On the Mechanism of Cu-Catalyzed Enantioselective Extended Conjugate Additions: A Structure-Based Approach
On the Mechanism of Cu-Catalyzed Enantioselective Extended Conjugate Additions: A Structure-Based Approach
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DOI：
10.1021/cs501297s
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发表时间：
2015-02-01
期刊：
影响因子：
12.9
通讯作者：
Feringa, Ben L.
中科院分区：
文献类型：
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作者：
den Hartog, Tim;Huang, Yange;Feringa, Ben L.
不饱和羰基化合物的对映体选择性1，6-加成反应为研究铜催化的选择性范围提供了独特的机会。在这里，报道了一种底物-试剂方法来获得关于扩展共轭加成机理的结构信息。研究了几种卤化物在格氏试剂和铜源中对1，6-不对称加成反应的影响，结果表明，以乙基溴化镁为格氏试剂，CuI为铜源是有利的。此外，对含有几种烷基酯的底物的探索表明，TBU-酯底物增强了1，6-加成的对映识别能力，并允许BnCH2MgBr的加入。具有不同吸电子基团的底物也被研究，确定酯底物是1，6-加成的最佳底物。另外两项研究的特点是Me取代的烯烃底物和具有所有可能的烯烃几何构型的底物。这些研究表明，当使用a-Me底物时，1，6-加成反应具有前所未有的高对映选择性，并为1，6-加成反应的机理提供了相关的见解。最后，研究了含三个或四个烯烃与吸电子基团共轭的底物。本文报道了1，8-加成反应，以合理的产率、区域选择性和立体选择性合成了相应的产物。结合这些研究结果，阐明了关键底物和试剂参数，提出了1，6-对映体选择性加成的适应机理。该机理的特征是用等价格氏试剂活化二聚预催化剂，活性催化剂配位到铜-i-pi-络合物中底物的内部烯烃，然后催化剂配位到远程烯烃形成另一个铜-i-pi-络合物。从后者的铜-I-络合物，氧化加成得到一个铜-III-西格玛-在三角洲-碳，然后转移的烷基部分到三角洲-位置。这种还原消除产生产物，并通过与另一分子格氏试剂的易金属化来改造活性铜-I催化剂。
The enantioselective 1,6-addition to unsaturated carbonyl compounds otters unique opportunities to study the range of selectivities one can obtain using Cu catalysis. Here, a substrate-reagent approach to obtain structural information on the mechanism of extended conjugate additions is reported. By studying the influence of several halides in the Grignard reagent and in the Cu source on the enantioselective 1,6-addition, it was shown that it is advantageous to use a combination of EtMgBr as Grignard reagent and CuI as Cu source. Furthermore, exploring substrates bearing several alkyl esters revealed that tBu-ester substrates enhance the enantiodiscrimination in the 1,6-addition and allow the addition of BnCH2MgBr. Substrates with a variety of electron-withdrawing groups were investigated as well, identifying that ester substrates are optimal for the 1,6-addition. Two other investigations feature Me-substituted olefin substrates and substrates with all possible olefin geometries. These studies show unprecedented high enantioselectivity in the 1,6-addition when a-Me substrates are used and give relevant insight into the 1,6-addition mechanism. Finally, substrates with three or four olefins in conjugation with the electron-withdrawing groups were studied. Here, a 1,8-addition is reported that gives the corresponding products in reasonable yield, regio- and stereoselectivity. With the combined results of these studies, elucidating key substrate and reagent parameters, an adapted mechanism for the enantioselective 1,6-addition is proposed. This mechanism features the activation of a dimeric precatalyst by an equivalent of Grignard reagent, active catalyst coordination to the internal olefin of the substrate in a Cu-I-pi-complex, followed by coordination of the catalyst to the remote olefin forming another Cu-I-pi-complex. From the latter Cu-I-complex, an oxidative addition gives a Cu-III-sigma-complex at the delta-carbon, followed by transfer of the alkyl moiety to the delta-position. This reductive elimination yields the product and reforms the active Cu-I catalyst via transmetalation with another molecule of Grignard reagent.