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Exploration of intermediates that enable chemoselective cycloaddition reactions and expeditious construction of fused- or bridged-ring systems is a continuous challenge for organic synthesis. As an intermediate of interest, the oxyallyl cation has been harnessed to synthesize architectures containing seven-membered rings via (4+3) cycloaddition. However, its potential to access five-membered skeletons is underdeveloped, largely due to the thermally forbidden (3+2) pathway. Here, the combination of a tailored precursor and a Pd(0) catalyst generates a Pd-oxyallyl intermediate that cyclizes with conjugated dienes to produce a diverse array of tetrahydrofuran skeletons. The cycloaddition overrides conventional (4+3) selectivity by proceeding through a stepwise pathway involving a Pd-allyl transfer and ring closure sequence. Subsequent treatment of the (3+2) adducts with a palladium catalyst converts the heterocycles to the carbocyclic cyclopentanones.

The first realization of the amino‐trimethylenemethane chemistry is reported using a deprotonation strategy to simplify the synthesis of the amino‐trimethylenemethane donor in two steps from commercial and inexpensive materials. A broad scope of cycloaddition acceptors (seven different classes) participated in the chemistry, chemo‐, regio‐, diastereo‐, and enantioselectively generating various types of highly valuable complex amino cycles. Multiple derivatization reactions that further elaborated the initial amino cycles were performed without isolation of the crude product. Ultimately, we applied the amino‐trimethylenemethane chemistry to synthesize a potential pharmaceutical in 8 linear steps and 7.5 % overall yield, which previously was achieved in 18 linear steps and 0.6 % overall yield.

The first realization of the amino‐trimethylenemethane chemistry is reported using a deprotonation strategy to simplify the synthesis of the amino‐trimethylenemethane donor in two steps from commercial and inexpensive materials. A broad scope of cycloaddition acceptors (seven different classes) participated in the chemistry, chemo‐, regio‐, diastereo‐, and enantioselectively generating various types of highly valuable complex amino cycles. Multiple derivatization reactions that further elaborated the initial amino cycles were performed without isolation of the crude product. Ultimately, we applied the amino‐trimethylenemethane chemistry to synthesize a potential pharmaceutical in 8 linear steps and 7.5 % overall yield, which previously was achieved in 18 linear steps and 0.6 % overall yield.

We report a Zn‐ProPhenol catalyzed asymmetric Mannich reaction between butenolides and polyfluorinated alkynyl ketimines to obtain vinylogous products featuring two contiguous tetrasubstituted stereogenic centers. Notably, this is the first successful use of ketimines in the ProPhenol Mannich process, and the reaction offers a new approach for the preparation of pharmaceutically relevant products possessing trifluoromethylated tetrasubstituted alkylamines. The reaction can be performed on large scale with reduced catalyst loading without impacting its efficiency. Moreover, the acetylene moiety can be further elaborated using various methods.

We report a Zn‐ProPhenol catalyzed asymmetric Mannich reaction between butenolides and polyfluorinated alkynyl ketimines to obtain vinylogous products featuring two contiguous tetrasubstituted stereogenic centers. Notably, this is the first successful use of ketimines in the ProPhenol Mannich process, and the reaction offers a new approach for the preparation of pharmaceutically relevant products possessing trifluoromethylated tetrasubstituted alkylamines. The reaction can be performed on large scale with reduced catalyst loading without impacting its efficiency. Moreover, the acetylene moiety can be further elaborated using various methods.