Two Versatile and Parallel Approaches to Highly Symmetrical Open and Closed Natural Product‐Based Structures

Two parallel approaches for preparing diverse and highly symmetrical homohybrids derived from a series of mono‐ and diterpenes, steroids, and alkaloids are reported. Both procedures are based on the mono‐addition of bis(alkynyl) dilithium reagents to natural products having a carbonyl group to produce the corresponding alkynyl derivatives. The Glaser–Hay Cu‐promoted homocoupling of these alkynyl natural product mono‐adducts as well as the Huisgen Cu‐catalyzed azide–alkyne cycloaddition (CuAAC) reaction resulted in the synthesis of steroid‐, terpene‐, and alkaloid‐based homohybrid derivatives incorporating diverse spacers to join the natural product scaffolds. Straightforward entries to novel closed highly symmetrical and complex estrone‐based macrocyclic and cage architectures by means of the Glaser–Eglinton homocoupling and the CuAAC reaction have been devised.