As part of ongoing methodologies for making high-value alkyne building blocks for chemical synthesis, this work introduces new processes for generating hydrocarbon-tethered 1,6-diynes, with a particular focus on those bearing different terminal substituents. Such 1,6-diynes are traditionally difficult to make, and here they are derived in a few steps from commercially available 1,3-cyclohexanediones (e.g., dimedone). A tandem addition/fragmentation process produces the first alkyne tethered to a β-keto ester; this intermediate can be differentially substituted using the rich and complementary chemistry of terminal alkynes and β-keto esters. Several options have been developed for conversion of the β-keto ester into the second alkyne. The resulting 1,6-diynes are excellent building blocks for reaction discovery and target-oriented synthesis, taking advantage of many annulation and cycloisomerization of tethered π-systems. In particular, neopentylene-tethered 1,6-diynes (derived from dimedone) provide convenient synthetic entry into a variety of sesquiterpenoid structural motifs such as alcyopterosins. Recent examples from this methodology will be highlighted.

Synthesis of 1,6-diynes via tandem nucleophilic addition/fragmentation pathways and application for the synthesis of Alcyopterosins

ACS Spring Meeting 2021

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