Introduction

The first section of the book illustrates how much asymmetric multicatalysis based on the use of catalysts belonging to the same discipline has contributed to the development of various types of powerful enantioselective tandem reactions. It collects all the major progress in the field of enantioselective tandem reactions promoted by multiple (two or three) organocatalysts, two metal catalysts, or two or more biocatalysts. It demonstrates the power of these remarkable one-pot processes of two or more bond-forming reactions, occurring with minimum workup or change in conditions in which the subsequent transformation takes place at the functionalities obtained in the former transformation, following the same principles that are found in biosynthesis in nature. The first section of the book is subdivided into five chapters, dealing successively after this introduction (Chapter 1) with reactions catalysed by multiple organocatalysts (Chapter 2), reactions catalysed by two metals (Chapter 3), and multienzyme-catalysed reactions (Chapter 4) followed by conclusions (Chapter 5). The two catalysts can interact in a cooperative, relay or sequential manner; these three types of catalysis will be treated successively in chapters 2 and 3. In cooperative catalysis, both the two catalysts are present at the onset of the reaction, and share the same catalytic cycle, activating two different functional groups cooperatively to achieve the bond-formation steps. On the other hand, in relay or sequential catalysis, the substrate first reacts with one catalyst to give an intermediate through a first catalytic cycle. Then, this former intermediate reacts with the second catalyst to provide, through a second catalytic cycle, the final product or an intermediate for subsequent transformations. The difference between relay and sequential catalysis consists of the presence or not of the two catalysts at the onset of the reaction. Thus, relay as well as sequential catalysis involves a set of reactions independently catalysed by two catalysts in a consecutive manner but, while in relay catalysis the two compatible catalysts are both present from onset, in sequential catalysis the addition of the second catalyst during the course of the reaction is necessary to avoid compatibility issues. Chapter 4 dealing with multienzyme-catalysed reactions is divided into three sections concerning multienzymatic synthesis of chiral alcohols, multienzymatic synthesis of chiral amines and amino acids, and other multienzymatic reactions.

Reactions Catalysed by Multiple Organocatalysts

2.1 Introduction

Organocatalysts are known to be the most robust catalysts, well tolerating impurities and traces of water. Additionally, they are usually readily available, easy to handle, and present a high compatibility which is a significant advantage. Furthermore, a wide variety of organocatalysts is able to induce different types of transformations through different activation models. These advantages allow the combination of different organocatalysts to be achieved to design novel enantioselective tandem reactions. The two (or three) organocatalysts can interact in a cooperative, relay or sequential manner; these three types of catalysis will be treated successively in the text. In cooperative catalysis, both the two catalysts are present at the onset of the reaction, and share the same catalytic cycle, activating two different functional groups cooperatively to achieve the bond-formation steps. On the other hand, in relay or sequential catalysis, the substrate first reacts with one catalyst to give an intermediate through a first catalytic cycle. Then, this former intermediate reacts with the second catalyst to provide, through a second catalytic cycle, the final product or an intermediate for subsequent transformations. The difference between relay and sequential catalysis consists of the presence or not of the two catalysts at the onset of the reaction. Thus, relay as well as sequential catalysis involves a set of reactions independently catalysed by two catalysts in a consecutive manner but, while in relay catalysis the two compatible catalysts are both present from onset, in sequential catalysis the addition of the second catalyst during the course of the reaction is necessary to avoid compatibility issues. Various types of organocatalysts, such as phosphoric acids, L-proline and its derivatives, cinchona alkaloids, ureas, thioureas, amino acids, N-heterocyclic carbenes, pyrrolidines, and various (di)amines, have already been combined to induce enantioselective domino and multicomponent domino reactions evolving through cooperative as well as relay catalysis, but also used sequentially to achieve enantioselective tandem reactions. In a number of examples, both the two organocatalysts employed are chiral which is possible when one does not interfere with the activity of the other. Their simultaneous use is particularly useful when a synergistic effect is present as in the case of cooperative catalysis which is the most developed.

2.2 Cooperative Catalysis

In 2007, a chiral tertiary amine, such as (-)-spartein, was used by Hong et al. to enhance the nucleophilic character of an enamine intermediate by deprotonation and effectively shield one of the enantiotopic faces of this intermediate, thus improving the stereoselectivity of a reaction. This enamine was the intermediate of an enantioselective Robinson condensation occurring between two α, β-unsaturated aldehydes, providing the corresponding chiral cyclohexadienes in good yields and enantioselectivities of up to 93% ee, as shown in Scheme 2.1.

In the same year, Zhou and List reported a novel one-pot tandem reaction which, for the first time, combined chiral Brønsted acid catalysis with enamine and iminium catalysis. Later, on the basis of control experiments and ESI-MS/MS analysis, a reasonable mechanism was proposed (Scheme 2.2). The initial step of this tandem reaction was mediated by achiral p-ethoxyaniline (PEP-NH2) and chiral phosphoric acid (R)-TRIP; either reagent alone was inefficient in promoting this aldol condensation to afford the first iminium intermediate. The following step was a conjugate reduction which was also Brønsted acid and amine co-catalysed, and no further conversion took place in the absence of either catalyst. The final step was an acid-catalysed reductive amination. This novel sequence allowed the highly enantioselective synthesis of...