Ken Suzuki

Iron-Catalyzed Asymmetric Olefin cis-Dihydroxylation with 97 % Enantiomeric Excess†

The rising number of pharmaceuticals with chiral centers has heightened the necessity to discover catalysts that provide asymmetric induction into the products of their respective reactions. In addition, stringent constraints on trace impurities allowed in the marketed pharmaceutical products make the use of catalysts composed of physiologically benign metal centers increasingly attractive. The cis-dihydroxylation of olefins has become an important chemical reaction in the design of pharmaceuticals and natural product synthesis because this reaction is both stereospecific and, through the use of the Sharpless asymmetric dihydroxylation (AD) mixes, enantiospecific. A potential disadvantage of the Sharpless procedure is the extraordinary toxicity associated with the osmium metal in the AD mixes. In contrast, nature has evolved an important class of nonheme iron enzymes, called the Rieske dioxygenases, that perform a novel, asymmetric cis-dihydroxylation of arene C=C bonds. Such enzymes can be used as biocatalysts, but they are effective for only a narrow range of substrates, limiting their applicability. The catalytically relevant mononuclear iron center in the Rieske dioxygenases is coordinated by the 2-His1-carboxylate facial triad, a common structural motif among nonheme iron enzymes, which leaves cis-oriented available coordination sites on the iron octahedron for the activation of dioxygen. Inspired by these enzymes, researchers have developed the first examples of biomimetic complexes involving iron or manganese that catalyze olefin cisdihydroxylation using H2O2 as oxidant. Two of these complexes (4 and 5 in Figure 1) incorporate the optically active trans-1,2-diaminocyclohexane backbone into the ligand framework and exhibit asymmetric cis-dihydroxylation of cis-2-heptene with ee values of 29 and 79%. With the goal of achieving greater ee values, the trans-1,2-diaminocyclohexane unit was replaced by bipyrrolidine to give the tetradentate ligands (R,R)-BPBP, (R,R)-BQBP, and (R,R)-6-Me2-BPBP (Figure 1). Herein, we compare the asymmetric cis-dihydroxylation abilities of three iron complexes and find the 6-Me2BPBP complex capable of achieving up to 97% enantiomeric excess of the cis-diol product from two cis-disubstituted olefins. These ee values are comparable to those obtained with the osmium-based AD mixes. The ligands (R,R)-BPBP, (R,R)-BQBP, and (R,R)-6-Me2BPBP (Figure 1) were obtained by following literature procedures, and corresponding iron(II) complexes were obtained by the reactions of equimolar amounts of ligand and Fe(OTf)2·2NCMe [13] in CH2Cl2 under a N2 atmosphere (OTf= trifluoromethanesulfonate). Overnight stirring and subsequent solvent removal gave light brown powders, which were recrystallized from CH2Cl2/ether to afford pale yellow crystals, formulated as [Fe(BPBP)(OTf)2] (1), [Fe (BQBP)(OTf)(EtOH)](OTf) (2), and [Fe(6-Me2-BPBP)(OTf)2] (3). These crystals were suitable for X-ray crystallographic analysis, and the structures of the three complexes are shown in Figure 2. In all three structures, the BPBP ligands coordinate the iron center in a cis-a topology, in which equivalent available coordination sites (occupied by triflate or ethanol in the solid Figure 1. Optically active ligands (chiral centers indicated by *) and their corresponding iron complexes (in which the ligand coordinates in either a cis-a or cis-b topology) capable of promoting asymmetric olefin cis-dihydroxylation.