Enantio‐ and Diastereodivergent Sequential Catalysis Featuring Two Transition‐Metal‐Catalyzed Asymmetric Reactions

Abstract

This study demonstrates the feasibility and inherent benefits of combining two distinct asymmetric transitionmetal-catalyzed reactions in one pot. The reported transformation features a Pd-catalyzed asymmetric allylic alkylation and a Rh-catalyzed enantioselective 1,4-conjugate addition, effectively converting simple allyl enol carbonate precursors into enantioenriched cyclic ketones with two remote stereocenters. Despite the anticipated challenges associated with controlling stereoselectivity in such a complex system, the products are obtained in enantiomeric excesses ranging up to > 99 % ee, exceeding those obtained from either of the individual asymmetric reactions. In addition, since the stereoselectivity of both steps is under catalyst control, this one-pot reaction is enantio-and diastereodivergent, enabling facile access to all stereoisomers from the same set of starting materials.Scheme 1. Stereodivergence and enantiomeric enrichment in asymmetric catalysis.

Chiral Diene Ligands in Asymmetric Catalysis

“…Another one-pot reaction is a combination of the palladium-catalyzed asymmetric allylation of allyl enol carbonates 180 and rhodium-catalyzed asymmetric conjugate addition (Scheme c) . The reaction mixture containing enantioenriched cyclohexenone 181 , which was obtained from 180 by catalysis with a t BuPhox-palladium complex, was subjected to the asymmetric conjugate arylation via the addition of arylboronic acid and a chiral diene ( L6f )–rhodium catalyst.…”

“…Another one-pot reaction is a combination of the palladiumcatalyzed asymmetric allylation of allyl enol carbonates 180 and rhodium-catalyzed asymmetric conjugate addition (Scheme 43c). 208 The reaction mixture containing enantioenriched cyclohexenone 181, which was obtained from 180 by catalysis with a t BuPhox-palladium complex, was subjected to the asymmetric conjugate arylation via the addition of arylboronic acid and a chiral diene (L6f)−rhodium catalyst. Although the enantioselectivity of the first palladium-catalyzed allylation is not high, that of the second conjugate addition with the diene− rhodium catalyst is very high, and the final product 182 is eventually produced with a high % ee and a dr of 10:1−5/:1.…”

Stereodivergent Construction of 1,4‐Nonadjacent Stereocenters via Hydroalkylation of Racemic Allylic Alcohols Enabled by Copper/Ruthenium Relay Catalysis

“…On the other hand, the existing methodologies with the strategies of stereodivergent synergistic catalysis or relay catalysis mainly focused on the construction of 1,2‐adjacent [7–9] or 1,3‐nonadjacent stereocenters [9t,u] . For the remoter and more challenging 1,4‐nonadjacent stereocenters, to our knowledge, only one successful example merging Pd‐catalyzed asymmetric allylic alkylation with Rh‐catalyzed enantioselective 1,4‐conjugate addition was recently reported by the Lautens group, [7d] in which full set of stereoisomers of enantioenriched ketones bearing cyclic 1,4‐nonadjacent stereocenters could be achieved with good yields and high diastereoselectivities. Therefore, the development of a novel catalytic system for the stereodivergent synthesis of chiral compounds bearing acyclic 1,4‐nonadjacent stereogenic centers is of great significance and in high demand.…”

Bimetallic Catalysis in Stereodivergent Synthesis

“…In 2021, Lautens and co‐workers reported a sequential Pd/Rh catalytic system that combined two different asymmetric reactions (Scheme 21). [43, 44] The first reaction is a Pd‐catalyzed rearrangement of allylic enol carbonates and the second reaction is a Rh‐catalyzed 1,4‐conjugate addition of α,β‐unsaturated ketones. The reaction proceeds sequentially and cyclic ketones bearing two remote stereocenters were obtained in good yields and with high stereoselectivities.…”