Iridium-Catalyzed Enantioselective Allylic Substitution of Enol Silanes from Vinylogous Esters and Amides

Abstract

The enol silanes of vinylogous esters and amides are classic dienes for Diels-Alder reactions. Here, we report their reactivity as nucleophiles in Ir-catalyzed, enantioselective allylic substitution reactions. A variety of allylic carbonates react with these nucleophiles to give allylated products in good yields with high enantioselectivities and excellent branched-to-linear ratios. These reactions occur with KF or alkoxide as the additive, but mechanistic studies suggest that these additives do not activate the enol silanes. Instead, they serve as bases to promote the cyclometalation to generate the active Ir catalyst. The carbonate anion, which was generated from the oxidative addition of the allylic carbonate, likely activates the enol silanes to trigger their activity as nucleophiles for reactions with the allyliridium electrophile. The synthetic utility of this method was illustrated by the synthesis of the anti-muscarinic drug, fesoterodine.

Figure 1

Proposed Ir-catalyzed enantioselective allylic substitution with Danishefsky's diene and Rawal's diene.

Figure 2

Representive enantioenriched bisarylalkane containing natural products and pharmaceuticals.

Scheme 1. Allylic Substitution of 1a with Enol Silane 3 in the Presence of the Ir–Ethylene Complex 7 as the Catalyst

Scheme 2. Analysis of the Identity and Reactivity of the Resting State of the Catalytic System^a

^a(I) Resting state of the reaction with the catalyst generated in situ. (II) Comparison of the reaction at room temperature catalyzed by the cyclometalated ethylene complex 7 and by the catalyst generated in situ.

Scheme 3. Enantioselective Synthesis of Fesoterodine