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Total Synthesis of (-)-Conophylline and (-)-ConophyllidineYuku Han-ya, Hidetoshi Tokuyama, and Tohru Fukuyama
Wipf Group- Current LitertureBenjamin R. Eyer
June 18, 2011
Angew. Chem. Int. Ed. 2011, 50, 4884DOI: 10.1002/anie.201100981
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Kam T.S.; Loh K.-Y.; Lim, L.-H.; Loong, Chuah, C.-H.; Wei, C. Tet. Let. 1992, 33, 969.Kam T.S.; Loh K.-Y; Wei, C. J. Nat. Prod. 1993, 56, 1865.Image from: http://www.jungleseeds.com/SeedShop/Conservatory2.htm
Isolation, Structural Determination and Biological Activity
•Tabernaemontana divaricata–Popular garden plant in native to India–Significant variation in alkaloid natural products
•2 kg of ground leaves from Petaling Jaya, Malaysia–650 mg of conophylline–43 mg of conophyllidine
•Characterized by 1H- and 13C-NMR, MS, IR, UV, MPand X-ray crystallography
•Bis(indole) alkaloid with two pentacyclic aspidospermaskeletons
•Potent inhibitor the ras function–Potential chemotherapeutic drug
•Induces beta cell differentiation–Regeneration treatment for Diabetes Type I
Umezawa, K.; Ohse, T.; Yamamoto, T.; Koyano, T.; Takahashi, Y. Anticancer Res. 1994, 14, 2413.Amino, N.; Ohse, T.; Koyano, T.; Umezawa, K. Anticancer Res. 1996, 16, 55.Ogata, T.; Li, L.; Yamada, S.; Yamamoto, Y.; Tanaka, Y.; Takei, I.; Umenzawa, K.; Kojima, I. Diabetes. 2004, 53, 2596.
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(+)-Vincadifformine and (-)-Tabersonine
N H
CO2MeNH
(+)-Vincadifformine
N H
CO2MeNH
(-)-TabersonineKobayashi, S.; Peng, G.; Fukuyama, T. Tet. Let. 1999, 40, 1519.
(-)-Vindoline
Kobayashi, S.; Ueda, T.; Fukuyama, T. Synlett. 2000, 883.
NO2
HO
1)MsCl2) Pd/C, H23) Ac2O; HNO3
NHAc
NO2MsO
1) 10% HCl/MeOH2) NaNO2, HCl, AcOEt;
KI
I
NO2MsO1) Heck Rxn with Acrolein2) NaBH43) Ac2O
NO2MsO
OAc1) Zn2) HCO2H3) POCl3NCMsO
OAc
MsO NBoc
I
OAc
1) Stille2) Na2CO3
1) nBu3SnH, AIBN;I2
2) Boc2O
MsO NBoc
OH
CO2Me
N H
CO2MeNMe
(-)-Vindoline
HOMeO
30
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Synthesis of the Indole Core Structures of Conophylline
Ando, S.; Okamoto, Y.; Umezawa, K.; Otsuka, M. J. Heterocycl. Chem. 2008, 45, 1803.
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Retrosynthetic Analysis
Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Angew Chem. Int. Ed. 2011, 50, 4884.
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Polonovski-Potier Reaction
• Potier Modification– TFAA in place of Ac2 O or AcCl– Allowed for milder reaction conditions – Can be stopped at iminium ion
Polonovski, M; Polonovski, M. Bull. soc. chim. 1927, 1190.Polonovski, M. Bull. soc. chim. Belg. 1930, 39, 1190.Cave, A.; Kan-Fan, C.; Potier, P.; Le Man, J. Tetrahedron. 1967, 23, 4681.
Henriques, A.; Kan, C.; Chiaroni, A.; Richie, C.; Husson, H.-P.; Kan, S.-K.; Lounasmaa, M. J. Org. Chem. 1982, 47, 803
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Title Paper: Synthesis of Indole 12
Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Angew Chem. Int. Ed. 2011, 50, 4884.
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Title Paper: Synthesis of Dinitrobenzenesulfonamide 21
Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Angew Chem. Int. Ed. 2011, 50, 4884.Kobayashi, S.; Peng, G.; Fukuyama, T. Tet. Let. 1999, 40, 1519.Yokoshima, T; Kobayashi, S.; Ueda, T.; Sato, A.; Kuboyama, T,; Tokuyama, H; Fukuyama, T. JACS. 2002, 124, 2137.
OHC
Et
Ph
Et
PhNC
OAc
Et
PhNC
OH O
Et
NC
O
Et
HNDNs
1)NaCN, AcOH, RT2) Ac2O, pyr, RT
95%
Lipase PS, THF-H2O50oC
54%, 97% ee
1) O3, MeOH, DCM-78oC; Me2S
2) MsCl, NEt3, toluene0 to 80oC
LiAlH4, THF,-10oC to RT;H2O, NaOH;DNsCl, DCM
75%
65%
21
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Title Paper: Synthesis of lower indole segment 27
Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Angew Chem. Int. Ed. 2011, 50, 4884.
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Title Paper: Synthesis of upper indole 29 and 36
Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Angew Chem. Int. Ed. 2011, 50, 4884.
30+21
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Title Paper: Completion of (-)-conophylline (1)
Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Angew Chem. Int. Ed. 2011, 50, 4884.
N
O
H
CO2Me
NH
OAllyl
N H
CO2MeNTroc
MsO
MeO
MeO
O
N H
CO2MeNTroc
MsO
MeO
MeO
O
mCPBA, DCM0oC
TFAA, DCM, 0oC to RT
N
O
H
CO2Me
NH
OAllyl
N H
CO2MeNTroc
MsO
MeO
MeO
O
27
29
33
N
O
H
CO2Me
NH
O
N H
CO2MeNTroc
MsO
MeO
MeO
OH
[Pd(PPh3)4],pyrrolidineDCM, RT
3450%
3576%
N
O
H
CO2Me
NH
O
NOH
H
CO2MeNH
HO
MeO
MeO
1
LDA, THF-78 to 0oC
72%
-O
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Title Paper: Completion of (-)-conophyllidine (2)
Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Angew Chem. Int. Ed. 2011, 50, 4884.
N H
CO2Me
NH
OAllyl
N H
CO2MeNTroc
MsO
MeO
MeO
O
N H
CO2MeNTroc
MsO
MeO
MeO
O
mCPBA, DCM0oC
TFAA, DCM, 0oC to RT
N H
CO2Me
NH
OAllyl
N H
CO2MeNTroc
MsO
MeO
MeO
O
27
36
33
N H
CO2Me
NH
O
N H
CO2MeNTroc
MsO
MeO
MeO
OH
[Pd(PPh3)4],pyrrolidineDCM, RT
3755%
72%
N H
CO2Me
NH
O
NOH
H
CO2MeNH
HO
MeO
MeO
2
LDA, THF-78 to 0oC
67%
-O
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Conclusions
• First total synthesis of (-)-conophylline and its congener (-)-conophyllidine via a convergent route
• Key Steps– Tin-mediated radical cyclization to produce indole core– Stereoselective intramolecular Michael addition/Mannich reaction cascade– Potentially biomimetic cascade to couple two pentacyclic aspidosperma skeletons utilizing a regio-
and diastereoselective Polonovski-Potier reaction• Convergent route leaves open the possibility for SAR analysis to probe biological activity
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