49669-45-6Relevant articles and documents
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Maryanoff,B.E.
, p. 4410 - 4419 (1979)
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Copper-Catalyzed Selective Pyrrole Functionalization by Carbene Transfer Reaction
Rodríguez, Anabel M.,Molina, Francisco,Díaz-Requejo, M. Mar,Pérez, Pedro J.
supporting information, p. 1998 - 2004 (2020/03/04)
1H-Pyrroles can be directly functionalized by means of the incorporation of carbene groups from diazo compounds, in a process catalyzed by TpxCu complexes (Tpx=hydrotrispyrazolylborate ligand). The reactions take place with a complete selectivity toward the formal insertion of the carbene into the Cα?H bond, leading to alkylated pyrroles, with no modification of the Cβ?H, N?H or C=C bonds of the pyrrole unit. Alkyl substituents at C-ring as well as alkyl, aryl, allyl or alkyne substitution at N atom are tolerated, the strategy affording 20 new pyrrole derivatives. The observance of partial deuteration at the methylene group when the reaction is carried out with added D2O serves to discard the direct insertion of the carbene group into the Csp2?H bond, the alternative electrophilic attack to the pyrrole ring being feasible. (Figure presented.).
Directed Evolution of a Cytochrome P450 Carbene Transferase for Selective Functionalization of Cyclic Compounds
Brandenberg, Oliver F.,Chen, Kai,Arnold, Frances H.
supporting information, p. 8989 - 8995 (2019/06/13)
Transfers of carbene moieties to heterocycles or cyclic alkenes to obtain C(sp2)-H alkylation or cyclopropane products are valuable transformations for synthesis of pharmacophores and chemical building blocks. Through their readily tunable active-site geometries, hemoprotein "carbene transferases" could provide an alternative to traditional transition metal catalysts by enabling heterocycle functionalizations with high chemo-, regio-, and stereocontrol. However, carbene transferases accepting heterocyclic substrates are scarce; the few enzymes capable of heterocycle or cyclic internal alkene functionalization described to date are characterized by low turnovers or depend on artificially introduced, costly iridium-porphyrin cofactors. We addressed this challenge by evolving a cytochrome P450 for highly efficient carbene transfer to indoles, pyrroles, and cyclic alkenes. We first developed a spectrophotometric high-throughput screening assay based on 1-methylindole C3-alkylation that enabled rapid analysis of thousands of P450 variants and comprehensive directed evolution via random and targeted mutagenesis. This effort yielded a P450 variant with 11 amino acid substitutions and a large deletion of the non-catalytic P450 reductase domain, which chemoselectively C3-alkylates indoles with up to 470 turnovers per minute and 18000 total turnovers. We subsequently used this optimized alkylation variant for parallel evolution toward more challenging heterocycle carbene functionalizations, including C2/C3 regioselective pyrrole alkylation, enantioselective indole alkylation with ethyl 2-diazopropanoate, and cyclic internal alkene cyclopropanation. The resulting set of efficient biocatalysts showcases the tunability of hemoproteins for highly selective functionalization of cyclic targets and the power of directed evolution to enhance the scope of new-to-nature enzyme catalysts.