The Phosphinamide-Based Catalysts: Discovery, Methodology Development, and Applications in Natural Product Synthesis

In the total synthesis of natural products, synthetic efficiency has been an important driver for designing and developing new synthetic strategies and methodologies. To this end, the step, atom, and time economy and the overall yield are major factors to be considered. On the other hand, developing unified routes that can be used for synthesizing multiple molecules, specifically skeletally different classes of molecules, are also important aspects with which to be concerned. In the efforts toward efficient and flexible synthesis of structurally unique terpenoid and indole alkaloid natural products, we have designed and developed several phosphinamide-based new catalysts and reaction methodologies that have been compellingly demonstrated to be widely useful as strategic protocols for the diverse synthesis of various complex terpenoids and indole alkaloids. The important progress of these results will be summarized in this Account.In the first part, we present the stories of successful design and establishment of a novel method for the synthesis of P-stereogenic phosphinamides (SPhos) via a Pd-catalyzed C-H desymmetric enantioselective arylation, as well as the flexible derivatization of the P-stereogenic phosphinamides into various types of skeletally unique tricyclic and N,P-bidentate P-stereogenic compounds. Subsequently, the discovery of P-stereogenic phosphinamides as chiral organocatalysts for the desymmetric enantioselective reduction of cyclic 1,3-diketones and of phosphinamide-based cyclopalladium complex (C-Pd) as precatalysts for highly efficient Suzuki-Miyaura cross-coupling reaction of sterically congested nonactivated enolates is introduced. The notable features of the P-stereogenic phosphinamide-catalyzed desymmetric enantioselective reduction are highlighted by the broad substrate compatibility and excellent stereoselectivity, as well as most significantly, the good recoverability and reusability of catalysts. With regard to the sterically congested nonactivated enolates, such substrates are challenging for Suzuki cross-coupling reactions. We demonstrate that the phosphinamide-based cyclopalladium is a type of highly active precatalyst that allows the reaction to proceed under mild conditions and to be easily scaled up. Following the methodology development, the practical applications of these methods serving as strategic transformations are highlighted by the unified synthesis of four cyathane-type and two hamigeran-type terpenoids.In the second part, we describe the development of a robust method for oxidative Heck cross-coupling of indolyl amides by using the phosphinamide-based cyclopalladium as catalyst or phosphinamide as coligand. The method provides a general and straightforward method for diverse synthesis of indolyl δ-lactam derivatives, which present as a common core in a variety of Aspidosperma-derived indole alkaloids. The successful demonstration of this protocol for a concise and divergent synthesis of leuconodine-type indole alkaloids is also presented. We believe the results presented in this Account would have significant implications beyond our results and would find further applications in the field of synthetic methodology and natural product synthesis.