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.