Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Dec 10;130(49):16490-1.
doi: 10.1021/ja8074852.

Total syntheses of (+/-)-massadine and massadine chloride

Shun Su  1 , Ian B Seiple, Ian S Young, Phil S Baran
Affiliations

Total syntheses of (+/-)-massadine and massadine chloride

Shun Su et al. J Am Chem Soc. .

Abstract

The total synthesis of the complex pyrrole–imidazole alkaloids (±)–massadine and (±)–massadine chloride is described using a carefully orchestrated sequence of manipulations on highly polar and structurally complex intermediates. Key to the completion of this synthetic endeavor was the exploration of a unique and chemoselective method to oxidize unprotected guanidines under aqueous conditions in air. This oxidation has been optimized and applied to a selection of spirocyclic guanidines of varying complexity. Additionally, the 3,7–epi analogues of these interesting natural products have been synthesized and fully characterized.

PubMed Disclaimer

Figures

Figure 1
Figure 1
(A) Structures of the massadines (1–2) and axinellamines (3–4). (B) Retrosynthetic analysis of the massadines (1–2). (C) Chemoselective silver(II) oxidation. (D) Selected failed approaches.
Scheme 1
Scheme 1
Total syntheses of the massadines.a aReagents and conditions: (a) Sodium diformylamide (1.2 equiv), TBAI (0.1 equiv), THF, 23 °C, 2 h, 72%; (b) 2:1 TFA:DCM, 23 °C, 2 h, quant; (c) silver(II)picolinate (2.5 eq), 9:1 H2O:TFA, 23 °C, 35 min, then TFA (to 1:1 v:v), 38 °C, 18 h, 84%; (d) cyanamide (excess), 0.2 M NaOH (to pH 5.0), 78 °C, 2 h, 24% 5, 32% 6; (e) DMDO (1.3 equiv), 9:1 H2O:TFA, 0 °C, 1h (f) TFA, 23 °C, 3 h, 71% over two steps, 1:3.7 22:23, (65% for −OH series, 1:1.9); (f) PtO2 (0.3 equiv), H2 (1 atm), 19:1 H2O:TFA, 1 h, 23 °C; (g) 24 (16 equiv), iPr2EtN (16 equiv) DMF, 14 h, 23 °C, 34% (22→2), 44% (23→25) (40% for 1 and 40% for 20, −OH series). TBAI = tetrabutylammonium iodide, TFA = trifluoroacetic acid, DMDO = dimethyldioxirane, R = 5–(2,3–dibromopyrrole).
See this image and copyright information in PMC

References

    1. For original isolation, see: Kinnel RB, Gehrken H-P, Scheuer PJ. J. Am. Chem. Soc. 1993;115:3376. Kinnel RB, Gehrken H-P, Swali R, Skoropowski G, Scheuer PJ. J. Org. Chem. 1998;63:3281.. For reassignment of the original structure, see: Grube A, Köck M. Angew. Chem. Int. Ed. 2007;46:2320. Buchanan MS, Carroll AR, Addepalli R, Avery VM, Hooper JNA, Quinn RJ. J. Org. Chem. 2007;72:2309. Kobayashi H, Kitamura K, Nagai K, Nakao Y, Fusetani N, van Soest RWM, Matsunaga S. Tetrahedron Lett. 2007;48:2127. Buchanan MS, Carroll AR, Quinn RJ. Tetrahedron Lett. 2007;48:4573.

    1. Nishimura S, Matsunaga S, Shibazaki M, Suzuki K, Furihata K, van Soest RWM, Fusetani N. Org. Lett. 2003;5:2255. - PubMed
    2. Grube A, Immel S, Baran PS, Köck M. Angew. Chem. Int. Ed. 2007;46:6721. - PubMed
    1. Urban S, Leone P, de A, Carroll AR, Fechner GA, Smith J, Hooper JNA, Quinn RJ. J. Org. Chem. 1999;64:731. - PubMed
    1. Grube A, Köck M. Org. Lett. 2006;8:4675. - PubMed

    1. For work done through early 2007, see the following reviews and references therein: Hoffmann H, Lindel T. Synthesis. 2003:1753. Jacquot DEN, Lindel T. Curr. Org. Chem. 2005;9:1551. Köck M, Grube A, Seiple IB, Baran PS. Angew. Chem. Int. Ed. 2007;46:6586.. Reports late 2007 to present: Lanman BA, Overman LE, Paulini R, White NS. J. Am. Chem. Soc. 2007;129:12896. Sivappa R, Hernandez NM, He Y, Lovely CJ. Org. Lett. 2007;9:3861. Tang L, Romo D. Heterocycles. 2007;74:999. Cernak TA, Gleason JL. J. Org. Chem. 2008;73:102. Wang S, Romo D. Angew. Chem. Int. Ed. 2008;47:1284. Bultman MS, Ma J, Gin DY. Angew. Chem. Int. Ed. 2008;47:6821. Zancanella MA, Romo D. Org. Lett. 2008;10:3685.

Publication types