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

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pd ii catalysed cyclisations in the total synthesis of natural products

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

slide6

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.

slide9

Pd(II)-catalysed aminocarbonylation& Finalisation

P. Szolcsányiet al.: Tetrahedron: Asymmetry 2000, 11, 2579.

slide10

Pd(II)/CuCl2-catalysed chlorocyclisation

P. Szolcsányi, T. Gracza: Tetrahedron 2006, 62, 8498.

slide11

Mechanistic proposal of the Pd(II)/CuCl2-catalysed

chloroaminocyclisation and bicyclisation

P. Szolcsányi, T. Gracza: Chem. Commun. 2005, 3948.

slide12

Synthesis of new analogues of iminoalditols

P. Szolcsányi, T. Gracza: Tetrahedron 2006, 62, 8498.

slide14

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.

slide15

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.

slide17

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.

slide18

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.

slide20

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.

slide21

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.

slide22

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.

slide24

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.

slide25

Racemic total synthesis of calvine and 2-epicalvine

b) Finalisation - Pd(II)-catalysed carbonylation of rac-aminoalkenitol

slide26

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
acknowledgments
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

slide28

Known precedents of Pd(II)/CuCl2-catalysed

haloaminocyclisation yielding 6-membered azacycles

slide31

Observed interconversion of calvine and 2-epicalvine in protic media

But no epimerisation reported with:

slide32

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.

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