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TOWARD IDEAL ASYMMETRIC CATALYSIS

Jian Zhou and Jin-Sheng Yu

1.1 INTRODUCTION

The past 50 years have witnessed tremendous achievements in the field of asymmetric catalysis, with its importance being widely recognized by the society, as evidenced by the 2001 Nobel Prize in Chemistry awarded to Sharpless, Knowles, and Noyori for their contribution to chiral metal catalysis [1]. Today, chiral products have found many applications in many areas of daily life, from perfumes, food additives to drugs and many others. As one of the most promising methods to produce chiral products, it is no exaggeration to say that better the asymmetric catalysis, better the human beings' lives. Apart from the vast demands for chiral products from the pharmaceutical industry, other applications such as agricultural chemicals, flavors, fragrances, chiral polymers, and liquid crystals constitute the ever-increasing demands. In particular, two-thirds of prescription drugs are chiral, and the majority of new chiral drugs are single enantiomers [2]. On the one hand, the demands for optically active compounds, often as single enantiomers, stimulate intensive researches to invent efficient synthetic methods; on the other hand, the gradually easier access of chiral compounds escalates their applications in more aspects of modern life, which in turn motivates the further development of efficient and economic asymmetric synthesis.

Since Nozaki and Noyori reported the first asymmetric reaction using a chiral copper complex as the catalyst in 1966 [3], new concepts and new chiral metal catalysts have been continuously created and applied to various unprecedented enantioselective reactions, which greatly facilitate the synthesis of optically active compounds. The asymmetric synthesis is further greatly fueled by the rediscovery of asymmetric organocatalysis as we enter the new millennium [4]. Currently, metal catalysis, biocatalysis, and organocatalysis are the three pillars that asymmetric catalysis is built upon. By these well-established and complementary tools, it becomes increasingly convenient to achieve a useful level of enantioselectivity (>90% ee) for the synthesis of given chiral products, given careful combination of a suitable chiral catalyst and reaction parameters.

Along with the triumph over the accomplishments, some may argue that the field of asymmetric catalysis is in its twilight, as the basic concepts and outlines have been established, which results in opinions that the development of catalytic asymmetric reactions is no longer challenging and intriguing, because excellent enantioselectivity for a specific reaction could be finally achieved as long as intensive screenings of reaction parameters are conducted. This could not be farther from the truth, if existing catalytic asymmetric protocols are under scrutiny by the criterion of the ideal synthesis [5]: a product must be "prepared from readily available, inexpensive starting materials in one simple, safe, environmentally acceptable, and resource-effective operation that proceeds quickly and in quantitative yield." In 2009, the Nobel laureate, professor R. Noyori further emphasizes that [6], to synthesize our future, synthetic chemists should "aim at synthesizing target compounds with a 100% yield and 100% selectivity and avoid the production of waste. The process must be economical, safe, resource efficient, energy efficient and environmentally benign. In this regard, the atom economy [7] and the E-factor [8] should be taken into account." Although such lofty goals might never be realized, the ambition and basic ideas outlined in these principles show the right but formidable way that chemists in the field of asymmetric catalysis should take to further their researches, considering the immense obligations of chemists to tack a range of existing or predicted social and global issues associated with environment, ecology, energy, resources, and health [9].

Not surprisingly, if evaluated strictly by the standards of "ideal synthesis," most catalytic enantioselective protocols developed to date have great potential to be improved, presumably because the past and current attention is primarily paid to how to ensure excellent selectivity and reasonable yield. Generally, the development of a highly enantioselective asymmetric catalytic reaction involves three important procedures:

1. Catalyst Screening and Evolution. The purpose of this step is to identify a promising chiral catalyst. Usually, intensive screening of chiral catalysts that could be readily available is conducted at this step. If lucky enough, the ideal chiral catalyst which could achieve excellent stereoselectivity comes out soon. Otherwise, the modification of the optimal chiral catalysts to improve the selectivity is necessary, which is unfortunately unavoidable in most studies.
2. Substrate Modification. The manipulation plays an important role in reaction development, especially when initial screenings fail to afford a promising chiral catalyst capable of achieving excellent stereoselectivity. The purpose of this procedure is to modify the substrates with a suitable auxiliary group to interplay with the chiral catalyst, to maximize the reactivity and stereoselectivity of a given reaction. The decoration of substrates could be conducted from two directions. One is to introduce an activating group to at least one of the reaction partners to increase the reactivity, which enables the reaction to be run at low temperature to improve the selectivity, and the other is to install a bulky shielding group to enlarge the face discrimination for better enantiofacial control. The substrate modification is an effective and widely adopted approach to improve the selectivity; however, it inevitably decreases the synthetic efficiency, as the introduction and removal of such groups entails at least two extra steps. In addition, the activating group or the bulky shielding group will not present in the final product, which lowers down the atom utilization of the whole process to synthesize a given chiral product and inevitably increases waste generation.
3. Optimization of Reaction Parameters. A lot of factors, including temperature, solvent, and additive, remarkably influence the reactivity and stereoselectivity of catalytic asymmetric reactions. The influences are so great that the reversal of stereoselectivity happens in some extreme cases, by altering the reaction solvent, temperature, or additive, even if the chiral catalyst remains the same. Accordingly, careful optimization of reaction parameters is a routine procedure for the establishment of a suitable reaction condition to obtain excellent yield and selectivity. In most cases, better enantioselectivity is obtained by running the reaction at low temperature, which leads to prolonged reaction time and aggravates the consumption of energy. The use of aqueous solution or non-toxic organic solvent is favorable, but toxic solvents such as benzene and poly-halogenated solvents have to be used in many cases, for the sake of excellent ee values. Additives are versatile to improve the reactivity and selectivity, although their role remains to be investigated.

Obviously, these procedures mainly focus on how to improve stereoselectivity, and pay little attention on atom utilization, energy consumption, and E-factor for the synthesis of a given chiral product. Of course, it is not that chemists in the field of asymmetric catalysis do not care about the guidelines of "ideal synthesis," but they are in a dilemma as to pursue excellent enantioselectivity or to achieve low E-factor.

A good example to elucidate the aforementioned dilemma is the catalytic asymmetric Strecker synthesis of a-aminonitriles [10], which are versatile precursors of a-amino acids and diamines. This reaction, discovered by Adolph Strecker in 1850 [11], comprises a one-pot three component condensation of an aldehyde 1 with ammonium chloride and KCN (Scheme 1.1). Driven by the vast demand of various non-natural optically active a-amino acids, the corresponding catalytic asymmetric synthesis has been intensively studied, but the use of amine protecting groups to realize excellent enantioselectivity and yield is indispensable for all available protocols. Since the pioneering work of the Lipton group in 1996 [12], various types of N-protected preformed imines 4 have been tried, allowing highly enantioselective synthesis of a broad scope of N-protected a-aminonitriles 2. In terms of atom economy and enantioselectivity, these protocols are unambiguously successful (100% atom economy and >90% ee for the Strecker reaction step). While the N-protecting groups of the thus obtained a-aminonitriles are useless for further transformation, they must be removed and will no longer be present in the desired a-amino acids, if the unprotected a-amino acids are the desired products. As a consequence, the use of N-protecting groups, either to improve the enantiofacial control or to enhance the reactivity, inevitably decreases the atom utilization of the Strecker synthesis of unprotected amino acids. It should also be noted that the molecular weight (MW) of the discarded auxiliary is much higher than the desired product in some extreme cases. For example, in the synthesis of phenylglycine, the molecular weight of several types of protecting groups is higher than that of...