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Development of an enolate alkynylation approach towards the synthesis of the taiwanschirin natural products† † Electronic supplementary information (ESI) available. CCDC 2072549. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1sc04247e

ABSTRACT: Through the use of model studies, an approach was conceived towards the synthesis of the taiwanschirin family of natural products. These are structurally complex compounds which represent highly challenging and biologically active targets for total synthesis. This work describes a successful synthesis of the complex taiwanschirin fused [8,6,5] core through a novel alkynylation reaction coupled with an intramolecular Heck reaction used to construct the 8-membered ring. Key enolate alkynylation and ring closing Heck reactions have been used to make the core of the taiwanschirin natural products.

SUBMITTER: Haughey M

PROVIDER: S-EPMC8528008 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

Dataset Information

Development of an enolate alkynylation approach towards the synthesis of the taiwanschirin natural products† † Electronic supplementary information (ESI) available. CCDC 2072549. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1sc04247e

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