Enantioselective Phosphine‐Catalyzed Formal [4+4] Annulation of α,β‐Unsaturated Imines and Allene Ketones: Construction of Eight‐Membered Rings

Abstract

The first highly enantioselective phosphine-catalyzed formal [4+4] annulation has been developed. In the presence of amino-acid-derived phosphines, the unprecedented [4+4] annulations between benzofuran/indole-derived α,β-unsaturated imines and allene ketones proceeded smoothly, thus affording azocines, bearing either a benzofuran or an indole moiety, in excellent yields and with nearly perfect enantioselectivities (≥98 % ee in most cases). This work marks the first efficient asymmetric construction of optically enriched eight-membered rings by phosphine catalysis.

Palladium‐Titanium Relay Catalysis Enables Switch from Alkoxide‐π‐Allyl to Dienolate Reactivity for Spiro‐Heterocycle Synthesis

“…[6] Notably,all these reported systems are based on the classical reactivity of electrophilic Pd-p-allyl (plus nucleophilic alkoxide). [7] Theaurone 1a [8] (Table 1) and the corresponding imines [9] have found much use in stereoselective cycloadditions in the past few years.V arious benzofuran-fused heterocycles were prepared in this way,a nd is ac ommon structural motif in al arge number of bioactive compounds. In particular,a n unprecedented umpolung of VECs is achieved: I is converted into anucleophilic dienolate species with palladium-titanium relay catalysis,w hich enables ah ighly diastereoselective [4+ +2] cycloaddition to access [6,5] spirocycles (pathway B).…”

“…It is noteworthy that during the preparation of our manuscript, the group of Kleij reported am echanistically related and elegant example of self-coupling of VECs through allylic alkylation of the enolate. [7] Theaurone 1a [8] (Table 1) and the corresponding imines [9] have found much use in stereoselective cycloadditions in the past few years.V arious benzofuran-fused heterocycles were prepared in this way,a nd is ac ommon structural motif in al arge number of bioactive compounds. [10] Based on our previous synthesis of nine-membered heterocycles, [5] we hypothesized that the switch of 1a might enable an attack of the alkoxide to the internal position of the Pd-p-allyl system in the final cyclization step for the synthesis of the seven-membered heterocycle 3.D espite much experimentation by modifying the palladium-catalyzed procedure,n o formation of 3 was observed.…”

Dearomatization of 3‐Nitroindoles by a Phosphine‐Catalyzed Enantioselective [3+2] Annulation Reaction

“…[2] Our research group has been active in this research field;w ei ntroduced as eries of amino acid derived bifunctional phosphines and applied them to aw ide range of enantioselective transformations. [3] Very recently,w ed isclosed the enantioselective construction of synthetically useful bicyclics ystems through intramolecular Rauhut-Currier (RC) reactions,w hich involve the oxidative dearomatization of phenols and subsequent desymmetrization of cyclohexadienones. [4] Building upon these earlier successes,w ew ere keen to develop further synthetically useful strategies that would combine phosphine catalysis and an enantioselective dearomatization process to enable the asymmetric synthesis of important structural motifs in astraightforward manner.…”

Palladium‐Catalyzed Asymmetric [4+3] Cyclization of Trimethylenemethane: Regio‐, Diastereo‐, and Enantioselective Construction of Benzofuro[3,2‐b]azepine Skeletons

“…To achieve the aforementioned goals we envisaged that benzofuran-derived azadienes, [13] in which the aza-diene may exist as 1,4-dipolar resonant structure RS I (driven by aromatization), might serve as 4p components in asymmetric [4+ +3] cyclizations with Pd-TMM species to generate ringfused azepines (Scheme 2). Several issues should be considered in this scenario,including:1)the regioselectivity caused by potentially competitive [3+ +2] cyclizations of imines or alkenes,a nd 2) the compromise between reactivity and diastereo-or enantioselectivity.T oa ddress these challenges, we report herein the Pd-catalyzed asymmetric [4+ +3] cyclization of TMM donors with benzofuran-derived azadienes, which led to the construction of aseries of structurally diverse benzofuro [3,2-b]azepine scaffolds with generally excellent diastereo-and enantioselectivities.T his reaction not only represents the first catalytic asymmetric [4+ +3] cyclization of Pd-TMM species but also provides an alternative approach to chiral, fused azepine scaffolds by atransition-metal-catalyzed [4+ +3] cyclization process.…”