Asymmetric multi-component trifunctionalization reactions with α-Halo Rh-carbenes

Abstract

Multi-component multi-functionalization reactions involving active intermediates are powerful tools for rapidly generating a wide array of compounds. Metal carbynoids, with their distinct reactivity, hold great promise for developing synthetic methodologies. However, their application in catalytic transfer reactions has been hindered by the limited availability of suitable precursors. In this study, we investigate the catalytic potential of α-halo Rh-carbenes, leveraging the concept of metal carbynoids in multi-functionalization reactions. Through a chiral phosphoric acid-catalyzed asymmetric trifunctionalization, we have developed a method for synthesizing a variety of chiral α-cyclic ketal β-amino esters with high yields and excellent enantioselectivity. Our extensive experimental and computational studies reveal that α-halo Rh-carbenes exhibit carbynoid properties, which facilitate the transformation into functionalized Fischer-type Rh-carbenes through the decomposition of the C-halo bond.

Fig. 1. Transformations with metal carbynoids.

A Transformations with metal carbynoids. B Previous works with α-halo metal carbenes. C Asymmetric trifunctionalization with α-halo metal carbenes (This work).

Fig. 2. Reaction optimization.

The reactions were conducted on a 0.1 mmol scale: To the mixture of corresponding catalyst (2.0 mol%), CPA 4 (5.0 mol%), 2a (0.30 mmol), 3a (0.10 mmol), and 4 Å MS (150 mg) in CH₂Cl₂ (1.5 mL) was added a solution of diazo compound 1 in cold CH₂Cl₂ (1.5 mL) via a syringe pump in 0.5 h under a nitrogen atmosphere at 0 °C; The yields were given as isolated yields, and the ee values were determined by chiral HPLC analysis; N.D. = not detected; *The reaction concentration was diluted to 0.011 mol/L; **15.0 mol% CPA (S)-4d was used.

Fig. 3. Substrate scope with α-bromo Rh-carbenes.

The reactions were conducted on a 0.1 mmol scale: To the mixture of 3 (0.10 mmol), 2 (0.30 mmol), Rh₂(OAc)₄ (2.0 mol %), CPA 4 d (3.3 mg, 5.0 mol%), Cs₂CO₃ (0.30 mmol) and 4 Å MS (150 mg) in CH₂Cl₂ (1.5 mL) was added a solution of diazo compound 1 (0.30 mmol) in cold CH₂Cl₂ (1.5 mL) via a syringe pump in 0.5 h under a nitrogen atmosphere at 0 °C, and the reaction was running for 4 h under these conditions; The yields were given as isolated yields, the dr were determined by crude NMR and the ee values were determined by chiral HPLC analysis. *5.0 mol % Rh₂(OAc)₄ was used.

Fig. 4. Substrate scope with α-chloro Rh-carbenes.

Standard conditions as in Fig. 3.

Fig. 5. Synthetic generality.

Expanding reactions with a range of nucleophiles.

Fig. 6. Control Experiments.

a The reaction was performed with diol 2bm. b Compound 7 was subjected to standard reaction conditions. c Compound 8 and imine 3a were subjected to standard reaction conditions. d The reaction was performed with chiral rhodium catalyst. e The study of nonlinear effect. f The synthesis of CP-Cs and the calculated gibbs free energy changes for CPA and CP-Cs. g The reaction was performed with CP-Cs as the chiral catalyst.

Fig. 7. Free energy profile for the CPA catalyzed enantioselective trifunctionalization with α-bromo Rh-carbenes.

Both the non-bromine products pathway (A, in red) and bromine products pathway (B, in blue) are explored. The former pathway was proved to be more favored.

Fig. 8. Key transition states and IGMH analysis of the non-covalent interactions for the A-TS3_S and A-TS3_R.

Noncovalent interactions play a pivotal role in the enantioselectivity control.

Fig. 9. Reaction mechanism.

Proposed reaction mechanism for chiral phosphoric acid-catalyzed asymmetric trifunctionalization involving α-halo Rh-carbenes.

Fig. 10. Synthetic applications.

a Large scale synthesis of compound 5 g. b Derivative transformations of compound 5a or 5g.