David Mountford and Prof. Donald Craig Centre for Chemical Synthesis, Department of Chemistry,

1. Stereoselective Claisen and Related Rearrangements: Fundamental Methodology and Synthetic Applications David Mountford and Prof. Donald Craig Centre for Chemical Synthesis, Department of Chemistry, Imperial College London. SW7 2AZ Industrial Supervisor: Dr Paul King, GSK 13th September 2005

2. The Claisen Rearrangement • The Claisen rearrangement is the [3,3] sigmatropic rearrangement of an allyl-vinyl ether. • Many variants exist… • Ireland-Claisen Rearrangement.

3. Felkin-Anh Model in Pericyclic Reactions • The Felkin-Anh model can be applied to a wide range of pericyclic processes by the replacement of C=O by C=CH-EWG'. • In the Claisen rearrangement.

4. Belluš−Claisen Rearrangement(Aza-Claisen, Zwitterionic Claisen Rearrangement) • in situ generation of a ketene. • Activation with a suitable Lewis acid. • Addition to a tertiary allyllic amine. (Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 1999, 121,9726).

5. Aim of Project • 1,2-Asymmetric Induction.

6. Initial Studies • Cyclic amines have a greater nucleophilicity compared to acyclic amines. • Diagnostic morpholine protons in 1H NMR would aid analysis of diastereomeric mixtures. • anti diastereomer formed exclusively.

7. Synthesis of Chiral Allylic Amine Substrate • Neighbouring group effects gave selective reduction to the aldehyde. • The presence of BF3∙OEt2 prevented 1,4-reduction.

8. Chiral Allylic Amine Claisen Rearrangement • Deprotected allylic alcohol generated by the hydrolysis of an intermediate vinyl aziridine. (Ohno, H.; Toda, A.; Fujii, N.; Ibuka, T. Tetrahedron: Asymmetry1998, 9, 3929).

9. Optimisation of Lewis Acid and Reaction Conditions • AlCl3, BF3·OEt2, Sc(OTf)3, SnCl4 and ZnCl2 gave very low yields of rearranged product. • What about a milder titanium Lewis acid?

10. Optimisation of Titanium Lewis Acid • Optimum conditions found were 0.1 equiv. TiCl(OTf)3, with a 0.17M solution of the acid chloride added dropwise over 5 hours.

11. Application of Optimised Conditions to Chiral Substrate • 0.1 equiv. TiCl(OTf)3 – Starting material. • 1.2 equiv. TiCl(OTf)3 – 13% deprotected rearranged product. • Lewis acid coordinating with Boc group. • Lowering the temperature reduced decomposition but inhibited rearrangement. • Solution: Use a less Lewis basic tosyl group…

12. Synthesis of New Chiral Allylic Amine Substrate • 0.2, 1.5 and 2.5 equiv. TiCl(OTf)3 – Starting material. • Steric hindrance may also be contributing to the lack of reactivity. • Due to lack of reactivity and the large quantities of AgOTf being used a new method was required…

13. Belluš−Claisen Modification

14. Extension of Modification to Other Ketenes and Silylating Agents • Catalytic TMSOTf gave a lower yield of rearranged product (44%) and recovery of starting material (48%). • This is due to the generation of TMSCl, which is less active than TMSOTf.

15. Catalytic Belluš−Claisen Modification • Carboxylic Acid Activation Approach. • Pentafluorophenol Ester Approach.

16. Wolff−Belluš−Claisen Rearrangement • Wolff Rearrangement Approach. • In the presence of a tertiary amine and silver salts, α-diazoketones undergo the Wolff rearrangement.

17. Wolff−Belluš−Claisen Rearrangement • Wolff Rearrangement Approach. • In the presence of a tertiary amine and silver salts, α-diazoketones undergo the Wolff rearrangement. (Steer, J. T. Ph.D. Thesis, University of London, 2002).

18. Extension of Modification to Other Substrates

19. Return to Chiral Nitrogen Substrates • New protecting group strategy. • Direct reduction using DIBAL-H or lithium aluminium hydride led only to decomposition.

20. Synthesis of Chiral Oxygen Substrates • Substrate synthesis. • The analogous methyl ether failed to undergo rearrangement due to the ether oxygen sequestering the silylating agent.

21. Rearrangement of Chiral Oxygen Substrates • Claisen rearrangement. (Mulzer, J.; Shanyoor, M. Tetrahedron Lett. 1993, 34, 6545).

22. Rearrangement of Chiral Carbon Substrates • Will rearrangement proceed with good 1,2-asymmetric induction in the absence of a heteroatom in the chiral substituent?

23. Decarboxylative Claisen Rearrangement Reaction • Reaction catalytic in both BSA and KOAc. • Silylating agent essential, no reaction with only KOAc or NaH. • If 1 equiv. BSA and no KOAc used then rearranged acid formed.

24. Application and Development of the Decarboxylative Claisen

25. Asymmetric Induction in the Decarboxylative Claisen

26. Heteroaromatic Claisen Rearrangements • The Claisen rearrangement of heteroaromatic substrates. (Thomas, A. F.; Ozainne, M. J. Chem. Soc. C1970, 220). (Raucher, S.; Lui, A. S.-T.; Macdonald J. E. J. Org. Chem. 1979, 44, 1885).

27. Heteroaromatic Decarboxylative Claisen • Ts group on nitrogen essential for synthesis and stability of ester.

28. Extension of Heteroaromatic Substrates • However, • No rearrangement. • Secondary alcohol derived ester.

29. Mechanistic Details • Proposed Mechanism, • What about indoles?

30. Indoles as Heteroaromatic Substrates • Considering electron density… • Try again

31. Mechanistic Studies • 1H NMR Studies. • Secondary alcohol derived ester.

32. Carboaromatic Claisen Rearrangements • Allyl phenyl ethers undergo Claisen rearrangement, benzyl vinyl • ethers however, will not generally undergo rearrangement. • An Eschenmoser-Claisen rearrangement. (Felix, D.; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. Helv. Chim. Acta. 1969, 52, 1030).

33. Carboaromatic Decarboxylative Claisen • No evidence of Claisen rearrangement observed.

34. Alkylation of Carboaromatic Substrates • Proposed mechanism. • Attempts to facilitate both a radical-induced reaction and a • Lewis acid-catalysed rearrangement led only to decomposition.

35. Conclusion Belluš−Claisen Rearrangement • Refined experimental procedure for Belluš−Claisen rearrangement. • Developed a novel, metal free variant of the Belluš−Claisen rearrangement. • Applied new methodology to a range of ketenes and allylic amines, substrates with exopericyclic substituents shows good selectivity. Decarboxylative Claisen Rearrangement Reaction • Decarboxylative Claisen rearrangement applied to a wide range of substrates, including heteroaromatics. • Microwaves greatly increased reaction rate and removed need for solvent.

36. Thanks to… • Prof. Donald Craig • Dr Paul King (GSK) • The Craig Group, especially Drs Damien Bourgeois, John Caldwell and Tanya Wildman • Ian Campbell (Microwaves) • Dr Andrew White (Crystal Structures) • Dick Shepard, Peter Haycock and Sean Lynn (NMR) • EPSRC • GSK (CASE Studentship)