Enantioselective Aldol Cyclodehydrations Catalyzed by Antibody 38C2

Aldolase antibody 38C2 catalyzes the enantioselective aldol cyclodehydration of 4-substituted-2,6-heptanediones (3) to give enantiomerically enriched 5-substituted-3-methyl-2-cyclohexen-1-ones (4). Yields, enantioselectivities, and product purities are markedly increased compared to the l-proline-catalyzed reactions

Proline-Catalyzed Direct Asymmetric Aldol Reactions

Most enzymatic transformations have a synthetic counterpart. Often though, the mechanisms by which natural and synthetic catalysts operate differ markedly. The catalytic asymmetric aldol reaction as a fundamental C−C bond forming reaction in chemistry and biology is an interesting case in this respect. Chemically, this reaction is dominated by approaches that utilize preformed enolate equivalents in combination with a chiral catalyst.1 Typically, a metal is involved in the reaction mechanism.1d Most enzymes, however, use a fundamentally different strategy and catalyze the direct aldolization of two unmodified carbonyl compounds. Class I aldolases utilize an enamine based mechanism,2 while Class II aldolases mediate this process by using a zinc cofactor.3 The development of aldolase antibodies that use an enamine mechanism and accept hydrophobic organic substrates has demonstrated the potential inherent in amine-catalyzed asymmetric aldol reactions.4 Recently, the first small-molecule asymmetric class II aldolase mimics have been described in the form of zinc, lanthanum, and barium complexes.5,6 However, amine-based asymmetric class I aldolase mimics have not been described in the literature.7 Here we report our finding that the amino acid proline is an effective asymmetric catalyst for the direct aldol reaction between unmodified acetone and a variety of aldehydes

A short enantioselective synthesis of 1-deoxy-L-xylulose by antibody catalysis

A new efficient synthesis of 1-deoxy-l-xylulose (1) is presented. The key step is achieved by a highly enantioselective aldol addition of hydroxyacetone to benzyloxyacetaldehyde via antibody catalysis. The synthesis described here should provide a convenient route to isotopically labeled derivatives. A two step enantioselective synthesis of 1-deoxy-L-xylulose has been achieved utilizing aldolase antibody 38C2 (Aldrich #47,995-0

Enantioselective Total Synthesis of Some Brevicomins Using Aldolase Antibody 38C2

Antibody catalysis has been used for the first time in a very efficient and highly enantioselective synthesis of natural products. Aldolase antibody 38C2 (Aldrich no. 47,995‐0) catalyzes the aldol reaction between α‐hydroxylated ketones and aldehydes to give syn‐α,β‐dihydroxy ketones with ee values>99% (see below). Since 38C2 also catalyzes the retro‐aldol reaction, it is possible to prepare the other enantiomers by kinetic resolution. This has been applied in total syntheses of ten brevicomins

Electrochemical synthesis of polypyrrole nanowires

Through a hole in a poly(ethyl acrylate) (PEA) layer that is electrochemically grafted to the surface of a vitreous carbon electrode-that is the route that must be taken by a growing polypyrrole nanowire in the electropolymerization of pyrrole. Chain growth is controlled by diffusion of the monomer through the DMF-swollen PEA layer, which acts as a template for the formation of nanowires (shown in the picture) with diameters of 400-1000 nm and lengths of up to 300 m

Aldolase Antibodies of Remarkable Scope

This paper describes the substrate specificity, synthetic scope, and efficiency of aldolase catalytic antibodies 38C2 and 33F12. These antibodies use the enamine mechanism common to the natural Class I aldolase enzymes. Substrates for these catalysts, 23 donors and 16 acceptors, have been identified. The aldol acceptor specificity is expected to be much broader than that defined here since all aldehydes tested, with the exception polyhydroxylated aldehydes, were substrates for the antibodies. 38C2 and 33F12 have been shown to catalyze intermolecular ketone−ketone, ketone−aldehyde, aldehyde−ketone, and aldehyde−aldehyde aldol addition reactions and in some cases to catalyze their subsequent dehydration to yield aldol condensation products. Substrates for intramolecular aldol reactions have also been defined. With acetone as the aldol donor substrate a new stereogenic center is formed by attack on the si-face of the aldehyde with ee's in most cases exceeding 95%. With hydroxyacetone as the donor substrate, attack occurs on the re-face, generating an α,β-dihydroxy ketone with two stereogenic centers of the α-syn configuration in 70 to >98% ee. With fluoroacetone donor reactions, the major product is a syn α-fluoro-β-hydroxy ketone with 95% ee. Studies of retroaldol reactions demonstrate that the antibodies provide up to 108-fold enhanced efficiency relative to simple amine-catalyzed reactions

A Catalytic Enantioselective Route to Hydroxy-Substituted Quaternary Carbon Centers: Resolution of Tertiary Aldols with a Catalytic Antibody

Aldolase antibody 38C2-catalyzed resolutions of tertiary aldols were studied. Tertiary aldols proved to be very good substrates for antibody catalyzed retro-aldol reactions. The catalytic proficiency, (kcat/KM)/kuncat, of the antibody for these reactions was on the order of 1010 M-1. A fluorogenic tertiary aldol allowed for the quantitative study of enantiomeric excess as a function of reaction conversion, revealing an E value of ca. 160 in this case. Study of a variety of substrates demonstrated that antibody-catalyzed retro-aldolization provides rapid entry to highly enantiomerically enriched tertiary aldols, typically >95% ee, containing structurally varied, heteroatom-substituted quaternary carbon centers. The utility of this approach to natural product syntheses has been demonstrated with the syntheses of (+)-frontalin, the side chain of Saframycin H, and formal syntheses of (+)- and (−)-mevalonolactone

Immune Versus Natural Selection: Antibody Aldolases with Enzymic Rates But Broader Scope

Structural and mechanistic studies show that when the selection criteria of the immune system are changed, catalytic antibodies that have the efficiency of natural enzymes evolve, but the catalytic antibodies are much more accepting of a wide range of substrates. The catalytic antibodies were prepared by reactive immunization, a process whereby the selection criteria of the immune system are changed from simple binding to chemical reactivity. This process yielded aldolase catalytic antibodies that approximated the rate acceleration of the natural enzyme used in glycolysis. Unlike the natural enzyme, however, the antibody aldolases catalyzed a variety of aldol reactions and decarboxylations. The crystal structure of one of these antibodies identified the reactive lysine residue that was selected in the immunization process. This lysine is deeply buried in a hydrophobic pocket at the base of the binding site, thereby accounting for its perturbed pKa

Breaking the one antibody–one target axiom

Studies at the interface of chemistry and biology have allowed us to develop an immunotherapeutic approach called chemically programmed antibodies (cpAbs), which combines the merits of traditional small-molecule drug design with immunotherapy. In this approach, a catalytic antibody catalyzes the covalent conjugation of a small molecule or peptide to the active site of the antibody, effectively recruiting the binding specificity of the conjugated molecule to the antibody. In essence, this technology provides the tools for breaking the “one antibody–one target axiom” of immunochemistry. Our studies in this area have focused on using the chemistry of the well studied aldolase catalytic antibodies of which mAb 38C2 is a member. Previously, we explored reversible assembly of cpAbs available through diketone chemistry. In this article, we explore a unique proadapter assembly strategy wherein an antibody 38C2-catalyzed transformation unveils a reactive tag that then reacts to form a stable covalent bond with the antibody. An integrin α(v)β(3) antagonist was synthesized with the designed proadapter and studied using human breast cancer cell lines MDA-MB-231 and MDA-MB-435. We demonstrate that this approach allows for (i) the effective assembly of cpAbs in vitro and in vivo, (ii) selective retargeting of 38C2 to integrin α(v)β(3) expressing breast cancer cell lines, (iii) intracellular delivery of cpAbs into cells, (iv) dramatically increased circulatory half-life, and (v) substantial enhancement of the therapeutic effect over the peptidomimetic itself in animal models of breast cancer metastasis. We believe that this technology possesses potential for the treatment and diagnosis of disease