All-Carbon Quaternary Centers in Natural Products and Medicinal Chemistry: Recent Advances (2023)


A remaining challenge in the field of synthetic chemistry is the formation of all-carbon quaternary centers, a feature found in many natural products, especially in spirocyclic ring systems.1Methods that can readily stereoselectively generate asymmetric quaternary centers are highly desirable. This area of ​​research represents an untapped opportunity to discover new chemical reactivities for new chemicals to treat human diseases. Natural products (NPs) are a rich source of therapeutic potential due to their diverse chemical scaffolds, which often contain all-carbon quaternary stereocenters. In fact, more than 50% of all drugs currently in clinical use are derived from NPs.1Although the use of small molecules has become routine in drug discovery programs, natural product synthesis remains an important part of basic research and continues to contribute to medicinal chemistry programs.1

This short report will focus on recent advances in the synthesis of all quaternary carbon centers, in particular the formation of spirocycles and the application of some pharmaceutically valuable compounds.

Here we review recent progress (2010–2015) in the creation of all quaternary carbon centers, and Overman, Marek, Aggarwal, and Stoltz et al. detailing other related works not included. 2 , 3 , 4 , 5 , 6 This review also highlights the total synthesis of selected natural products containing all-carbon quaternary helix centers and promising medicinal properties, illustrating how the field of natural products is progressing in drug discovery. still play an important role in the process.

partial fragment

general principles

Classical methods for generating all quaternary carbon centers from simple synthons (Figure 1) include i) alkylation, ii) allylation, iii) conjugate addition, iv) rearrangement, v) metal-mediated induced responses and changes in these responses.2These chemical processes are described in detail in the literature. 2, 3, 4, 8 The current state of organic chemistry strongly favors the preparation of enantiomerically pure molecules, and their synthetic strategies follow atomic

Reactions mediated by metals: titanium

Tsubouchi and co-workers disclose a practical synthesis for the construction of a wide range of titanium-mediated acyclic quaternary carbon centers.10cHighly diastereoselective reactions of γ,γ-disubstituted allyl titanium species3- Created in situ from allyl sulfide1i react2, with aliphatic or aromatic ketones4Provide suitable high-functioning acyclic products5or6(Option one). A synthetic product with two adjacent fully substituted carbons

Section B: Methods for Helicoidal All-Carbon Quaternary Centers

Efficient asymmetric synthetic methods for the formation of all-carbon quaternary spiro compounds are highly desirable, since these molecules are widely found in natural and unnatural medically relevant compounds. The following methods and total syntheses highlight the ability to rethink classical methods to solve contemporary synthetic problems for generating these structurally challenging molecular structures.


Secondary metabolites and unnatural molecules containing all quaternary carbon centers have a rich history as important reservoirs of bioactive properties, possibly due to their unusual frameworks. Significant progress has been made in the past five years, which has enabled the further development of medicinal chemistry involving the structure of these molecules to study their biological properties. Future chemical synthesis of complex molecules will be improved using these new chemical tools

Thank you

We are very grateful for the financial supportAmerican United Charities Lebanon-Syria (ALSAC).We thank dr. Cherise Guess of the Science Newsroom for editorial support at St. Mary's Children's Research Hospital. Judas.

Taotao LingHe earned his doctorate in organic chemistry at UCSD and worked with prof. by E.A. on the complete synthesis of natural products. Theodorakis. Post-doctoral work with Prof. K.C. Nicolaou of the Scripps Research Institute works with diazoamide A and azapyridine. He is currently a research associate in the Department of Chemical Biology and Therapy at the Children's Research Hospital St. Judas.

cited (165)

  • Aryl carbamylation of living olefin radicals to generate amides with all carbon quaternary stereocenters

    2023, European Journal of Organic Chemistry

    Here we report on Ag+/S2Europa82−Induction measurements of functionalized succinamides with all-carbon quaternary centers via a radical carbamylation/aryl migration/desulfonylation cascade. An improved process was developed by radical Smiles rearrangement using readily available and inexpensive oxalic acid monoamides as carbamoyl radical precursors. Furthermore, oxygen and water tolerance, ease of operation, convenient reagents, and scalability increase the practical value of the proposed synthetic strategy.

  • Electron-controlled regioselective hydroarylation of gem-difluoropropadiene

    2022 Cell Reports Physical Science

    All-carbon quaternary centers are ubiquitous structural motifs in natural products, bioactive molecules, and drugs. The formation of these crowded carbon centers is notoriously challenging, and methods to access them remain in high demand. Transition metal-based strategies have emerged as efficient approaches for quaternary carbons, mainly relying on cross-coupling reactions and alkene arylation processes. Presented here is a simple method for generating benzylic all-carbon quaternary centers usinggem- difluoropropadiene. Features of the method include C–H functionalization at room temperature, intercalationgem-difluoroalene, and productsgem- Difluoroalkene products with wide application in synthesis and pharmaceutical sciences. Mechanistic studies support rhodium-catalyzed C–H cleavage-limiting transformations, possibly via a coordinated metalation-deprotonation pathway. selective region insertiongem-Difluoropropadiene is controlled by electronic effects.

  • Indium-mediated 1,2-addition of iododifluoromethyl ketone to α,β-unsaturated ketones

    2022, tetraedar

    Excerpt from the quote:

    Controlling the regioselectivity to achieve addition at different sites has been one of the challenges. Traditional 1,2-addition reactions are mainly carried out with polar organometallic reagents, especially organozinc [5], organoaluminum [6] or Grignard reagents [7]. However, due to cumbersome preparation, potential hazards and reactive reactivity, research progress has been difficult [4].

    The novel indium-mediated difluoroalkylation of iododifluoromethyl ketones with α,β-unsaturated ketones provides an apparently important route to 1,2-addition products with excellent regioselectivity. The method has a wide range of substrates, high efficiency and mild reaction conditions. In addition, this method has also been applied to the synthesis of difluoro derivatives of bioactive molecules containing unsaturated ketone structures, which can serve as potentially valuable fluorinated intermediates in drug discovery.

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All-Carbon Quaternary Centers in Natural Products and Medicinal Chemistry: Recent Advances (1)

Taotao LingHe earned his doctorate in organic chemistry at UCSD and worked with prof. by E.A. on the complete synthesis of natural products. Theodorakis. Post-doctoral work with Prof. K.C. Nicolaou of the Scripps Research Institute works with diazoamide A and azapyridine. He is currently a research associate in the Department of Chemical Biology and Therapy at the Children's Research Hospital St. Judas.

All-Carbon Quaternary Centers in Natural Products and Medicinal Chemistry: Recent Advances (2)

Fatima RivasShe received her bachelor's degree from Cal State University, Dominguez Hills, and her PhD in organic chemistry from UC San Diego, where she worked with E.A. Theodorakis. Postdoctoral work with prof. K.C. Nicolaou worked on the total synthesis of myeritin at the Scripps Research Institute. She is currently an assistant professor at the Department of Chemical Biology and Therapy at the Children's Research Hospital St. Judas. Her research group is focused on the synthesis of biologically active natural products for the treatment of pediatric malignancies.

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