The SadPhos family is a new generation of adaptive ligands with multiple coordination centers. It was developed by Professor Zhang Junliang’s research group. Its name comes from the English name of the sulfenamide phosphine ligand.
sulfinamide phosphine abbreviation; After 9 years of research and development, SadPhos The family has Ming-Phos develop into Xiao-Phos、Xu-Phos、GF-Phos、W-Phos、Rong-Phos（2023）and a variety of ligands, and are still being expanded.
Figure 1: Structure and advantages of SadPhos ligand
SadPhos ligand has the following characteristics:
The synthesis is relatively simple: only 2-5 steps of reaction are required;
Non-C2 symmetry: There are different chiral environments on both sides of the metal center;
Combining rigidity and softness: having both a rigid skeleton and flexible side chains, taking into account both selectivity and substrate range;
Both soft and hard: soft and hard coordination atoms P, S, O, N, etc., can coordinate with both soft and hard metals.
New application progress of SadPhos family ligands
Pd(0)/GF-Phos catalyzes the asymmetric synthesis of Tröger base analogues at the nitrogen stereocenter[1]
The development of efficient and selective methods to achieve enantioenriched stereocenters is key to modern synthetic research. Compared with the construction of C and other heteroatom stereocenters, nitrogen atom stereocenters tend to racemize rapidly due to low interconversion barriers, making their enantioselective synthesis more challenging. Enantioselective synthetic strategies for chiral nitrogen stereogenic centers typically include amine N-oxides, nitrogen-centered metal coordination, and nitrogen-centered quaternary ammonium salts. In addition to the above methods, another strategy is to form a rigid tertiary amine backbone to prevent the lone pair inversion of nitrogen.
Among rigid chiral tertiary amine compounds, a particularly fascinating structure is the Tröger base. It has two mutually perpendicular aromatic rings fused to a central bicyclic [3.3.1] skeleton capable of forming a rigid cleft, like a V-shaped scaffold, with two nitrogen stereocenters. Therefore, the application of Tröger bases in self-assembly studies, molecular recognition, DNA interaction probes, and Lewis base catalysts in organic synthesis has attracted considerable attention. However, the synthesis and separation of such compounds is difficult.
Figure 2:Tröger base analogs
Accordingly, Professor Zhang Junliang's research group developed an effective method for the asymmetric synthesis of rigid cleft-like compounds with nitrogen stereocenters catalyzed by Pd and homemade GF-Phos. This method allows the simultaneous construction of a wide range of chiral Tröger base analogs (Figure 2) that contain one C and one N stereocenter and are characterized by high stability, high yields, and high selectivity. It provides a new strategy for the catalytic asymmetric synthesis of Tröger base analogs from simple starting materials (Figure 3). This synthetic application is demonstrated by its utility as a novel class of chiral organocatalysts and precursors for chiral transition metal scaffolds in a batch of transformations. DFT calculations indicate that NH··O hydrogen bonds and weak interactions between substrate and ligand are responsible for the high selectivity. In-depth study of this mechanism could stimulate future developments in ligand design.
Figure 3: Pd-catalyzed and homemade GF-Phos-catalyzed asymmetric synthesis of Tröger base analogues
Asymmetric Heck/Tsuji-Trost reactions of amino-tethered 1,3-cyclohexadiene with aryl and alkenyl halides catalyzed by Pd/PC-Phos[2]
Chiral perhydroindoles are found in many natural products and bioactive compounds. Therefore, it is crucial to develop new asymmetric methods to rapidly access this core. Application of palladium/PC-Phos to catalyze the asymmetric Heck/Tuji–Trost reaction of readily available amino-linked 1,3-cyclohexadiene with aryl and alkenyl halides (Figure 6) with high enantioselectivity Provides various functionalized chiral hexahydroindoles with high stability (up to 98% ee.) and high yield (up to 96%). The simple synthesis of (-)-α-lycopene using this reaction demonstrates the effectiveness of this reaction. DFT calculation results show that the difference in ΔEdis of the two migration-insertion transition states determines the enantioselectivity of the reaction.
Figure 2 Pd/PC-Phos Catalytic asymmetry of amino-tethered 1,3-cyclohexadiene with aryl and alkenyl halides Heck/Tsuji-Trost reaction
Asymmetric three-component arylsilylation of N-sulfonylhydrazones catalyzed by Pd/Ming-Phos: enantioselective synthesis of gem-dimethylsilane[3]
Enantioselective three-component reaction of N-sulfonylhydrazones, aryl bromides, and silylborates catalyzed by Pd/Ming-Phos (Figure 4) using newly identified Ming-Phos with high enantioselectivity Chiral gem-diarylmethinesilane was synthesized. Compared with N-toluenesulfonyl group, the N-homomethylenesulfonyl group, which is easier to decompose, is more suitable as a masking group for electron-rich hydrazone to improve reaction efficiency. This reaction features a wide range of coupling substrates, high enantioselectivity, and mild reaction conditions.
Figure 4: Pd/ Ming-Phos Catalytic Enantioselective Three-Component Reactions of N-Sulfonylhydrazones, Aryl Bromides, and Silylborates
Enantioselective Mizoroki-Heck reaction of naphthalene catalyzed by Pd/Xu-Phos[4]
Chiral organosilanes have proven to be a very valuable class of molecular scaffolds due to their diverse applications in medicinal chemistry and materials science; although great progress has been made in asymmetric catalytic synthesis methods for chiral benzylsilanes, such as alkenes Symmetric hydrosilylation, through Transition metal-catalyzed chiral transfer reactions and asymmetric carbene insertion, etc., but most transformations are limited to arylalkylmethine silanes, chiral geminidiarylmethine silanes with two spatially similar aromatic substituents. The efficient catalytic synthesis of silanes remains a big challenge.
The Mizoroki−Heck reaction is one of the reactions that forms important carbon-carbon bonds through the cross-coupling of organic halides (or triflates) with classical alkenes. Recently, the dearomatized Heck reaction has opened up a new research space for Heck reactions by employing endocyclic π-aromatic compounds as coupling partners. Despite the inherent challenges in overcoming the energy to break aromaticity, the enantioselective dearomatization Heck reaction remains an efficient and straightforward strategy to obtain optically active polycyclic compounds. In this context electron-rich heteroaromatics, including indoles, pyrroles, benzofurans, and furans have been enantioselectively arylated or vinylated to provide a number of structurally unique heterocyclic molecules bearing quaternary stereocenters. Naphthalene and benzene have higher aromatic stabilization energies than those of electronically biased heteroaromatics, and their asymmetric Heck reactions are more challenging and undocumented.
Figure 5: palladium/ Enantioselectivity of naphthalene Mizoroki-Heck reaction
Based on this, Professor Zhang Junliang’s research group developed the enantioselective Mizoroki-Heck reaction of naphthalene catalyzed by Pd/Xu-Phos. The reaction begins with dearomatization migration insertion followed by delta-hydride elimination. The chiral sulfonamidephosphine ligand Xu-Phos was found to be very effective in this reaction due to the interruption of the undesired competitive C−H arylation reaction (Figure 5). Reactions of naphthoic acid-derived substrates and naphthylamine-based substrates provide a broad range of spirooxindoles and spiroisoindolin-1-ones in moderate to excellent yields with ee up to 95% .
References
Chun Ma, Yue Sun, Junfeng Yang*, Hao Guo*, and Junliang Zhang*. ACS Cent. Sci. 2023, DOI: 10.1021/acscentsci.2c01121
Juan Feng,‡ Jiayi Shi,‡ Lan Wei,‡ Mingqing Liu, Zhiming Li, * Yuanjing Xiao* and Junliang Zhang*. Angew. Chem. Int. Ed. 2022, e202215407
Bin Yang, Kangning Cao, Guofeng Zhao, Junfeng Yang*, and Junliang Zhang*. J. Am. Chem. Soc. 2022, 144, 15468–15474.
Xiao-Qing Han‡, Lei Wang‡, Ping Yang‡, Jing-Yuan Liu, Wei-Yan Xu, Chao Zheng, Ren-Xiao Liang, Shu-Li You*, Junliang Zhang*, and Yi-Xia Jia*. ACS Catal. 2022, 12, 655–661.
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[S(R)]-N-[(S)-][2-(Diphenylphosphino)phenyl]phenylmethyl[S(R)]-N-[(S)-][2-(Dicyclohexylphosphino)phenyl]phenylmethyl[S(R)]-N-[(1S)-2-(Diphenylphosphino)-1-][2-(diphenylphosphino)phenyl]ethyl[S(R)]-N-[(S)-(Phenyl)][5-(Diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl](phenyl)methyl
向阳 翟
