Chiral sulfide and achiral sulfonic acid cocatalyzed enantioselective electrophilic tandem selenylation semipinacol rearrangement of allenols

Abstract

A highly enantioselective electrophilic selenylation/semipinacol rearrangement of allenols has been developed, which is enabled by the cooperative catalysis of a chiral sulfide and an achiral sulfonic acid. The designed and synthesized chiral sulfide catalyst and selenylating reagent play a crucial role in enhancing both enantioselectivity and reactivity. This approach exhibits excellent regio-, chemo-, and enantioselectivity, providing access to diverse enantioenriched cyclopentanones featuring an arylselenovinyl-substituted quaternary carbon stereocenter. Furthermore, these products can be transformed into synthetically valuable alkyne, vinyl bromide, and aniline derivatives. Mechanistic studies reveal that the combination of a chiral sulfide and an achiral sulfonic acid not only facilitates the formation of catalytically active species, but also governs the enantioselectivity of the reaction. Meanwhile, density functional theory calculations disclose that four hydrogen bond interactions and a π‧‧‧π interaction are responsible for the observed enantioselectivity.

Fig. 1. Design of catalytic asymmetric electrophilic selenylation/semipinacol rearrangement of allenols.

a Asymmetric electrophilic addition/semipinacol rearrangement of allylic alcohols. b Asymmetric electrophilic addition/semipinacol rearrangement of allenols. c Our design. d The potential challenges. e Our strategies. f This work: enantioselective electrophilic selenylation/semipinacol rearrangement of allenols.

Fig. 2. Scope of this reaction^a.

^aReaction conditions: unless otherwise noted, the reaction was conducted with 2 (0.1 mmol), 3 (0.1 mmol), (R, S, S)-1i (0.01 mmol), 2-NSA (0.01 mmol), and 5 Å MS (30 mg) in CHCl₃ (2.0 mL) at −40 °C for 12–120 h under Ar. Isolated yields are shown. The ee values were determined by SFC or HPLC. ^bThe reaction was performed at −50 °C. ^cThe reaction was performed at −20 °C. ^dThe reaction was performed at −10 °C. ^eThe reaction was performed at −60 °C. ^f0.3 equiv of 2-NSA was used. ^g2s, cis:trans = 5.0:1. ^h2t, cis:trans = 2.9:1. ⁱ2u, cis:trans = 2.9:1. ^j2v, cis:trans = 1.7:1. ^k2w, cis:trans = 4.4:1. ^l2x, cis, single diastereoisomer. 2-NSA 2-naphthalenesulfonic acid, MS molecular sieve, Bn benzyl, SFC supercritical fluid chromatography, HPLC high-performance liquid chromatography.

Fig. 3. Limitations and mechanistic studies.

a Limiting allenol substrates. b The effects of catalyst and acid. c NMR and HRMS experiments. d Non-linear effect of catalyst (R, S, S)-1i. e Hammett plot. 2-NSA 2-naphthalenesulfonic acid, MS molecular sieve, MsOH methylsulfonic acid, BINSA 1,1’-binaphthyl-2,2’-disulfonic acid, CSA camphorsulfonic acid, TfOH triflic acid, TFA trifluoroacetic acid, (PhO)₂P(O)OH diphenyl hydrogen phosphate, NMR nuclear magnetic resonance, HRMS high-resolution mass spectrometry.

Fig. 4. Computational studies on the reaction pathway and the origin of enantioselectivity.

a Gibbs free energies profiles for the enantioselective electrophilic selenylation/semipinacol rearrangement of allenols. Orange dashed line: chalcogen-bonding interaction. Green dashed line: hydrogen-bonding interaction. Red dashed line: π‧‧‧π interaction. b Structures analysis of transition states. Bond lengths are given in Å. Gibbs free energies are shown in kcal/mol. 2-NSA 2-naphthalenesulfonic acid.

Fig. 5. Gram-scale reaction and synthetic applications.

a Gram-scale reaction of 2a. Reaction conditions: 2a (6.0 mmol), 3d (6.0 mmol), (R, S, S)-1i (0.6 mmol), 2-NSA (0.6 mmol), and 5 Å MS (1.20 g) in CHCl₃ (80 mL) at −40 °C for 70 h under Ar. b Further transformations of 4a. Reaction conditions: (i) 85% m-CPBA (1.1 equiv), CH₂Cl₂, 0 °C, 3 min; (ii) DABCO (1.0 equiv), toluene, rt to 90 °C, 8 min; (iii) PhI (1.2 equiv), Pd(PPh₃)₂Cl₂ (0.02 equiv), CuI (0.04 equiv), Et₃N, rt, 11 h; (iv) MMPP·6H₂O (2.0 equiv), NaHCO₃ (3.0 equiv), MeOH, rt, 12 h; (v) DBDMH (1.0 equiv), CH₂Cl₂, rt, 11 h; (vi) NBS (6.0 equiv), CH₂Cl₂, rt, 10 h; (vii) Zn (5.0 equiv), AcOH/THF/H₂O, 60 °C, 1 h; (viii) TMSOTf (2.5 equiv), DMF, 70 °C, 3 h; (ix) 3,5-CF₃C₆H₃N = C = S (1.1 equiv), THF, rt, 24 h; (x) NaBH₄ (1.5 equiv), MeOH, 0 °C, 1 h; (xi) NH₂OH·HCl (2.0 equiv), pyridine, 90 °C, 36 h. Isolated yields are shown. The ee values were determined by SFC. m-CPBA m-chloroperbenzoic acid, DABCO 1,4-diazabicyclo[2.2.2]octane, MMPP magnesium monoperoxyphthalate, DBDMH 1,3-dibromo-5,5-dimethyl-hydantoin, NBS N-bromosuccinimide, AcOH acetic acid, THF tetrahydrofuran, TMSOTf trimethylsilyl trifluoromethanesulfonate, DMF N,N-dimethylformamide. SFC supercritical fluid chromatography.