Dragmacidin D

Dragmacidin D

The dragmacidins represent an emerging class of bioactive marine natural products obtained by an exhaustive set of protocols from a number of deep water sponges including Dragmacidon, Halicortex, Spongosorites, and Hexadella, and the tunicate Didemnum candid.[1][2]

Dragmacidin D , which has been found to serve as a potent inhibitor of serinethreonine protein phosphatases,[2] has received particular attention as a lead compound for treating Parkinson’s, Alzheimer’s, and Huntington’s diseases.  Dragmacidins exhibit prominent structural features such as two indole–pyrazinone bonds  and an aminoimidazole moiety.  Because of their unique chemical structures and promising biological activities, dragmacidins have been synthetic targets for many chemists.

In 2002, Stoltz and coworkers reported the first, and only, synthesis of dragmacidin D using Pd- catalyzed Suzuki–Miyaura cross-coupling as a key reaction.[3]  Thereafter, Itami and Yamaguchi have been synthesized it via Direct C–H couplings.[4]

 

  • References

[1]  (a) Kohmoto, S.; Kashman, Y.; McConnell, O. J.; Rinehart, K. L., Jr.; Wright, A.; Koehn, F. J. Org. Chem. 1988, 53, 3116.

DOI: 10.1021/jo00248a040 (b) Morris, S. A.; Andersen, R. J. Tetrahedron 1990, 46, 715. DOI:10.1016/S0040-4020(01)81355-7 (c) Fahy, E.; Potts, B. C. M.; Faulkner, D. J.; Smith, K. J. Nat. Prod. 1991, 54, 564. DOI: 10.1021/np50074a032

[2]  (a) Wright, A. E.; Pomponi, S. A.; Cross, S. S.; McCarthy, P. J. Org. Chem. 1992, 57, 4772. DOI: 10.1021/jo00043a045
(b) Capon, R. J.; Rooney, F.; Murray, L. M.; Collins, E.; Sim, A. T. R.; Rostas, J. A. P.; Butler, M. S.; Carroll, A. R. J. Nat. Prod. 1998, 61, 660. DOI: 10.1021/np970483t (c) Cutignano, A.; Bifulco, G.; Bruno, I.; Casapullo, A.; Gomez-Paloma, L.; Riccio, R. Tetrahedron 2000, 56, 3743. DOI:10.1016/S0040-4020(00)00281-7

[3] “The First Total Synthesis of Dragmacidin D”

Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179. DOI: 10.1021/ja027822b

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The first total synthesis of the biologically significant bis-indole alkaloid dragmacidin D (5) has been achieved. Thermal and electronic modulation provides the key for a series of palladium-catalyzed Suzuki cross-coupling reactions that furnished the core structure of the complex guanidine- and aminoimidazole-containing dragmacidins. Following this crucial sequence, a succession of meticulously controlled final events was developed leading to the completion of the natural product.

[4] “Synthesis of Dragmacidin D via Direct C–H Couplings”

Mandal, D.; Yamaguchi, A. D.; Yamaguchi, J.; Itami, K. J Am Chem Soc 2012, 133, 19660. DOI:10.1021/ja209945x

ja-2011-09945x_0004

Dragmacidin D, an emerging biologically active marine natural product, has attracted attention as a lead compound for treating Parkinson’s and Alzheimer’s diseases. Prominent structural features of this compound are the two indole–pyrazinone bonds and the presence of a polar aminoimidazole unit. We have established a concise total synthesis of dragmacidin D using direct C–H coupling reactions. Methodological developments include (i) Pd-catalyzed thiophene–indole C–H/C–I coupling, (ii) Pd-catalyzed indole–pyrazine N-oxide C–H/C–H coupling, and (iii) acid-catalyzed indole–pyrazinone C–H/C–H coupling. These regioselective catalytic C–H couplings enabled us to rapidly assemble simple building blocks to construct the core structure of dragmacidin D in a step-economical fashion.

 

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