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Total synthesis and isolation of citrinalin and cyclopiamine congeners



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.

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Figure 1: Selected prenylated indole alkaloids.
Figure 2: Retrosynthetic analysis plan for cyclopiamine B and citrinalin B.
Figure 3: Preparation of fused hexacycle 25.
Figure 4: Face-selective oxygenation of fused hexacycle 25.
Figure 5: Completion of the syntheses of ent-citrinalin B and cyclopiamine B.
Figure 6: Isolation of two new citrinalins and 13C labelling studies.
Figure 7: Biosynthetic proposal for citrinalins.

Accession codes

Data deposits

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 ( under accession codes CCDC 984477, CCDC 984478, CCDC 984480 and CCDC 984479, respectively.


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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.

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Authors and Affiliations



R.S. conceived and directed the synthetic aspects of the research, and wrote the majority of the manuscript (with input from all authors) except the section on biosynthesis, which was contributed by S.R., E.F.P., D.E.W., R.J.A. and R.G.S.B. The synthetic plan was designed by R.S. with input from E.V.M.-M. and P.G.-R. who carried out the plan under the supervision of R.S. Oxidation catalyst 32 was provided by D.K.R. and S.J.M., who, along with P.G.-R., E.V.M.-M. and R.S., designed the oxidation studies of 25, which were done by P.G.-R. The computational NMR studies of 1, 2 and 3 were designed and performed by M.W.L. and D.J.T. with input from P.G.-R., E.V.M.-M. and R.S. Biosynthetic studies were designed and conducted by S.R., E.F.P. and R.G.S.B., who also isolated and characterized 3, 37 and 38. D.E.W. and R.J.A. provided facilities and contributed to the purification, data analysis and structural analysis of 3, 37 and 38.

Corresponding authors

Correspondence to Roberto G. S. Berlinck or Richmond Sarpong.

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The authors declare no competing financial interests.

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This file contains Supplementary Text, Supplementary Figures 1-48, Supplementary Tables 1-12 and additional references (See Contents for details). (PDF 19125 kb)

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Mercado-Marin, E., Garcia-Reynaga, P., Romminger, S. et al. Total synthesis and isolation of citrinalin and cyclopiamine congeners. Nature 509, 318–324 (2014).

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