A Pd(0)-mediated indole (macro)cyclization reaction.

Herein we report a systematic study of the Larock indole annulation designed to explore the scope and define the generality of its use in macrocyclization reactions, its use in directly accessing the chloropeptin I versus II DEF ring system as well as key unnatural isomers, its utility for both peptide-derived and more conventional carbon-chain based macrocycles, and its extension to intramolecular cyclizations with formation of common ring sizes. The studies define a powerful method complementary to the Stille or Suzuki cross-coupling reactions for the synthesis of cyclic or macrocyclic ring systems containing an embedded indole, tolerating numerous functional groups and incorporating various (up to 28-membered) ring sizes. As a result of the efforts to expand the usefulness and scope of the reaction, we also disclose a catalytic variant of the reaction, along with a powerful Pd(2)(dba)(3)-derived catalyst system, and an examination of the factors impacting reactivity and catalysis.

Synthesis and stereochemical determination of complestatin A and B (neuroprotectin A and B).

Recently, we reported the first total synthesis of chloropeptin II (1, complestatin), the more strained and challenging of the two naturally occurring chloropeptins. Central to the design of the approach and by virtue of a single-step, acid-catalyzed ring expansion rearrangement of chloropeptin II to chloropeptin I, the route also provided a total synthesis of chloropeptin I. Herein, we report a complementary and divergent oxidation of chloropeptin II (1, complestatin) to either complestatin A (2, neuroprotectin A) or complestatin B (3, neuroprotectin B), providing the first synthesis of the natural products and establishing their remaining stereochemical assignments.

Total syntheses of heimiol A, hopeahainol D, and constrained analogues.

Unlabelled: [Image: see text]

Idsi To The Rescue: Use of a carefully designed cascade process empowered by the unique iodonium-reagent IDSI [(EtSI)Cl•SbCl] provided the means to construct the entire [3.2.2]-bicyclic core of both targets in a single, stereocontrolled operation.

Total synthesis of complestatin: development of a Pd(0)-mediated indole annulation for macrocyclization.

Full details of the initial development and continued examination of a powerful intramolecular palladium(0)-mediated indole annulation for macrocyclization closure of the strained 16-membered biaryl ring system found in complestatin (1, chloropeptin II) and the definition of factors impacting its intrinsic atropodiastereoselectivity are described. Its examination and use in an alternative, second-generation total synthesis of complestatin are detailed in which the order of the macrocyclization reactions was reversed from our first-generation total synthesis. In this approach and with the ABCD biaryl ether ring system in place, the key Larock cyclization was conducted with substrate 36 (containing four phenols, five secondary amides, one carbamate, and four labile aryl chlorides) and provided the product 37 (56%) exclusively as a single atropisomer (>20:1, detection limits) possessing the natural (R)-configuration.

Total synthesis of diverse carbogenic complexity within the resveratrol class from a common building block.

Although biomimetic approaches have proven capable of converting resveratrol (1) concurrently into many of the more complex oligomers produced by plants throughout the world (such as 2-10), methods to access single members of the family have proven far more difficult to identify. Herein is described a strategy-level solution based on the use of a common building block, one distinct from Nature's starting material, that can participate in a variety of highly selective, reagent-controlled reaction cascades. These endeavors have led to the controlled synthesis of 25 natural products and analogues, molecules whose architectures encompass nearly all the carbogenic diversity of the resveratrol family.

Converting gem-dimethyl groups into cyclopropanes via Pd-catalyzed sequential C-H activation and radical cyclization.

A novel route to the synthesis of cyclopropane derivatives is described. 1,1-Dimethyls in 2-(1,1-dimethylalkyl)dimethyloxazolines are first converted into 1,3-diiodide derivatives via Pd-catalyzed sequential C-H activation and then radically cyclized to provide 2-(1-alkylcylclopropyl)dimethyloxazolines. The use of EtOAc as a solvent is crucial for the diiodination of the functionalized substrates.