Mechanistic identification and improvement of a direct enantioconvergent transformation in copper-catalyzed asymmetric allylic alkylation

Abstract

Recently, our group reported on the development of an unprecedented process in copper-catalyzed Asymmetric Allylic Alkylation. This method allowed for the quantitative transformation of a racemic substrate into an enantioenriched product. While a high level of asymmetric induction (up to 99% ee) was observed, the mechanistic understanding of the reaction remained fuzzy. In the present article, a thorough mechanistic analysis, based on computational investigations, led to the identification of the reaction pathway. Notably, it uncovered that both enantiomers of the starting material converged independently to the same product via two different mechanistic routes. This specific feature established this process as a rare example of Direct Enantioconvergent Transformation. Finally, the modelling results prompted a valuable improvement of the reaction, relying on the use of a more accessible range of substrates

Guanidine–Copper Complex Catalyzed Allylic Borylation for the Enantioconvergent Synthesis of Tertiary Cyclic Allylboronates

“…After oxidative addition and the release of bromide, the transition states lead to a common intermediate intB‐ R (see the Supporting Information, p. S62), which ultimately forms the R ‐configured product. Although the reaction is different from Ito's previous report, we propose that a direct enantioconvergent transformation mechanism is plausible, and the reaction to be consistent with this definition as no erasure of the substrate chiral center is involved …”

Enantioselective and Enantiospecific Transition-Metal-Catalyzed Cross-Coupling Reactions of Organometallic Reagents To Construct C–C Bonds

“…In the present example, Cu/ L32 engages ( R )- 313 through an S N 2′ oxidative addition, whereas ( S )- 313 reacts by an S N 2 oxidative addition, both converging to Cu III complex 315 . 253 …”

Rhodium-catalysed asymmetric allylic arylation of racemic halides with arylboronic acids

“…of 21-25, respectively, with no further optimization of the reaction conditions. We found that vinylboronic acids can also be used as nucleophiles under the same reaction conditions (entries [25][26][27] to give 26-28, respectively. Here, good yields and high levels of enantioselectivity were observed when the reaction time was extended from one to four hours.…”

“…Pd-catalysed processes that convert a racemic mixture of starting materials into a new single-enantiomer product are commonly referred to as dynamic kinetic asymmetric transformations (DYKATs), as originally developed by Trost and co-workers 24 . DYKATs can now be used with a wide variety of stabilized nucleophiles and an array of metal catalysts 24 and several non-stabilized sp 3 -hybridized nucleophiles can now be used in certain related procedures [25][26][27][28] .…”