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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