Non-enzymatic catalysts

As an example of non-enzymatic catalyst using oxazaborolidines [10], Corey and his associates have described an efficient synthesis of (-i-)-l(S),5(R),8(S)-8-phenyl-2-azabicyclo[3.3.0]octan-8-ol (2.) and its enantiomer. The B-methyloxazaborolidine derivatives (3) of these amino alcohols are excellent catalysts -or chemzymes- for the enantioselective reduction of a variety of achiral ketones to chiral secondary alcohols [11]. 

Robinson, D. E. J. E. Bull, S. D. (2003) Kinetic resolution strategies using non-enzymatic catalysts.. Tetrahedron Asymmetry 14 1407-1446... 

Desymmetrization of an achiral, symmetrical molecule through a catalytic process is a potentially powerful but relatively unexplored concept for asymmetric synthesis. Whereas the ability of enzymes to differentiate enantiotopic functional groups is well-known [27], little has been explored on a similar ability of non-enzymatic catalysts, particularly for C-C bond-forming processes. The asymmetric desymmetrization through the catalytic glyoxylate-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote [28] and internal [29] asymmetric induction (Scheme 8C.10) [30]. The (2/ ,5S)-s> i-product is obtained with >99% ee and >99% diastereoselectivity. The diene thus obtained can be transformed to a more functionalized compound in a regioselective and diastereoselective manner. 

The general rule seems to be that the B-value changes during resolution and that the e.e.-value depends on the degree of conversion during asymmetization. Principally this should not be restricted to enzymatic catalysis, but also be valid for reactions catalyzed by non-enzymatic catalysts. 

It is interesting to recall that the first catalytic asymmetric reaction was performed on a racemic mixture (kinetic resolution) in an enzymatic reaction carried out by Pasteur in 1858. The organism Penicillium glauca destroyed (d)-am-monium tartrate more rapidly from a solution of a racemic ammonium tartrate [ 1 ]. The first use of a chiral non-enzymatic catalyst can be traced to the work of Bredig and Faj ans in 1908 [2 ]. They studied the decarboxylation of camphorcar-boxylic acid catalyzed by nicotine or quinidine, and they estabhshed the basic kinetic equations of kinetic resolution. 

Of all the functions of proteins, catalysis is probably the most important. In the absence of catalysis, most reactions in biological systems would take place far too slowly to provide products at an adequate pace for a metabolizing organism. The catalysts that serve this function in organisms are called enzymes. With the exception of some RNAs (ribozymes) that have catalytic activity (described in Sections 11.7 and 12.4), aU other enzymes are globular proteins (section 4.3). Enzymes are the most efficient catalysts known they can increase the rate of a reaction by a factor of up to 10 ° over uncatalyzed reactions. Non-enzymatic catalysts, in contrast, typically enhance the rate of reaction by factors of 102 to 104... 

In addition to catalysts 5,10 and 11, a series of catalysts 12-19 (Scheme 3.5) have been shown to activate anhydrides (or acyl chlorides) for the KR of various alcohols 20-26 (Scheme 3.6), including 2-substituted cycloalkanols, 1,2-diol monoesters, 2-amido alcohols, primary as well as tertiary alcohols with generally excellent enantioselectivities [7a, 40]. These results have definitively demonstrated that non-enzymatic catalysts could be capable of competing with lipases in terms of substrate generality. Some of the best results are shown in Table 3.2. 

Temperature Sensitivity.— This is shown by two important characteristics—heat-inactivation and heat-acceleration. The irreversible inactivation by heat is used to distinguish enzymes from non-enzymatic catalysts, and is one of the means of detecting enzymes. 

Bellemin-Laponnaz S, Twedel J, Ruble JC, Breitling FM, Fu GC (2000) The kinetic resolution of allylic alcohols by a non-enzymatic acylation catalyst application to natural product synthesis. Chem Conunun 1009-1010... 

For practical applications of HNLs as catalysts for the preparation of chiral cyanohydrins, three objectives have been achieved first, to get high enantioselec-tivity it is decisive to suppress the non-enzymatic addition of HCN to the substrate ... 

The active form of the catalyst must transfer the electrons or the hydride ion to NAD(P)+, but not directly to the substrate. Otherwise, this non-enzymatic reduction will lead to low chemoselectivity and/or low enantioselectivity. 

Enzymatic ester hydrolysis is a common and widespread biochemical reaction. Since simple procedures are available to follow the kinetics of hydrolytic reactions, great efforts have been made during the last years to explain this form of catalysis in chemical terms, i.e., in analogy to known non-enzymatic reactions, and to define the components of the active sites. The ultimate aim of this research is the synthesis of an artificial enzyme with the same substrate specificity and comparable speeds of reaction as the natural catalyst. 

The chiral bicyclic phosphines 5 (and in particular 5a [7b]) are currently the most active phosphorus-based acylation catalysts, enabling use of low reaction temperatures. Under these conditions (i.e. —40 °C) selectivity factors as high as 370-390 were achieved (Scheme 12.2). This is the best selectivity factor ever reported for metal-free, non-enzymatic kinetic resolution. As a consequence, very good enantiomeric purity of both the isobutyric esters 7 and the remaining alcohols 6 was obtained, even at substrate conversions approaching 50% (Scheme 12.2) [7, 8],... 

The levels of selectivity achieved in these reactions are amongst the highest reported for non-enzymatic acylative KR, and the scope of the method has been reviewed by Vedejs [40], as has its application in PKR [43]. The PBO catalysts 2a-c are prepared by a multi-step enantioselective synthesis from lactate esters [42, 44] and are air-sensitive hence, the reactions are generally run in de-oxygenated solvents. However, the air-stable tetrafluoroboric acid salts of these catalysts can also be employed with in-situ deprotonation by EtsN these conditions give results comparable with those obtained using the original protocol [45]. (For experimental details see Chapter 14.17.1). 

By simulating evolution in vitro it has become possible to isolate artificial ribozymes from synthetic combinatorial RNA libraries [1, 2]. This approach has great potential for many reasons. First, this strategy enables generation of catalysts that accelerate a variety of chemical reactions, e.g. amide bond formation, N-glycosidic bond formation, or Michael reactions. This combinatorial approach is a powerful tool for catalysis research, because neither prior knowledge of structural prerequisites or reaction mechanisms nor laborious trial-and-error syntheses are necessary (also for non-enzymatic reactions, as discussed in Chapter 5.4). The iterative procedure of in-vitro selection enables handling of up to 1016 different compounds... 

In summary, scalemic secondary alcohols can be obtained by non-enzymatic kinetic resolution and in some cases with excellent selectivities. Although these results in general fall short when compared with those obtained with the esterase-promoted resolutions, it is expected that a more thorough understanding of the enantiodis-criminating event in these processes will result in the development of even more efficient catalysts. 

---