Total Synthesis of Farnesin through an Excited‐State Nazarov Reaction

Abstract

The asymmetric total synthesis of farnesin, a rearranged ent-kaurenoid, was achieved through a convergent approach involving photo-Nazarov and intramolecular aldol cyclizations to build the syn-syn-syn hydrofluorenol ABC ring system and bicyclo[3.2.1]octane CD ring system in the first application of a UV-light-induced excited-state Nazarov cyclization of a non-aromatic dicyclic divinyl ketone in a total synthesis. Unlike the conventional acid-promoted ground-state Nazarov reaction, the excited-state Nazarov reaction enables stereospecific formation of the highly strained syn-syn-synfused hydrofluorenone scaffold through a disrotatory cyclization.

Recent Applications of Asymmetric Organocatalytic Methods in Total Synthesis

“…In 2020, Gao and co‐workers reported a convergent approach for the total synthesis of farnesin ( 514 , Scheme 54). [101] One of the key intermediates of this synthesis, intermediate 506 , was obtained from an NHC‐catalyzed reaction. As shown in Scheme 54, they first synthesized the aldehyde 504 , which was allowed to react with formaldehyde under the catalysis of the NHC catalyst generated in‐situ from the thiazolium salt 505 .…”

“…Further elaborations of this molecule afforded farnesin ( 514 ) via a multistep sequence that included photo‐Nazarov reaction, intramolecular aldol reaction, and oxidation (Scheme 54). [101] …”

Advances in N‐Heterocyclic Carbene Catalysis for Natural Product Synthesis

“…One example is rotenoids, structurally related compounds isolated from Derris and Lonchocarpus species. [25] Many rotenoids feature a cis-fused tetrahydrochromeno[3,4-b]chromene core (B and C rings), such as 12a-hydroxymunduserone (36), tephrosin (37), 12a-hydroxyrotenone (38) and milletosin (39). These compounds exhibit anti-tumor, anti-inflammatory and even anti-insect activities.…”

“…[35] Our group recently achieved its asymmetric total synthesis via photo-Nazarov cyclization to afford the cis-fused tetracyclic structure and an intramolecular aldol reaction to furnish the bicyclo-[3.2.1]octane (C-D ring) (Scheme 12). [36] Ring-closing metathesis and an NHC-catalyzed hydroxymethylation reaction yielded the Isodarparvinol B (56) was isolated from the heartwood of the medicinal plant Dalbergia parviflora in Thailand. [37] In 2020, Ema and co-workers reported the total synthesis of isodarparvinol B (56) via an NHC-catalyzed intramolecular benzoin reaction to assemble the benzoin skeleton (Scheme 13).…”

“…The acafarnane‐type diterpenoid farnesin ( 53 ), which has a cis ‐fused tetracyclic structure, was isolated from the seeds of Acacia farnesiana by Sahu and co‐workers in 1997 . Our group recently achieved its asymmetric total synthesis via photo‐Nazarov cyclization to afford the cis ‐fused tetracyclic structure and an intramolecular aldol reaction to furnish the bicyclo[3.2.1]octane (C‐D ring) (Scheme ) . Ring‐closing metathesis and an NHC‐catalyzed hydroxymethylation reaction yielded the C ring fragment.…”