Transient [3,3] Cope rearrangement of 3,3-dicyano-1,5-dienes: computational analysis and 2-step synthesis of arylcycloheptanes

Abstract

Unexpectedly mild [3,3] rearrangement computed transition state analysis, regio- and diastereoselecitve transformations multicomponent couplings, convergent 2-step arylcycloheptene synthesis.

Function‐Oriented and Modular (+/−)‐cis‐Pseudoguaianolide Synthesis: Discovery of New Nrf2 Activators and NF‐κB Inhibitors

“…Recently, ring‐closing enyne metathesis was used to synthesize the related guaianolide framework in ≈12 steps [49] . Notably, our proposal to synthesize terpenoid scaffolds from Knoevenagel adducts and allyl/propargylic electrophiles is in line with some of our recent work aimed at simple and modular cycloheptene‐scaffold synthesis [59–61] . We are targeting cis ‐pseudoguaianolides for a few reasons (Figure 2 B): (1) necessity—this route at present yields the cis ‐fusion (vide infra).…”

“…As expected, both epi-11b and 11 b show ad osedependent increase in Nqo1 mRNA levels, aw ell-established target gene of Nrf2 ( Figure 6A). NQO1i sa lso as uppressor of the NF-kBt arget gene, inducible nitric oxide synthase (iNOS), [55,61] and therefore Nrf2 target gene inductionw as expected to translate into reduced NO levels.I ndeed, we observed inhibition of NO at low micromolar concentrations for both compounds,w ith epi-11b being 3-fold more potent again than 11 b [ Figure 6B,T able 1].…”

“…[49] Notably,o ur proposal to synthesize terpenoid scaffolds from Knoevenagela dducts and allyl/propargylic electrophiles is in line with some of our recent work aimed at simple and modular cycloheptene-scaffold synthesis. [59][60][61] We are targeting cis-pseudoguaianolides for af ew reasons (Figure 2B): (1) necessity-this route at presenty ields the cisfusion (vide infra). (2) Cis-fused bicycles are topologically distinct from their trans-counterparts.…”

Functional Group Interconversion of Alkylidenemalononitriles to Primary Alcohols by a Cooperative Redox Operation

“…Such scaffolds would be readily available from alkylidenemalononitriles and allylic electrophiles by deconjugative allylation yielding 3,3-dicyano-1,5dienes followed by thermal Cope rearrangement. 21,[48][49][50][51][52][53] Thus alkylidenemalononitrile redox functional group interconversion to 1° alcohols would provide a straightforward route to 1,6-hexenols 4a-4d. Notably, such products would bear resemblance to 'oxy-Cope products', [54][55][56][57] but via an alternative route (Scheme 4A vs Scheme 4B).…”

Convergent Synthesis of Trisubstituted Tetrahydrofurans via Bis-Thermally Reactive 1,5-Diene-Tert-Butyl Carbonates.

“…We have been advancing the classic Cope rearrangement (that of 3,3-dicyano-1,5-dienes) for application in modern chemical synthesis. [32][33][34][35][36][37] Considering that Cope rearrangement results in allylic transposition and an electrophilic alkylidenemalononitrile, we hypothesized that "trapping" with tethered nucleophiles could result in additional bond formation and structural complexity.…”