An official website of the United States government
Abstract 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.
more »
« less
Recent Advances in the Synthesis of Piperazines: Focus on C–H Functionalization
Piperazine ranks as the third most common nitrogen heterocycle in drug discovery, and it is the key component of several blockbuster drugs, such as Imatinib (also marketed as Gleevec) or Sildenafil, sold as Viagra. Despite its wide use in medicinal chemistry, the structural diversity of piperazines is limited, with about 80% of piperazine-containing drugs containing substituents only at the nitrogen positions. Recently, major advances have been made in the C–H functionalization of the carbon atoms of the piperazine ring. Herein, we present an overview of the recent synthetic methods to afford functionalized piperazines with a focus on C–H functionalization.
more »
« less
- Award ID(s):
- 1650766
- PAR ID:
- 10323801
- Date Published:
- Journal Name:
- Organics
- Volume:
- 2
- Issue:
- 4
- ISSN:
- 2673-401X
- Page Range / eLocation ID:
- 337 to 347
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Direct and regioselective functionalization of pyridine is a topic of high scientific and technological importance. In spite of extensive efforts, the regioselective functionalization of pyridine still remains a significant challenge due to their low reactivity and presence of Lewis‐basic sp2nitrogen. Here, we studied the effect of hydrogen bonding interactions on the regiochemical outcome of Pd‐mediated C−H activation of pyridine by utilizing DFT calculations. We demonstrated that hydrogen bonding can act as a second independent factor to override the inherent regioselectivity of pyridine. This novel approach complements previously reported strategies, such as: (a) coordination of pyridine to transition metal center via its N‐center, (b) installation of directing group (DG) and then coordination of pyridine to the transition metal center via this DG (i. e. chelation assistant strategy), (c) protection of its nitrogen lone pair with N‐oxide or N‐imino groups or with Lewis acids, (d) the inherent positional reactivity of C−H bonds based on the electronic or steric properties of the substituents, and (e) by the identity of the oxidant used. We have also demonstrated that the oxidation state of the Pd catalyst has impact on the regiochemical outcome of the C−H activation step in pyridine. The implications of our study for regioselective C−H functionalization catalyst design of heteroarenes are twofold: It demonstrates (1) hydrogen bonding as a viable design principle, and (2) Pd(IV) as a catalyst for C−H functionalization.more » « less
-
The selective functionalization of remote C–H bonds via intramolecular hydrogen atom transfer (HAT) is transformative for organic synthesis. This radical-mediated strategy provides access to novel reactivity that is complementary to closed-shell pathways. As modern methods for mild generation of radicals are continually developed, inherent selectivity paradigms of HAT mechanisms offer unparalleled opportunities for developing new strategies for C–H functionalization. This review outlines the history, recent advances, and mechanistic underpinnings of intramolecular HAT as a guide to addressing ongoing challenges in this arena. 1 Introduction 2 Nitrogen-Centered Radicals 2.1 sp3 N-Radical Initiation 2.2 sp2 N-Radical Initiation 3 Oxygen-Centered Radicals 3.1 Carbonyl Diradical Initiation 3.2 Alkoxy Radical Initiation 3.3 Non-alkoxy Radical Initiation 4 Carbon-Centered Radicals 4.1 sp2 C-Radical Initiation 4.2 sp3 C-Radical Initiation 5 Conclusionmore » « less
-
Given the prevalence of nitrogen-containing heterocycles in commercial drugs, selectively incorporating a single nitrogen atom is a promising scaffold hopping approach to enhance chemical diversity in drug discovery libraries. We harness the distinct reactivity of sulfenylnitrenes, which insert a single nitrogen atom to transform readily available pyrroles, indoles, and imidazoles into synthetically challenging pyrimidines, quinazolines, and triazines, respectively. Our additive-free method for skeletal editing employs easily accessible, benchtop-stable sulfenylnitrene precursors over a broad temperature range (−30 to 150°C). This approach is compatible with diverse functional groups, including oxidation-sensitive functionalities such as phenols and thioethers, and has been applied to various natural products, amino acids, and pharmaceuticals. Furthermore, we have conducted mechanistic studies and explored regioselectivity outcomes through density functional theory calculations.more » « less
-
In this review, recent examples featuring C–H functionalization in the synthesis of complex natural products are discussed. A focus is given to the way in which C–H functionalization can influence the logical process of retrosynthesis, and the review is organized by the type and method of C–H functionalization.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/org2040018
