Synthesis and Stereochemical Determination of Complestatins: Development of a Palladium(0)-Mediated Indole (Macro)cyclization Reaction

The chloropeptin and complestatin families of glycopeptides are complex natural products with potent anti-HIV properties whose activity is mediated through two complementary sites of action. Previously, our laboratory reported the first total synthesis of chloropeptin II (complestatin), the more strained and challenging of the two naturally occurring chloropeptins. Key to the synthesis was the development of a Pd(0)-mediated macrocyclization that furnished the indole and closed the 16.17-membered DEF macrocycle in a single, high yielding step with excellent control of atropselectivity. Herein, we disclose macrocyclization studies detailing the scope and the factors governing the atropselectivity, its use in directly accessing the chloropeptin I versus II DEF ring system as well as key unnatural isomers, and its utility for both peptide-derived and more conventional carbon-chain based macrocycles. The studies further 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. We also disclose a catalytic variant of the reaction along with a powerful Pd2(dba)3 derived catalyst system and its extension to intramolecular cyclizations with formation of common ring sizes.;By virtue of a single-step, acid-catalyzed ring expansion rearrangement of chloropeptin II to chloropeptin I, both syntheses of chloropeptin II also provided a total synthesis of chloropeptin I. Herein, we examine the factors governing the acid-catalyzed rearrangement on the DEF macrocycle.;We report a complementary and divergent oxidation of chloropeptin II (complestatin) to either complestatin A (neuroprotectin A) or complestatin B (neuroprotectin B), providing the first synthesis of the natural products and establishing their remaining stereochemical assignments. Key to the approach was development of mild reaction conditions to synthesize each natural product in a single step from chloropeptin II (complestatin). Studies conducted on the DEF ring system of complestatin were key to the unambiguous assignment of the stereochemistry as well as the exploration and development of the mild oxidation conditions used in the synthesis.