Approaches to taxanes from carbohydrate precursors.
thesisposted on 2015-11-19, 08:45 authored by Joshua. Howarth
This thesis is a continuation of the work by Bonnert to produce taxanes from glucose. The application of a Stork silyl methylene radical cyclisation to the allylic alcohol (1) led to the diol (2). This has a trans ring junction and has introduced regiospecifically a hydroxy methylene group adjacent to an hydroxyl group. This provides the necessary stereochemistry for the B-C ring junction in taxanes. However the ring hydroxyl group has the wrong stereochemistry for taxinine. In an endeavour to correct this, the allylic alcohol (1) was inverted and the radical cyclisation performed again. This resulted though in the radical and the hydrogen atom adding trans, once more, despite the fact that this gave rise to the formation of two cis ring junctions. Therefore, this too produced the wrong stereochemistry at the B-C ring junction. A series of studies were undertaken to assess the generality of the Robinson annulation of a carbohydrate. This study was extended to the incorporation the C-7 hydroxyl group in taxol during this annulation. A study of the C-ring functionality was performed leading to the formation of a carbohydrate oxetane. Several attempts at the production of 2-trimethyl-3-lithiobutadiene, as a synthetic building block, resulted in failure. Following previous work at Leicester, involving the use of intramolecular Diels-Alder reactions in the synthesis of taxanes, studies were initiated to convert (2) and (3) into diene-dienophile systems. The first approach was to construct the dienophile, prior to the diene, on C-9 (C-1 carbohydrate numbering). This approach failed due to the difficulties encountered when differentially protecting several similar hydroxyl groups. Altering our initial ideas, such that the diene is built before the dienophile, on C-6, has met though with more success. However, before attempting the construction of the diene on our intermediate (4) a model study was undertaken on a simple carbohydrate aldehyde, using a selenium directed synthesis. This was successful and so this approach has the potential for providing the means for the formation of a diene-dienophile system in our intermediate (4), and hence eventually resulting in the creation of a highly substituted taxane skeleton.
Date of award1990-01-01
Awarding institutionUniversity of Leicester