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• Chemistry @ Oxford

Total Synthesis

Natural products continue to represent an unparalleled source of new drug leads for human medicine, and are the basis of around 60% of all currently used drugs including more than 75% of anticancer treatments. Of prime importance is the supply of such molecules, and when the harvesting of natural products from the environment becomes either costly, low-yielding, or ethically unsound, a concise and efficient chemical synthesis can provide a viable alternative for supplies of these potential medicines.

We regard natural products not only as valuable commodities for medicinal chemistry applications, and of course as challenging synthetic targets, but also as “catalysts” for the development of new synthetic methods. In designing a route towards a selected molecule, we seek to develop and optimize new methodology, which extends beyond the specific setting of the natural product towards more generalised reactivity. In this way, total synthesis not only represents a goal in its own right, but also a vehicle for the development of new chemistry.

The research themes of a number of our total synthesis projects are described below.

The Schisandra family of natural products:

Lancifodilactone G and rubriflordilactone A are two members of a large (>60) family of nortriterpenoid natural products isolated from Chinese herbal plants of the Schisandra genus by Sun and co-workers.¹ Many of these natural products have been shown to possess moderate-to-good levels of anti-HIV activity and are therefore appealing synthetic targets. They are characterised by highly complex polycyclic oxygenated skeletons which pose a serious challenge to synthetic chemists.

Using a palladium-catalysed cascade carbopalladation / cross-coupling / electrocyclisation reaction developed within the group, we have prepared the CDE cores of both lancifodilactone G and rubriflordilactone A (the latter using an intramolecular variant).² These reactions lay a sound foundation for our planned synthesis as they efficiently solve the problem of preparing the challenging molecular cores. In the course of this work, we also found that the use of an aromatic furan cross-coupling partner (towards lancifodilactone G) led to further rearomatisation-driven pericyclic processes, and the isolation of three unusual byproducts.

In ongoing work, we are constructing more advanced cyclisation substrates suitable for elaboration to these natural products – we hope to report details of this work in the near future!

• This work is supported by the EPSRC (EP/E055273/1) (Studentship to Marie-Caroline Cordonnier) and by the DAAD (Fellowship to Dr Birgit Gockel)

Cepacin A / Mutafuran A:

Cepacin A is an antibiotic isolated from Pseudomonas cepacia SC 11783 in 1984.¹ It features an unusual and sensitive allene-diyne-epoxide motif which we regarded as a fascinating target for synthesis. We hope to prepare the highlighted region of cepacin A in a single step, using palladium-catalysed allene synthesis.

Although palladium catalysis is well-known in the synthesis of achiral or racemic allenes from propargylic electrophiles,² it is by no means a solved problem in the field of asymmetric allene synthesis. We expect that our work on cepacin A will lead to an improved understanding – and to improved methodology – in this area.

In related work, we are also studying a palladium-catalysed furan synthesis which enables the stereoselective preparation of cis- and trans-fused THFs – a reaction which we are applying to the synthesis of the mutafuran family of natural products.³ More details of these projects are included in the "methodology" section of the website.

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

Incednine:

Incednine is a 24-membered macrolactam isolated from a culture broth of Streptomyces sp. ML694-90F3 by Imoto and co-workers.¹ Treatment of multidrug-resistant lung cancer cell lines with incednine restores the apoptosis-inducing effects of chemotherapeutic agents to which they are (normally) resistant. As a novel, cell-permeable molecule with a new mode of action, it therefore represents an exciting target for both biology and chemical synthesis.

Synthetically, we recognize the challenge of the polyunsaturated macrolactam skeleton, and are particularly focusing on developing methodology to assemble the C8–C13 polyene attachment segment with its distinctive chiral diol motif and differential Z- and E-polyene linkages. As with other areas of our research, the methods we intend to use to control this stereochemistry-rich region can be extended to other chemistry, for example the synthesis of carbohydrates featuring quaternary stereocentres. A number of other methodology opportunities have arisen in the course of this work – we hope to reveal more details soon!

• This work is supported by an A*GA National Science Scholarship to Diane Lim.

Khellin and khellinone:

The voltage-gated potassium channel Kv1.3 plays a crucial role in the activation of human T cells, blocking of which could have implications for the development of therapies for autoimmune diseases such as multiple sclerosis, type I diabetes, and rheumatoid arthritis. In a series of recent reports,¹ derivatives of the natural products khellin and khellinone have been found to exhibit potent and selective blocking activity against this potassium channel.

The biological appeal of these natural products is thus evident, and we additionally felt that they would represent an ideal testing ground for our arylsilane oxidation chemistry,² as they feature four distinct oxygen environments on the aromatic ring. In ongoing studies towards these molecules, we are using 1,4-dimethoxybenzene as a cheap and readily available starting material, which we are working on elaborating to the more challenging hexasubstituted benzene ring of the natural products. We hope to achieve completely protecting-group free syntheses of these compounds in eight steps.

• This work is supported by Pfizer (CASE award to Liz Rayment).