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The Skaggs Institute For Chemical Biology
Scientific Report 1997-1998


Antibody-Catalyzed Organic and Organometallic Transformations and Chemical Libraries of Annonaceous Acetogenins


E. Keinan, S.C. Sinha,* F. Grynszpan,* P. Neogi, H. Avedissian, A. Yazbak, S.C. Sinha, D. Shabat, H. Itzhaky, A. Haskel, S. Nimri, O. Levy, S. Saphier, H. Shulman, A. Shulman, A. Brik

* The Scripps Research Institute

Antibody-Catalyzed Organic and Organometallic Transformations

Catalytic antibodies offer unique opportunities to examine mechanistic hypotheses and the relative importance of individual design elements in catalysis. We showed that antibodies elicited against the cyclopropenone hapten 1 (in Fig. 1) catalyze ester hydrolysis with a 1000-fold enhancement in rate. Because hapten 1 does not mimic the shape of the transition state, yet elicits efficient catalysts, it most likely generates the necessary charge complementarity in the active site. Thus, haptenic tetrahedral geometry is a desirable feature but not a prerequisite for generating hydrolytic antibodies.

This study, together with information reported about a cyclopropenone-containing protease inhibitor, highlights the potential applications of the rarely used cyclopropenone functionality in the future design of both haptens and enzyme inhibitors. The versatility of the antibodies to hapten 1 was indicated by their ability to catalyze the ring opening of epoxides to the corresponding chlorohydrins.

One obvious need in antibody catalysis, particularly for practical applications in organic synthesis, is an increase in the cost-effectiveness of the antibodies. We reported the first successful noncovalent entrapment of catalytic antibodies in a sol-gel matrix. Antibodies entrapped directly within a tetramethoxysilane-derived glass retained their activity for long periods. This finding suggests that this continuous-flow-reactor approach is the method of choice for preparative-scale organic synthesis that uses catalytic antibodies. We envisage that the catalytic reactor will allow convenient changes in reaction conditions, the substrate, and even the reaction type.

We showed that catalytic antibodies elicited against a metalloporphyrin hapten mimic some of the enzymatic features of cytochrome P-450. We improved the haptens designed to elicit substrate-selective catalytic antibodies that function as P-450 analogs. For example, a water-stable porphyrin hapten (2 in Fig. 1) presents the metalloporphyrin cofactor together with the organic substrate in the correct orientation to mimic the transition state of several oxygenation reactions, including epoxidation, sulfoxidation, and hydroxylation.

The importance of selective isotopic labeling of organic compounds stems not only from the value of such labeling in elucidating chemical mechanisms and biosynthetic pathways but also from the usefulness of labeled compounds in biomedical applications. Deuteration of ketones at the α-position with deuterium oxide requires strong basic conditions. Moreover, with polyfunctional ketones, the lack of selectivity and the occurrence of side reactions are serious drawbacks.

The mechanism by which catalytic lysine antibodies, such as the antibody 38C2, promote the aldol condensation involves activation of the carbonyl donor in the enamine form. In the absence of a proper carbonyl acceptor, this enamine can only hydrolyze back to its ketone precursor. This equilibrium provides the means for efficient exchange of the α-hydrogens with the water hydrogens within the binding site of the antibody. Lysine antibodies can be highly selective catalysts for α-deuteration of ketones and aldehydes, allowing chemoselective, regioselective, and enantioselective reactions to be carried out under neutral aqueous conditions at room temperature. Preliminary experiments with the antibody 38C2 indicated that deuterium labeling of ketones with this catalyst occurs with rate enhancements that rival those of enzyme catalysis.

Chemical Libraries of Annonaceous Acetogenins

Annonaceous acetogenins, particularly those with adjacent bis-tetrahydrofuran (THF) rings, have remarkable cytotoxic, antitumor, antimalarial, immunosuppressive, pesticidal, and antifeedant activities. Many of these fatty acid derivatives have similar carbon skeletons; their striking diversity originates mainly from the relative and absolute configuration of their various stereogenic oxygen functions.

We used our "naked carbon skeleton" strategy to synthesize many naturally occurring and nonnatural analogs of bis-THF acetogenins. In this approach, enantioselective olefin oxidation methods are combined with ligand-assisted chirality transfer techniques based on the chemistry of rhenium(VII) oxides. A set of empirical rules has been deduced to predict the stereochemistry of the THF rings on the basis of the behavior of 4 possible isomeric dienol substrates. These rules are valid for polycyclization with trifluoroacetylperrhenate of polyenols in a single step producing a single isolatable compound. The acetogenins synthesized include mono-THF structures, such as solamin and reticulatacin; bis-THF compounds, such as asimicin, bullatacin, trilobacin, trilobin, uvaricin, squamotacin, and rolliniastatin; and tris-THF molecules, such as goniocin and its isomers.

Publications

Grynszpan, F., Keinan, E. Use of antibodies to dissect the components of a catalytic event: The cyclopropenone hapten. Chem. Commun. 865, 1998.

Neogi, P., Doundoulakis, T., Yazbak, A., Sinha, S.C., Keinan, E. Total synthesis of mucocin. J. Am. Chem. Soc., in press.

Shabat, D., Shulman, H., Itzhaky, H., Reymond, J.L., Keinan, E. Enantioselectivity vs kinetic resolution in antibody catalysis: Formation of the (S) product despite preferential binding of the (R) intermediate. Chem. Commun. 1759, 1998.

Shulman, A., Shabat, D., Barbas, C.F. III, Keinan, E. Teaching catalytic antibodies to undergraduate students: An organic chemistry lab experiment. J. Chem. Educ., in press.

Sinha, S.C., Keinan, E., Sinha, S.C. Rules of stereoselectivity in the tandem oxidative cyclization reaction with rhenium(VII) oxides. J. Am. Chem. Soc. 120:9076, 1998.

Sinha, S.C., Sinha, A., Sinha, S.C., Keinan, E. Tandem oxidative cyclization with rhenium oxide: Total synthesis of 17,18-bisepi-goniocin. J. Am. Chem. Soc. 119:12014, 1997.

Sinha, S.C., Sinha, A., Sinha, S.C., Keinan, E. Total synthesis of goniocin and cyclogoniodenin T: Unique biosynthetic implications. J. Am. Chem. Soc. 120:4017, 1998.

Yazbak, A., Sinha, S.C., Keinan, E. Total synthesis of uvaricin. J. Org. Chem. 63:5863, 1998.

 

 







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