Enantioselective Organocatalytic Cascade Approach to Different Classes of Benzofused Acetals

Abstract

A novel enantioselective organocatalytic strategy is presented for the synthesis of tetrahydrofurobenzofuran and methanobenzodioxepine natural product core structures. The strategy is based on a pair of divergent reaction pathways in which hydroxyarenes react with γ-keto-α,β-unsaturated aldehydes, catalyzed by a chiral secondary amine. One reaction pathway, which leads to chiral 5,5-fused acetals with two stereocenters-the tetrahydrofurobenzofuran scaffolds-proceeds in moderate yields and up to 96 % ee. The other reaction pathway provides 5,6-bridged methanobenzodioxepine scaffolds with three stereocenters in moderate to good yields and up to 95 % ee. The reaction is remarkable as it can proceed with catalyst loadings as low as 0.25 mol %, providing one of the highest known turnover numbers in iminium ion catalysis. Furthermore, the hemiacetal tetrahydrofurobenzofuran can undergo functionalizations including reduction, oxidation, and allylation. Finally, the effects involved in the substrate control for the divergent pathways, based on both experimental and computational studies, have been investigated. A model involving steric, electronic and stereoelectronic interactions is discussed to rationalize the observed selectivities.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…[80] An organocatalytic asymmetric domino FriedelCrafts 1,4-addition followed by substitution-controlled regio-ands tereoselective lactonization involving gketo-a,b-unsaturated aldehydes 167 and hydroxyarenes 168 was recently reported by Jørgensen andc oworkers. [81] Then ature of the Rs ubstituent in 167 dictated the outcome of this domino reaction. If Rw as an aromatic substituent, hemiacetal 170 was the major product,w hich was further reducedt o5 ,6-bridged methanobenzodioxepine scaffolds 171.I n contrast, when Rwas an aliphatic substituent, 172 was the major isomer, which was further transformed to tetrahydrofurobenzofurans 173 (Scheme 43).…”

“…Ther eactionm echanism, regio-ands tereoselectivities,a nd the involvement of water molecule in the catalytic cycle were furthere lucidated by control experiments and theoretical calculations. [81] An organocatalyzeda symmetric domino oxa-Michael/aldol reactiono fa lkynals 72 and2 -trifluoroacetylphenols 174 was utilized by He,D ai, Huang, and co-workers to synthesize trifluoromethyl-substituted chromene derivatives 175 (Scheme44). [82] Ther eaction was proposedt op roceed via the allenamine intermediate 176,f ormed from the oxa-Michael addition of 174 to the iminium ion intermediate that was formed from the reaction of 72 and catalyst 82.T he authors also examined the reaction mechanism by using DFT calculations.…”

A Short Synthesis of (+)‐Brefeldin C through Enantioselective Radical Hydroalkynylation

“…Gratifyingly, treatment of 7 in methanol with 4 m aqueous HCl afforded the clean deprotected alcohol 8 in 89 % yield. After another extensive screening of furan oxidation conditions, we used a two‐step one‐pot procedure inspired by the work of Jørgensen, Kobayashi, and Blair . Furan 8 was first treated with NBS in H 2 O/acetone in the presence of NaHCO 3 followed by treatment with pyridine to give the ring‐opened 4‐oxo‐2‐alken1‐al intermediate 9 that was rapidly filtered through a pad of silica gel.…”

Organocatalytic Asymmetric Synthesis of Bridged O,O‐Ketals with Spirooxindole Motif

“…Chiral O , O ‐acetals and ketals are prevalent in many natural products and pharmaceuticals and a wide range of bioactivities are associated with them Thus a large number of synthetic research groups are engaged in the asymmetric synthesis of these compounds . A number of valuable approaches has been reported for the synthesis of mono cyclic acetals, fused acetals and spiroketals . In contrary, the asymmetric synthesis of bridged O , O ‐acetals and ketals has been less studied despite their presence in procyanidin A1, epicoccolide A, cholinesterease inhibitor[8a] and other bioactive compounds (Figure ) .…”