1 / 36

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

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

luana
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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)

More Related