Enantioselective Rhodium‐Catalyzed Allylic CH Activation for the Addition to Conjugated Dienes

Abstract

Transition-metal-catalyzed C H activation has the potential to streamline organic synthesis because it can provide novel disconnections in the retrosynthetic analysis of a target molecule. A synthetically useful C H activation method should be diastereoselective and more importantly, enantioselective, if one or more stereocenter is generated in this process. Although significant progress has been made in transition-metal-catalyzed C H activation reactions, the progress of enantioselective C H activation and subsequent C C bond formations through metal insertion has lagged behind. Several impressive examples in this area have emerged. For example, the research groups of Mikami, Murai, and Bergman and Ellman have all reported pioneering work on the enantioselective coupling reactions of vinylic and aromatic C H bonds with alkenes. Enantioselective hydroacylation reactions of alkenes and ketones through the cleavage of an acyl C H bond have also been reported. Yu and co-workers have developed an elegant palladium(II)-catalyzed enantioselective coupling reaction of aromatic C H bonds with boronic acids and styrenes using a desymmetrization strategy. By using a similar approach, Albicker and Cramer achieved enantioselective palladiumcatalyzed direct arylations. Despite these notable advances in the enantioselective sp C H activation reactions, the enantioselective sp C H activation/C C bond formation through the intermediate formation of carbon–metal bonds remains elusive. The lack of progress may be attributed to the limited methods for sp C H activation, the harsh reaction conditions required for the cleavage of an sp C H bond, and the paucity of ligands available for enantioselective C H activations. One example of an enantioselective sp C H activation/C C bond formation came from Yu and coworkers, who reported a palladium(II)-catalyzed pyridinedirected reaction that occurred with a promising 37% ee. For enantioselective allylic C H oxidations, White and coworkers achieved a 63% ee for the palladium(II)-catalyzed allylic oxygenation of terminal olefins. Even though it is challenging to achieve asymmetric sp C H activation with high enantioselectivity, considering its synthetic importance, continuous endeavors to meet such a challenge are required. Recently, our research group has developed a conjugateddiene-assisted, rhodium-catalyzed addition of allylic C H bonds to conjugated dienes to furnish multifunctional tetrahydropyrrole, tetrahydrofuran, and cyclopentane compounds. The two new stereogenic centers in the final products had good to excellent diastereoselectivity (see the reaction shown in Table 1). We were eager to develop an asymmetric version of this allylic C H activation/C C bond formation reaction, which would provide efficient and easy access to the multifunctional chiral tetrahydropyrrole, tetrahydrofuran, and cyclopentane compounds. The two challenges for this enantioselective reaction are the asymmetric allylic C H activation/C C bond formation, and the asymmetric synthesis of a quaternary carbon center, which has been a longstanding challenge in organic synthesis. Herein, we report the first example of a highly enantioselective allylic C H activation/ C C bond formation reaction through metal insertion. We show that the present reaction provides an easy route to the asymmetric synthesis of two adjacent sp carbon centers, one of which is a quaternary carbon center. Our study began with the identification of an effective chiral ligand for the target reaction (Table 1). We found that chelating diphosphines such as binap inhibited the reaction, therefore we focused our effort on screening themonodentate ligands. Chiral phosphoramidites, which are a class of easily accessible and highly modulable ligands, were tested. Fortunately, the application of phosphoramidite ligandAunder our previous reaction conditions gave a high yield and a promising ee value (Table 1, entry 1). This encouraging result led us to further optimize the reaction conditions. We observed that changing the silver source from AbSbF6 to AgOTf improved the enantioselectivity (entry 2). Better enantioselectivity was obtained when DME or benzene were used as the solvent (entries 3 and 4, respectively) compared with DCE (entry 2), although the reaction in benzene was slower. The use of [{Rh(coe)2Cl}2] as a catalyst precursor provided a faster reaction rate (entry 5), presumably as a result of the faster dissociation of the coe ligand from the catalyst precursor. Next, we tested a variety of phosphoramidite ligands. A slight increase of the steric bulk on the nitrogen center improved the ee value, for example, phosphoramidites bearing diethyl amine (B), diisopropyl amine (C), piperidine (D), and morpholine (E) gave 90%, 89%, 87%, and 90% ee, respec[*] Q. Li, Prof. Dr. Z.-X. Yu Beijing National Laboratory of Molecular Sciences (BNLMS) Key Laboratory of Bioorganic Chemistry and Molecular Engineering College of Chemistry, Peking University, Beijing, 100871 (China) Fax: (+86)10-6275-1708 E-mail: yuzx@pku.edu.cn