Antibody-catalyzed Aldol Reactions

Aldolase antibody-catalyzed aldol reactions and kinetic resolution are an efficient means of synthesis of highly enantiomerically pure aldols. These processes have been used for the total synthesis of cytotoxic natural products epothilone A (48) and C (49) (Scheme 6.6) [21]. These compounds have... 

Figure 1. Kinetic parameters for the selection of antibody-catalyzed aldol and retro-aldol reactions, reflecting the biocatalyst s ability to accept substrates that differ clearly with respect to their molecular geometry. No background reaction was observed for the self-condensation of cyclopentanone. The indicated value for cyclopentanone addition to pentanal was estimated using the published kuncat value of 2.28 X 10 M s for the aldol addition of acetone to an aldehyde. Reproduced with permission of the authors and the American Association for the Advancement of Science.

Antibody Catalysis. Recent advances in biocatalysis have led to the generation of catalytic antibodies exhibiting aldolase activity by Lemer and Barbas. The antibody-catalyzed aldol addition reactions display remarkable enantioselectivity and substrate scope [18]. The requisite antibodies were produced through the process of reactive immunization wherein antibodies were raised against a [Tdiketone hapten. During the selection process, the presence of a suitably oriented lysine leads to the condensation of the -amine with the hapten. The formation of enaminone at the active site results in a molecular imprint that leads to the production of antibodies that function as aldol catalysts via a lysine-dependent class I aldolase mechanism (Eq. 8B2.12). 

A wide range of donor ketones, including acetone, butanone, 2-pentanone, cyclopentanone, cyclohexanone, hydroxyacetone, and fluoroacetone with an equally wide range of acceptor aromatic and aliphatic aldehydes were shown to serve as substrates for the antibody-catalyzed aldol addition reactions (Chart 2, Table 8B2.6). It is interesting to note that the aldol addition reactions of functionalized ketones such as hydroxyacetone occurs regioselectively at the site of functionaliztion to give a-substitutcd-fi-hydroxy ketones. The nature of the electrophilic and nucleophilic substrates utilized in this process as well as the reaction conditions complement those that are used in transition-metal and enzymatic catalysis. 

TABLE 8B2.6. Antibody-catalyzed aldol addition reactions (Eq. 8B2.11)"... 

It soon became clear that aldolase antibody 38C2 catalyzed the aldol reaction with both efficiency and broad scope. For example, compounds 7 to 13 could all be synthesized in antibody 38C2 catalyzed aldol reactions (Hoffmann et al, 1998). 

In addition to broad-scope substrate specificity, 38C2 exhibits high enantioselectivity for the aldol reaction. Although this high degree of enantioselectivity has been observed for antibody-catalyzed ester hydrolysis reactions, it is certainly not a feature common to all such catalysts (Janda et al., 1989 Lo et al., 1997 Pollack et al., 1989 Tanaka et al., 1996 Wade and Scanlan, 1996). Furthermore, the rules for the enantioselectivity for 38C2-catalyzed aldol reactions are both simple and general (Hoffmann et al., 1998). For most ketone donors, attack occurs on the si side of the acceptor. However, when a ketone with an a-hydroxy substituent (such as hydroxyacetone) acts as donor, attack occurs on the reside (Scheme 5). 

Bahmanyar S, Houk KN (2001a) The origin of stereoselectivity in proline-catalyzed intramolecular aldol reactions. J Am Chem Soc 123 12911-12912 Bahmanyar S, Houk KN (2001b) Transition states of amine-catalyzed aldol reactions involving enamine intermediates theoretical studies of mechanism, reactivity, and stereoselectivity. J Am Chem Soc 123 11273-11283 Bahmanyar S, HoukKN, Martin HJ, ListB (2003) Quantum mechanical predictions of the stereoselectivities of proline-catalyzed asymmetric intermolec-ular aldol reactions. J Am Chem Soc 125 2475-2479 Barbas CF 3rd, Heine A, Zhong G, Hoffmann T, Gramatikova S, Bjoernstedt R, List B, Anderson J, Stura EA, Wilson I, Lemer RA (1997) Immune versus natural selection antibody aldolases with enzymic rates but broader scope. Science 278 2085-2092... 

Table 8.7 lists the kinetic par ameters for antibody-catalyzed aldol and retm-eAAo reactions. 

Table 8.7. Kinetic parameters for antibody-catalyzed aldol and retra-aldol reactions [Refs in 4971-...

See The Chemistry of... Antibody-catalyzed Aldol Condensations in WileyPLUS for a method that uses the selectivity of antibodies to catalyze aldol reactions. 

The first iyn-selective organocatalytic aldol reaction was disclosed by Barbas III et al. [98]. Based on previous studies on antibody-mediated aldol reactions, they envisaged that the aldol reaction of unmodified hydroxyacetone with an aldehyde should proceed through the (Z)-enamine intermediate in the transition state and thus produce a yn-aldol. Indeed, the reaction catalyzed by O-tBu-L-thyrosine proceeds with high yn-stereoselectivity. Subsequently, the catalyst loading was decreased to 5 mol% by replacing the tyrosine derivative with the O-acylated cysteine (80) [99,90e]. Importantly, donors and acceptors can be used in stoichiometric amounts (Chart 3.10). 

Together vith our colleagues, we have developed antibodies that catalyze aldol reactions via the covalent enamine mechanism of natural class I aldolases. Natural class I aldolases utilize the e-amino group of a lysine in their active site to form an enamine, a carbon nucleophile, in their catalyzed aldol reactions [2]. One of the most important issues for development of such antibody catalysts is the pK of the active site lysine e-amino group. The pK of the e-amino group of lysine in aqueous solution is 10.7 [3], and the e-amino group is protonated at neutral pH and thus is not nucleophilic... 

Aldolase Antibody-catalyzed Aldol and Retro-aldol Reactions I 279... 

Stereochemistry of antibody 38C2-catalyzed aldol reactions and kinetic resolution. 

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