Total Synthesis of Chloropeptin II (Complestatin) and Chloropeptin I

Abstract

The first total synthesis of chloropeptin II (1, complestatin) is disclosed. Key elements of the approach include the use of an intramolecular Larock indole synthesis for the initial macrocyclization, adopting conditions that permit utilization of a 2-bromoaniline, incorporating a terminal alkyne substituent (−SiEt3) that sterically dictates the indole cyclization regioselectivity, and benefiting from an aniline protecting group (−Ac) that enhances the atropdiastereoselectivity and diminishes the strained indole reactivity toward subsequent electrophilic reagents. Not only did this key reaction provide the fully functionalized right-hand ring system of 1 in superb conversion (89%) and good atropdiastereoselectivity (4:1 R: S), but it also represents the first reported example of what will prove to be a useful Larock macrocyclization strategy. Subsequent introduction of the left-hand ring system enlisting an aromatic nucleophilic substitution reaction for macrocyclization with biaryl ether formation completed the assemblage of the core bicyclic structure of 1. Intrinsic in the design of the approach and by virtue of the single-step acid-catalyzed conversion of chloropeptin II (1) to chloropeptin I (2), the route also provides a total synthesis of 2.

Recent Advances in Substrate-Controlled Asymmetric Induction Derived from Chiral Pool α-Amino Acids for Natural Product Synthesis

“…Memory of chirality is a very special case. Recently, Kim et al reported the first total synthesis of (−)-penibruguieramine A (22), employing a biomimetic approach (Scheme 4) [17,18]. Acid 17 was coupled with L-proline t-butyl ester (18) in the presence of DCC, providing amide 19, an intramolecular aldol reaction precursor, in 79% yield.…”

“…The pivotal arylation of diketopiperazine 25 with advanced electrophile 26 in the presence of (CuOTf) 2 PhMe and L2 provided desired pyrroloindoline 27 in moderate yield. Final compound 28 was conveniently constructed from tetracyclic intermediate 27 using a Larock indolization strategy [21,22]. Additionally, another natural product, (+)-naseseazine B, was obtained stereoselectively from cyclic proline-tryptophan precursor 29, employing a similar synthetic sequence.…”

Solving the Supply of Resveratrol Tetramers from Papua New Guinean Rainforest Anisoptera Species That Inhibit Bacterial Type III Secretion Systems

“…Hopeaphenol (1, 20 mg, 0.02 mmol) was dissolved in CH3OH-CH2Cl2 (1:1, 1.5 mL) at room temperature before TMS-diazomethane (2.0 M in Et2O, 650 µL, 1.30 mmol) was added dropwise. 67 The reaction was stirred overnight at room temperature, and then evaporated to dryness. The crude reaction mixture was adsorbed to C18- Plates were incubated at 26 °C for 1 h followed by incubation at 37 °C for 3 h and then transferred back to 26 °C for 15 min.…”

Hypervalent iodine reagents in the total synthesis of natural products

“…77,78 The oxidation of a complex substrate bearing a primary alcohol has been described by Hirama and co-workers (Scheme 5). ROMPM, 114,115,118,183 ROBn, 80,90,104,106,110,124,191,192 ROTr, 180 ROMe, 94,101,107,113,192 RONPhth, 88 RON=CMe 2 , 88 ArOAllyl, 193 ArOMe, 108,130,131,192,194,195 ArOBn, 127,131 ArOTBS, 174 R 2 NBoc, 174,[194][195][196][197] 208 This IBX analogue generates only water during the oxidation, while DMP releases acetic acid. When DMP was applied the required keto ester was obtained in only 60%, with 40% of the starting lactone recovered (Scheme 6).…”