aldehyde. This activated intermediate can then undergo the electrophilic substitution. This method led to the trans cyclisation product in up to 40:1 ratio.
In order to increase the level of diastereocontrol our group have investigated a methodology based on an intramolecular tandem carbenoid insertion and ylide rearrangement reaction of a diazoketone. This diazoketone undergoes a nucleophilic attack onto an empty d orbital of the transition metal. The transition metal back donates the electrons of one of its d orbital to the carbon to form the metal carbenoid with elimination of nitrogen. Attack of one of the lone pair of the oxygen onto the carbon bonded to the
transition metal led to the formation of the oxonium ylide which undergoes [2,3]-sigmatropic rearrangement. Previous studies made within the group have proved Cu(acac)2 to be the best catalyst for the synthesis of the trans-2,5-dialkyl tetrahydrofuran-3-ones. The stereochemistry observed could be explained by the stereochemistry of the substituent R1. The transition state shows clearly that the trans- rearrangement product is favoured.
We have decided to apply this methodology to the synthesis of the (6S, 7S, 9S, 10S)-6,9-epoxynonadec-18-ene-7,10-diol. and the functionalised A-ring fragment of gambieric acid.
||natural product synthesis, oxonium ylide, 2,3 sigmatropic rearrangement, gambieric acid, 6,9-epoxynonadec-18-ene-7,10-diol
||Q Science > QD Chemistry
||College of Science and Engineering > School of Chemistry
||Clark, Prof J.S.
|Date of Award:
Miss Delphine S. Rabiller
||Copyright of this thesis is held by the author.
||03 Dec 2009
||10 Dec 2012 13:37
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