Enantioselective synthesis of all-carbon quaternary stereogenic centers by catalytic asymmetric conjugate additions of alkyl and aryl aluminum reagents to five-, six-, and seven-membered-ring β-substituted cyclic enones
Enantioselective synthesis of all-carbon quaternary stereogenic centers by catalytic asymmetric conjugate additions of alkyl and aryl aluminum reagents to five-, six-, and seven-membered-ring β-substituted cyclic enones
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DOI：
10.1002/anie.200802910
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Hoveyda, Amir H.
中科院分区：
文献类型：
--
作者：
May, Tricia L.;Brown, M. Kevin;Hoveyda, Amir H.
碳基亲核试剂与 β, β-二取代烯酮的催化不对称共轭加成 (ACA) 反应提供了一种对映选择性合成全碳四元立体中心 [1] 的有效方法，该中心位于合成多功能烯醇化物附近 [Eq.(1)]。尽管最近在烷基金属（主要是二烷基锌）试剂的催化 ACA 反应方面取得了进展，[2-5]但许多关键缺点仍未得到解决。一个值得注意的挑战涉及 β-取代环戊烯酮的转化，该过程通常效率较低 [6, 7]（与较大环的反应相比），但可以提供可用于对映选择性合成各种生物活性天然产物的产品。 [8]先前报道的涉及锌基试剂的方法仅在烯酮带有额外的活化取代基时对五元环底物有效。 [4]在三种情况下，由手性亚磷酰胺铜催化的三烷基铝试剂与β-取代的环戊烯酮的加成反应已被证明可以进行。然而，仅在一个实例中观察到了高选择性（ACA 与 Et3Al；96.5：3.5 er，93% ee）。[5a] 在此，我们公开了一套有效的方案，用于烷基和芳基铝试剂与一系列未活化的 β-取代环烯酮（包括环戊烯酮）进行 ACA 催化反应。在手性二齿 N-杂环卡宾 (NHC) 铜络合物 (5 mol%) 存在下促进的反应是高效的（产率高达 97%）且选择性高（高达 > 99:< 1 er，大于 98% ee）。在涉及添加芳基单元的转化的情况下，所需的铝基试剂由市售的二甲基氯化铝和相应的芳基锂化合物原位制备。
Catalytic asymmetric conjugate addition (ACA) reactions of carbon-based nucleophiles to β, β-disubstituted enones present an efficient approach to enantioselective synthesis of allcarbon quaternary stereogenic centers [1] that reside adjacent to synthetically versatile enolates [Eq.(1)]. In spite of recent advances involving catalytic ACA reactions of alkyl metal (mostly dialkyl zinc) reagents,[2–5] a number of critical short-comings remain unaddressed. One noteworthy challenge concerns transformations of β-substituted cyclopentenones, processes that are often less efficient [6, 7](vs. reactions of larger rings) but can deliver products that may be used in enantioselective syntheses of a variety of biologically active natural products.[8] Previously reported approaches, involving zinc-based reagents, are only effective with fivememberedring substrates when the enone bears an additional activating substituent.[4] Additions of trialkyl aluminum reagents to β-substituted cyclopentenones catalyzed by chiral copper phosphoramidites have been shown to proceed in three cases. In only a single instance, however, is high selectivity observed (ACA with Et3Al; 96.5: 3.5 er, 93% ee).[5a] Herein, we disclose an efficient set of protocols for catalytic ACA reactions of alkyl and aryl aluminum reagents with a range of unactivated β-substituted cyclic enones, including cyclopentenones. Reactions, promoted in the presence of a chiral bidentate N-heterocyclic carbene (NHC) copper complex (5 mol%), are efficient (up to 97% yield) and highly selective (up to> 99:< 1 er, greater than 98% ee). In the case of transformations involving additions of aryl units, the requisite aluminum-based reagents are prepared in situ from commercially available dimethylaluminum chloride and the corresponding aryl lithium compounds.