Themove from the more deliberate, traditional approach to catalyst discovery to combinatorial approaches, has spurred great interest in the development of parallel-screening methods. As Crabtree and Loch recently put it, ideally one seeks TMan appropriate chemical sensor in a rapid parallel assay to detect rate and perhaps selectivity∫.[1] Herein, we describe the use of enzymes to report rapidly on reaction rate, for a set of parallel reactions. Seto and Abato recently described the use of enzymes to report on (enantio)selectivity.[2] From a broader perspective, these developments may be regarded as adding to the versatility of enzymes as tools for the organic chemist, an area that has seen remarkable expansion from asymmetric processing of unnatural substrates[3±5] and protecting-group cleavage under mild conditions,[6] to the creation of artificial enzymatic pathways.[7, 8] There is currently great interest in TMcombinatorial catalysis∫,[9] especially in transition-metal (TM) catalyzed reactions, for which reaction discovery and optimization often involve varying 1) the metal, 2) the ligand (type, structure, and stoichiometry), and 3) the substrate structure. By choosing such a model reaction, we sought both to establish proof of principle and to assess the ability of the screen to evaluate such variables one at a time. In our approach, the organic reaction under study is coupled, in situ, with an enzymatic reaction that permits continuous UV spectroscopic monitoring of the reaction. We term this approach ×in situ enzymatic screening× (ISES). This method is complementary to the previously communicated screening techniques,[10±19] in that it provides 1) evidence of product formation (not directly available using the elegant IR-thermography method of the Morken and Reetz groups)[11] and 2) relative rate profiles (not easily available with time-point detection systems employing gas[12] or liquid chromatography[10, 13] or mass spectrometry),[14] 3) without the need to alter the substrate, by installing a chromophore,[15] a fluorophore,[16] , or an azo-dye precursor.[17] Consonant with our interest in developing synthetic methodology toward densely functionalized , -unsaturated amino acids[20] as inhibitors of PLP-dependent (PLP pyridoxal phosphate) enzymes,[21] we chose a TM-mediated allylicamination reaction as our model reaction. We were influenced, in this regard, by an important precedent from Trost et al. ;[22a] scalemic vinylglycinol had been synthesized through Pd0-mediated allylic amination.[22] We set out to use ISES to identify other TMs, including less expensive ones, which were capable of catalyzing the intramolecular allylic-amination reaction illustrated in Scheme 1.[23] Success here would, in principle, validate the use of ISES in screening other variants of the allylic-displacement reaction.[24]
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Nov 19, 2002
Philip N Collier + 3
Open Access