A Change from Kinetic to Thermodynamic Control Enables trans- Selective Stereochemical Editing of Vicinal Diols

Abstract

Here, we report the selective, catalytic isomerization of cis-1,2-diols to trans-diequatorial-1,2-diols. The method employs triphenylsilanethiol (Ph₃SiSH) as a catalyst and proceeds under mild conditions in the presence of a photoredox catalyst and under blue light irradiation. The method is highly chemoselective, broadly functional group tolerant and provides concise access to trans-diol products which are not readily obtained using other methods. Mechanistic studies reveal that isomerization proceeds through a reversible hydrogen atom transfer pathway mediated by the silanethiol catalyst.

Figure 1.

(A) Stereoselective synthetic logic. (B) Stereochemical editing logic. (C) This work: efficient access to trans-diequatorial diols using stereochemical editing logic.

Figure 2.

Reaction conditions optimization. (A) Isomerization of cyclohexanediol. Conditions: 0.1 mmol scale, 1 mol % IrF, 10 mol % quinuclidine, 30 mol % “thiol”, 0.2 M CH₃CN, 23 °C, 24 h, 456 nm blue LED; yield of 2 and recovered 1 were determined by ¹H NMR with nitrobenzene as internal standard; IrF, [Ir(dF(CF₃)ppy)₂-(dtbpy)]PF₆; RSM, recovered starting material; N.R., no reaction. (B) Reaction timecourse data carried out under Ph₃SiSH- and AdSH-catalyzed conditions.

Figure 3.

Mechanistic experiments and proposed mechanism. (A) Cyclic voltammetry studies interrogating Ph₃SiSH-catalyzed conditions. (B) Cyclic voltammetry studies interrogating AdSH-catalyzed conditions. Proposed (C) thiolate and (E) quinuclidine quenching mechanisms. (D) Reversible HAA/HAD leads to thermodynamic control. (F) Sequential HAA/HAD leads to kinetic control. See Supporting Information for full experimental details.

Figure 4.

Synthetic scope of cis/trans epimerization of vicinal diols. Standard conditions: 0.1–1.0 mmol scale, 1 mol % IrF, 10 mol % DABCO, 30 mol % Ph₃SiSH, 0.2 M MeCN, 23 °C, 24 h, 456 nm blue LED. Percent yields reported are isolated yields (average of two runs). See the Supporting Information for full experimental details. ^aReaction was performed with 1 mol % IrF, 10 mol % quinuclidine, 50 mol % AdSH, 0.2 M MeCN, 23 °C, 24 h, 456 nm blue LED. ^bReaction was performed under standard conditions. Number in parentheses is ¹H NMR yield with nitrobenzene as internal standard. ^cReaction was performed with the trans-diaxial diol isomer 25 under standard conditions for 48 h. Number in parentheses is ¹H NMR yield with nitrobenzene as internal standard. ^dThe identity of the major and minor diastereomer was not determined.

Figure 5.

Deuterium incorporation studies showing selective α-hydroxy C–H bond isomerization starting from (A) cis-diol, and (B) trans-diol substrates.