Towards the Synthesis of Dihydrooxepino[4,3-b]pyrrole-Containing Natural Products via Cope Rearrangement of Vinyl Pyrrole Epoxides

Abstract

An approach to the dihydrooxepino[4,3-b]pyrrole core of diketopiperazine natural products which utilizes a vinyl pyrrole epoxide Cope rearrangement was investigated. It was found that an ester substituent on the epoxide was essential for the [3,3]-rearrangement to occur. Density functional calculations with M06-2X provided explanations for the effects of the pyrrole and ester groups on these rearrangements.

Catalytic Enantioselective Synthesis of 2,5‐Dihydrooxepines

“…[ 3,3]-Sigmatropic rearrangement is an efficient strategy to access dihydrooxepines in as tereospecific manner. [5,6] Cope rearrangement of 1,2divinyl epoxides provides 4,5-dihydrooxepine derivatives. [5] A similar transformation with cyclopropane derivatives where one of the vinyl groups is replaced with aC = Ogroup,known as the retro-Claisen rearrangement, leads to 2,5-dihydrooxepine derivatives through an analogous mechanism.…”

“…[5,6] Cope rearrangement of 1,2divinyl epoxides provides 4,5-dihydrooxepine derivatives. [5] A similar transformation with cyclopropane derivatives where one of the vinyl groups is replaced with aC = Ogroup,known as the retro-Claisen rearrangement, leads to 2,5-dihydrooxepine derivatives through an analogous mechanism. [6] While retro-Claisen rearrangements of this type are quite common for 2,5-dihydrooxepines,a symmetric examples of this reac-tion are rare.…”

“…[10] Enantioselective formation of 2,5-dihydrooxepine was first examined with a-bromoacrolein and g-methyl-a-vinyl diazoester in the presence of COBI catalyst 3a.W hen the reaction was carried out at À78 8 8Cinpropionitrile,chiral 2,5dihydrooxepine 2a was formed in 50 %y ield with 58 % ee ( Table 1, entry 1). Use of dichloromethane or toluene as the solvent was found to be less effective than using propionitrile (entries [4][5]. Interestingly,while there are some reports that high temperature is required for retro-Claisen rearrangement, [4c] otherwise mixtures of cis-FVC and 2,5-dihydrooxepine form, [6b-c, 9b-c] cis-FVC 1awas not observed with these reaction conditions.I ta ppeared that all of the cis-FVC 1a was immediately transformed into 2,5-dihydrooxepine 2athrough retro-Claisen rearrangement at low temperature (path a).…”

“…Oxepine and hydrooxepine derivatives form the structural core of numerous naturally occurring biologically active compounds and present interesting challenges as potential synthetic targets (Figure 1). [1] While av ariety of synthetic methods have been developed through the years for their synthesis, [2][3][4][5][6] few approaches exist for the preparation of enantioenriched hydrooxepines from achiral starting materials. [4] Thed evelopment of new stereoselective methods to access substituted hydrooxepines from simple,achiral starting materials is thus highly desirable.…”

“…When a3,5-dimethylphenyl Ar substituent was used, the desired product was obtained with 97 % ee albeit in moderate yield (entry 3). Use of dichloromethane or toluene as the solvent was found to be less effective than using propionitrile (entries [4][5]. The sterically hindered catalyst system 3d,w hich has a3 ,5dimethylphenyl Ar substituent and an isopropyl Rs ubstituent, gave the best result (entry 6).…”