Densely functionalized cyclopentanes are found in myriads of highly sought after bioactive molecules and natural products attractive to the pharmaceutical industry. Preparation of highly substituted cyclopentanes often requires many challenging reaction steps and harsh conditions, thus highlighting the need for simple, mild conditions for their construction. Substituted allenes, which are easily obtained from readily available materials, provide an attractive entryway into this class of molecules. Previously, we have described a method for the cycloisomerization of allenes which employed a gold catalyst and a Lewis acidic additive to furnish substituted cyclopentenes with preferential anti diastereoselectivity. Although this system tolerated a variety of substituents on the allene, increasing the steric congestion of allene substituents resulted in little to no cylcopentene product. In order to access the cyclopentene derivatives of these bulkier allenes, palladium-catalyzed cycloisomeration conditions utilizing Pd2dba3 were developed and able to succeed where the gold-catalyzed reaction had failed. While tolerating significantly more steric congestion, palladium-catalyzed cycloisomerations resulted in comparable yields; however, these new conditions favored syn stereochemistry. Additional versatility of the palladium cycloisomerizations can be seen in the ability to cross-couple and cyclize allenes in a one pot reaction. This tandem cross-coupling and cycloisomerization reaction is attractive as it allows for the formation of two new carbon-carbon bonds in a single operation. Experiments exploring the scope of this transformation as well as optimizations to afford high yields of densely functionalized cyclopentenes via palladium catalysis are detailed.

Palladium-catalyzed cycloisomerization of allenes to access densely functionalized cyclopentenes

2019 Fall National Meeting

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