Enantioselective Total Synthesis of (−)-Acetylaranotin, a Dihydrooxepine Epidithiodiketopiperazine

Abstract

The first total synthesis of the dihydrooxepine-containing epidithiodiketopiperazine (ETP) (−)-acetylaranotin (1) is reported. The key steps of the synthesis include an enantioselective azomethine ylide (1, 3)-dipolar cycloaddition reaction to set the absolute and relative stereochemistry, a rhodium-catalyzed cycloisomerization/chloride elimination sequence to generate the dihydrooxepine moiety, and a stereoretentive diketopiperazine sulfenylation to install the epidisulfide. This synthesis provides access to (−)-1 in 18 steps from inexpensive, commercially available starting materials. We anticipate that the approach described herein will serve as a general strategy for the synthesis of additional members of the dihydrooxepine ETP family.

Epidithiodioxopiperazines. occurrence, synthesis and biogenesis

“…135 Pyrrolidine 254 was synthesized with >98% ee by (1,3)-dipolar cycloaddition of cinnamaldimine 253 to t -butyl acrylate ( 252 ) and subsequent cleavage of the t -butyl ester (Scheme 24). Protection of the amine and ozonolytic cleavage of the alkene provided lactone 255 in good yield.…”

“…135 Elimination of HCl and hydrolysis of the ester gave acid 260 , while deprotection of the Teoc group and HCl elimination of the same compound gave amine 261 . BOP-Cl–mediated coupling of 260 and 261 delivered amide 262 , which readily cyclized to dioxopiperazine 263 after TBAF·( t -BuOH) 4 –induced desilylation.…”

Biosynthetic Pathway for the Epipolythiodioxopiperazine Acetylaranotin in Aspergillus terreus Revealed by Genome-Based Deletion Analysis

“…Total synthesis of acetylaranotin ( 1 ) was recently accomplished by the Reisman group and the Tokuyama group. 21,22 Yet, several obstacles have hindered an elaborate study of the biosynthesis of acetylaranotin ( 1 ) and the potential genes involved. First, the production yield of acetylaranotin ( 1 ) in A. terreus is low.…”

Enantioselective Synthesis of (−)-Acetylapoaranotin

“…9 The silyl-protected cyclohexadienol 7 was envisioned to arise from siloxyenone 8 , which we expected to be available in short order from pyrrolidine 9 . In analogy to our synthesis of 1 , 9 would be prepared from the product of a Cu-catalyzed asymmetric (1,3)-dipolar cycloaddition 14 using simple starting materials: acrylamide 10 , cinnamaldehyde ( 12 ), and ethyl glycinate ( 11 ).…”

“…17 Amide coupling between acid 17 and dihydrooxepine-containing amine 18 was achieved in high yield using BOP-Cl. Treatment of dipeptide 19 with TBAF·( t BuOH) 4 in acetonitrile at 60 °C—the conditions developed for global desilylation and DKP formation in our synthesis of acetylaranotin 9 —led to elimination of the dienyl alcohol to give the corresponding arene. 18 This undesired reactivity could be mitigated when the reaction was conducted with excess TBAF at room temperature, providing diol 20 in 47% yield.…”