Pd(II) - Catalysed Cyclisations in the Total Synthesis of Natural Products

1. Pd(II)-Catalysed Cyclisations in theTotal Synthesis of Natural Products XII. Blue Danube Symposium on Heterocyclic Chemistry June 10th - 13th, 2007Tihany, Hungary Dr. Peter Szolcsányi Department of Organic Chemistry Slovak University of Technology Bratislava, Slovak Republic

2. Pd(II)-activation of C=C bond and subsequent transformations

3. Versatility of Pd(II)-catalysed cyclisations of aminoalkenes

4. Synthesis of (un)natural piperidine alkaloids

5. Total synthesis of unnaturalanalogues of 1-deoxynojirimycin

6. 1-Deoxynojirimycin Inhibition: Ki = 32 nM (a-D-glucosidase) Activity: anti-diabetes, anti-HIV, ... Applications: Tay-Sachs, Gaucher, ... White mulberry (Morus alba) Reference: Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond, Ed. A. E. Stütz, Wiley, 1999.

7. Retrosynthetic analysis of new analogues of 1-DNJ

8. Substrate preparation

9. Pd(II)-catalysed aminocarbonylation& Finalisation P. Szolcsányiet al.: Tetrahedron: Asymmetry 2000, 11, 2579.

10. Pd(II)/CuCl2-catalysed chlorocyclisation P. Szolcsányi, T. Gracza: Tetrahedron 2006, 62, 8498.

11. Mechanistic proposal of the Pd(II)/CuCl2-catalysed chloroaminocyclisation and bicyclisation P. Szolcsányi, T. Gracza: Chem. Commun. 2005, 3948.

12. Synthesis of new analogues of iminoalditols P. Szolcsányi, T. Gracza: Tetrahedron 2006, 62, 8498.

13. Formal total synthesis of alkaloid (+)-2-epipinidinone

14. Ladybird Beetles (Coccinellidae) Mealybug ladybird beetle (Cryptolaemus montrouzieri) Mexican bean beetle (Epilachna varivestis) Reports on (epi)pinidinone occurrence: V. W. Brown, P. B. Moore: Aust. J. Chem. 1982, 35, 1255. A. B.Attygalle, S. Ch.Xu, K. D.McCormick, J.Meinwald, C. L.Blankespoor, T.Eisner:Tetrahedron 1993, 49, 9333.

15. Coniferous Trees (Pinaceae) Colorado spruce (Picea pungens) Ponderosa pine (Pinus ponderosa) Reports on (epi)pinidinone occurrence: J. N. Tawara, A. Blokhin, T. A. Foderaro, F. R. Stermitz, J. Org. Chem. 1993, 58, 4813. F. R. Stermitz, J. N. Tawara, M. Boeckl, M. Pomeroy, T. A. Foderaro, F. G. Todd, Phytochemistry 1994, 35, 951.

16. Retrosynthetic analysis of (+)-2-epipinidinone

17. Formal total synthesis of (+)-2-epipinidinone a) Preparation of the substrate andits Pd(II)-catalysed methoxycarbonylation Substrate preparation: D. J. Dixon, S. V. Ley, W. E. Tate: J. Chem. Soc., Perkin Trans. 1 2000, 2385. A. Fürstner, K. Langemann: Synthesis 1997, 792.

18. Formal total synthesis of (+)-2-epipinidinone b) Deprotection and completion of the formal synthesis Debenzylation: T. Momose, N. Toyooka, J. Makoto: J. Chem. Soc., Perkin Trans. 1 1997, 2005. Finalisation:M. J. Munchhof, A. I. Meyers: J. Am. Chem. Soc. 1995, 117, 5399.

19. Short total synthesis of racemicalkaloids calvine and 2-epicalvine

20. Ladybird Beetles (Coccinellidae)[1] Calvia 10-guttata Calvia 14-guttata These insects are rarely eaten by predators due to the production of toxic alkaloids in their haemolymph. When disturbed or molested, they release small droplets of yellow “blood” at their knee joints (so called reflex bleeding) [2] [1] A. G. King, J. Meinwald: Chem. Rev. 1996, 96, 1105. [2] G. M. Happ, T. Eisner: Science 1961, 134, 329.

21. Structure elucidation of (+)-calvine and (+)-2-epicalvine The relative configuration was established on the basis of NMR and HRMS studies and subsequently confirmed via racemic total synthesis.[3]The absolute configuration was determined by enantioselective total synthesis.[4] [3] J.-C. Braekman, A. Charlier, D. Daloze, S. Heilporn, J. Pasteels, V. Plasman, S. Wang: Eur. J. Org. Chem. 1999, 1749. [4] P. Laurent, J.-C. Braekman, D. Daloze: Eur. J. Org. Chem. 2000, 2057.

22. Known total syntheses of (+)-calvine and (+)-2-epicalvine a) CN(R,S)-methodology - use of chiral N-cyanomethyloxazolidine 12% total yield over 7 steps P. Laurent, J.-C. Braekman, D. Daloze: Eur. J. Org. Chem. 2000, 2057. b) CM-strategy - olefin cross-metathesis reaction 15% total yield over 9 steps P. Dewi-Wülfling, J. Gebauer, S. Blechert: Synlett 2006, 487. • Known formal syntheses of (+)-calvine and (+)-2-epicalvine c) Davies‘ Li-amide 1,4- addition & Intramolecular Mannich-type reaction S. Rougnon-Glasson, Ch. Tartrat, J.-C. Canet, P. Chalard, Y. Troin: Tetrahedron:Asymmetry 2004, 15, 1561. d) Diastereoselective reduction of piperidine b-enamino esters S. Calvet-Vitale, C. Vanucci-Bacqué, M.-C. Fargeau-Bellassoued, G. Lhommet: Tetrahedron 2005, 61, 7774.

23. Retrosynthetic analysis of calvine and 2-epicalvine

24. Racemic total synthesis of calvine and 2-epicalvine a) Preparation of the substrate for the Pd(II)-catalysed aminocarbonylation The identical sequence on analogous compounds: A. Fürstner, K. Langemann: Synthesis 1997, 792.

25. Racemic total synthesis of calvine and 2-epicalvine b) Finalisation - Pd(II)-catalysed carbonylation of rac-aminoalkenitol

26. Conclusions • Intramolecular Pd(II)-catalysed methoxycarbonylation and/or • chlorocyclisation of aminoalkenes represents a novel synthetic approach • to (poly)substituted piperidines • Such structures may well serve as key building blocks for the total • syntheses of various nitrogen-containing natural products • Both transformations were developed intoeffectivesynthetic methodologies • that were successfully employed in the total synthesis of alkaloids as well as • their unnatural analogues

27. Acknowledgments Generous support Prof. Dr. Tibor Gracza Co-workers Ing. Kristína Csatayová Katarína Reichová Technical support Mária Krajčírová GC, MALDI Dr. Ivan Špánik HPLC Dr. Katarína Hroboňová NMR Dr. Nadežda Prónayová IR Silvia Markusová Grant APVT-20-000904

28. Known precedents of Pd(II)/CuCl2-catalysed haloaminocyclisation yielding 6-membered azacycles

29. Reports on Pd(II)/Cu(II)-heterobimetallic complexes

30. Proposed mechanism of the Pd(II)-catalysed carbonylation

31. Observed interconversion of calvine and 2-epicalvine in protic media But no epimerisation reported with:

32. Formation of the undesired ketone side product via MPV-type mechanism The only literature precedent: B. G. Kovalev et al.: Zh. Org. Khim. 1975, 11, 1183.