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

Here we report an Ag⁺/S₂O₈^2-measurement induced for functionalized succinyl diamides containing an all-carbon quaternary stereocenter via an aminoformylation/aryl-migration/radical desulfonylation cascade. The improved process is developed by employing readily available and inexpensive oxalic monoamide as a precursor to the carbamoyl radical via the Smiles rearrangement of the radical. Furthermore, oxygen and water tolerance, operational simplicity, convenient reagents, as well as scalability, enhance the practical value of the proposed synthesis strategy.

Quaternary carbon centers are ubiquitous structural motifs in natural products, bioactive molecules and pharmaceuticals. Forming these crowded carbon centers is well known to be challenging, and methods for accessing them remain in high demand. Transition metal-based strategies have emerged as a powerful approach for quaternary carbons, relying mainly on cross-coupling reactions and olefin arylation processes. Here is presented a direct method to create quaternary centers of benzylic carbon employingegg yolk-difluoroalenes. The characteristics of this method include C-H functionalization at room temperature, excellent regioselectivity in the insertion ofegg yolk-difluoroalenes and generation ofegg yolk-difluoroalkene products, which have widespread applications in synthesis and pharmaceutical sciences. Mechanistic studies support a rhodium-catalyzed C-H cleavage limiting turnover that likely occurs through a concerted metalation deprotonation pathway. regioselective insertion of theegg yolk-difluoroalene is controlled by electronic effects.

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.

Tetrahedron: Asymmetry, Volume 28, Issue 11, 2017, pp. 1633-1643

A practical synthesis of new phosphoramidite, phosphite and diamidophosphiteP,N-ligands derived from (R,R)-Tartaric acid. A study of these chiral inducers showed that they provide up to 93%simin the Pd-catalyzed asymmetric allylations of (E)-1,3-diphenylallyl acetate, up to 84%simin the Pd-catalyzed asymmetric alkylation of cinnamyl acetate with ethyl 2-oxocyclohexane-1-carboxylate and up to 63%simin the Pd-catalyzed desymmetrization ofN,N′-ditosyl-meso-cyclopent-4-ene-1,3-diol biscarbamate. The effects of structural modules, such as the nature of the ring containing phosphorus or exocyclic substituent, as well as the nature of the palladium source on catalytic activity and enantioselectivity were investigated.

Tetrahedron, Volume 73, Issue 29, 2017, pp. 4023-4038

Pericyclic reactions can be challenging processes to make asymmetric, due to the concerted and non-polar nature of the transition states. Several examples have been reported where a suitable catalyst binds to a heteroatom-containing substituent on the substrate and accelerates the reaction rate. The requirement to coordinate functionalized substrates has limited the generality of such asymmetric transformations. Multifunctional Brønsted acids are promising catalysts that represent a new paradigm in asymmetric pericyclic reactions. These chiral catalysts rely on multiple non-covalent interactions in the transition state for asymmetric induction, which has been used to activate more general classes of substrates. In this review, we will cover recent advances in Brønsted acid-catalyzed pericyclic reactions and discuss the impact of catalyst design on expanding the substrate scope for highly enantioselective processes.

Main chiral auxiliary applications, 2014, pp. 173-261

Comprehensive Organometallic Chemistry IV, Volume 13, 2022, pp. 132-193

The transition metal-catalyzed difunctionalization of unsaturated organics is a powerful bond-forming strategy in organic chemistry. The installation of combinations of amino, oxo, carbo and halo groups on a carbon-carbon double or triple bond allows for the rapid accumulation of molecular complexity in a highly selective and efficient manner. This chapter focuses on reactions of the general type in which a transition metal mediates the addition of coupling partners across a double or triple bond. Reactions in which the transition metal plays an auxiliary role (without adding or binding to the unsaturated species) are not covered. Given the broad scope of the topic, the material in this chapter is not intended to be comprehensive in nature; rather, the chapter is written with the aim of presenting an overview of the topics covered. Representative examples were chosen to highlight the state of the art and draw attention to outstanding challenges and limitations of current methods.

Tetrahedron Letters, Volume 60, Issue 42, 2019, Article 151148

The reactions of a catalytically generated pot of bicyclic zinc enolate with various electrophiles are reported. Zinc enolate as a key intermediate is efficiently provided from the Ni catalyzed reductive cyclization of alkynyl cyclohexadienone. Employing aldehydes, imine, nitroalkene and α,β-unsaturated carbonyl compounds as electrophiles, this new class of one-pot reactions gave multifunctionalitycis-hydrobenzofurans and octahydro-4,7-ethanebenzofuran-9-one derivatives in moderate to good yields.

Cell Reports Physical Science, Volume 2, Issue 5, 2021, Article 100406

The development of catalytic generation of allyl-metal complexes through the allylic C-H cleavage of alkenes without pre-functionalization followed by the formation of site and stereoselective carbon-carbon bonds is of great importance in organic synthesis, providing a direct and economical approach to introduce a Allyl group versatile solution in organic molecules. Although significant advances have been achieved in enantioselective transformations of electrophilic allyl-metal complexes and allyl radicals, enantioselective reactions of nucleophilic allyl-metal intermediates provided via allylic C-H cleavage remain undeveloped. Here, we identify a multitasking chiral catalyst derived from a commercially available phosphine ligand and cobalt salt that precisely controls the chemoselective formation of the allyl-cobalt complex and the stereoselective and local addition to carbonyls, providing a broad scope of homoallyl alcohols in high yield. and stereoselectivity. This work can establish a platform for the development of enantioselective transformations of nucleophilic organometallic complexes generated from the catalytic functionalization of C–H.