Ni-Catalyzed Enantioselective Desymmetrization: Development of Divergent Acyl and Decarbonylative Cross-Coupling Reactions

Abstract

Ni-catalyzed asymmetric reductive cross-coupling reactions provide rapid and modular access to enantioenriched building blocks from simple electrophile precursors. Reductive coupling reactions that can diverge through a common organometallic intermediate to two distinct families of enantioenriched products are particularly versatile but underdeveloped. Here, we describe the development of a bis(oxazoline) ligand that enables the desymmetrization of meso-anhydrides. When secondary benzylic electrophiles are employed, doubly stereoselective acyl cross-coupling proceeds to give ketone products with catalyst control over three newly formed stereogenic centers. Alternatively, the use of primary alkyl halides in the presence of an additional halogen atom transfer catalyst results in decarbonylative alkylation to give enantioenriched β-alkyl acids. Analysis of reaction rates for a range of both catalysts and substrates supports the notion that tuning the different electrophile activation steps with the two catalysts is required for enhanced reaction performance. These studies illustrate how reaction design can diverge a common Ni-acyl intermediate to either acyl or decarbonylative coupling products and highlight how dual ligand systems can be used to engage unactivated alkyl halides in Ni-catalyzed asymmetric reductive coupling.

Figure 1

Ni-catalyzed reductive cross-coupling reactions and context for the current study.

Figure 2

Initial reactivity studies and optimization of the doubly stereoselective acyl RCC. Reactions were performed on a 0.2 mmol scale. Yields were determined by ¹H NMR analysis of the crude reaction mixture using an internal standard. The dr and ee were determined using liquid chromatography/supercritical fluid chromatography (LC/SFC) with a stationary phase.

Figure 3

Proposed divergent mechanism and optimization of the decarbonylative alkylation of anhydride 1b. Reactions were performed on a 0.2 mmol scale. Yields were determined by ¹H NMR analysis of the crude reaction mixture using an internal standard. The ee was determined by using liquid chromatography/supercritical fluid chromatography (LC/SFC) with a chiral stationary phase.

Figure 4

Electroanalytical studies of rates of C(sp³) electrophile activation. (a) Series of alkyl halides selected for rate studies. (b) Rate of activation and yield data for complexes with different electrophiles. All CV data were collected for 1.0 mM Ni complex in 100 mM solution of TBABr in DMA using a 0.071 cm² boron-doped diamond working electrode. Blue bars = rates, black squares = % yield. (c) Representative cyclic voltammograms of 1.0 mM L7·NiBr₂ and L9·NiBr₂ complex. CV data for L7·NiBr₂ were collected in a 100 mM solution of TBAPF₆ in THF using a 0.071 cm² boron-doped diamond working electrode and Ag/AgNO₃ reference electrode. CV data for L9·NiBr₂ were collected in a 100 mM solution of TBABr in DMA using a 0.071 cm² boron-doped diamond working electrode and Ag/AgCl reference electrode. All CVs are from the second scan. (d) Relative rates of activation of electrophiles 2a and 4a by L7·Ni^I and L9·Ni^I.

Figure 5

Evaluation of the substrate scope of the acyl and decarbonylative cross-coupling. The absolute configurations of 3aa, 6ba, and 6gd were determined by X-ray crystallographic analysis, and the stereochemistry of all other products were assigned by analogy. The dr and ee were determined using SFC-MS or LC-SFC with a chiral stationary phase. (a) (S,S)-L7 catalyst was used for entries 3ac, 3af, 3ag, 3aj, 3ak, 3al, 3ca, and 3ea. Compounds 3aa–3af, 3ah, 3aj–3al, 3ba–3ea, and 3ga were isolated as the corresponding methyl esters upon treatment with TMS diazomethane. (b) (R,R)-L7 L7 catalyst was used for entries 6bc, 6bf, 6da, and 6ia. Compounds 6aa and 6ga were isolated as the corresponding methyl esters upon treatment with TMS diazomethane. The corresponding alkyl iodide was used as a coupling partner for entries 6bf–6bi. i) NiCl₂·DME (20 mol %) and L7 (30 mol %) were used. ii) Yield values reflect product quantification by ¹H NMR relative to tetrachloronitrobenzene as the internal standard. Value in parentheses represent the isolated yield. iii) NiCl₂·DME (30 mol %) and L8 (10 mol %) were used. iv) Anhydride (0.1 mmol), NiCl₂·DME (52.5 mol %), and L7 (50 mol %) were used.