Manganese-Catalyzed Enantioselective Dearomative Epoxidation of Naphthalenes with Aqueous Hydrogen Peroxide

Abstract

Arenes are abundantly occurring molecules of significant interest as versatile starting materials in organic reactions. Typically, oxidation of arenes yields planar molecules such as phenols and quinones. However, several iron dependent oxygenases can disrupt the aromaticity of arenes through oxidation and introduce C(sp³)─O stereogenic centers, resulting in precious enantioenriched epoxide or diol products. Emulating this enzymatic behavior with synthetic catalysts has met little success until now. Herein we describe a catalytic chemo- and enantioselective dearomative epoxidation of naphthalenes. The singular chemo- and enantioselectivity features of the reaction critically rely on a manganese catalyst that combines electron donating groups and steric demand on the ligand and activates hydrogen peroxide under mild conditions and short reaction times. Assisted with an N-protected amino acid, this catalyst epoxidizes a range of naphthalenes providing chemically versatile diepoxides in moderate to good yields and high levels of enantioselectivity. Straightforward elaboration gives diverse access to densely functionalized 3D structurally rich oxygenated molecules. The reaction constitutes a paradigmatical example of expedient access to stereochemically rich, valuable oxygenated molecules from readily available feedstocks, enabled by highly reactive yet selective biologically inspired oxidation catalysts.

Keywords: Arenes; Bioinspired catalysis; Enantioselectivity; Epoxidation; Hydrogen peroxide.

Figure 1

a) Pharmaceutical compounds based on a tetralin core. b) Rearrangement products of arene oxides. c) Classical organic methodologies to synthesize naphthalene oxides. d) Arenophile mediated dearomative epoxidation of arenes. e) Epoxidation of polyarenes using a porphyrin manganese catalyst. f) This work: enantioselective dearomative epoxidation of naphthalenes.

Figure 2

Catalyst screening. Yields determined by ¹H‐NMR. Enantioselectivities determined by SCF‐HPLC. [2 ^anti /2 ^syn ] ratio (in parentheses) determined by ¹H‐NMR from the crude mixture. Average of two runs, replicates are included in Table S7. *1% of 1‐naphthol formation.

Figure 3

Carboxylic acid and amino acid screening. Yields determined by ¹H‐NMR. Enantioselectivities determined by SCF‐HPLC. [2 ^anti /2 ^syn ] ratio (in parentheses) determined by ¹H‐NMR from the crude mixture.

Figure 4

Proposed mechanism for arene epoxidation where second epoxidation step is not shown. The proposal is based in the DFT‐computed mechanism for epoxidation with related manganese catalyst‐carboxylic acid cocatalyst.^{[ 63} , ⁶⁷ , ^{68 ]}

Figure 5

Substrate scope of different naphthalene derivatives for 2 formation. a) Isolated yields. Absolute configuration was determined by comparing the optical rotation with literature.^{[ 70 ]} Reaction conditions: 1 equiv substrate, 3 mol% catalyst (upon three additions during the 30′ or 1 h of the reaction time), 3 equiv H₂O₂ (upon three additions during the 30′ or 1 h of the reaction time), Conditions A: 15% Boc‐D‐Tle‐OH, 15% Lutidine, CH₃CN, 30′, and 0 °C, Conditions B: 15% Piv‐D‐Tle‐OH, CH₃CN:C₆D₆ (3:1), 1 h, and −20 °C. b) [2 ^anti /2 ^syn ] ratio (in parentheses) determined by ¹H‐NMR from the crude mixture. c) Enantiomeric excess anti‐isomer – Enantiomeric excess syn‐isomer (%) determined by SFC‐HPLC. d) Isolated yield through azide derivatization. e) syn isomer could not be isolated due to decomposition. a) Unsubstituted naphthalenes. b) 2‐Substituted naphthalenes. c) 1‐Substituted naphthalenes. d) Functionalized alkylnaphthalenes.

Figure 6

Derivatization of 2a to produce different molecules and prove the versatility of the products for further elaboration. Enantiomeric excesses determined by SFC‐HPLC. a) Isolated yield corresponding to the mixture of the isomers syn and anti. b) [2 ^anti /2 ^syn ] ratio determined by ¹H‐NMR from the crude mixture.