不对称双酸催化3,4-二氢-2H-吡喃的反电子Hetero-Diels-Alder反应

研究了双酸催化剂不对称催化烯醚和β,γ-不饱和α-酮酸酯的反电子Hetero-Diels-Alder (HDA)反应, 为手性合成3,4-二氢-2H-吡喃类化合物提供了一种新的催化合成方法. InBr₃与手性磷酸钙盐Ca(1c)₂组合的手性双路易斯酸催化体系能够有效催化3,4-二氢-2H-吡喃和β,γ-不饱和α-酮酸酯的反电子HDA反应, 反应给出优秀的产率(最高达98%), 中等到良好的非对映选择性(最高达89:11)和良好到优秀的对映选择性(最高可达94%). 并且该双酸催化体系也能成功实现其它烯醚(如: 2,3-二氢-2H-呋喃, 乙烯基乙醚)的HDA反应, 获得优秀的非对映选择性(>94:6)和良好的对映选择性.

Asymmetric Binary-Acid Catalysis in the Inverse-Electron-Demanding Hetero-Diels-Alder Reaction of 3,4-Dihydro-2H-Pyran

Chiral dihydropyrans are important structural units in a plethora of bio-active natural products.Inverse-electrondemanding hetero-Diels-Alder reaction between α,β-unsaturated enones/enals and olefins represents one of the most straightforward pathway to access chiral dihyropyrans moieties.Though this reaction has been much explored in asymmetric catalysis,new catalytic strategy or catalysts are still desirable in order to further address the limited scopes and applicability.Previously,we have developed asymmetric binary acid catalysis(ABC) as a powerful combinatorial approach for chiral strong acid catalysis.In principle,the ABC strategy utilizes chiral Br nsted acid,e.g.chiral phosphoric diester acid,as dual ligand and acid,in concert with typical metal Lewis acid,resulting in synergistic catalysis due to their mutually enhanced acidity/electrophilicity as well as the endowed multi-activation sites.To advance the application of ABC strategy in the above mentioned reaction,we have found that the use of metal salt of chiral phosphoric acid instead of free phosphoric acid in the presence of an achiral Lewis acid,led to much improved activity and stereoselectivity,thus providing a conceptual advance to include two Lewis acids combinations in ABC catalysis.The obtained optimal Lewis acids combination,InBr3 and Ca(1c)2,was found to be an effective and selective catalyst for the HDA reaction of 3,4-dihydro-2H-pyrans.In the presence of InBr3(2.5 mol%) and Ca(1c)(2.5 mol%),the reaction occurred smoothly to afford the desired 3,4-dihydro-2H-pyrans in high yield(85%—98%),with moderate to excellent diastereoselectivity(70∶30—99∶1,endo/exo) and enantioselectivity(up to 94% ee) under 25 ℃ in CH2Cl2.Different enol ethers 2 and β,γ-unsaturated α-ketoesters 3 all worked well with excellent diastereoselectivity(94∶6) and good enantioselectivity under the optimal reaction conditions.