Modular Synthesis of Drimane Meroterpenoids Leveraging Decarboxylative Borylation and Suzuki Coupling

Abstract

Drimane meroterpenoids have attracted an increasing amount of attention in the discovery of therapeutically important probes, while the laggard synthetic accessibility is a conspicuous challenge. A new paradigm merging decarboxylative borylation and Suzuki coupling was developed as a powerful platform. Key features include the mild conditions, good chemoselectivity, operational facility, scalability, and easy availability of the coupling partners. This practical strategy enables the expedient formal synthesis of a large number of natural products and rapid generation of analogues.

Practical Synthesis and Antifungal Investigation of Drimane Meroterpenoids Enabled by Nickel-Catalyzed Decarboxylative Coupling

“…Expensive palladium catalysts were employed previously, and the utilization of low-cost abundant metal catalysts remains largely elusive. We also faced the predicament of directly combining the key drimane intermediate 3 with aromatic segments containing phenolic hydroxy groups, esters, and aldehydes . To expand the chemical space of drimane meroterpenoids efficiently, we were motivated to devise an alternative tactic starting from the easily available and bench-stable drimane equivalent 4 (Figure B), which resulted in the discovery of the Ni-catalyzed decarboxylative coupling method presented herein.…”

“…Wu’s group invented the hydrazone intermediate 2 from the same feedstock as a drimane precursor to develop a palladium-catalyzed carbene migratory insertion . Our group reported a new paradigm starting from the much cheaper natural feedstock sclareol for acquiring drimanyl Bpin 3 as a coupling partner for Suzuki coupling, enabling the biological exploration of a large variety of drimane meroterpenoids. , Herein, we would like to disclose a new modular and practical method for constructing drimane meroterpenoids (Figure B), featuring the utilization of an inexpensive nickel catalyst under mild conditions with tolerance for challenging functional groups encountered previously.…”

Biological activities of meroterpenoids isolated from different sources

“…Several researchers have reported the total synthesis of meroterpenoids or precursor molecules leading to the synthesis of meroterpenoids. Strongylophorines; gujadial; psidial A; (+) yahazunol; guadials B and C; guapsidial A and psiguajadial D; drimane meroterpenoids; naphthoquinone-based meroterpenoids; ganocins B and C; (+) ledene; (+)-viridiflorol; (-)-palustrol; (+)-spathulenol; psiguadials A, C, and D; (±) berkeleyone A; and biscognienyne B have been attempted ( Laube et al, 2002 ; Lawrence et al, 2010 ; Tran and Cramer, 2014 ; Liu Y. et al, 2016 ; Yu et al, 2016 ; Elkin et al, 2017 ; Miles et al, 2017 ; Dethe et al, 2018 ; Wang et al, 2020 ). Petrovčič et al have critically reviewed the synthesis protocols adopted by various studies that have attempted the total synthesis of meroterpenoids since 2015.…”

Single Electron Transfer-Induced Redox Processes Involving N-(Acyloxy)phthalimides

“…In another exemplary demonstration of the strength of RCC, very recently, Li adopted Baran and Blackmond’s Cu-catalyzed decarbox­ylative borylation protocol for the synthesis of bench-stable drimanyl Bpin 228 , which following a Pd-catalyzed Suzuki coupling with a variety of aryl halides furnished a diverse array of pharmaceutically relevant drimane meroterpenoids (Scheme ). Importantly, such a merger of Cu-catalyzed RCC-mediated borylation and Pd-catalyzed Suzuki coupling provided a new powerful platform to provide rapid access to important building blocks such as 229 (87%) and 230 (88%), thereby completing the formal synthesis of the natural products yahazunol and chromazonarol and allowing rapid generation of pelorol analogues …”