Diastereoselective Indole-Dearomative Cope Rearrangements by Compounding Minor Driving Forces.

Reported herein is the discovery of a diastereoselective indole-dearomative Cope rearrangement. A suite of minor driving forces (substrate destabilizing effects; product stabilizing effects) are what promote this otherwise unfavorable dearomatization reaction. These include the following that work in concert to overcome the penalty for dearomatization: (i.) steric congestion in the starting material, (ii.) alkylidene malononitrile and stilbene conjugation events in the product, and (iii.) an unexpected intramolecular p–p* stack on the product side of the equilibrium. The key substrates are rapidly assembled from alkylidenemalononitriles and indole-phenylmethanol derivatives resulting in many successful examples (high yields and diastereoselectivity). The products are structurally complex bearing vicinal stereocenters generated by the dearomative Cope rearrangement. They also contain a variety of functional groups for interconversion to complex architectures. On this line, also described herein are proof-of-concept strategies for achieving enantioselectivity and conversion of the dearomative products to valuable and functionalized small drug-like molecules.

Dearomative [4 + 3] cycloaddition of furans with vinyl-N-triftosylhydrazones by silver catalysis: stereoselective access to oxa-bridged seven-membered bicycles

The first example of dearomative [4 + 3] cycloaddition between furans and vinyl-N-sulfonylhydrazones as vinylcarbene precursors is reported. The merger of silver catalysis and easily decomposable vinyl-N-triftosylhydrazones enabled the efficient synthesis of a variety of skeletally and functionally diverse oxa-bridged seven-membered bicyclic compounds with complete and predictable stereoselectivity. The combination of experimental studies and DFT calculations disclosed that the silver-catalyzed reaction proceeds via a concerted [4 + 3] cycloaddition mechanism, rather than the generally accepted cyclopropanation / Cope rearrangement pathway by rhodium catalysis.

Direct C(sp3)–H allylation of 2-alkylpyridines with Morita–Baylis–Hillman carbonates via a tandem nucleophilic substitution/aza-Cope rearrangement

A base- and catalyst-free C(sp3)–H allylic alkylation of 2-alkylpyridines with Morita–Baylis–Hillman (MBH) carbonates is described. A plausible mechanism of the reaction might involve a tandem SN2’ type nucleophilic substitution followed by an aza-Cope rearrangement. Various alkyl substituents on 2-alkylpyridines were tolerated in the reaction to give the allylation products in 26–91% yields. The developed method provides a straightforward and operational simple strategy for the allylic functionalization of 2-alkypyridine derivatives.

Direct C(sp3)-H allylation of 2-alkylpyridines with Morita-Baylis-Hillman carbonates via a tandem nucleophilic substitution/aza-Cope rearrangement

A base- and catalyst-free C(sp3) – H allylic alkylation of 2-alkylpyridines with Morita-Baylis-Hillman (MBH) carbonates was described. A plausible mechanism of the reaction might involve a tandem SN2’ type nucleophilic substitution followed by an aza-Cope rearrangement. Various alkyl substituents on 2-alkylpyridines were tolerated in the reaction to give the allylation products in 26-91% yields. The developed method provides a straightforward and operational simple strategy for the allylic functionalization of 2-alkypyridine derivatives.

A [6+4]-cycloaddition adduct is the biosynthetic intermediate in streptoseomycin biosynthesis

Streptoseomycin (STM, 1) is a bacterial macrolactone that has a unique 5/14/10/6/6-pentacyclic ring with an ether bridge. We have previously identified the biosynthetic gene cluster for 1 and characterized StmD as [6 + 4]- and [4 + 2]-bispericyclase that catalyze a reaction leading to both 6/10/6- and 10/6/6-tricyclic adducts (6 and 7). The remaining steps, especially how to install and stabilize the required 10/6/6-tricyclic core for downstream modifications, remain unknown. In this work, we have identified three oxidoreductases that fix the required 10/6/6-tryciclic core. A pair of flavin-dependent oxidoreductases, StmO1 and StmO2, catalyze the direct hydroxylation at [6 + 4]-adduct (6). Subsequently, a spontaneous [3,3]-Cope rearrangement and an enol-ketone tautomerization result in the formation of 10/6/6-tricyclic intermediate 12b, which can be further converted to a stable 10/6/6-tricyclic alcohol 11 through a ketoreduction by StmK. Crystal structure of the heterodimeric complex NtfO1-NtfO2, homologues of StmO1-StmO2 with equivalent function, reveals protein-protein interactions. Our results demonstrate that the [6 + 4]-adduct instead of [4 + 2]-adduct is the bona fide biosynthetic intermediate.

Stereoselective Tandem Iridium-Catalyzed Alkene Isomerization-Cope Rearrangement of ω-diene Epoxides: Efficient Access to Acyclic 1,6-Dicarbonyl Compounds

The Cope rearrangement of 2,3-divinyloxiranes, a rare example of epoxide C-C bond cleavage, results in 4,5-dihydrooxepines which are amenable to hydrolysis, furnishing 1,6-dicarbonyl compounds containing two contiguous stereocenters at the 3- and 4- positions. We employ...