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

ABSTRACT: 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.

SUBMITTER: Jamison CR

PROVIDER: S-EPMC9815142 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Jamison Christopher R CR Badillo Joseph J JJ Lipshultz Jeffrey M JM Comito Robert J RJ MacMillan David W C DWC

Nature chemistry 20170724 12

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 iterativel ...[more]

PMID: 29168485

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Project description:Drugs are discovered through the biological screening of collections of compounds, followed by optimization toward functional end points. The properties of screening collections are often balanced between diversity, physicochemical favorability, intrinsic complexity, and synthetic tractability (Huggins, D. J.; et al. ACS Chem. Biol. 2011, 6, 208; DOI: 10.1021/cb100420r ). Whereas natural product (NP) collections excel in the first three attributes, NPs suffer a disadvantage on the last point. Academic total synthesis research has worked to solve this problem by devising syntheses of NP leads, diversifying late-stage intermediates, or derivatizing the NP target. This work has led to the discovery of reaction mechanisms, the invention of new methods, and the development of FDA-approved drugs. Few drugs, however, are themselves NPs; instead, NP analogues predominate. Here we highlight past examples of NP analogue development and successful NP-derived drugs. More recently, chemists have explored how NP analogues alter the retrosynthetic analysis of complex scaffolds, merging structural design and synthetic design. This strategy maintains the intrinsic complexity of the NP but can alter the physicochemical properties of the scaffold, like core instability that renders the NP a poor chemotype. Focused libraries based on these syntheses may exclude the NP but maintain the molecular properties that distinguish NP space from synthetic space (Stratton, C. F.; et al. Bioorg. Med. Chem. Lett. 2015, 25, 4802; DOI: 10.1016/j.bmcl.2015.07.014 ), properties that have statistical advantages in clinical progression (Luker, T.; et al. Bioorg. Med. Chem. Lett. 2011, 21, 5673, DOI: 10.1016/j.bmcl.2011.07.074 ; Ritchie, T. J.; Macdonald, S. J. F. Drug Discovery Today 2009, 14, 1011, DOI: 10.1016/j.drudis.2009.07.014 ). Research that expedites synthetic access to NP motifs can prevent homogeneity of chemical matter available for lead discovery. Easily accessed, focused libraries of NP scaffolds can fill empty but active gaps in screening sets and expand the molecular diversity of synthetic collections.

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

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

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