Dr Mike Porter
The research carried out within the group is directed towards the synthesis of complex natural products such as tagetitoxin (1), sarain A (2) and nakadomarin A (3). These compounds exhibit a range of biological activities including inhibition of RNA polymerase III, plant growth suppression, and potent cytotoxicity. In order to obtain sufficient quantities of these compounds and their analogues for further testing it will be necessary to develop concise routes for their synthesis; such routes, it is hoped, will also enable us to develop novel synthetic methods which may be of more general use.
The Stevens rearrangement, a [1,2]-shift from sulfur to carbon in sulfur ylides, has been known for many years. Traditionally, the ylides are generated by deprotonation of sulfonium salts, but more recently the generation of sulfur ylides by catalytic decomposition of diazo compounds in the presence of sulfides has been show to be an efficient process. The chemistry, however, has been under-utilised in the synthesis of natural products. We have discovered that treatment of a 1,3-oxathiolane 4 with a silylated diazoester and a metal catalyst leads, via the sulfur ylid 5, to a ring-expanded 1,4-oxathiane product 6:
This chemistry has been modified to allow us to synthesise the skeleton of tagetitoxin. Treatment of diazoester 7 with catalytic rhodium(ii) acetate effects an intramolecular ylide formation to give 8. Unlike the simpler analogue 5, this does not undergo spontaneous rearrangement; however, we were delighted to find that irradiation of the ylide with UV light does induce a [1,2]-shift to give the tagetitoxin skeleton 9. We are now in the process of applying this methodology to the synthesis of tagetitoxin itself.
A New Iodination Method
As an unexpected spin-off of the sarain synthesis project, we have discovered a new method for the conversion of alcohols to alkyl iodides. Crystalline salt 10 is readily prepared by reaction of N,N-dimethylthioformamide with methyl iodide. Reaction with a range of primary or secondary alcohols 11 leads, via intermediates 12 and 13, to alkyl iodides 14 in a very clean reaction, with the only by-products being the volatile DMF and methanethiol. We are currently trying to expand this chemistry to incorporate nucleophiles other than iodide.
- M. Ioannou, M.J. Porter and F. Saez. Conversion of 1,3-oxathiolanes to 1,4-oxathianes using a silylated diazoester. Tetrahedron 2005, 61, 43-50.
- G.S. Nandra, M.J. Porter and J.M. Elliott. Reductive cyclisation of azidolactams with Bu3P/LiAlH4. Synthesis 2005, 475-479.
- G.S. Nandra, P.S. Pang, M.J. Porter and J.M. Elliott. Synthesis of vinylogous carbamates by rhodium(II)-catalyzed olefination of tertiary formamides with a silylated diazoester. Org. Lett. 2005, 7, 3453-3455
- M.J. Porter, F. Saez and A.K. Sandhu. Direct conversion of tert-butyl 2-hydroxyalkyl sulfides to 1,3-oxathiolanes. Tetrahedron 2006, 62,931-936
- S. Ishaq and M.J. Porter. Allylsilyl propargyl ethers as substrates for intramolecular Pauson-Khand reactions. Synth. Commun. 2006, 36, 547-557.
- J. Plet and M.J. Porter. Synthesis of the bicyclic core of tagetitoxin. Chem. Commun. 2006, 1197-1199.
- A.J.P. Mortimer, P.S. Pang, A.E. Aliev, D.A. Tocher and M.J. Porter. Concise synthesis of bicyclic aminals and their evaluation as precursors to the sarain core. Org. Biomol. Chem. 2008, 6, 2941-2951.
- A.R Ellwood, A.J.P. Mortimer, D.A. Tocher and M.J. Porter. Diastereoselective thia-Claisen rearrangement of pyrrolidinone-derived ketene N,S-acetals. Synlett 2008, 2199-2203. [Correction: Synlett 2009, 3052.]
- A.J.P. Mortimer, A.E. Aliev, D.A. Tocher and M.J. Porter. Synthesis of the tagetitoxin core via photo-Stevens rearrangement. Org. Lett. 2008, 10, 5477-5480.
- A.R. Ellwood and M.J. Porter. Selective conversion of alcohols into alkyl iodides using a thioiminium salt. J. Org. Chem. 2009, 74, 7982-7985.
- J.R.H. Plet, A.K. Sandhu, M. Sehailia and M.J. Porter. Approaches to tagetitoxin and its decarboxy analogue from D-glucose. Synlett 2009, 3258-3262.
- M.J. Porter and J. Skidmore. Asymmetric epoxidation of electron-deficient olefins. Chem. Commun., 2000, 1215-1225.
- M.J. Porter and P.S. Pang. Ethyl diazo(triethylsilyl)acetate. e-EROS Encyclopedia of Reagents for Organic Synthesis, 2008.
- M.J. Porter. Alkanols: Synthesis by Oxidation in Science of Synthesis, J. Clayden, Ed.; Thieme, Stuttgart (2008), vol. 36 pp 17-54.
- M.J. Porter. Benzylic Alcohols in Science of Synthesis, J. Clayden, Ed.; Thieme, Stuttgart (2008), vol. 36 pp 573-582.
- M.J. Porter and J. Skidmore. Asymmetric Epoxidation of Electron-Deficient Olefins, Org. React., 2009, 74, 425-672.