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 13 th 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 1 H 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 BF 3 ∙OEt 2 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: Asymmetry 1998, 9, 3929).

9. Optimisation of Lewis Acid and Reaction Conditions AlCl 3, BF 3 ·OEt 2, Sc(OTf) 3, SnCl 4 and ZnCl 2 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. Lewis AcidYield of Product TiCl 4 79% Ti(OiPr) 4 No product isolated TiCl(OiPr) 3 No product isolated TiCl 2 (OiPr) 2 44% TiCl 3 (OiPr)61% TiCl 2 (OTf) 2 73% TiCl(OTf) 3 84% “Ti(OTf) 4 ”68%

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. C 1970, 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 Secondary alcohol derived ester. However, No rearrangement.

29. Mechanistic Details Proposed Mechanism, What about indoles?

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

31. Mechanistic Studies 1 H 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)