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New Synthetic Methods:

We aim to develop complexity-inducing reactions which lead to a wide range of useful products, themselves functionalised for further chemistry. Examples of some of the methodology projects ongoing in the group are detailed below:

Palladium-mediated cascade cyclisation reactions of haloenynes:

Inspired by the complex skeletons of the anti-HIV natural products lancifodilactone G and rubriflordilactone A (see Synthesis page) we have developed a cascade process to access a diverse range of fused bi- and tricyclic ring systems. This reaction builds on established carbopalladation technology,¹ and sequences a carbopalladation / Stille cross-coupling with an electrocyclisation (6π or 8π) to form the polycylic product.² The latent reactivity built into our substrates leads to enhanced product utility – we are now expoiting this functionality to rapidly diversify the types of molecules we can prepare.

We are also looking to extend the methodology through the application of carbopalladation to unusual or unprecedented reaction substrates. Further details in this area will be reported as soon as we are able!

• This work is supported by the EPSRC (EP/E055273/1) (Studentship to Marie-Caroline Cordonnier) and by Syngenta (Industrial CASE award to Becky Greenaway).

Palladium-mediated synthesis of chiral allenes and furans:

The synthesis of chiral allenes from chiral propargylic electrophiles is a fairly well-established reaction that enables allenes to be prepared by formal SN2’ displacement without recourse to Grignard reagents or stoichiometric organocuprates. We are investigating a range of novel electrophiles in this reaction, with the hope of enhancing the degree of stereochemical transfer and / or reaction rate. The nature of the products is such that we again hope to engineer cascade processes, or make further use of the allene products – with the aim of enhancing the utility of the methodology. To date, we have particularly examined Suzuki cross-coupling reactions as a route to aryl allenes.

In the course of examining various leaving groups in this reaction, we discovered a surprising side reaction – a synthesis of propargylic furans from appropriately functionalized starting materials. We have optimized this reaction into a highly stereoselective route to these valuable building blocks; details of this will be reported soon.

• This work is supported by the EPSRC (EP/E055273/1) (Studentship to David Daniels).

Organosilicon methodology

In the course of our work on rubriflordilactone A, we needed to introduce an aryl hydroxyl group through a Tamao oxidation¹ of an arylsilane. Unlike the aliphatic equivalent, this reaction has not been widely studied but seemed to represent an attractive and mild route for the synthesis of phenols.

We have prepared a wide range of aryl silanes via silylation of lithiated aromatics using Et₂NSiMe₂Cl, which leads to an aminosilane. This can undergo direct oxidation to the phenol, or can be “trapped” (i.e. stablised) by derivatisation as the isopropoxysilane. Both silanes are suitable for oxidation under modified Tamao conditions. Our optimization of this reaction² has revealed several features:

• The reaction can be effected using catalytic amounts of fluoride promoter. This is in contrast to most Tamao-type procedures which employ 2 equivalents of fluoride.
• The reaction can be performed at room temperature. Most literature precedents involve some heating to effect oxidation.
• The reaction is tolerant of trialkylsilyl ethers. Due to the use of only 10% TBAF promoter, even a primary benzylic TBS ether is tolerated in the oxidation.

A range of other silicon-based methodologies are now under development in the group and will be described in due course.

• This work is supported by The Clarendon Trust (Scholarship to Sonia Bracegirdle) and by Pfizer (CASE award to Liz Rayment).