Functional-group-tolerant, nickel-catalyzed cross-coupling reaction for enantioselective construction of tertiary methyl-bearing stereocenters

Abstract

The first Negishi nickel-catalyzed stereospecific cross-coupling reaction of secondary benzylic esters is reported. A series of traceless directing groups is evaluated for ability to promote cross-coupling with dimethylzinc. Esters with a chelating thioether derived from commercially available 2-(methylthio)acetic acid are most effective. The products are formed in high yield and with excellent stereospecificity. A variety of functional groups are tolerated in the reaction including alkenes, alkynes, esters, amines, imides, and O-, S-, and N-heterocycles. The utility of this transformation is highlighted in the enantioselective synthesis of a retinoic acid receptor agonist and a fatty acid amide hydrolase inhibitor.

Figure 1

Bioactive small molecules containing a tertiary benzylic stereocenter.

Figure 2

Evaluation of leaving groups for cross-coupling with dimethylzinc.a ^aNickel sources used in this reaction included NiCl₂•DME, Ni(acac)₂, or Ni(COD)₂. Ligands included DPEphos, rac-BINAP, or Xantphos. Solvents included PhMe, THF, or Et₂O. Reaction temperatures ranged between rt and 50 °C. The optimal results for each directing group are shown. For a complete list of reaction conditions for each experiment, please refer to the SI. Yields were determined either by ¹H NMR based on comparison with PhTMS as internal standard or by GC analysis with dodecane as internal standard. Enantiospecificity (es) = (ee_product/ee_substrate) × 100%; determined by chiral SFC chromatography. ^bDPEphos as ligand. ^cXantphos as ligand.

Scheme 1

Traceless directing group strategy for promoting challenging organometallic transformations.

Scheme 2

Synthesis of enantioenriched benzylic alcohol derivatives for Negishi cross-coupling.

Scheme 3

Cross-coupling of indole electrophiles.

Scheme 4

Enantioselective synthesis of retinoic acid receptor ligand 2. (a) Mg, THF, rt, 2 h; (b) B(OMe)₃, Et₂O, 0 °C, 1 h, 94%; (c) 1 M HCl; (d) i) Et₂Zn (6.0 equiv), PhMe, 65 °C, 24 h, ii) 48, 49 (0.10 equiv), PhMe, 0 °C, 24 h; (e) 51, DCC, DMAP, CH₂Cl₂, rt, 12 h, 90%; (f) NiCl₂•DME (10 mol%), Xantphos (20 mol%), ZnMe₂ (3.0 equiv), PhMe, 0 °C, 24 h; (g) 1 N NaOH, THF:MeOH (1:1), 60 °C, 2 h, 92%.

Scheme 5

Synthesis of FAAH inhibitor 3. (a) 54 (1.0 equiv), THF, −78 °C to rt, 1 h, 75%; (b) MnO₂ (20 equiv), CH₂Cl₂, rt, 9 h, 72%; (c) (S)-Me-CBS (10 mol%), H₃B•SMe₂ (2.0 equiv), THF, 0 °C, 16 h, 99%, 67% ee, recrystallized to 95% ee; (d) 51, DCC, DMAP, CH₂Cl₂, rt, 12 h, 83%; (e) NiCl₂•DME (10 mol %), DPEphos (20 mol %), ZnMe₂ (3.0 equiv), PhMe, rt, 24 h; (f) Br₂, THF, 0 °C, 6 h, 24%; (e) NiCl₂•DME (10 mol %), DPEphos (20 mol %), ZnMe₂ (3.0 equiv), PhMe, rt, 24 h, 75%; (g) TFA, CH₂Cl₂, rt, 30 min; (h) 61, CH₂Cl₂, rt, 20 h 68% over 2 steps.