Asymmetric conjugate reduction of α,β-unsaturated esters using a chiral phosphine-copper catalyst
Asymmetric conjugate reduction of α,β-unsaturated esters using a chiral phosphine-copper catalyst
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DOI：
10.1021/ja992366l
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发表时间：
1999-10-13
影响因子：
15
通讯作者：
Buchwald, SL
中科院分区：
文献类型：
--
作者：
Appella, DH;Moritani, Y;Buchwald, SL
目前，很少有催化剂可以将碳碳双键还原成具有立体中心β的羰基并且具有高对映体过量（ee）的产物。在这一领域，亲核试剂与R，β-不饱和酮的不对称共轭加成反应已被深入研究（方案1）;这些反应的最佳催化剂对有限数量的底物和亲核试剂都能很好地起作用。1在某些情况下，不对称氢化催化剂还提供了获得具有立体中心β至羰基的产物的途径。2分子的R，β-不饱和羰基部分的不对称共轭还原也可以产生立体中心β至羰基。3尽管有许多催化剂可用于共轭还原，4但只有Pfaltz的手性半钴体系是不对称共轭还原的高效催化剂。在该系统中，硼氢化钠用作化学计量的还原剂。5，6我们已经开始研究具有手性膦配体的氢化铜是否可以用作使用硅烷试剂作为化学计量还原剂的不对称共轭还原的催化剂。非手性膦-铜氢化物络合物，如[（Ph 3 P）CuH] 6，已经显示出与苯基硅烷或苯基二甲基硅烷组合用作R，β-不饱和羰基化合物的共辄还原的催化剂。7，8我们现在报道了由p-tol-BINAP、9 CuCl和NaOt-Bu形成的催化剂在相对于底物4当量的聚甲基氢硅氧烷（PMHS）存在下影响R，β-不饱和酯的不对称共轭还原。我们认为，使用PMHS，一种安全且廉价的聚合物，以前曾在金属催化还原酮10和亚胺11中用作化学计量还原剂，将大大提高我们开发的任何工艺的实用性。在实践中，我们能够通过首先将（S）-p-tol-BINAP，CuCl和NaOt-Bu在甲苯中混合，然后加入PMHS，原位生成有效的催化剂。对于一系列R，β-不饱和酯，在室温下，在5mol%催化剂和4当量PMHS下，共轭还原通常需要24 h。如表1中所示，以良好的ee's和优异的产率获得产物。当催化剂的量降低到1mol%时，需要更长的反应时间才能完成反应，但产物的ee不变。该反应在无空气条件下进行时效果最好，这可能是由于铜离子对氧气的敏感性。
Currently, there are few catalysts that can reduce carboncarbon double bonds to generate products with stereocenters β to carbonyls and with high enantiomeric excess (ee). In this area, asymmetric conjugate additions of nucleophiles to R, β-unsaturated ketones have been intensely investigated (Scheme 1); the best catalysts for these reactions work well for a limited number of substrates and nucleophiles. 1 In some cases, asymmetric hydrogenation catalysts also provide access to products with stereocenters β to carbonyls. 2 Asymmetric conjugate reduction of an R, β-unsaturated carbonyl portion of a molecule can also generate a stereocenter β to a carbonyl. 3 Despite the numerous catalysts available for conjugate reduction, 4 only Pfaltz’s chiral semicorrin cobalt system is a highly effective catalyst for asymmetric conjugate reductions. In this system, sodium borohydride is used as the stoichiometric reducing agent. 5, 6 We have begun to investigate whether a copper hydride, with a chiral phosphine ligand, can be used as a catalyst for asymmetric conjugate reduction using a silane reagent as the stoichiometric reductant. Achiral phosphine-copper hydride complexes, such as [(Ph3P) CuH] 6, have been shown to act as catalysts for conjugate reductions of R, β-unsaturated carbonyl compounds in combination with phenylsilane or phenyldimethylsilane. 7, 8 We now report that a catalyst formed from p-tol-BINAP, 9 CuCl, and NaOt-Bu affects the asymmetric conjugate reduction of R, β-unsaturated esters in the presence of 4 equiv of polymethylhydrosiloxane (PMHS) relative to the substrate. We felt that using PMHS, a safe and inexpensive polymer that has been previously employed as a stoichiometric reductant in metal-catalyzed reductions of ketones10 and imines, 11 would greatly enhance the utility of any process that we would develop.In practice, we were able to generate an efficient catalyst in situ by first combining (S)-p-tol-BINAP, CuCl, and NaOt-Bu in toluene, followed by addition of PMHS. For a series of R, β-unsaturated esters, conjugate reductions usually took 24 h at room temperature with 5 mol% catalyst and 4 equiv of PMHS. As shown in Table 1, products were obtained with good ee’s and in excellent yields. When the amount of catalyst was lowered to 1 mol%, a longer reaction time was necessary for the reaction to go to completion, but the ee of the product was unchanged. The reaction worked best when carried out under air-free conditions, presumably due to the sensitivity of copper hydrides to oxygen.