A Boron Alkylidene–Alkene Cycloaddition Reaction: Application to the Synthesis of Aphanamal

We describe an unusual net [2+2] cycloaddition reaction between boron alkylidenes and unactivated alkenes. This reaction provides a new method for the construction of carbocyclic ring systems bearing versatile organoboronic esters. Aside from surveying the scope of this reaction, we provide details about the mechanistic underpinnings of this process, and examine its application to the synthesis of the natural product aphanamal.     

Four Oxidation States in a Single Photoredox Nickel‐Based Catalytic Cycle: A Computational Study

The computational characterization of the full catalytic cycle for the synthesis of indoline from the reaction between iodoacetanilide and a terminal alkene catalyzed by a nickel complex and a photoactive ruthenium species is presented. A variety of oxidation states of nickel, Ni⁰, Ni^I, Ni^II, and Ni^III, is shown to participate in the mechanism. Ni⁰ is necessary for the oxidative addition of the C?I bond, which goes through a Ni^I intermediate and results in a Ni^II species. The Ni^II species inserts into the alkene, but does not undergo the reductive elimination necessary for C?N bond formation. This oxidatively induced reductive elimination can be accomplished only after oxidation to Ni^III by the photoactive ruthenium species. All the reaction steps are computationally characterized, and the barriers for the single‐electron transfer steps calculated using a modified version of the Marcus Theory.     

Iterative Arylation of Amino Acids and Aliphatic Amines via δ‐C(sp3)−H Activation: Experimental and Computational Exploration

Directed C?H functionalization has been realized as a complementary tool to the traditional approaches for a straightforward access of non‐proteinogenic amino acids; albeit such a process is restricted mostly up to the γ‐position. In the present work, we demonstrate the diverse (hetero)arylation of amino acids and analogous aliphatic amines selectively at the remote δ‐position by tuning the reactivity controlled by ligands. An organopalladium δ‐C(sp³)?H activated intermediate has been isolated and crystallographically characterized. Mechanistic investigations carried out experimentally in conjunction with computational studies shed light on the difference in the mechanistic picture depending on the substrate structure.     

Palladium‐Catalyzed Annulation of Diarylamines with Olefins through C?H Activation: Direct Access to N‐Arylindoles

A palladium‐catalyzed dehydrogenative coupling between diarylamines and olefins has been discovered for the synthesis of substituted indoles. This intermolecular annulation approach incorporates readily available olefins for the first time and obviates the need of any additional directing group. An ortho palladation, olefin coordination, and β‐migratory insertion sequence has been proposed for the generation of olefinated intermediate, which is found to produce the expected indole moiety.     

Synthesis and Identification of Key Biosynthetic Intermediates for the Formation of the Tricyclic Skeleton of Saxitoxin

Saxitoxin (STX) and its analogues are potent voltage‐gated sodium channel blockers biosynthesized by freshwater cyanobacteria and marine dinoflagellates. We previously identified genetically predicted biosynthetic intermediates of STX at early stages, Int‐A′ and Int‐C′2, in these microorganisms. However, the mechanism to form the tricyclic skeleton of STX was unknown. To solve this problem, we screened for unidentified intermediates by analyzing the results from previous incorporation experiments with ¹⁵N‐labeled Int‐C′2. The presence of monohydroxy‐Int‐C′2 and possibly Int‐E′ was suggested, and 11‐hydroxy‐Int‐C′2 and Int‐E′ were identified from synthesized standards and LC‐MS. Furthermore, we observed that the hydroxy group at C11 of 11‐hydroxy‐Int‐C′2 was slowly replaced by CD₃O in CD₃OD. Based on this characteristic reactivity, we propose a possible mechanism to form the tricyclic skeleton of STX via a bicyclic intermediate from 11‐hydroxy‐Int‐C′2.     

Access to Multifunctionalized Benzofurans by Aryl Nickelation of Alkynes: Efficient Synthesis of the Anti‐Arrhythmic Drug Amiodarone

An unconventional nickel‐catalyzed reaction was developed for the synthesis of multifunctionalized benzofurans from alkyne‐tethered phenolic esters. The transformation involves the generation of a nucleophilic vinyl Ni^II species by the regioselective syn‐aryl nickelation of an alkyne, which then undergoes an intramolecular cyclization with phenol ester to yield highly functionalized 1,1‐disubstituted alkenes with 3‐benzofuranyl and (hetero)aryl substituents. The methodology can be used for the late‐stage benzofuran incorporation of various drug molecules and natural products, such as 2‐propylvaleric acid, gemfibrozil, biotin, and lithocholic acid. Furthermore, this arylative cyclization method was successfully applied for the efficient synthesis of the anti‐arrhythmic drug amiodarone.     

A Scalable Total Synthesis of the Antitumor Agents Et‐743 and Lurbinectedin

An efficient and scalable approach is described for the total synthesis of the marine natural product Et‐743 and its derivative lubinectedin, which are valuable antitumor compounds. The method delivers 1.6 % overall yield in 26 total steps from Cbz‐protected (S)‐tyrosine. It features the use of a common advanced intermediate to create the right and left parts of these compounds, and a light‐mediated remote C?H bond activation to assemble a benzo[1,3]dioxole‐containing intermediate.