Stereoselective Access to Polyfunctionalized Nine‐Membered Heterocycles by Sequential Gold and Palladium Catalysis

Abstract

We report herein a gold and palladium sequential catalysis system to access furan-fused nine-membered heterocycles in high efficiency and enantioselectivity. In this one-pot procedure, easily accessible enynamides undergo cyclization to generate azadienes in situ that participate in enantioselective formal [5+4] cycloaddition with vinyl ethylene carbonates. Conformation-controlled highly diastereoselective derivatizations of these medium-sized rings, coupled with oxidative furan cleavage, have enabled the access to diverse densely-functionalized nine-membered lactams.Medium-sized heterocycles (8 to 11-membered rings) are important structural motifs in various bioactive natural products. [1] The synthesis of these medium-sized rings, however, still remains a great challenge for catalytic method development. Out of the different synthetic strategies developed for medium-sized ring formation, intramolecular cyclization or ring expansion is most explored. [2,3] As an alternative and synthetically flexible approach, intermolecular dipolar cycloaddition provides a significant advantage of directly coupling two building blocks (serving as dipoles and dipolarophiles) to produce medium-sized heterocycles. [4] However, success along these lines remains limited, with cycloaddition of only a few classes of 1,4-dipolarophiles reported in the literature. Our group has introduced a dihydrobenzofuran-derived azadiene [5] to realize highly stereoselective Pd-catalyzed cycloadditions for the preparation of nine-or ten-membered benzofuran/indole-fused heterocycles. [5b-d] The same substrate was also used by the Lu group to achieve phosphine-catalyzed enantioselective eight-membered heterocycle synthesis. [6] The Shibata group has introduced CF 3 -substituted benzooxazinones for Pd-catalyzed decarboxylative cycloaddition to access benzo-fused nine-or twelve-membered heterocycles. [7] The formal [5+4] cycloaddition using ortho-quinone methides to access enantioenriched benzo-fused nine-membered rings have also been reported by the Fan group and the Guo group. [8] Despite these advances, it is important to note that due to the special Scheme 1. Diverse nine-membered heterocycles prepared from in situ generated azadienes.

Catalyst-controlled cycloisomerization/[4 + 3] cycloaddition sequence to construct 2,3-furan-fused dihydroazepines and 2,3-pyrrole-fused dihydrooxepines

“…5 As derivatives of enyne-ones, 6 recently, enyne-amides 7 which could be converted into dipolarophiles (dihydrofuran-supported azadiene) in situ under metal catalysis have been developed into an important synthetic strategy to access ring-fused heterocycles. 8 For example, the Chi group has elegantly demonstrated that gold and N-heterocyclic carbene co-catalyzed formal [4 + 2] cycloaddition utilizing azadiene as the intermediate could be realized to deliver furan-fused six-membered lactams in high efficiency and enantioselectivity (eqn (1), Scheme 1b). 8 a Meanwhile, Moreau et al described a relay catalytic strategy using the complementary activation of gold catalysis and aminocatalysis for the stereoselective formation of enantioenriched furan-fused tetrahydropyridine motifs.…”

Advances in Palladium‐Catalyzed Decarboxylative Cycloadditions of Cyclic Carbonates, Carbamates and Lactones

“…Subsequently, another enantioselective decarboxylative [5+4] cycloadditions of VECs 8 and enynamide 63 were disclosed by Zhao and coworkers via a gold and palladium sequential catalysis system (Scheme 37). [23c] A wide range of furan‐fused nine‐membered heterocycles 65 were obtained in high yields and enantioselectivities. The actual reactant was the azadiene 64 easily generated from the Au(I)‐catalyzed intramolecular cyclization of enynamide 63 , which was captured by species 2.2A through Oxy‐Michael addition to produce sulfonamide‐derived zwitterion 2.2J .…”

Recent Advances in Decarboxylative Conversions of Cyclic Carbonates and Beyond

“…Interestingly, all four diastereoisomers of the -lactone could be synthesized using different combinations of NHC precatalyst and ligands. Recently, Zhao and co-authors 3 reported a highly enantioselective formal [5+4] cycloaddition reaction of enamide partners and VCCs under the dual catalysis of Ph 3 AuCl and Pd(Ph 3 P) 4 , affording various polyfunctionalized nine-membered heterocycles with satisfactory yields and enantioselectivities (up to 98% ee) (Scheme 2b). It was found that the TsNH 2 additive might establish an interaction between the azadiene and/or the Pd--allyl alkoxide species; this interaction was the key to controlling the enantioselectivity.…”