All-carbon quaternary stereogenic centers by enantioselective Cu-catalyzed conjugate additions promoted by a chiral N-heterocyclic carbene
All-carbon quaternary stereogenic centers by enantioselective Cu-catalyzed conjugate additions promoted by a chiral N-heterocyclic carbene
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DOI：
10.1002/anie.200604511
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Hoveyda, Amir H.
中科院分区：
文献类型：
--
作者：
Brown, M. Kevin;May, Tricia L.;Hoveyda, Amir H.
设计新的手性催化剂用于对映选择性合成全碳四元立体中心是现代化学中一项重要而具有挑战性的目标这种催化剂必须是对映分化的，但也特别活跃，因为所需的反应涉及到在空间拥挤的亲电位点上添加碳亲核试剂。在此，我们公开了一种易于获得的手性n -杂环碳（NHC），可用于促进有机锌试剂对环g-酮酯的催化不对称共轭加成（ACA）[2] [Eq.(1)]；这些转化产生了对映选择性的全碳四元立体中心，在高达95%的ee中具有易于官能化的羧酸酯取代基。[3-5]在几乎所有的催化ACA反应中（有一个例外），新的手性NHC（原位生成的Cu配合物）比以前报道的系统具有更高的效率和不对称诱导。我们首先考察了由1 [5a]和2 [5c]（方案1）与（CuOTf） 2·C6H6反应生成的Cu配合物促进Me2Zn的ACA生成五元和六元环酮酯4和5的能力（表1）。以环戊酮4a为底物，在双萘基1和（CuOTf） 2·C6H6 （2.5 mol%）存在的情况下，24 h后转化率低于10%（表1，条目1）。当使用联苯配合物2时，转化率仅为15%，6以30%的ee生成（表1，条目2）。对于六元环烯酮5a，由1和2衍生的cu基配合物（表1，条目4-5）更有效地促进了Me2Zn的ACA（60%和> 98%的转化率），并提高了对映选择性（73% ee和33% ee），但仅与环戊烯酮4a的反应相比，而不是合成有用的水平。面对1和2的Cu配合物较差的活性和不对称诱导，我们开始寻找一种更有效的手性催化剂。这一倡议使我们发现，配合物3，> a含磺酸的手性NHC（表1，第3项），以更高的效率促进Me2Zn向4a的加成（>转化率为98%，17 h，而1和2的转化率< 15%）和优越的对映体选择性（84% ee， 1和2的30% ee）。此外，Me2Zn对环己酮5a的催化ACA在3原位生成的Cu络合物中有效进行，在75%的ee中提供7。因此，在一种情况下(比较
The design of new chiral catalysts for enantioselective synthesis of all-carbon quaternary stereogenic centers is a critical and challenging objective in modern chemistry.[1] Such catalysts must be enantio-differentiating but also especially active because the desired reactions involve additions of carbon nucleophiles to sterically congested electrophilic sites. Herein, we disclose a readily available chiral N-heterocyclic carbene (NHC) that can be used to promote the catalytic asymmetric conjugate addition (ACA)[2] of organozinc reagents to cyclic g-keto esters [Eq.(1)]; these transformations give rise to the enantioselective formation of all-carbon quaternary stereogenic centers that bear a readily functionalizable carboxylic ester substituent in up to 95% ee.[3–5] In nearly all of the catalytic ACA reactions (one exception), the new chiral NHC (Cu complex generated insitu) delivers significantly higher efficiency and asymmetric induction than the previously reported systems. We began our investigation by examining the ability of Cu complexes generated from the reaction of 1 [5a] and 2 [5c](Scheme 1) with (CuOTf) 2· C6H6 in promoting the ACA of Me2Zn to five-and six-membered ring g-keto esters 4 and 5 (Table 1). With cyclopentenone 4a as the substrate and in the presence of binaphthyl-based 1 and (CuOTf) 2· C6H6 (2.5 mol%), less than 10% conversion is detected after 24 h (Table 1, entry 1). When biphenyl complex 2 is used, there is only 15% conversion and 6 is formed in 30% ee (Table 1, entry 2). With six-membered ring enone 5a, Cu-based complexes derived from 1 and 2 (Table 1, entries 4–5) promote the ACA of Me2Zn more efficiently (60% and> 98% conversion) and with improved enantioselectivity (73% ee and 33% ee), but only in comparison to the reactions of cyclopentenone 4a and not at synthetically useful levels. Faced with the inferior activity and asymmetric induction provided by the Cu complexes of 1 and 2, we set out to identify a more effective chiral catalyst. This initiative led us to discover that complex 3,[6] a sulfonate-containing chiral NHC (Table 1, entry 3), promotes the addition of Me2Zn to 4a with substantially higher efficiency (> 98% conversion, 17 h versus< 15% conversion with 1 and 2) and superior enantioselectivity (84% ee versus 30% ee with 1 and 2). Furthermore, catalytic ACA of Me2Zn to cyclohexenone 5a proceeds efficiently with the Cu complex generated in situ from 3, which affords 7 in 75% ee. Thus, in one case (compare