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Catalyst-controlled oligomerization for the collective synthesis of polypyrroloindoline natural products


In nature, many organisms generate large families of natural product metabolites that have related molecular structures as a means to increase functional diversity and gain an evolutionary advantage against competing systems within the same environment. One pathway commonly employed by living systems to generate these large classes of structurally related families is oligomerization, wherein a series of enzymatically catalysed reactions is employed to generate secondary metabolites by iteratively appending monomers to a growing serial oligomer chain. The polypyrroloindolines are an interesting class of oligomeric natural products that consist of multiple cyclotryptamine subunits. Herein we describe an iterative application of asymmetric copper catalysis towards the synthesis of six distinct oligomeric polypyrroloindoline natural products: hodgkinsine, hodgkinsine B, idiospermuline, quadrigemine H and isopsychotridine B and C. Given the customizable nature of the small-molecule catalysts employed, we demonstrate that this strategy is further amenable to the construction of quadrigemine H-type alkaloids not isolated previously from natural sources.

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Figure 1: Nature's method for the construction of polypyrroloindoline oligomers.
Figure 2: Design of orthogonal monomers and catalyst-controlled oligomerization.
Figure 3: Synthesis of hodgkinsine and hodgkinsine B, quadrigemine H and isopsychotridine B and C.
Figure 4: Synthesis of two putatively unnatural quadrigemines.


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We are grateful for the financial support provided by the NIHGMS (RO1 GM103558-04) and kind gifts from Merck. We are also grateful to L. Verotta for providing extracts from P. muscosa, C. Kraml, N. Byrne and L. Wilson (Lotus Separations) and E. Rowley (Chiromics) for compound purification, P. Jeffrey for assistance with X-ray structure determination and I. Pelczer and K. Conover for assistance with NMR sspectroscopy.

Author information




C.R.J., J.J.B., J.M.L. and R.J.C. performed and analysed the experiments. C.R.J., J.J.B., J.M.L., R.J.C. and D.W.C.M. designed the experiments. C.R.J., J.J.B., J.M.L. and D.W.C.M. prepared this manuscript.

Corresponding author

Correspondence to David W. C. MacMillan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 18333 kb)

Supplementary information

Crystallographic data for compound 2. (CIF 30 kb)

Supplementary information

Crystallographic data for compound Quadrigemine H tetramethiodide salt. (CIF 955 kb)

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Jamison, C., Badillo, J., Lipshultz, J. et al. Catalyst-controlled oligomerization for the collective synthesis of polypyrroloindoline natural products. Nature Chem 9, 1165–1169 (2017).

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