Asymmetric catalytic synthesis of α-aryloxy alcohols:: Kinetic resolution of terminal epoxides via highly enantioselective ring-opening with phenols
Asymmetric catalytic synthesis of α-aryloxy alcohols:: Kinetic resolution of terminal epoxides via highly enantioselective ring-opening with phenols
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DOI：
10.1021/ja9910917
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发表时间：
1999-06-30
影响因子：
15
通讯作者：
Jacobsen, EN
中科院分区：
文献类型：
--
作者：
Ready, JM;Jacobsen, EN
对映体纯的R-芳氧基醇（1）是不对称合成的有价值的目标，因为它们在各种药物重要化合物中作为关键合成中间体的作用。1原则上，可以通过几种途径获得这些结构单元，包括芳氧基酮的不对称还原2或对映体纯末端环氧化物与酚的开环。其中，后者可能是最通用和最直接的，但用于将酚加成到环氧化物上的可用方法非常有限。还没有设计出用于末端环氧化物的酚类开环的催化方法，3并且非催化反应需要强制条件，例如在极性溶剂中在酚盐存在下将环氧化物加热至高温。这些热方法通常是低产量的，并且特别不适合于敏感的基底。因此，尽管最近发现了用于获得高光学纯度的末端环氧化物的一般方法4，但是通过用酚进行环氧化物开环来开发对映体纯的R-芳氧基醇的路线仍然是一个未解决的问题。外消旋形式的末端环氧化物的容易获得性使得末端环氧化物与酚的动力学拆分成为一种潜在的有吸引力的路线1（方案1，Nu）OAr）。在最近报道的水解动力学拆分的末端环氧化物与催化剂3b 4（方案1，Nu）OH）中获得的高选择性表明，（salen）Co（III）配合物也可能作为有效的催化剂，用于对映选择性加成苯酚到环氧化物。这一策略已被证明是成功的，我们在这里报告的第一个例子的动力学拆分环氧化物与酚，与分离的1-芳氧基2-醇（1）在高ee的和产率。2-环氧己烷（2a）与苯酚（4a）在（salen）Co（OAc）络合物3b存在下的反应（0.044当量）在叔丁基甲基醚（TBME）中的反应导致在室温下55小时后苯酚的转化率为61%，生成的1-苯氧基-2-己醇（1a）的ee为94%。我们评估了多种反应参数，目的是鉴定更具反应性的体系。在这种情况下，（salen）钴络合物的抗衡离子的身份被证明是重要的，全氟叔丁醇盐络合物显示出上级反应性。因此，在与上述条件相同的条件下使用络合物3c 5，在18小时内苯酚转化率为80%，在96%的时间内形成1-苯氧基-2-己醇作为主要产物。
Enantiopure R-aryloxy alcohols (1) are valuable targets for asymmetric synthesis as a result of their role as key synthetic intermediates in a variety of pharmaceutically important compounds. 1 In principle, access to these building blocks may be provided by several routes, including asymmetric reduction of aryloxy ketones2 or the ring opening of enantiopure terminal epoxides with phenols. Of these, the latter is probably the most versatile and direct, but available methods for the addition of phenols to epoxides are extremely limited. No catalytic methods have been devised for phenolic opening of terminal epoxides, 3 and forcing conditions are required for the uncatalyzed reaction, such as heating epoxide in the presence of a phenoxide salt to high temperatures in a polar solvent. These thermal methods are generally low-yielding and are particularly unsuitable for sensitive substrates. Thus, despite the recent discovery of general methods for accessing terminal epoxides in high optical purity, 4 the development of routes to enantiopure R-aryloxy alcohols via epoxide ring-opening with phenols remains an unsolved problem. The ready accessibility of terminal epoxides in racemic form renders kinetic resolution of terminal epoxides with phenols a potentially attractive route to 1 (Scheme 1, Nu) OAr). The high selectivities obtained in the recently reported hydrolytic kinetic resolution of terminal epoxides with catalyst 3b4 (Scheme 1, Nu) OH) suggested that (salen) Co (III) complexes might also serve as effective catalysts for the enantioselective addition of phenols to epoxides. This strategy has proven successful, and we report here the first examples of kinetic resolution of epoxides with phenols, with the isolation of 1-aryloxy 2-alcohols (1) in high ee’s and yields.Reaction of 2.2 equiv of (()-1, 2-epoxyhexane (2a) with phenol (4a) in the presence of (salen) Co (OAc) complex 3b (0.044 equiv) in tert-butyl methyl ether (TBME) led to 61% conversion of phenol after 55 h at room temperature, with 1-phenoxy-2-hexanol (1a) generated in 94% ee. Encouraged by the observation of high enantioselectivity in this reaction, we evaluated a variety of reaction parameters with the goal of identifying a more reactive system. The identity of the counterion for the (salen) cobalt complex proved to be important in this context, with the perfluoro tert-butoxide complex displaying superior reactivity. Thus, the use of complex 3c5 under conditions otherwise identical to those outlined above resulted in 80% conversion of phenol in 18 h and formation of 1-phenoxy-2-hexanol as the major product in 96%