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Robert Stockman

Associate Professor and Reader of Organic Chemistry, Faculty of Science

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Biography

Having completed a PhD at Bristol (working for Tim Gallagher) in 1997 and a postdoctoral fellowship at the University of Texas at Austin (working for Philip Magnus, FRS), Robert Stockman started his independent career at the University of East Anglia in 1999, where he initiated a number of projects aimed at the use of novel heterocyclic chemistry within the context of the total synthesis of biologically important natural and un-natural products. In April 2007 he was awarded an EPSRC Advanced Research Fellowship and was promoted to Senior Lecturer at UEA. In September 2007 he joined the University of Nottingham as Associate Professor of Organic Chemistry, and was promoted to Associate Professor and Reader in 2010.

Research Summary

Research Areas:

1. New Methods for Heterocycle Synthesis

Aziridines: Over the past few years the Stockman Group has been developing a synthetic programme aimed at the direct synthesis and exploitation of highly functionalised aziridines as versatile functionalised building blocks for complex molecule synthesis. As part of this programme, we needed to develop a direct synthesis of a range of functionalised aliphatic aziridines in a stereoselective manner. We have therefore extended the known sulfur ylide addition to aryl aldimines to encompass alkyl[1],[2],[3] and even ketimine[4] substrates. Further, by using the chiral tert-butylsulfinyl group on nitrogen, we have been able to access aziridines in high diastereoselectivity, and achieve deprotection to reveal the NH aziridines. We have also developed a versatile one-pot synthesis of chiral N-sulfinyl imines.[5]

2. Total Synthesis of Complex Natural Products.

A second research theme is combining bi-directional synthesis[6] and tandem reactions[7] to generate routes to complex molecules that are direct and generate complexity in the most efficient manner possible. To date these studies have resulted in the concise total syntheses of several natural products:

Perhydrohistrionicotoxin: The histrionicotoxins are a family of sixteen spirocyclic alkaloids isolated from the skin extracts of the Columbian "poison arrow" frogs, of the family Dendrobatidae.[8] Histrionicotoxin (HTX) and its hydrogenation product, the non-natural perhydrohistrionicotoxin (pHTX), are both useful biochemical tools for probing the mechanisms of trans-synaptic transmission of neuromuscular impulses.[9] This remarkable biological activity, in combination with the parent compound's low abundance in nature (less than 200 ug is isolated per frog skin), and challenging azaspirocyclic framework, have prompted considerable synthetic interest over the last few decades, culminating in four syntheses of HTX and numerous syntheses of pHTX.[10] We have developed an entirely bi-directional synthesis of (±)-perhydrohistrionicotoxin,[11] utilising a tandem oxime formation / Michael addition / [3+2] cycloaddition as the key step, forming the core structure of the histrionicotoxins in one step from a linear symmetrical substrate. This approach has yielded a 9-step synthesis of perhydrohistrionicotoxin that also constitutes formal syntheses of (±)-histrionicotoxin and (±)-histrionicotoxin 235A.[12]

Histrionicotoxin: We have recently refined our synthesis of the symmetrical tandem reaction precursors by using cross-metathesis, and, in collaboration with Prof. Philip Fuchs (Purdue), who contributed a solution for the bis-enyne synthesis, we have developed a 9 step synthesis of histrionicotoxin. The synthesis was published in J. Am. Chem. Soc.[13] at the end of 2006.

Hippodamine: We have also demonstrated the use of combining bi-directional synthesis with tandem reactions in a very concise entry into the quinolizidine skeleton.[14] A protected amine was converted in just one step to 4,6-disubstituted quinolizidine, using a tandem deprotection / double intramolecular Michael addition. This process was used in a synthesis of (±)-hippodamine, providing the shortest synthesis of this natural product to date.[15]

Anatoxin A: Using a desymmetrising ozonolysis, followed by a Horner-Wadsworth Emmons homologation and a tandem Michael Addition / Mannich cyclisation / elimination reaction, we have developed a short and efficient route to the fresh water algal bloom toxin anatoxin A. We are currently developing this method for further efficiency, dynamic kinetic resolution, and for the synthesis of other bioactive analogues of anatoxin-a.[16]

Other research in the group is also concerned with the use of bi-directional strategies towards the synthesis of halichlorine[17], dispiroketals[18] of the type found in many marine toxins and ionophores (e.g. pinnatoxin), and on new tandem reactions.[19],[20]

References:1. D. Morton, D. Pearson, R. A. Field and R. A. Stockman, Synlett 2003, 1985.2. L. G. Arini, A. Sinclair, P. Szeto, D. L. Hughes and R. A. Stockman, Tetrahedron Lett. 2004, 45, 1589.3. D. Morton, D. Pearson, R. A. Field and R. A. Stockman, Org. Lett. 2004, 6, 2377.4. D. Morton, D. Pearson, D. L. Hughes, R. A. Field and R. A. Stockman, Chem. Commun. 2006, 1833.5. L. Sasraku-Neequaye, D. MacPherson and R. A. Stockman, Tetrahedron Lett., in press.6. S. R. Magnuson, Tetrahedron 1995, 51, 2167.7. R. A. Bunce, Tetrahedron 1995, 51, 13103.8. (a) Witkop, B. Experientia 1971, 27, 1121. (b) Daly, J.W.; Karle, I.; Meyers, W.; Tokuyama, T.; Waters, J.A.; Witkop, B. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1870. (c) Tokuyama, T.; Venoyama, K.; Brown, G.; Daly, J. W.; Witkop, B. Helv. Chim. Acta 1974, 57, 2597. (d) Karle, I. J. Am. Chem. Soc. 1973, 95, 4036. (e) Daly, J. W.; Spande, T. F.; Whittaker, N.; Highet, R. J.; Feigl, D.; Nishimori, N.; Tokuyama, T. J. Nat. Prod. 1986, 49, 265. (f) Daly, J. W. J. Nat. Prod. 1998, 61, 162.9. (a) Rapier, C.; Wannacot, S.; Lunt, G. G.; Alberquerque, E. X. FEBS Lett. 1987, 212, 292. (b) Oliviera, L.; Madison, B. W.; Kapai, H.; Sherby, S. M.; Swanson, K. L.; Edelfraui, M. E.; Alberquerque, E. X. Eur. J. Pharmacol. 1987, 140, 331. (c) Sobel, A.; Heidmann, T.; Hofler, J.; Changeaux, J.P. Proc Natl. Acad. Sci. U.S.A. 1978, 75, 510.10. A. Sinclair and R. A. Stockman, Nat. Prod. Rep. 2007, 24, 298.11. R. A. Stockman, A. Sinclair, L. G. Arini, P. Szeto and D. L. Hughes, J. Org. Chem. 2004, 69, 1598.12. R. A. Stockman, Tetrahedron Lett. 2000, 41, 9163.13. M. S. Karatholuvhu, A. Sinclair, A. F. Newton, M-L. Alcaraz, R. A. Stockman and P. L. Fuchs, J. Am. Chem. Soc. 2006, 128, 12656.14. M. Rejzek and R. A. Stockman, Tetrahedron Lett. 2002, 43, 6505.15. M. Rejzek, D. L. Hughes and R. A. Stockman, Org. Biomol. Chem. 2005, 3, 73.16. S. J. Roe and R. A. Stockman, Chem. Commun. 2008, 3432.17. L. G. Arini, P. Szeto, D. L. Hughes and R. A. Stockman, Tetrahedron Lett. 2004, 45, 8371.18. P. McDermott and R. A. Stockman, Org. Lett. 2005,7, 27.19. M. Rejzek, R. A. Stockman, J. H. van Maarseveen and D. L. Hughes, Chem. Commun. 2005, 4461.20. A. Sinclair, L. G. Arini, M. Rejzek, P. Szeto and R. A. Stockman, Synlett 2006, 2321.

Selected Publications

School of Chemistry

University Park Nottingham, NG7 2RD

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