Transcript Synthetic Studies Towards C
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 Slovak University of Technology Bratislava, Slovak Republic
Pd(II)-activation of C=C bond and subsequent transformations R + PdX 2 L 2 R PdX 2 L 2
-Pd-complex
YH Y=O, NPG YH - HX Y Y R
-H -elim.
R PdXL 2 Y
-Pd-complex
+ CuX 2 - PdX 2 R X Y Y=NPG, X=Cl, Br + CO (T < -20°C) O O R=OH R O Y PdXL 2
-Pd-CO-complex
+ MeOH Y R O OMe
Versatility of Pd(II)-catalysed cyclisations of aminoalkenes N PG O O R 1 C O =O H /P d(I I) O N PG Pd (II )/C uC R 2 l 2 =O H C O /P d( II) M eO H N PG O OMe R 2 R 1 NH PG Pd (II) /C uC 2 l N PG Cl
Synthesis of (un)natural piperidine alkaloids OH OH HO OH HO OH Cl N H OH N H homo-1-DNJ 6-Cl-L-ido-1-DNJ (analogues of glucosidase inhibitor 1-deoxynojirimycin from Morus sp.) O N H (+)-EPIPINIDINONE (defense alkaloid and deterent of C. montrouzieri and E. varivestis) C 5 H 11 N O (+)-CALVINE O (defense alkaloid and deterent of C. 10-guttata and C. 14-guttata)
Total synthesis of unnatural analogues of 1-deoxynojirimycin
1-Deoxynojirimycin OH HO OH OH N H 1-Deoxynojirimycin (1,5-dideoxy-1,5-imino-D-glucitol) Inhibition: K i = 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. St ütz, Wiley, 1999.
Retrosynthetic analysis of new analogues of 1-DNJ HO OH OH N H homo-1-DNJ OH PGO OPG O N PG O PGO OPG OH NH PG OH HO OH Cl N H 6-Cl-L-ido-1-DNJ PGO OPG OH NH PG SUGAR
Substrate preparation
Pd(II)-catalysed aminocarbonylation & Finalisation OH OBn OBn NHBn CO (balloon) 0.1 eq. PdCl 2 1 eq. BQ BnO 2 eq. LiCl 2 eq. AcONa THF, r.t.
17 hrs, 66% OBn N Bn
D-gluco
O O + BnO (4 : 1) OBn N Bn
L-ido
O O BnO OBn N Bn O 1. LiBH 4 , THF 0°C - r.t., 64% O 2. H 2 (balloon) 10% Pd/C, HCl MeOH, r.t., 90% HO OH N H .
HCl OH OH homo-1-DNJ P. Szolcsányi et al.: Tetrahedron: Asymmetry 2000, 11, 2579.
Pd(II)/CuCl 2 -catalysed chlorocyclisation OH OBn OBn NHBn 0.1 eq. PdCl 2 3 eq. CuCl 2 3 eq. AcONa glacial AcOH r.t., 2 days, 70% BnO OBn N Bn
L-ido
OH Cl + BnO (19 : 1) OBn N Bn
D-gluco
OH Cl OH OBn OBn NHBn 0.1 eq. PdCl 2 3 eq. CuCl 2 BnO 3 eq. AcONa r.t., DMF, 53% OBn N Bn
L-altro
OH Cl + BnO (15 : 1) OBn N Bn
D-galacto
OH Cl BnO + O N Bn (11%) OH P. Szolcsányi, T. Gracza: Tetrahedron 2006, 62, 8498.
Mechanistic proposal of the Pd(II)/CuCl 2 -catalysed chloroaminocyclisation and bicyclisation CHLORIDE L 2 PdCl 2 BnHN BnO OH BnO
D-galacto
L 2 PdCl 2 BICYCLE BnO OH Cl N Bn Pd Cu Cl Cl OBn
-Pd/Cu-complex II
CuCl 2
CHLOROCYCLISATION Si-attack
BnO OH H PdCl OBn NHBn 2 BnO OH NBn PdCl OBn
-Pd-complex II
HCl
BICYCLISATION
Cl Cl 2 BnO OH Pd H NHBn
Re-attack
OBn Cl Pd BnO OH HCl NBn OBn
-Pd-complex I
Pd BnO OH Cl Cu Cl NBn OBn
-Pd/Cu-complex I
CuCl 2 P. Szolcsányi, T. Gracza: Chem. Commun. 2005, 3948.
Synthesis of new analogues of iminoalditols Cl BnO N Bn HO OBn 1
C
4 (J 4,5 = 3.0 Hz) (J 2,3 ~ J 3,4 = 4.8 Hz) H 2 (1 atm) 10 % Pd/C EtOH, HCl 100 % Cl HO N H .
HCl HO OH 1
C
4 (J 4,5 = 1.5 Hz) (J 2,3 ~ J 3,4 = 3.5 Hz)
L-ido
Cl HO BnO N Bn OBn 1
C
4 (J 3,4 = 2.3, J 4,5 = 6.7 Hz) H 2 (1 atm) 10 % Pd/C EtOH, HCl 100 % Cl HO HO N H .
HCl OH 1
C
4 (J 4,5 = 10.4 Hz) (J 2,3 ~ J 3,4 = 3.5 Hz)
L-altro
O OH BnO NBn H 2 (1 atm) 10 % Pd/C EtOH, HCl 100 % O OH HO NH .
HCl
D-galacto
P. Szolcsányi, T. Gracza: Tetrahedron 2006, 62, 8498.
Formal total synthesis of alkaloid (+)-2-epipinidinone
O O N H N H (-)-Pinidinone (+)-2-Epipinidinone (2R,6R)/(2S,6R)-6-methyl-2-(2 , -oxo-propyl)piperidine
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.
Coniferous Trees (
Pinaceae
) Ponderosa pine (Pinus ponderosa) Colorado spruce (Picea pungens) 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.
Retrosynthetic analysis of (+)-2-epipinidinone O N H (+)-2-Epipinidinone N PG O OMe NH PG
Formal total synthesis of (+)-2-epipinidinone a) Preparation of the substrate and its Pd(II)-catalysed methoxycarbonylation Substrate preparation: D. J. Dixon, S. V. Ley, W. E. Tate: J. Chem. Soc., Perkin Trans. 1 2000, 2385.
A. F ürstner, K. Langemann: Synthesis 1997, 792.
Formal total synthesis of (+)-2-epipinidinone b) Deprotection and completion of the formal synthesis N Bn O OMe H 2 (balloon) 0.15 eq. Pd(OH) 2 MeOH, 18 hrs, 62% N H O 1. Weinreb OMe 2. MeMgBr O N H (+)-2-epipinidinone 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.
Short total synthesis of racemic alkaloids calvine and 2-epicalvine
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.
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.
• Known total syntheses of (+)-calvine and (+)-2-epicalvine a) CN( R,S )-methodology - use of chiral 12% total yield over 7 steps N -cyanomethyloxazolidine P. Laurent, J.-C. Braekman, D. Daloze:
Eur. J. Org. Chem.
2000, 2057.
b) CM-strategy - olefin cross 15% total yield over 9 steps -metathesis reaction 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 -enamino esters S. Calvet-Vitale, C. Vanucci Bacqué, M.-C. Fargeau-Bellassoued, G. Lhommet:
Tetrahedron
2005,
61
, 7774.
Retrosynthetic analysis of calvine and 2-epicalvine C 5 H 11 N O (Epi)calvine O C 5 H 11 NH OH C 5 H 11 OTs
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. F ürstner, K. Langemann: Synthesis 1997, 792.
Racemic total synthesis of calvine and 2-epicalvine
b) Finalisation - Pd(II)-catalysed carbonylation of rac -aminoalkenitol
C 5 H 11 NH OH rac-aminoalkenitol CO (balloon) 0.1 eq. PdCl 2 2 eq. CuCl 2 2 eq. AcONa dioxane, 40°C 7 hrs, 55% C 5 H 11 N O rac-calvine O + (2.2 : 1) C 5 H 11 N O rac-2-epicalvine O
26% total yield over 5 steps
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 into effective synthetic methodologies that were successfully employed in the total synthesis of alkaloids as well as their unnatural analogues
Generous support Co-workers Technical support GC, MALDI HPLC NMR IR Grant Acknowledgments Prof. Dr. Tibor Gracza Ing. Kristína Csatayová Katarína Reichová Mária Krajčírová Dr. Ivan Špánik Dr. Katarína Hroboňová Dr. Na dežda Prónayová Silvia Markusová APVT-20-000904
Known precedents of Pd(II)/CuCl 2 -catalysed haloaminocyclisation yielding 6-membered azacycles
Reports on Pd(II)/Cu(II)-heterobimetallic complexes
Proposed mechanism of the Pd(II)-catalysed carbonylation
Observed interconversion of calvine and 2-epicalvine in protic media But no epimerisation reported with:
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.