Quaternary carbon centers in natural products and medicinal chemistry: recent advances (2023)


A remaining challenge in the field of synthetic chemistry is the formation of quaternary carbon centers, a feature found in many natural products, particularly in spirocycle systems.1Methodologies that can easily generate stereoselectively asymmetric quaternary centers are highly desirable. This area of ​​research offers an untapped opportunity to discover new chemical reactivities to access new chemical materials to treat human disease. Natural products (NPs) are a rich source of therapeutic leads because of their diverse chemical scaffolds, which often contain a quaternary carbon stereocenter. In fact, currently more than 50% of all drugs in clinical use are derived from NPs.1Although the use of small molecules has become routine in drug discovery programs, the synthesis of natural products remains an essential component of basic research and continues to contribute to medicinal chemistry programs.1

This brief report will highlight recent advances in the synthesis of all quaternary carbon centers, particularly the formation of spirocycles and some applications in compounds of medicinal value.

Here we survey the most recent advances (2010–2015) to generate all quaternary carbon centers, other relevant efforts not included have been described in detail by Overman, Marek, Aggarwal, and Stoltz, among others.2, 3, 4, 5 , 6 The review also highlights a select number of natural product total syntheses containing quaternary carbon spirocenters and promising medicinal properties, illustrating how the field of natural products continues to play a significant role in the drug discovery process.

section excerpts

General principles

Classical approaches to generating all quaternary carbon centers from single synthons (Fig.1) include i) alkylation reactions, ii) allylations, iii) conjugate additions, iv) rearrangement reactions, v) metal-mediated reactions and variations of these reactions.2These chemical processes are well described in the literature.2, 3, 4, 8 The current state of organic chemistry strongly prefers that molecules be prepared enantiomerically pure and that their synthetic strategies follow an atom

Metal mediated reactions: titanium

A practical synthesis for constructing a wide range of titanium-mediated acyclic quaternary carbon centers has been reported by Tsubouchi et al.10cA highly diastereoselective reaction of γ,γ-disubstituted allyl-titanium species3— generated in situ from allyl sulfides1and reagent2, with aliphatic or aromatic ketones4to provide the corresponding highly functionalized acyclic products5or6(Scheme 1). The resulting product containing two adjacent fully substituted carbons

Section B: methods for spiro quaternary carbon centers

Efficient asymmetric synthetic methods to form quaternary carbon spirocyclic compounds are highly desirable because these molecules are widely found in both natural and unnatural medicinally relevant compounds. The following methods and total syntheses emphasize the power of re-evaluating classical methods to solve contemporary synthetic problems in order to generate these structurally challenging molecular architectures.

Final remarks

Secondary metabolites and unnatural molecules containing all quaternary carbon centers have a rich history as important reservoirs for biologically active properties, presumably due to their unusual structure. Significant progress has been made in the last five years to allow further development of medicinal chemistry involving these molecular structures to interrogate their biological properties. Future chemical syntheses of complex molecules using these new chemical tools will improve


We appreciate the financial support ofAmerican Libanese Syrian Associated Charities (ALSAC). We thank Dr. Cherise Guess of the Science Editing Department for editorial support, St. Jude Children's Research Hospital.

Taotao Lingreceived his PhD from UCSD in organic chemistry from his work on total synthesis of natural products with Professor E.A. Theodorakis. He carried out postdoctoral work with Professor K.C. Nicolaou at the Scripps Research Institute working with diazonamide A and azaspiracid. He is currently an associate scientist in the Department of Chemical Biology and Therapeutics at St. Jude Children's Research Hospital.

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

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    Quote Excerpt:

    That controlling regioselectivity to achieve addition in different places has always been one of the challenges. Traditional 1,2 addition reactions are carried out mainly by polar organometallic reagents, particularly organozinc [5], organoaluminum [6] or Grignard reagents [7]. However, research progress is difficult to advance due to cumbersome preparation, potential danger and active reactivity [4].

    A novel indium-mediated difluoroalkylation of iododifluoromethyl ketones with α, β-unsaturated ketones, which provides an obviously significant route to access the 1,2 addition product with excellent regioselectivity. This method has a wide range of substrate scope, good efficiency and mild reaction conditions. Furthermore, this method has been applied to the synthesis of difluoro derivatives of biologically active molecules containing unsaturated ketone structures, which can serve as potentially valuable fluorinated intermediates in drug discovery.

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Quaternary carbon centers in natural products and medicinal chemistry: recent advances (1)

Taotao Lingreceived his PhD from UCSD in organic chemistry from his work on total synthesis of natural products with Professor E.A. Theodorakis. He carried out postdoctoral work with Professor K.C. Nicolaou at the Scripps Research Institute working with diazonamide A and azaspiracid. He is currently an associate scientist in the Department of Chemical Biology and Therapeutics at St. Jude Children's Research Hospital.

Quaternary carbon centers in natural products and medicinal chemistry: recent advances (2)

Fatima Rivasreceived his BS from California State University California, Dominguez Hills and obtained his PhD from UCSD in organic chemistry from his synthetic work on zoantamines with Professor E.A. Theodorakis. She carried out postdoctoral work with Professor K.C. Nicolaou at the Scripps Research Institute working on synthetic studies for the full synthesis of maitotoxin. She is currently an assistant professor in the Department of Chemical Biology and Therapeutics at St. Jude Children's Research Hospital. Her research group focuses on synthetic efforts for biologically active natural products for the treatment of pediatric malignancies.

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