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Synthesis of the Tetracyclic Framework of Polycyclic Spiro Lignan Natural Products.

ABSTRACT: Polycyclic spiro lignans are a new family of lignan natural products recently isolated from Gymnotheca involucrata. The first synthesis of two model substrates of this rare family of natural products was achieved in six steps. An efficient strategy that features Suzuki coupling and Friedel-Crafts acylation was employed to construct the ABC tricyclic fluorene framework. Subsequently, Grignard reaction followed by acid-mediated cyclization furnished the spiro cyclic ether ring D.

SUBMITTER: Ali G

PROVIDER: S-EPMC7178799 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Synthesis of the Tetracyclic Framework of Polycyclic Spiro Lignan Natural Products.

Ali Ghada G Cuny Gregory D GD

ACS omega 20200408 15

Polycyclic spiro lignans are a new family of lignan natural products recently isolated from <i>Gymnotheca involucrata</i>. The first synthesis of two model substrates of this rare family of natural products was achieved in six steps. An efficient strategy that features Suzuki coupling and Friedel-Crafts acylation was employed to construct the ABC tricyclic fluorene framework. Subsequently, Grignard reaction followed by acid-mediated cyclization furnished the spiro cyclic ether ring D. ...[more]

PMID: 32337465

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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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Synthesis of the Tetracyclic Framework of Polycyclic Spiro Lignan Natural Products.

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Synthesis of the Tetracyclic Framework of Polycyclic Spiro Lignan Natural Products.

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