Total Synthesis of (+)-11,11'-Dideoxyverticillin A

Abstract

The fungal metabolite (+)-11,11'-dideoxyverticillin A, a cytotoxic alkaloid isolated from a marine Penicillium sp., belongs to a fascinating family of densely functionalized, stereochemically complex, and intricate dimeric epidithiodiketopiperazine natural products. Although the dimeric epidithiodiketopiperazines have been known for nearly four decades, none has succumbed to total synthesis. We report a concise enantioselective total synthesis of (+)-11,11'-dideoxyverticillin A via a strategy inspired by our biosynthetic hypothesis for this alkaloid. Highly stereo- and chemoselective advanced stage tetrahydroxylation and tetrathiolation reactions, as well as a mild strategy for the introduction of the epidithiodiketopiperazine core in the final step were developed to address this highly sensitive substructure. Our rapid functionalization of the advanced molecular framework aims to mimic plausible biosynthetic steps and offers an effective strategy for the chemical synthesis of other members of this family of alkaloids.

Total Synthesis of (+)-Chaetocin and its Analogues: Their Histone Methyltransferase G9a Inhibitory Activity

“…7,8 Based on the total synthesis of 2, they installed disulfide bridges into the octacyclic core through R-hydroxylation with [Ag(py) 2 ]MnO 4 as a stoichiometric oxidant. In spite of their successes, the chemical synthesis of 1 still poses the additional problem of how to prevent facile -elimination of serine units, if serine is used as a starting material.…”

“…DKP 9 was synthesized without epimerization in 69% yield (5 steps) starting from known N-Cbz-protected N-methyl-D-serine (7) 12 and commercially available D-Try-OMe•HCl (8). 13 The obtained DKP was subjected to the bromocyclization reaction with NBS to afford 10 in 88% yield.…”

Structure, Bioactivity and Synthesis of Natural Products with Hexahydropyrrolo[2,3‐b]indole

“…In the total synthesis of (+)-11,11'-dideoxyverticillin A, Movassaghi et al used bromine and acetonitrile to obtain 3a-bromo-HPIC. [120] de Lera et al studied the mechanism and proposed the addition of pyridinium p-toluenesulfonate (PPTS) to improve the yield of the bromocyclized product in the reaction with NBS. [121] Synthesis of 3a-hydroxy-HPIC: Photochemical oxidation of N b ,N 1 -dimethyltryptamine (85) in CH 2 Cl 2 using pyridine Noxide as oxygen source afforded the HPI (AE )-87.…”

A Unified Strategy Targeting the Thiodiketopiperazine Mycotoxins Exserohilone, Gliotoxin, the Epicoccins, the Epicorazines, Rostratin A and Aranotin

“…To the best of our knowledge, however, only gliotoxin has so far been produced by total synthesis, [19] although other synthetic strategies directed towards some of the thiodiketopiperazines, including rostratin C, [20] the epicoccins A, C and D (3 a-c), [21] gliotoxin (1) [22] and MPC1001, [23] have been reported. Our results in the construction of C 2 -symmetrical and unsymmetrical diketopiperazines in a one-step procedure from proline-type amino acids, [24] as well as the impressive thiolation results of Movassaghi and co-workers, [25] prompted us to target the synthesis of these thiodiketopiperazines. Our preliminary results relating to the construction of the scaffold of epicoc-A C H T U N G T R E N N U N G cins A, C and D were published earlier.…”