Many natural products that contain basic nitrogen atoms—for example alkaloids like morphine and quinine—have the potential to treat a broad range of human diseases. However, the presence of a nitrogen atom in a target molecule can complicate its chemical synthesis because of the basicity of nitrogen atoms and their susceptibility to oxidation. Obtaining such compounds by chemical synthesis can be further complicated by the presence of multiple nitrogen atoms, but it can be done by the selective introduction and removal of functional groups that mitigate basicity. Here we use such a strategy to complete the chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C (which contains a bicyclo[2.2.2]diazaoctane structural unit) through carbon-13 feeding studies, support the existence of a common bicyclo[2.2.2]diazaoctane-containing biogenetic precursor to these compounds, as has been proposed previously.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
A sample of the P. citrinum strain F53 is deposited at the Brazilian Collection of Environmental and Industrial Microorganisms under the accession code CBMAI 1186. Crystallographic data for crystal structures ent-2•HCl, 6, 27 and 36 have been deposited at the Cambridge Crystallographic Data Centre (http://www.ccdc.cam.ac.uk) under accession codes CCDC 984477, CCDC 984478, CCDC 984480 and CCDC 984479, respectively.
Stocking, E. M., Sanz-Cervera, J. F. & Williams, R. M. Reverse versus normal prenyl transferases in paraherquamide biosynthesis exhibit distinct facial selectivities. Angew. Chem. Int. Ed. 38, 786–789 (1999)
Finefield, J. M., Frisvad, J. C., Sherman, D. H. & </author> Williams, R. M. Fungal origins of the bicyclo[2.2.2]diazaoctane ring system of prenylated indole alkaloids. J. Nat. Prod. 75, 812–833 (2012)
Miller, K. A. & Williams, R. M. Synthetic approaches to the bicyclo[2.2.2]diazaoctane ring system common to the paraherquamides, stephacidins and related prenylated indole alkaloids. Chem. Soc. Rev. 38, 3160–3174 (2009)
Tsuda, M. et al. Citrinadin A, a novel pentacyclic alkaloid from marine-derived fungus Penicillium citrinum. Org. Lett. 6, 3087–3089 (2004)
Mugishima, T. et al. Absolute stereochemistry of citrinadins A and B from marine-derived fungus. J. Org. Chem. 70, 9430–9435 (2005)
Kushida, N. et al. PF1270A, B and C, novel histamine H3 receptor ligands produced by Penicillium waksmanii PF1270. J. Antibiot. (Tokyo) 60, 667–673 (2007)
Bian, Z., Marvin, C. C. & Martin, S. F. Enantioselective total synthesis of (−)-citrinadin A and revision of its stereochemical structure. J. Am. Chem. Soc. 135, 10886–10889 (2013)
Kong, K. et al. An enantioselective total synthesis and stereochemical revision of (+)-citrinadin B. J. Am. Chem. Soc. 135, 10890–10893 (2013)
Bond, R. F., Boeyens, J. C. A., Holzapfel, C. W. & Steyn, P. S. Cyclopiamines A and B, novel oxindole metabolites of Penicillium cyclopium westling. J. Chem. Soc. Perkin Trans. I 1751–1761 (1979)
Pimenta, E. F. et al. Use of experimental design for the optimization of the production of new secondary metabolites by two penicillium species. J. Nat. Prod. 73, 1821–1832 (2010)
Parry, R., Nishino, S. & Spain, J. Naturally-occurring nitro compounds. Nat. Prod. Rep. 28, 152–167 (2011)
Lodewyk, M. W., Siebert, M. R. & Tantillo, D. J. Computational prediction of 1H and 13C chemical shifts: a useful tool for natural product, mechanistic and synthetic organic chemistry. Chem. Rev. 112, 1839–1862 (2012)
Jewett, J. C. & Rawal, V. H. Total synthesis of pederin. Angew. Chem. Int. Ed. 46, 6502–6504 (2007)
Omura, K. & Swern, D. Oxidation of alcohols by “activated” dimethyl sulfoxide. A preparative, steric and mechanistic study. Tetrahedron 34, 1651–1660 (1978)
Ohira, S. Methanolysis of dimethyl (1-diazo-2-oxopropyl) phosphonate: generation of dimethyl (diazomethyl) phosphonate and reaction with carbonyl compounds. Synth. Commun. 19, 561–564 (1989)
Grotjahn, D. B. & Lev, D. A. A general bifunctional catalyst for the anti-Markovnikov hydration of terminal alkynes to aldehydes gives enzyme-like rate and selectivity enhancements. J. Am. Chem. Soc. 126, 12232–12233 (2004)
Kishi, Y. et al. Synthetic approach towards tetrodotoxin. I. Diels-Alder reaction of alpha-oximinoethylbenzoquinones with butadiene. Tetrahedr. Lett. 11, 5127–5128 (1970)
Johnson, C. R. et al. Direct alpha-iodination of cycloalkenones. Tetrahedr. Lett. 33, 917–918 (1992)
Ghaffar, T. & Parkins, A. W. A new homogeneous platinum containing catalyst for the hydrolysis of nitriles. Tetrahedr. Lett. 36, 8657–8660 (1995)
Moriarty, R. M., Chany, C. J., II, Vaid, R. K., Prakash, O. & Tuladhar, S. M. Preparation of methyl carbamates from primary alkyl- and arylcarboxamides using hypervalent iodine. J. Org. Chem. 58, 2478–2482 (1993)
Herzon, S. B. & Myers, A. G. Enantioselective synthesis of stephacidin B. J. Am. Chem. Soc. 127, 5342–5344 (2005)
Myers, A. G. & Herzon, S. B. Identification of a novel Michael acceptor group for the reversible addition of oxygen- and sulfur-based nucleophiles. Synthesis and reactivity of the 3-alkylidene-3H-indole 1-oxide function of avrainvillamide. J. Am. Chem. Soc. 125, 12080–12081 (2003)
Marti, C. & Carreira, E. Construction of spiro[pyrrolidine-3,3′-oxindoles] − recent applications to the synthesis of oxindole alkaloids. Eur. J. Org. Chem. 2209–2219 (2003)
Guerrero, C. A. & Sorensen, E. J. Concise, stereocontrolled synthesis of citrinadin B core architecture. Org. Lett. 13, 5164–5167 (2011)
Grubbs, A. W., Artman, G. D., III, Tsukamoto, S. & Williams, R. M. A concise total synthesis of the notoamides C and D. Angew. Chem. Int. Ed. 46, 2257–2261 (2007)
Davis, F. A. & Stringer, O. D. Chemistry of oxaziridines. 2. Improved synthesis of 2-sulfonyloxaziridines. J. Org. Chem. 47, 1774–1775 (1982)
Kolundzic, F. et al. Chemoselective and enantioselective oxidation of indoles employing aspartyl peptide catalysts. J. Am. Chem. Soc. 133, 9104–9111 (2011)
Güller, R. & Borschberg, H.-J. A stereoselective transformation of pseudoindoxyls into oxindoles in a single operation. Tetrahedr. Lett. 35, 865–868 (1994)
Movassaghi, M., Schmidt, M. A. & Ashenhurst, J. A. Stereoselective oxidative rearrangements of 2-aryl tryptamine derivatives. Org. Lett. 10, 4009–4012 (2008)
Miller, D. G. & Wayner, D. D. M. Improved method for the Wacker oxidation of cyclic and internal olefins. J. Org. Chem. 55, 2924–2927 (1990)
Zhang, X. & Foote, C. S. Dimethyldioxirane oxidation of indole derivatives. Formation of novel indole-2,3-epoxides and a versatile synthetic route to indolinones and indolines. J. Am. Chem. Soc. 115, 8867–8868 (1993)
Borch, R. F. A new method for the reduction of secondary and tertiary amides. Tetrahedr. Lett. 9, 61–65 (1968)
Ding, Y. et al. Genome-based characterization of two prenylation steps in the assembly of the stephacidin and notoamide anticancer agents in a marine-derived Aspergillus sp. J. Am. Chem. Soc. 132, 12733–12740 (2010)
R.S. and P.G.-R. thank the US National Institutes of Health (NIH; NIGMS RO1 086374) for financial support. R.S. is a Camille Dreyfus Teacher Scholar. E.V.M.-M. acknowledges the US National Science Foundation (NSF) for a graduate fellowship (GRFP). S.R., E.F.P. and R.G.S.B. are grateful to the Brazilian National Council of Technological and Scientific Development (CNPq; grant 470643/2010-2) and the São Paulo Research Foundation (FAPESP; grant 2012/50026-3) for funding. D.E.W. and R.J.A. thank NSEPC for funding. M.W.L. and D.J.T. acknowledge support from the NSF (CHE-0957416 and supercomputing resources through a grant from the XSEDE programme: CHE-030089). S.J.M. is grateful to the NIH for support (GM096403). We thank A. DiPasquale for solving the crystal structures of ent-2•HCl, 6, 27 and 36 (supported by NIH Shared Instrumentation Grant S10-RR027172). We would like to thank T. Lebold, R. M. Williams and D. Sherman for discussions.
The authors declare no competing financial interests.
About this article
Cite this article
Mercado-Marin, E., Garcia-Reynaga, P., Romminger, S. et al. Total synthesis and isolation of citrinalin and cyclopiamine congeners. Nature 509, 318–324 (2014). https://doi.org/10.1038/nature13273
Nature Chemistry (2019)
Cycloexpansamines A and B: spiroindolinone alkaloids from a marine isolate of Penicillium sp. (SF-5292)
The Journal of Antibiotics (2015)
Synthesis of Structurally Diverse 2,3-Fused Indoles via Microwave-Assisted AgSbF6-Catalysed Intramolecular Difunctionalization of o-Alkynylanilines
Scientific Reports (2015)