Amir H. Hoveyda 33.1
The discovery and identification of an effective chiral catalyst that promotes a chemical reaction with desirable levels of efficiency and selectivity is a difficult business . Because only small energy gaps separate an inactive or nonselective catalyst from one that is potent and selective 1-2 kcal mol variance in transition-state energy), variations in reactivity and selectivity often arise unpredictably. Seemingly insignificant variations in the catalyst or substrate structure and reaction conditions (solvent polarity, temperature, etc.) can lead to entirely unexpected swings in yield, ee (enantiomeric excess), or both. To outline a new transformation and achieve maximum levels of reactivity and selectivity, myriad reaction parameters must therefore be explored and adjusted. In cases where an effective metal-catalyzed enantioselective process is the goal, the choice of an appropriate chiral ligand and metal salt is perhaps most crucial. In such instances, a blend of mechanistic knowledge and human intuition are typically used to identify a desirable metal-ligand combination.
Mechanistic knowledge is useful in allowing chemists to appreciate the general contours of a reaction pathway. Such information is critical in catalyst discovery; it aids us in deciding what class or classes of chiral ligands and what type of metal salts should be included in a study. However, mechanistic data alone cannot provide us with sufficient information to fully ''design''  a catalyst, without requiring any degree of trial and error. That is, a set of mechanistic data collected through examination of a single substrate under a particular set of conditions with a specific metal center and chiral ligand is often less general than one might like. Similar to mechanistic data, chiral catalysts are often not general. Once we do come across an attractive catalyst, it is seldom effective for a wide range of substrates. This result is not surprising; a selective catalyst that recognizes a certain structural type with great fidelity cannot - by nature - recognize and associate with a gamut of substrates and promote reactions selectively.
To address the above general uncertainties and fundamental difficulties, chemists have recently turned their attention to advances in combinatorial and highHandbook of Combinatorial Chemistry. Drugs, Catalysts, Materials. Vol. 2. Edited by K. C. Nicolaou, R. Hanko, and W. Hartwig Copyright © 2002 WILEY-VCH Verlag GmbH, Weinheim ISBN: 3-527-30509-2
throughput strategies . This movement arises from the realization that if the study of a large number of potential catalysts leads to a discovery, then why not perform the investigation systematically and more efficiently by covering a broad range of catalyst candidates? Another factor that supports the adoption of diversity-based approaches is that screening of a large number of compounds may allow chemists to identify an optimal catalyst for each particular substrate and thus overcome the problem of generality that often looms large when a small number of catalyst candidates are available. High-throughput screening can give rise to new mechanistic scenarios that are by nature more comprehensive, derived from a more extensive collection of data points. It would be idle to assume that screening is carried out at random or that diversity approaches to catalyst discovery are devoid of any mechanistic basis. Mechanistic information gained through examination of a large set of data can serve as the driving force behind additional investigations; it can lead to the blossoming of a symbiotic relationship between mechanistic inquiry and diversity-based screening that results in the discovery of more powerful and efficient catalysts of all types, and a deeper and more mature appreciation of the inner workings of various classes of catalysts.
Factors Critical to the Success of Diversity-based Reaction Development
Three important issues need to be addressed for the successful implementation of diversity-based catalytic asymmetric reaction development: (1) sources of diversity, (2) high-throughput synthesis of catalysts, and (3) high-throughput catalyst screening.
1 Sources of diversity. Variation of the ligand structures can generate an exponential number of catalysts with different steric and electronic attributes. When organo-metallic complexes are intended for use as catalysts, metal centers can be modified as well. Reaction conditions represent another dimension of diversity. Co-catalysts, additives, solvent, concentration, temperature, and reaction times are potential parameters that can be altered. It must be noted that the above protocols toward enhancing diversity are not mutually exclusive.
2 Catalyst candidates that lend themselves to diversity-based screening. To employ diversity-based strategies in an efficient and productive manner, the basic structural features of the targeted class of catalysts must lend themselves to such an approach. Accordingly, the following fundamental catalyst attributes are critical: - Facile modularity. Depending on the nature of the metal salts involved and the type of transformation that is being developed, it should be possible to alter ligand structures readily so that reactivity and selectivity levels are rapidly improved. The modularity of the chiral ligands has been critical to acceleration of their preparation by making the fabrication of each catalyst identical, regardless of structural variations. It must be noted that, in principle, all chiral ligands can be modified and thus labeled modular. Some classes of chiral li-gands are, however, more easily modified because their structural components
33.2 Factors Critical to the Success of Diversity-based Reaction Development | 993
are joined by bonds that are readily formed. These ligands are therefore most suitable for parallel library synthesis. Schiff bases and peptide linkages are among disconnections that fall into the latter category. If C-C, C-P, or C-N (nonpeptide linkage) bonds are to be modified to alter a ligand (e.g. binol- or biphen-based systems), then these constructs should be viewed as less readily modular.
- Symmetry. One of the more "established" dogma in the field of metal-catalyzed asymmetric catalysis is that symmetric, particularly C2-symmetric, chiral li-gands are preferred so that the number of energetically differentiable modes of catalyst-substrate association can be minimized and stereoselectivity can be more logically "designed." Many useful, efficient, and selective transformations have indeed been developed based on C2-symmetric chiral ligands ; it is likely that many more chiral ligands of this type will be developed in the future. However, recent studies from a number of laboratories indicate that non-C2-symmetric chiral ligands can also give rise to outstanding levels of selectivity and efficiency in a variety of synthetically important transformations
As far as diversity-based approaches are concerned, the less symmetric class of chiral ligands provides a more attractive option. With C2-symmetric systems, any structural alteration must be mirrored at the complementary region of the ligand structure, thus reducing the degree of available diversity.
- Multiple binding sites. Another common perception in the field of asymmetric catalysis is that the number of binding sites for the metal center within the chiral ligand should be minimized (often limited to a single point of binding). As such, chiral ligands have often served a single function in a particular transformation. The metal-ligand complex either serves as a Lewis acidic activator or as a nucleophilic agent. In a limited number of instances, both functions are delivered by two distinct molecules of the chiral catalyst (second order in catalyst) . Incorporation of multiple binding sites raises the intriguing possibility of multimetal systems and multifunctional catalysts
. Care must be taken, however, that different sites possess sufficiently diverse coordination properties so that, through association with various metal salts, chiral ligands give rise to complementary rather than competing effects
. Multiple binding sites are attractive from the point of view of high-throughput screening studies: they incorporate additional elements of structural modification and open the possibility of multimetal systems, which, in itself, represents a critical dimension in diversity.
3 High-throughput catalyst screening. This aspect is often the greatest bottleneck in assaying each catalyst for asymmetric induction. Although in combinatorial approaches to biological activity, mixtures of compounds can be analyzed simultaneously, such a strategy is by nature problematic in studies that pertain to identification of effective homochiral catalysts. Because subtle structural variations can lead to unexpected changes, or even reversal of enantioselectivity, examination of mixtures of catalysts can lead to conclusions that are misleading (low net selectivity by two effective catalysts that afford high ee values but in the opposite sense). Accordingly, recent reports generally involve testing individual systems.
It merits mention that the parallel screening strategy has also been applied in therapeutic discovery efforts because of the difficulties involved in the accurate deconvolution of various mixtures and because of the synergism that may exist between several active compounds. As such, combinatorial chemistry does not necessarily involve the generation of mixtures of compounds; it may be better characterized by the modular nature of the constituent compounds that in different combinations provide large numbers of molecular ensembles. Analysis of mixtures of candidates for activity (vs. selectivity) can be feasible however and may be accomplished effectively [3f ].
In search of a class of chiral ligands that satisfies the above-mentioned attributes (facile modularity, nonsymmetry, and multiple binding sites) and can promote a variety of C-C bond-forming reactions enantioselectively, we took note of Schiff base peptide ligand 1. In 1992, Inoue and coworkers reported that in the presence of 10 mol% Ti(OEt)4 and 10 mol% 1, addition of trimethylsilyl cyanide (TMSCN) to various aldehydes occurs with appreciable enantioselectivity . There are several characteristics that are represented by a ligand such as 1: (1) the ease of Schiff base and amide bond synthesis renders these entities as potential readily modular chiral ligands for a wide range of metal salts; (2) the requisite building blocks, aromatic aldehydes, and optically pure amino acids, are readily available; (3) peptidic structures can be prepared on solid support, allowing simultaneous synthesis and examination of a sizeable collection of catalyst candidates in an expeditious manner (see Figure 33.2).
Scheme 33.1. Ti-catalyzed enantioselective addition of cyanide to aldehydes in the presence of a dipeptide Schiff base.
Scheme 33.1. Ti-catalyzed enantioselective addition of cyanide to aldehydes in the presence of a dipeptide Schiff base.
Ti-Catalyzed Enantioselective Addition of Cyanide to Meso Epoxides
In 1995, we initiated a program wherein we utilized diversity-based protocols to introduce variations within a modular peptide-based ligand as the means to identify effective chiral ligands for enantioselective TMSCN addition to meso epoxides (Scheme 33.2) . In principle, 8000 (203) different chiral catalysts could be made from the 20 natural amino acids and 20 different aldehydes. To circumvent such a daunting requirement and control the numbers of compounds synthesized and screened, a representational search strategy was employed (concept illustrated in Fig. 33.1).
First, as shown in Scheme 33.3, we established that in the presence of 10 mol% ligand 4 and 10 mol% Ti(OiPr)4 the addition ofTMSCN to cyclohexene oxide 5 proceeds smoothly to afford 6 in @25% ee (<10% reaction in the absence of 4). To
improve the observed enantioselectivity, each of the three subunits in the modular ligand was successively optimized (see Fig. 33.2), such that the first amino acid 1 (AA1 - in box) was varied and the other two subunits were kept constant (with 5 as the substrate). Tert-leucine was found to be optimal at AA1 position and this structural element was retained in successive generations. The second position (AA2) was then altered, and O-tert-butyl-threonine was identified as the best AA2. Finally, from a pool of salicylic aldehydes, 3-fluorosalicylaldehyde was selected as the best Schiff base (SB). In the end, only a representative sampling of 60 (20 x 3) catalysts was necessary to identify one (see 10 in Table 33.1) that affords nearly a 95:5 ratio of enantiomers (89% ee). The initial catalyst provided the addition product with only 26% ee (cyclohexene oxide as substrate). Successive modifications of the ligand structure led us to identify in three steps a chiral ligand that delivers a synthetically attractive level of enantioselectivity. It is unlikely that any mechanistic considerations would have pointed to this specific peptidic complex as a more suitable one.
Scheme 33.3. Schiff base dipeptides promote the Ti-catalyzed enantioselective addition of cyanide to meso epoxides.
The above strategy for catalyst screening raises an intriguing question: ''Is the 'optimal catalyst' identified by this process truly the very best catalyst?'' And if it is not, does the attendant improvement in enantioselectivity (> 99% ee), assuming there will be no notable difference in efficiency, justify the additional effort that would be required to achieve it? In the approach described above, we have made certain assumptions about the additivity and absence of cooperativity between the three subunits of the ligand structure. At least for this small sampling, these assumptions seem to hold true, but without testing every combination we cannot definitively answer this question. Examination of every possibility would be taxing and detract from the efficiency of the general screening method. An important practical advantage of the above approach is that, in a relatively short amount of time, it allowed us to identify a selective catalyst for an entirely new asymmetric process. That is, the search strategy is not an open-ended odyssey but a well-structured
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