Mimicking enzyme active sites in synthetic shape-programmable macromolecules to create enantioselective hydrogen-bond activated catalysts

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The Chemical Catalysis Program of the NSF Division of Chemistry supports the efforts of Professor Christian E. Schafmeister of Temple University to develop molecules that mimic the rate enhancements and exquisite enantio-, diastereo-, and regioselectivity of biological enzymes. The group has developed an efficient and systematic approach to the synthesis of pre-organized and highly functionalized macromolecules ("spiroligomers") that can create shape-programmable pockets that resemble enzyme active sites. Spiroligomers are stereochemically rich ladder molecules constructed from chiral, functionalized bis-amino acids that are coupled through pairs of amide bonds. In collaboration with Professor Kenneth Houk and his group at the University of California, Los Angeles, the Schafmeister group combined theoretical enzyme design with spiroligomer synthetic methodology to construct new catalysts. These catalysts include an improved, modified proline aldol catalyst, a tri-functional acyl-transfer catalyst that mimics serine esterases and accelerates transesterification reactions, and a bifunctional hydrogen bond donating catalyst that mimics Ketosteroid Isomerase and accelerates Claisen rearrangements and Diels-Alder reactions. The research team is now developing more active spiroligomer-based catalysts for these reactions by assembling reactive groups within chiral pockets created by covalently locking three and four spiroligomer segments together to create pre-organized macromolecules (2,000 to 5,000 Daltons). Within these pockets, reactive groups are organized to match transition state models. The pockets engender stereo- and regioselectivity through shape complementary with their substrates. Unlike enzymes, spiroligomer-based catalysts are extremely robust; They are immune to denaturation and function in water or organic solvents and across a wide range of temperatures. These catalysts are designed using in-house developed software called CANDO. The CANDO program uses a modified "inside-out" design approach that the Houk laboratory developed together with the laboratory of Professor David Baker at the University of Washington to create artificial enzymes based on proteins. First and second year undergraduate students are trained to use the CANDO program to design their own catalysts and thus, are engaged in research prior to finishing their laboratory courses. The techniques of molecular modeling, transition state theory and scientific program are valuable in the technical job market.Biological enzymes are catalysts, molecules that alter other molecules without being changed themselves. Biological enzymes operate at ambient temperature and pressures while avoiding energy consumption and the generation of unwanted byproducts that impair many current man-made catalysts. Professor Christian Schafmeister and his group at Temple University develop systematic approaches towards enzyme-like catalysts that are highly active and selective while being much more robust than fragile biological enzymes. The team uses computer-aided design to predict catalytic sites and then assembles molecular building blocks (molecular Legos) to produce these reactive sites or pockets. The group enhances the reactivity of their catalysts by building them into larger, more selective and more active macromolecules. Undergraduate and graduate student researchers are encouraged to participate in all levels of the research from using computer programs to design their own catalysts to producing the catalyst in the laboratory and testing the molecules for reactivity and selectivity.