1,4-Pd Migration-Enabled Synthesis of Fused 4-Membered Rings.

1,4-Palladium migration has been widely used for the functionalization of remote C-H bonds. However, this mechanism has been limited to aryl halide precursors. This work reports an unprecedented Pd0-catalyzed cyclobutanation protocol producing valuable fused cyclobutanes starting from cycloalkenyl (pseudo)halides. This reaction takes place via alkenyl-to-alkyl 1,4-Pd migration, followed by intramolecular Heck coupling. The method performs best with cyclohexenyl precursors, giving access to a variety of substituted bicyclo[4,2,0]octenes. Reactants containing an N-methyl or methoxy group give rise to fused azetidines or oxetanes, respectively, via the same mechanism. Kinetic and deuterium-labeling studies point to a rate-limiting C(sp3)-H activation step.

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

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.

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

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.

GSK973 Is an Inhibitor of the Second Bromodomains (BD2s) of the Bromodomain and Extra-Terminal (BET) Family.

Pan-BET inhibitors have shown profound efficacy in a number of in vivo preclinical models and have entered the clinic in oncology trials where adverse events have been reported. These inhibitors interact equipotently with the eight bromodomains of the BET family of proteins. To better understand the contribution of each domain to their efficacy and to improve from their safety profile, selective inhibitors are required. This Letter discloses the profile of GSK973, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive preclinical in vitro and in vivo characterization.

Efficient and Divergent Total Synthesis of (-)-Epicoccin G and (-)-Rostratin A Enabled by Double C(sp3)-H Activation.

Dithiodiketopiperazines are complex polycyclic natural products possessing a variety of interesting biological activities. Despite their interest, relatively few total syntheses have been completed. We herein report the enantioselective, scalable, and divergent total synthesis of two symmetrical pentacyclic dithiodiketopiperazines, (-)-epicoccin G and (-)-rostratin A. A common intermediate was synthesized on a multigram scale from inexpensive, commercially available starting materials using an enantioselective organocatalytic epoxidation and a double C(sp3)-H activation as key steps, with the latter allowing the efficient simultaneous construction of the two five-membered rings. In addition to the cis,cis-fused target (-)-epiccocin G, the more challenging (-)-rostratin A, possessing two trans ring junctions, was obtained for the first time on a 500 mg scale through the optimization of each step and validation on multigram quantities. Both natural products were synthesized with high overall yields (13-20%). This study should facilitate access to this fascinating and yet understudied family of biologically active natural products.