Two-Carbon Ring Expansion of Cyclobutanols to Cyclohexenones Enabled by Indole Radical Cation Intermediate: Development and Application to a Total Synthesis of Uleine

Abstract

A single-electron transfer (SET) oxidation of indole or benzo [b]thiophene to a radical cation reverses the intrinsic polarity of these π-excessive bicyclic heteroarenes. Here we report an oxidative two-carbon homologation of cyclobutanols to cyclohexenones under a visible-light photoredox catalysis. 1-(Indol-2-yl)cyclobutan-1-ols are converted to 2,3,4,9-tetrahydro-1H-carbazol-1-ones, important structural motifs found in alkaloids and pharmaceuticals, with a broad substrate scope. A mechanistic study suggests that the reaction is initiated by an SET from an indole to an excited acridinium salt to generate the radical cation, which is followed by two consecutive 1,2-alkyl migrations and a rearomatization. Benzo[b]thiophene-substituted cyclobutanols are similarly converted to 2,3-dihydrodibenzo[b,d]thiophen-4(1H)-ones. A total synthesis of (±)-uleine featuring this ring-expansion process is documented.

Visible-light acridinium-based organophotoredox catalysis in late-stage synthetic applications

“…Zhu et al 52 reported visible-light photoredox catalysed an oxidative two-carbon homologation of cyclobutanols 26 to cyclohexenones 27 ( Scheme 16 ). In this present protocol, tetrahydrocarbazol-1-ones with various functionalizations, as well as their thio-analogues, were easily produced from the commonly available 1-(1 H -indol-2-yl)cyclobutan-1-ols and 1-(benzo[ b ]thiophen-2-yl)cyclobutan-1-ols owing to the reaction's broad substrate range.…”

Electrochemical Annulation of Indole-Tethered Alkynes Enabling Synthesis of Exocyclic Alkenyl Tetrahydrocarbazoles

“…Among the tetrahydrocarbazole derivatives, tetrahydrocarbazoles featuring exocyclic alkenyl moiety represent a special type of compounds, which also are found in natural products, such as sorzolon B and Uleine (Figure ). In particular, varieties of functional groups can be easily introduced via functionalization of the exocyclic alkenyl species on the tetrahydrocarbazole ring.…”

A Cyclobutanol Ring-Expansion Approach to Oxygenated Carbazoles: Total Synthesis of Glycoborine, Carbazomycin A and Carbazomycin B

“…[21][22][23][24][25][26][27][28][29][30][31][32][33][34] Elegant examples include an iron-mediated one-pot oxidative coupling by Knölker, 21,22,30,31 a radical cyclization by Crich and Rumthao, 32 and most recently, a one-pot domino benzannulation between indole-3-ynones and nitroalkanes by Mehta. 34 To complement these previously reported approaches to carbazole natural products, and encouraged by a recent total synthesis report utilizing a cyclobutanol ring expansion, 35 we were inspired to develop a strategy based on our previously developed cyclobutanol ring expansion methodology (Scheme 1, c). In 2018, we reported that heteroaromatic-substituted cyclobutanols undergo regioselective ring expansion to 4-tetralones by treatment with N-bromosuccinimide in acetonitrile.…”

“…To complement these previously reported approaches to carbazole natural products, and encouraged by a recent total synthesis report utilizing a cyclobutanol ring expansion, 35 we were inspired to develop a strategy based on our previously developed cyclobutanol ring expansion methodology (Scheme 1, c ). In 2018, we reported that heteroaromatic-substituted cyclobutanols undergo regioselective ring expansion to 4-tetralones by treatment with N -bromosuccinimide in acetonitrile.…”