Chalcogen bond-guided conformational isomerization enables catalytic dynamic kinetic resolution of sulfoxides

Abstract

Conformational isomerization can be guided by weak interactions such as chalcogen bonding (ChB) interactions. Here we report a catalytic strategy for asymmetric access to chiral sulfoxides by employing conformational isomerization and chalcogen bonding interactions. The reaction involves a sulfoxide bearing two aldehyde moieties as the substrate that, according to structural analysis and DFT calculations, exists as a racemic mixture due to the presence of an intramolecular chalcogen bond. This chalcogen bond formed between aldehyde (oxygen atom) and sulfoxide (sulfur atom), induces a conformational locking effect, thus making the symmetric sulfoxide as a racemate. In the presence of N-heterocyclic carbene (NHC) as catalyst, the aldehyde moiety activated by the chalcogen bond selectively reacts with an alcohol to afford the corresponding chiral sulfoxide products with excellent optical purities. This reaction involves a dynamic kinetic resolution (DKR) process enabled by conformational locking and facile isomerization by chalcogen bonding interactions.

Fig. 1. Chalcogen bonding in functional molecules and asymmetric synthesis.

a Chalcogen bond (ChB). b ChB in living systems, medicines, and agrochemicals. c Intermolecular (cationic) ChB in organic catalysis. d Intramolecular (neutral) ChB of substrate as enabling tools for asymmetric synthesis (of chiral sulfoxides). e Examples of functional chiral sulfoxides.

Fig. 2. Substrates scope of the reaction^a.

^aReaction conditions as stated in Table 1, entry 10. Yields are isolated yields after purification by column chromatography. Er values were determined via HPLC on chiral stationary phase. ^b50 °C and THF as solvent. ^c220 mol% 1a, DQ, K₃PO₄ and 100 mol% diol were used.

Fig. 3. Synthetic transformations and applications.

^aK₃PO₄, NBS, 4 Å MS, 30 °C, toluene; ^bMgSO₄, 4 h, CH₂Cl₂, NaBH₃CN; ^cNaBH₄, Ti(OEt)₄, CH₂Cl₂; ^dLiOH, THF:H₂O = 2:1, 2 h, then 1 M HCl; ^eMgSO₄, BnNH₂, 4 h, then NaBH₃CN; ^fPyrrolidine, 4 Å MS, CH₂Cl₂, 60 °C; ^gachiral NHC, AcOK, D₂O:CH₂Cl₂ = 4:1; ^hachiral NHC, TsNH₂, Et₂NH, 4 Å MS, toluene; ⁱachiral NHC, DQ, EtSH, K₃PO₄, CH₂Cl₂; ^jTMSCHN₂, LDA, THF, −78 °C; ^kCH₃PPh₃Br, KHMDS, THF; ^lPd/C, H₂, EtOH. a Synthetic transformation of 3a. b Synthetic applications.

Fig. 4. Mechanistic studies.

a Control experiments without chalcogen bonding interaction. b Quantify the strength of chalcogen bonding interaction via DFT calculations. c Addition barrier of NHC to aldehyde moieties. d Oxidized barrier of Breslow intermediates.