Development of a ring expansion approach toward (±)-Phyllantidine, ring expansion of tetramic acids to N-oxy-2,5-diketopiperazines, and total synthesis of (+)-Raistrickindole A.


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In 2020 we reported a concise total synthesis of (±)-phyllantidine, a member of the securinega alkaloid family of natural products, which contains a unique oxazabicyclo[3.3.1]nonane core. Our strategy features a ring expansion of a substituted cyclopentanone to a cyclic hydroxamic acid, which allows facile installation of the embedded nitrogen-oxygen (N-O) bond. Herein we discuss the optimization process of the ring expansion reaction on a series of modified substrates, along with the observed regiochemical outcomes, leading up to the eventual completion of the natural product. Additionally, computational analyses of the mechanistic underpinnings aided us in fine-tuning both the ring expansion system and the reaction conditions, in order to obtain a single regioisomer of the ring expansion product. (±)-Phyllantidine was completed in 12-steps from known materials (9% overall yield), or 14-steps from commercially-available 1,4-cyclohexadiene. N-oxy-2,5-diketopiperazines (DKPs) are prevalent in many biologically-relevant natural products, and current methods of accessing this functionality are typically fraught with difficulty. To overcome this, we describe a ring expansion of tetramic acids (pyrrolidine-2,4-diones) to N-oxy-2,5-DKPs, inspired by a similar 2-step ring expansion strategy used in our total synthesis of (±)-phyllantidine: oxidation of a hydroxamic acid moiety to a acyloxy nitroso, followed by nucleophilic cleavage of the appended acetate to effect carbon-carbon bond migration into the nitroso component giving the ring-expanded product. This method allows for the facile and late-stage construction of the N-O bond and can thereby serve as a general method for accessing N-oxy-2,5-DKP-containing natural products. Herein we develop several model substrates with varying functionality around the tetramic acid ring, and describe the different outcomes regarding regioselectivity and overall yield. We report the successful ring expansion of a Bn-substituted DMB-protected tetramic acid using optimized conditions in the 2-step sequence, with the expectation to apply this chemistry toward the synthesis of natural products. (+)-Raistrickindole A was isolated in 2019 by Li and co-workers and shows modest activity against the hepatitis C virus. (+)-Raistrickindole A is embedded in a tryptophan/phenylalanine-derived 1,2-oxazine-containing tetraheterocycle, and features an N-oxy-2,5-DKP core, posing an attractive synthetic challenge. There are currently no reports to date of this natural product. Our synthetic efforts evolved through the attempted use of our developed ring expansion to synthesize the DKP core of the natural product, and eventually transformed into the successful utilization of a regio- and diastereoselective intermolecular nitroso Diels-Alder (NDA) reaction. We completed the first total synthesis of (+)-raistrickindole A in 9 steps from known materials, and we believe that this method can be used to synthesize other potentially pharmacologically-useful N-oxy-DKP/1,2-oxazine-containing- natural products.