Pd‐Catalyzed Asymmetric Allylic Substitution Annulation Using Enolizable Ketimines as Nucleophiles: An Alternative Approach to Chiral Tetrahydroindoles

Abstract

A synthesis of chiral tetrahydroindoles has been developed via a Pd‐catalyzed asymmetric allylic substitution annulation using unstable enolizable ketimines as nucleophiles and our previously developed tBu‐RuPHOX as a chiral ligand. The reaction proceeds via an asymmetric desymmetrization of the meso‐diacetatecycloalkenes, providing the desired chiral tetrahydroindoles in moderate to good yields and with up to 96% ee. The annulation reaction could be performed on a gram‐scale in high yields and the resulting products can be transformed to several types of N‐hetereobicyclic derivatives. In addition, a chiral cis‐perhydroindolic acid derivative was also readily synthesized starting from a prepared chiral tetrahydroindole.magnified image

Recent Advances in Enantioselective Pd-Catalyzed Allylic Substitution: From Design to Applications

“… 729 More recently, Shen, Liu, and co-workers used Pd/RuPHOX as a catalyst to develop an alternative approach to the synthesis of tetrahydroindoles ( Scheme 297 b). 730 …”

“…Thus, You’s group reported the stereoselective formation of tetrahydrofurobenzofurans and tetrahydrobenzothienofurans through a Pd-catalyzed dearomative [3 + 2] cycloaddition of nitrobenzofurans using PHOX type ligand ( S )- L122 (Scheme a) . More recently, Shen, Liu, and co-workers used Pd/RuPHOX as a catalyst to develop an alternative approach to the synthesis of tetrahydroindoles (Scheme b) …”

Asymmetric cascades of the π-allyl complex: a journey from transition-metal catalysis to metallaphotocatalysis

“…Thus this time, they reacted ketimines 3a instead of 2b with acyclic allyl diacetate 3b under similar conditions to obtain the corresponding dihydropyrroles 3c in good yield and excellent enantioselectivity (Scheme 3). 22 In general, 5-membered cyclic diacetates gave products of low yield and low enantioselectivity. In contrast, the corresponding 6/7-membered congeners resulted in the formation of desired annulated dihydropyrroles in good yield and excellent selectivity.…”

Desymmetrization of meso-Dicarbonatecyclohexene with β-Hydrazino Carboxylic Esters via a Pd-Catalyzed Allylic Substitution Cascade

“…Our laboratory has had a long-standing interest in the exploration of novel Pd-catalyzed asymmetric allylic substitutions . Recently, we have focused on the catalytic enantioselective desymmetrization of meso -allyl substrates and established several straightforward protocols for accessing chiral oxygen- and nitrogen-containing [4,3,0] fused heterocycles . The efficient catalytic system prompted us to explore the construction of chiral hydrocinnolines, six-membered [4,4,0] fused azabicycles, which has not been reported so far.…”

“…However, the position of the CC bond in the terminal product is not identical to that of desired product 3a . This means that the sequence of the carbon and nitrogen nucleophilic substitution may proceed through a different pathway compared with our previously reported reaction . That is, after the formation of intermediate A , the cascade process involves nitrogen nucleophilic substitution prior to carbon nucleophilic substitution via intermediates B and C (pathway b).…”