Catalytic enantioselective 1,6-conjugate addition of Grignard reagents to linear dienoates
Catalytic enantioselective 1,6-conjugate addition of Grignard reagents to linear dienoates
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DOI：
10.1002/anie.200703702
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发表时间：
2008-01-01
影响因子：
16.6
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;Harutyunyan, Syuzanna R.;Feringa, Ben L.
实现选择性（化学和区域以及立体选择性）一直是有机合成中的主要挑战。[1]这对于共轭加成（CA）尤其明显。[2]在不对称共轭加成[3]（ACA）中，除了高的区域选择性（1，4-与1，2-加成）外，还实现了对立体选择性的良好控制。与1，4-ACA相比，与扩展迈克尔受体的缀合加成[4]需要额外的区域选择性控制。对于a，B，g，d-不饱和迈克尔受体，调节Cu试剂上的电子密度允许区域选择性的1，4-[5]或1，6-加成[6-8]，如Yamamoto埃塔尔的开创性工作所示。(for dienoates）和Krause埃塔尔(for enynes）。在对映选择性共轭加成到扩展的二烯酮和二烯酸酯方面只取得了适度的进展。[9]2005年Hayashi et al. [10]成功地在芳基化选定的（b-取代）[11]二烯酮在不对称的方式（高达98%ee）采用铑催化。2006年，Fillion et al. [12]报道了二烷基锌试剂对Meldrum酸的1，6-ACA选择性（高达84%ee）。最近，Jørgensen et al. [13]公开了使用有机催化剂将不同亲核试剂（酮酯和甘氨酸亚胺）的ACA转化为多种d-未取代的二烯酮和二烯酸酯（高达99%ee）。在所有这些方法中，优异的区域选择性与底物的特定结构特征相关。对映选择性共轭加成到特别具有挑战性的无环二烯酮或在B和d位单取代的二烯酸酯还没有报道。特别地，由于所获得的手性多官能结构单元的合成通用性，将简单的烷基基团加成到二烯酸酯是高度有必要的。在此，我们首次报道了铜催化的简单烷基Grignard试剂的ACA合成直链d-取代2，4-二烯酸酯。[14]本实验室最近对格氏试剂的1，4-ACA作用机理进行了广泛的研究。[15]注意到1，4-ACA和1，6-CA之间的机制相似性，[16]我们决定进一步扩展我们的催化体系[17]，以1，6-ACA。作为初始模型反应，我们选择将EtMgBr添加到山梨酸乙酯（4）中。[18]在788 ℃下使用反相josiphos配体（+）-3（方案1，所示为（+）-3），并且以优异的区域选择性和对映选择性获得B，g-不饱和1，6-加成产物5（表1，条目4和5）。值得注意的是，通过GC分析仅检测到痕量（< 2%）的1，4-加成产物7而没有检测到1，2-加成产物。此外，我们没有得到任何a，b-不饱和的1，6-加成产物，
Achieving selectivity (chemo-and regio-as well as stereoselectivity) has always been a major challenge in organic synthesis.[1] This is particularly evident for conjugate addition (CA).[2] In asymmetric conjugate addition [3](ACA), besides high regioselectivity (1, 4-vs. 1, 2-addition), excellent control of stereoselectivity has been achieved. Compared to 1, 4-ACA, conjugate addition to extended Michael acceptors [4] requires additional control of regioselectivity. For a, b, g, d-unsaturated Michael acceptors, tuning of the electron density on the Cu reagent allows regioselective 1, 4-[5] or 1, 6-addition [6–8] as shown in pioneering work by Yamamoto etal.(for dienoates) and Krause etal.(for enynes). Only modest progress has been made in enantioselective conjugate additions to extended dienones and dienoates.[9] In 2005 Hayashi et al.[10] succeeded in the arylation of selected (b-substituted)[11] dienones in an asymmetric fashion (up to 98% ee) employing Rh catalysis. In 2006 Fillion et al.[12] reported the 1, 6-ACA of dialkylzinc reagents to Meldrum s acids with good selectivity (up to 84% ee). Recently, Jørgensen et al.[13] disclosed the ACA of different nucleophiles (bketoesters and glycine imine) to a variety of d-unsubstituted dienones and dienoates employing an organocatalyst (up to 99% ee). In all of these methodologies the excellent regioselectivity is associated with specific structural features of the substrate. Enantioselective conjugate addition to particularly challenging acyclic dienones or dienoates monosubstituted at the b and d position has not been reported yet. In particular the addition of simple alkyl groups to dienoates is highly warranted owing to the synthetic versatility of the chiral multifunctional building blocks obtained. Herein, we report the first Cu-catalyzed ACA of simple alkyl Grignard reagents to linear d-substituted 2, 4-dienoates.[14] Recently, an extensive study on the mechanism of the 1, 4-ACA of Grignard reagents was reported from our laboratory.[15] Noting the proposed mechanistic similarities between the 1, 4-ACA and 1, 6-CA,[16] we decided to further expand our catalytic system [17] towards 1, 6-ACA. As an initial model reaction we chose the addition of EtMgBr to ethyl sorbate (4).[18] The reversed josiphos ligand (+)-3 (Scheme 1,(À)-3 shown) was employed at À788C, and the b, g-unsaturated 1, 6-addition product 5 was obtained with excellent regio-and enantioselectivity (Table 1, entries 4 and 5). Remarkably, only a trace (< 2%) of the 1, 4-addition product 7 and no 1, 2-addition product were detected by GC analysis. Furthermore, we did not obtain any of the a, b-unsaturated 1, 6-addition