Towards a Total Synthesis of Phenalinolactone Core Diterpenoid 6: Synthesis of a Racemic Decahydrobenzocyclobutaisobenzofuran with a trans‐anti‐cis Junction of the Isocyclic Rings

Abstract

Synthetic efforts towards the “phenalinolactone core diterpenoid 6” (5) are described. It contains a cyclohexyl alcohol (A ring), a cyclohexane (B ring), and a cyclohexene (C ring), which are angularly annulated trans and cis, respectively. What makes them unique is the trans‐ (or “anti”‐) relationship between the A and the C ring. The trans‐configured A/B ring junction was established in a novel cyclohexanone annulation. Anti‐selective cis‐annulations of the C ring failed when attempted with intramolecular Diels–Alder reactions with dienes of varied electron demand (21, 31). In contrast, an anti‐selective cis‐annulation of a C ring precursor based on an intramolecular [2+2]‐photocycloaddition succeeded. It provided the tetracycle 38 in 70 % yield. It contains a densely functionalized four‐membered ring. It should lend itself to ring‐opening(s) and/or rearrangement(s). Accordingly, compound 38 should be adoptable to proceeding to the target structure 5 in future work.

Atom-Economical Cross-Coupling of Internal and Terminal Alkynes to Access 1,3-Enynes

“…However, amides with small substituent groups (37 and 38) were more prone to isomerization, resulting in eroded stereoselectivity (vide infra). We further observed good yield and excellent selectivity with the different alkyl-substituted alkynes (39)(40)(41)(42). Introducing alkyl branching at the α-position (41) or introducing an additional methyl spacer between the alkyne and the directing group (42) showed comparable reactivity to the general substrates discussed above.…”

Atom-Economical Cross-Coupling of Internal and Terminal Alkynes to Access 1,3-Enynes

“…Epoxidation ( 55 ) on the alkene moiety and conversion of the alcohol to a bromide ( 56 ) were successfully carried out. Removing the TIPS protecting group on the alkyne moiety enabled other alkyne-functionalizing reactions such as Sonogashira arylation ( 58 ), hydrozirconation/iodination ( 59 ), and 1,2,3-triazole formation via click chemistry ( 60 ) . Additional transformations were carried out on the 1,3-enyne derived from propargyl carboxamides.…”

“…We further observed good yield and excellent selectivity with the different alkyl-substituted alkynes (39−42). Introducing alkyl branching at the α-position (41) or introducing an additional methyl spacer between the alkyne and the directing group (42) led to comparable reactivity compared to the substrates discussed above.…”

Atom-Economical Cross-Coupling of Internal and Terminal Alkynes to Access 1,3-Enynes

“…Epoxidation (55) on the alkene moiety and conversion of the alcohol to a bromide (56) were successfully carried out. Removing the TIPS protecting group on the alkyne moiety enabled other alkyne-functionalizing reactions such as Sonogashira arylation (58), 40 hydrozirconation iodination (59), 41 and 1,2,3-triazole formation via click chemistry (60). 42 Additional transformations were carried out on the 1,3-enyne derived from propargyl carboxamides.…”