Abstract
Polycyclic scaffolds are omnipresent in natural products and drugs, and the synthetic strategies and methods toward construction of these scaffolds are of particular importance. Compared to simple cyclic ring systems, polycyclic scaffolds have higher structure complexity and diversity, making them suitable for charting broader chemical space, yet bringing challenges for the syntheses. In this review, we surveyed progress in the past decade on synthetic methods for polycyclic natural product scaffolds, in which the key steps are one-pot reactions involving intermolecular or intramolecular alkyne annulation. Synthetic strategies of selected polycyclic carbocycles and heterocycles with at least three fused, bridged, or spiro rings are discussed with emphasis on the synthetic efficiency and product diversity. Recent examples containing newly developed synthetic concepts or toolkits such as collective and divergent total synthesis, gold catalysis, C–H functionalization, and dearomative cyclization are highlighted. Finally, several “privileged synthetic strategies” for “privileged polycyclic scaffolds” are summarized, with discussion of remained challenges and future perspectives.
Highlights
Natural products and their synthetic analogs have a broad range of biological activities, and they are essential sources of drug and drug candidates (Rodrigues et al, 2016; Huffman and Shenvi, 2019; Newman and Cragg, 2020)
In the past 10 years, significant progress has been made for construction of polycyclic natural products (PNPs) scaffolds with high step and atom economies, as well as structural complexity and diversity
Various alkyne-anticipated synthetic methods have been developed for rapid construction of diverse polycyclic heterocycles, among which at least two strategies have proved to be versatile
Summary
Natural products and their synthetic analogs have a broad range of biological activities, and they are essential sources of drug and drug candidates (Rodrigues et al, 2016; Huffman and Shenvi, 2019; Newman and Cragg, 2020). In the past two decades, we have witnessed blossoming of new synthetic toolkits including C–H functionalization (Chen and Youn, 2012; Yamaguchi et al, 2012; Gulías and Mascareñas, 2016; Abrams et al, 2018; Sambiagio et al, 2018; Zheng and Hua, 2018; Ghosh et al, 2020), palladium catalysis (Chinchilla and Najera, 2014; Düfert and Werz, 2016; Trost and Min, 2020), and gold catalysis (Fürstner, 2009; Zhang et al, 2014; Dorel and Echavarren, 2015; Pflästerer and Hashmi, 2016; Marín-Luna et al, 2019) These emerging synthetic methodologies enable new cascade reaction in mild conditions via substrate activation (for alkynes, their reaction partners, or both of them), expanding the utilization of alkynes for syntheses of polyheterocycles with higher efficiency and diversity. Synthesis of PNPs using arynes, which has been well-discussed in a recent review (Takikawa et al, 2018), is not covered except for works using alkynes for in situ generation of the aryne intermediates
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