Showing papers by "Olivier Baudoin published in 2020"

Multiple Catalytic C–H Bond Functionalization for Natural Product Synthesis

Abstract: In the past decade, multiple catalytic C-H bond functionalization has been successfully applied in natural product synthesis as a strategy to reduce the number of steps, increase overall yield and employ more easily available starting materials. This minireview presents selected examples making use of multiple C-H bond functionalization in conceptually different ways. First, linear syntheses are discussed, wherein multiple C-H functionalization is employed either from simple (hetero)cyclic cores, at a late stage, or to build polycyclic systems. Second, the use of multiple C-H functionalization as a strategic tool in convergent synthesis to access and couple complex fragments is discussed. Information on the scalability of the employed methods is provided when available. The presented cases indicate that multiple C-H functionalization strategies should play a great role to shape the future synthesis of functional complex molecules with improved sustainability.

Intermolecular Palladium(0)-Catalyzed Atropo-enantioselective C–H Arylation of Heteroarenes

Abstract: Atropisomeric (hetero)biaryls are motifs with increasing significance in ligands, natural products, and biologically active molecules. The straightforward construction of the stereogenic axis by ef...

Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through Double C-H Activation.

Abstract: Cyclopropanes are important structural motifs found in numerous bioactive molecules, and a number of methods are available for their synthesis. However, one of the simplest cyclopropanation reactions involving the intramolecular coupling of two C-H bonds on gem-dialkyl groups has remained an elusive transformation. We demonstrate herein that this reaction is accessible using aryl bromide or triflate precursors and the 1,4-Pd shift mechanism. The use of pivalate as the base was found to be crucial to divert the mechanistic pathway toward the cyclopropane instead of the previously obtained benzocyclobutene product. Stoichiometric mechanistic studies allowed the identification of aryl- and alkylpalladium pivalates, which are in equilibrium via a five-membered palladacycle. With pivalate, a second C(sp3)-H activation leading to the four-membered palladacycle intermediate and the cyclopropane product is favored. A catalytic reaction was developed and showed a broad scope for the generation of diverse arylcyclopropanes, including valuable bicyclo[3.1.0] systems. This method was applied to a concise synthesis of lemborexant, a recently approved anti-insomnia drug.

Synthesis of Amides and Esters by Palladium(0)-Catalyzed Carbonylative C(sp3)−H Activation

Abstract: The 1,4-palladium shift strategy allows the functionalization of remote C-H bonds that are difficult to reach directly. Reported here is a domino reaction proceeding by C(sp3 )-H activation, 1,4-palladium shift, and amino- or alkoxycarbonylation, which generates a variety of amides and esters bearing a quaternary β-carbon atom. Mechanistic studies showed that the aminocarbonylation of the σ-alkylpalladium intermediate arising from the palladium shift is fast using PPh3 as the ligand, and leads to the amide rather than the previously reported indanone product.

One-Pot Alkene Hydroboration/Palladium-Catalyzed Migratory Suzuki-Miyaura Cross-Coupling

Abstract: Chain-walking is a powerful approach towards the functionalization of C–H bonds remote to a functional group. Whereas various Pd-catalyzed migratory cross-couplings have been developed in the past ...

Divergent Synthesis of Bioactive Dithiodiketopiperazine Natural Products Based on a Double C(sp3)−H Activation Strategy

Abstract: This article provides a detailed report of our efforts to synthesize the dithiodiketopiperazine (DTP) natural products (-)-epicoccin G and (-)-rostratin A using a double C(sp3 )-H activation strategy. The strategy's viability was first established on a model system lacking the C8/C8' alcohols. Then, an efficient stereoselective route including an organocatalytic epoxidation was secured to access a key bis-triflate substrate. This bis-triflate served as the functional handles for the key transformation of the synthesis: a double C(sp3 )-H activation. The successful double activation opened access to a common intermediate for both natural products in high overall yield and on a multigram scale. After several unsuccessful attempts, this intermediate was efficiently converted to (-)-epicoccin G and to the more challenging (-)-rostratin A via suitable oxidation/reduction and protecting group sequences, and via a final sulfuration that occurred in good yield and high diastereoselectivity. These efforts culminated in the synthesis of (-)-epicoccin G and (-)-rostratin A in high overall yields (19.6 % over 14 steps and 12.7 % over 17 steps, respectively), with the latter being obtained on a 500 mg scale. Toxicity assessments of these natural products and several analogues (including the newly synthesized epicoccin K) in the leukemia cell line K562 confirmed the importance of the disulfide bridge for activity and identified dianhydrorostratin A as a 20x more potent analogue.