No abstract

We report a divergent and modular protocol for the preparation of acyclic molecular frameworks containing newly created quaternary carbon stereocenters. Central to this approach is a sequence composed of a (1) regioselective and -retentive preparation of allyloxycarbonyltrapped fully-substituted stereodefined amide enolates and of a (2) enantioselective palladium-catalyzed decarboxylative allylic alkylation reaction using a novel bisphosphine ligand.

According to a procedure reported by Savige and Fontana, 2 the indole is dissolved in dimethyl sulfoxide (10 equiv) and concentrated hydrochloric acid (12 N, 18 equiv) is added dropwise at ambient temperature. Reaction progress is monitored by LCMS and is typically complete in less than 30 minutes. The reaction mixture is neutralized (pH > 6) with concentrated ammonium hydroxide and extracted with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography to afford the oxindole product. General Procedure B. Tryptophan methyl ester oxidation. In order to prevent methyl ester hydrolysis, a modified procedure is used for tryptophan methyl ester derivatives. The indole is dissolved in dimethyl sulfoxide (10 equiv) and glacial acetic acid (5 mL/mmol indole) is added, followed by dropwise addition of concentrated hydrochloric acid (12 N, 18 equiv) at ambient temperature. Reaction progress is monitored by LCMS and is typically complete in less than 30 minutes. The reaction mixture is neutralized (pH > 6) with concentrated ammonium hydroxide and extracted with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography to afford the oxindole product. General Procedure C. Oxindole Peroxidation. A schlenk tube is flame dried, cooled under a stream of argon gas, and charged with oxindole (1 equiv) and copper(I) chloride (0.1 equiv). The tube is sealed, then evacuated and backfilled with argon (three times). Dichloromethane (5 mL/mmol oxindole) is added, followed by dropwise addition of tert-butyl hydroperoxide (6 M in decane, 2 equiv). The reaction is stirred at ambient temperature, and monitored by LCMS. If the reaction is incomplete after 12 h, an additional portion of tert-butyl hydroperoxide (6 M in decane, 2 equiv) is added, and stirred for an additional 12 h. Upon completion, the reaction mixture is dry-loaded onto silica gel, and purified directly by column chromatography to afford the 3-(tert-butylperoxy)oxindole product.

Lactams and imides have been shown to consistently provide enantioselectivities substantially higher than other substrate classes previously investigated in the palladium-catalyzed asymmetric decarboxylative allylic alkylation. We have designed several new substrates to probe the contributions of electronic, steric, and stereoelectronic factors that distinguish the lactam/imide series as superior alkylation substrates. These studies culminated in marked improvements on carbocyclic allylic alkylation substrates.

A highly efficient regio- and stereoselective total synthesis of (±)-grandifloracin via a tandem dearomative epoxidation/spontaneous Diels–Alder cyclodimerization from salicylic acid in only four steps is reported. The synthetic route allows for late-stage diversification of the core structure to give ready access to analogues of this promising agent against pancreatic cancer.

Enantioselective catalytic allylic alkylation for the synthesis of 2-alkyl-2-allylcycloalkanones and 3,3-disubstituted pyrrolidinones, piperidinones and piperazinones has been previously reported by our laboratory. The efficient construction of chiral all-carbon quaternary centers by allylic alkylation was previously achieved with a catalyst derived in situ from zero valent palladium sources and chiral phosphinooxazoline (PHOX) ligands. We now report an improved reaction protocol with broad applicability among different substrate classes in industry-compatible reaction media using loadings of palladium(II) acetate as low as 0.075 mol % and the readily available chiral PHOX ligands. The novel and highly efficient procedure enables facile scale-up of the reaction in an economical and sustainable fashion.

Herein, we report the palladium-catalyzed decarboxylative asymmetric allylic alkylation of αenaminones. In addition to serving as valuable synthetic building blocks, we exploit the αenaminone scaffold and its derivatives as probes to highlight structural and electronic factors that govern enantioselectivity in this asymmetric alkylation reaction. Utilizing the (S)-t-BuPHOX ligand in a variety of nonpolar solvents, the alkylated products are obtained in up to 99% yield and 99% enantiomeric excess.

The hamigeran family of natural products has been the target of numerous synthetic efforts due to its biological activity and interesting structural properties. Herein we disclose our efforts toward the synthesis of hamigerans C and D, unique among the initially isolated members due to their 6-7-5 carbocyclic core. Our approach directly targets this tricyclic motif by sequential Negishi and Heck coupling reactions, yielding an advanced intermediate with all necessary carbons and sufficient functionality poised for completion of the synthesis of these two natural products.