Benzannulation and Hydrocarboxylation Methods for the Synthesis of a Neopentylene-Fused Analogue of Ibuprofen

Abstract

Neopentylene ring fusions (ring-fused 4,4-dimethylcyclopentane polycycles) are found in many natural products, but they are largely absent from synthetic compound libraries and focused medicinal chemistry research. Here is reported a synthetic approach to one of the few non-natural product-based target compounds from medicinal chemistry that includes a neopentylene ring fusion: an analogue of ibuprofen referred to herein as “neoprofen”. The approach features ring-opening fragmentation reactions of dimedone derivatives coupled with transition metal-catalyzed benzannulation and hydrocarboxylation methods.

Synthesis of 4,4-Dimethyl-1,6-heptadiyne and Other Neopentylene-Tethered (NPT) 1,6-Diynes

“…The resulting crude was purified by column chromatography on silica gel (1−5% EtOAc/Hexanes) to give diyne monoester 15 (361 mg, 94%) as a light-yellow oil, R f = 0.61 (20% EtOAC/Hexanes). 1 H NMR (400 MHz, CDCl 3 ): δ 4.21 (q, J = 7.1 Hz, 2H), 2.37 (s, 2H), 2.22 (d, J = 2.7 Hz, 2H), 2.03 (t, J = 2.7 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.11 (s, 6H) ppm; 13 Ethyl (Z)-5,5-Dimethyl-3-(trifluoromethylsulfonyloxy)-2-octen-7ynoate (14). β-Keto ester 6 (1.05 g, 5.00 mmol, 1.0 equiv) was dissolved in hexanes (25 mL, 0.2 M) in a 100 mL round-bottom flask under open air.…”

“…We have been developing fragmentation reactions of cyclic vinylogous acyl triflates (VATs) to produce high-value alkyne building blocks, including NPT 1,6-enynes from dimedone (5,5-dimethyl-1,3-cyclohexanedione, Figure a) . We used NPT 1,6-enynes as valuable substrates for cycloisomerization methodologies − that might not have been discovered using substrates with heteroatom-rich tethers, and we have shown how these NPT 1,6-enynes can be leveraged in the synthesis of sesquiterpene targets including hirsutene, , illudol, , alcyopterosin A, and illudinine , (Figure b).…”