Total synthesis is considered by many as the finest combination of art and science. During the last decades, several concepts were proposed for achieving the perfect vision of total synthesis, such as atom economy, step economy, or redox economy. In this context, C−H functionalization represents the most powerful platform that has emerged in the last years, empowering rapid synthesis of complex natural products and enabling diversification of bioactive scaffolds based on natural product architectures. In this review, we present an overview of the recent strategies towards the total synthesis of heterocyclic natural products enabled by C−H functionalization. Heterocycles represent the most common motifs in drug discovery and marketed drugs. The implementation of C−H functionalization of heterocycles enables novel tactics in the construction of core architectures, but also changes the logic design of retrosynthetic strategies and permits access to natural product scaffolds with novel and enhanced biological activities.
The recovery of Tangshan following the Great 1976 Earthquake was an illustrative microcosm of the planning culture and the evolving national politics in China. The early recovery planning was driven by the central state’s ideological priorities. The national reform that started in the late 1970s catalyzed China’s shift toward a more pragmatic development approach. Within this changing national context, the Tangshan recovery plan was fundamentally adjusted in 1982. Although the earthquake recovery was a long, turbulent process, Tangshan ultimately emerged with a vastly improved built environment. This allowed the city to better capitalize on the national economic reforms after the earthquake recovery was completed.
Ring substituted derivatives of 2-(4-aminophenyl)benzothiazole, 1a, 1b–1g, are under development as anti-tumor agents. One derivative, 1f, has reached Phase 1 clinical trials as the pro-drug, 2f, Phortress (NSC 710305). These amines are activated by CYP450 1A1, apparently into hydroxylamines, 8a–8g, that are likely metabolized into esters that ionize into nitrenium ions responsible for cellular damage. Previously we showed that 9a, the acetic acid ester of 8a, generates the long-lived (530 ns) nitrenium ion 11a by hydrolysis or photolysis in water. In this study, azide trapping shows that 9b–9g generate 11b–11g via rate-limiting N-O heterolysis. Ion lifetimes, estimated from azide/solvent selectivities, range from 250–1150 ns with identical lifetimes for 11a and 11f. Differences in biological activity of the amines are likely not due to differences in the chemistry of the cations, but to differences in metabolic activation/deactivation of individual amines. Unlike the nitrenium ions, lifetimes of the esters are strongly dependent on the 3′-Me substituent. Esters containing 3′-Me (9b, 9f, 9g) have lifetimes of 5–10 s compared to 400–800 s for esters without 3′-Me (9a, 9c, 9d, 9e). This restricts 3′-Me esters to cells/tissues in which activation occurs, concentrating their effects in tumor cells if metabolism is restricted to those cells.
Invariant natural killer T (iNKT) cells are a subclass of T cells that initiates the secretion of T helper 1 and 2 cytokines after recognizing CD1d protein presented glycolipid antigens. In this Letter, we designed and synthesized a novel series of CD1d ligand α-galactosylceramides (α-GalCers) in which the acyl chain backbone of the lipid was incorporated with fluorine atoms. The in vivo evaluation of immunostimulatory activities revealed that the synthesized α-5-thio-galactopyranosyl-N-perfluorooctanoyl phytosphingosine exhibited a remarkable potency toward selectively enhancing T H 1 cytokine production with the IFN γ/IL-4 ratio of 9/1, while its perfluorotetradecanoyl counterpart showed T H 2 profile with an IFN γ/IL-4 ratio of 0.59/1. The analogues synthesized here would be used as probes to study lipid−protein interactions in α-GalCer/CD1d complexes.
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