An Approach to Mimicking the Sesquiterpene Cyclase Phase by Nickel-Promoted Diene/Alkyne Cooligomerization

Abstract

Artificially mimicking the cyclase phase of terpene biosynthesis inspires the invention of new methodologies, since working with carbogenic frameworks containing minimal functionality limits the chemist’s toolbox of synthetic strategies. For example, the construction of terpene skeletons from five-carbon building blocks would be an exciting pathway to mimic in the laboratory. Nature oligomerizes, cyclizes, and then oxidizes γ,γ-dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP) to all of the known terpenes. Starting from isoprene, the goal of this work was to mimic Nature’s approach for rapidly building molecular complexity. In principle, the controlled oligomerization of isoprene would drastically simplify the synthesis of terpenes used in the medicine, perfumery, flavor, and materials industries. This article delineates our extensive efforts to cooligomerize isoprene or butadiene with alkynes in a controlled fashion by zero-valent nickel catalysis building off the classic studies by Günther Wilke and coworkers.

Scalable, Enantioselective Synthesis of Germacrenes and Related Sesquiterpenes Inspired by Terpene Cyclase Phase Logic

“…[1] Earlier this year, we reported our initial forays into the redox-economic synthesis of terpenes that resemble 1 by oligomerization of unfunctionalized isoprene (Scheme 1 B, path a). [2] These studies ultimately led us to a new approach that utilizes the more advanced, yet readily available, C 15 building block farnesol (2, Scheme 1 A) as a starting point. In this Communication, a short, efficient, scalable, and enantioselective synthesis of 1 is described.…”

Bis(1,5-cyclooctadiene)nickel(0)

“…179 Diene-alkyne cycloisomerization has been extensively studied with Ni(cod) 2 , and an attempt to mimic the cyclase phase of terpene biosynthesis has been reported. 180 Although the desired cyclization of two isoprene units with an internal alkyne was unsuccessful due to complex reaction mixtures and unstable products, the cooligomerization of butadiene with internal alkynes produced desired cyclodecatrienes.…”

Mechanism, Reactivity, and Selectivity of Nickel-Catalyzed [4 + 4 + 2] Cycloadditions of Dienes and Alkynes

“…Inspired by the early work on Ni-catalyzed diene oligomerizations from Wilke, 4 Heimbach, 5 and others, 6 the Baran group proposed a Ni-catalyzed diene/alkyne cooligomerization that could mimic Nature’s cyclase approach to terpenes (Scheme 1 ). 7 From the nickel–butadiene complex 1 , the oxidative cyclization of dienes gives the nine-membered ring intermediate 2 . This intermediate, 2 , undergoes alkyne insertion to produce the 11-membered ring intermediate 5 .…”