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Why Is Organo/Metal Combined Catalysis Necessary?

1.1 Introduction

Molecular chirality has played an important role in a broad scope of fields, including synthetic chemistry, drug discovery, biological system, and materials science and will continue to exert a great impact on physical science. Such unparalleled significance of chirality leads to increasing demand for efficient asymmetric protocols to build up chiral structures.

Chiral resolution is the oldest way to isolate optically pure chiral molecules from the racemic form. Chiral pool- and auxiliary-induced asymmetric synthesis has frequently been synthetic strategies of choice to create chiral elements in organic synthesis [1]. Although chiral auxiliary-induced asymmetric synthesis has been prevalently applied to the asymmetric synthesis of natural products and pharmaceutically significant substances, and thus held the historical impact on synthetic chemistry [2], the installation and removal of chiral auxiliary basically require additional reaction steps to thereby attenuate the synthetic efficiency.

Asymmetric catalysis has globally been accepted as the most efficient concept to stereoselectively build up molecular chirality. Since the advent of asymmetric cyclopropanation and hydrogenation catalyzed by chiral copper and rhodium complexes, respectively [3, 4], asymmetric metal catalysis has continuously been the central focus of asymmetric synthesis. The versatility and robustness of metals in the activation of a wide spectrum of chemical bonds, even those with high bond energy, have rendered many families of asymmetric transformations to be accessed by either Lewis acid or transition metal catalysis [5, 6].

The control of stereochemistry in asymmetric metal catalysis principally relies on the chiral ligand and to a large degree on the ligand acceleration [7]. The stereochemical control events involved in the transition metal catalysis might be one or some of the typical elementary reactions including chiral ligand coordination, oxidative addition, insertion, and reductive elimination. The oxidative addition occurs more easily with an electronically richer and low-valent metal to increase the oxidation state and coordination number of the metal center; therefore the ligand coordination facilitates this reaction. The global and long-standing interest in the design and development of chiral ligands has culminated in the explosive appearance of privileged ligands [8], which actually propel the proliferation of elegant and practical asymmetric processes commencing with the oxidative addition, for example, asymmetric hydrogenation and cross-coupling reaction (Figure 1.1).

Figure 1.1 Transition metal-catalyzed reactions initiated with oxidative addition. (a) Hydrogenation. (b) Cross coupling.

High-valent transition metals have also been found to enable a tremendous number of organic reactions. In contrast to abundantly available chiral ligands for asymmetric catalysis beginning with the oxidative addition, which undergoes with low oxidation state metals, rather fewer chiral ligands are compatible with high-valent metal catalysis and reactions undergoing under oxidation conditions to pose a great challenge to the control of stereoselectivity. For example, although the high-valent metal-catalyzed transformations commencing with nucleometallation (Eq. (1), Figure 1.2), aryl and allylic C-H activation (Eqs. (2) and (3)), have been well established, a very limited number of chiral ligands can enable highly enantioselective variants, in particular, those using molecular oxygen as the terminal oxidant [9]. So far, chiral Lewis acids are successful representatives among massive asymmetric high-valent metal catalysis [10]. As such, a new concept to break the conventional wisdom that relies on the chiral ligand to control the stereochemistry of transition metal catalysis is greatly desirable.

Asymmetric organocatalysis represents an important tool, independent, and conceptually distinct from metal catalysis, to build up molecular chirality [11, 12]. The typical principles in organocatalysis for the activation of chemical bonds cover a broad scope of concepts, including amine catalysis by enamine raising highest occupied molecular orbital (HOMO) and iminium lowering lowest unoccupied molecular orbital (LUMO), Brønsted acid catalysis by hydrogen-bonding interaction or protonation, NHC catalysis via umpolung of aldehyde, Lewis base catalysis by nucleophilic addition to either carboxylic acid derivatives or electron-deficient carbon-carbon double bonds to form reactive enolate or acylammonium species, and phase transfer catalysis by using ammonium and phosphonium to form ion pairs with anionic nucleophiles [13]. Such versatile principles in the activation of chemical bonds and structural diversity of organocatalysts have enabled the explosive appearance of fundamentally novel asymmetric reactions and processes featured by environmentally benign, atom, and step economies. Nevertheless, the complete dependence upon the interactions between a highly active functionality and the organocatalyst (Table 1.1) poses the organocatalysis essential constraints to activate relatively inactive chemical bonds and unfunctionalized substrates.

Figure 1.2 Representatives of high-valent metal catalysis.

1.2 Early Stage of Organo/Metal Combined Catalysis and General Principles

The combination of asymmetric organocatalysis and metal catalysis integrates the catalytic activity of metals and organocatalysts, hence allows the simultaneous or sequential occurrence of multiply bond-breaking and forming events in stereochemical control to provide much more diverse ranges of concepts or principles capable of enabling unconventional enantioselective transformations that are toughly accessed by the individual catalyst [14]. Very early reports on the asymmetric organo/metal combined catalysis describe a Pd-catalyzed asymmetric allylic alkylation of an imino ester, in concert with chiral phase transfer catalysis [15]. Gong and coworkers found that the use of a cinchona alkaloid-derived ammonium bromide 4a that Corey developed [16] as the chiral phase transfer catalyst, in combination with an achiral palladium complex of triphenylphosphine, is able to enable the reaction to deliver 59% ee [15]. Takemoto identified that the electron density of the trivalent phosphorus ligand exerts considerable impact on the reaction performance and the highest enantioselectivity of 94% ee was obtained with 4b that Lygo introduced [17] in the presence of triphenyl phosphite ligand. In both the cases, the respective and synergistic action of the palladium complex and chiral PTC on the allylic ester 1 and nucleophile 2 renders the reaction to proceed more efficiently via a transition state TS-1 and allows the stereochemical control to be accessed by chiral phase transfer catalyst, alone (Figure 1.3). This strategy indicates that the stereoselection of metal-catalyzed reactions can be controlled without chiral ligand, instead, by a co-organocatalyst, thus opens up a window to seek unconventional modes to address issues of the stereochemical control encountered in the asymmetric metal catalysis.

Table 1.1 Typical activation modes in organocatalysis (OC).

Concepts of OC Active intermediates Applicable substrates Reaction types Enamine catalysis Enolizable aldehydes and ketones Aldol reaction
Mannich reaction
Michael addition Iminium catalysis Enal and enones Michael addition
Diels-Alder reaction
Friedel-Crafts reaction Brønsted acid catalysis Aldehydes, ketones, and imines, enal, and enones Reduction
Friedel-Crafts reaction
Michael addition NHC catalysis Aldehydes Annulation
Benzoin reaction
Stetter reaction Lewis base catalysis Ketene, acylhalides, anhydride, and other analogues [2+2] cyclization
[4+2] cyclization
Kinetic resolution Enals, enones, and a,ß-unsaturated esters [3+2] cycloaddition
Baylis-Hillman reaction Phase transfer catalysis Acidic nucleophiles Alkylation
Aldol reaction
Mannich reaction
Michael addition

Figure 1.3 Pd and PTC cooperative catalysis.

Figure 1.4 Pd and phosphine cooperative catalysis.

The cooperative catalysis of transition metal and Lewis base was first showcased by Krische and coworkers [18]. Tributylphosphine undergoes Rauhut-Currier type addition [19] with the enone moiety of 5 to generate a transient enolate and simultaneously, the palladium complex reacts with the allylic carbonate part to give...