Reactivity vs. Selectivity of Biomimetic Catalyst Systems of the Fe(PDP) Family through the Nature and Spin State of the Active Iron‐Oxygen Species

Abstract

Catalytic approaches to late-stage creation of new CÀ O bonds, especially via oxygenation of particular CÀ H groups in complex organic molecules, provide challenging tools for the synthesis of biologically active compounds and candidate drugs. In the last decade, significant efforts were invested in designing bioinspired iron based catalyst systems, capable of conducting selective oxidations of organic compounds. The key role of the oxygen-transferring high-valent iron-oxygen species in selective oxygenation is now well established; the next logical step would be gaining insight into the factors governing the oxidation chemo-and stereoselectivity, in relation to the peculiarities of their electronic structure, which would allow introducing the desired level of predictability into those catalytic transformations. In this Personal Account we analyze recent data on the reactivity of bioinspired formally oxoiron(V) catalytically active sites toward organic substrates having C=C and C(sp 3 )À H groups. While the majority of reported oxoiron(V) active species are low-spin (S = 1/2) complexes, the presence of strong electron-donating groups (NR 1 R 2 ) in the ligand backbone favors the high-spin (S = 3/2) ground state. Remarkably, the high-spin perferryl species exhibit higher chemo-, regio-, and stereoselectivity in the oxidations than their low-spin counterparts, thus witnessing the significance of these subtle electronic effects for the selectivity of oxidations conducted by bioinspired catalysts of the Fe(PDP) family.

Transition Metal-Catalyzed Direct Stereoselective Oxygenations of C(sp3)–H Groups

“…The introduction of strong hydrogen bond donating poly-β-fluorinated alcohols as reaction solvents allowed substantially improving the yield of the desired reaction productssecondary alcohols, including chiral ones . Also, one could mention the pioneering studies by Costas with co-workers who laid out a systematic basis for studying the effect of catalyst chirality on the regioselectivity − and, further, stereoselectivity − of the oxidation of complex substrates, including steroids.…”

“…A more focused mechanistic study by Talsi with co-workers established the correlation between the electrophilicity (and spin state) of the active species and the stereoselectivity of C2 hydroxylation of (+)-sclareolide . Reducing the electrophilicity of the iron catalyst ( 35 vs 36 , Figure ) enhanced the stereodiscrimination between 2α- and 2β-hydroxylation, with the Δ E a for the k ax / k eq (Scheme ) in the case of 36 being about 1.5 kJ/mol higher than for 35 . , …”

“…120 Reducing the electrophilicity of the iron catalyst (35 vs 36, Figure 19) enhanced the stereodiscrimination between 2α-and 2β-hydroxylation, with the ΔE a for the k ax /k eq (Scheme 5) in the case of 36 being about 1.5 kJ/mol higher than for 35. 120,121 More recently, the late-stage catalytic oxidative C−H functionalization of estrone 3-acetate, 17α-and 17β-estradiol 3-acetates in the presence of bioinspired nonheme Mn complexes of the types 32, 37−39 (Figure 19) was reported. 122 Changing the catalysts' chirality from (S,S)-to (R,R)-diverted the oxidation regioselectivity from preferential C9α-hydroxylation to C6α-hydroxylation, with high diastereoselectivity (α:β = 95:5) and in synthetically acceptable isolated yields (Figure 23).…”

Elusive Active Intermediates and Reaction Mechanisms of ortho-/ipso-Hydroxylation of Benzoic Acid by Hydrogen Peroxide Mediated by Bioinspired Iron(II) Catalysts

“…55 meta-Substituted benzoic acids were ortho-hydroxylated to form salicylates, whereas ortho-substituted substrates tend to undergo consecutive ipsohydroxylation/decarboxylation to produce phenolates. Based on the experimental findings, a two-oxidant mechanism [40][41][42][43][44][45][46][47][48][49][50]55 was proposed (Scheme 2a), in which the dichotomous yields are originated from two valence-resonance structures, i.e., Fe V (O)(anti-BzO) and Fe IV (O)(anti-BzO • ) oxidants, where the prefix anti refers to the orientation of the oxygen of BzO to the oxo of the Fe�O moiety. For the Fe V (O)(anti-BzO) oxidant, an electrophilic attack of the phenyl ring at the orthoposition generates the salicylate product; for the Fe IV (O)(anti-BzO • ) oxidant, consecutive decarboxylation via C−C homolysis and addition of the oxo to the ipso-position of the nascent Ph • radical generate a phenolate product.…”

“…meta -Substituted benzoic acids were ortho -hydroxylated to form salicylates, whereas ortho -substituted substrates tend to undergo consecutive ipso -hydroxylation/decarboxylation to produce phenolates. Based on the experimental findings, a two-oxidant mechanism − , was proposed (Scheme a), in which the dichotomous yields are originated from two valence-resonance structures, i.e. , Fe V (O)­( anti -BzO) and Fe IV (O)­( anti -BzO • ) oxidants, where the prefix anti refers to the orientation of the oxygen of BzO to the oxo of the FeO moiety.…”