From aryl bromides to enantioenriched benzylic alcohols in a single flask: Catalytic asymmetric arylation of aldehydes
From aryl bromides to enantioenriched benzylic alcohols in a single flask: Catalytic asymmetric arylation of aldehydes
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DOI：
10.1002/anie.200600741
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发表时间：
2006-01-01
影响因子：
16.6
通讯作者：
Walsh, Patrick J.
中科院分区：
文献类型：
--
作者：
Kim, Jeung Gon;Walsh, Patrick J.
芳基对醛的催化不对称加成反应引起了人们的极大关注。[1]所产生的二芳基甲醇是生物活性化合物的重要成分，例如氯马斯汀、[2]奥芬那君、[3，4]新苯诺定、[3，4]氯苯那敏、[5，6]西唑立汀[7]和卡比沙明。[8]虽然大多数对映选择性醛芳基化反应依赖于使用昂贵的二苯基锌（$55-75 gg/l），但已经报道了使用其他芳基转移试剂（例如芳基硼酸[9，10]和Ph 2Si（OMe）2 [11]）的重要进展。尽管有限数量的芳基硼酸是可商购的，但它们也相当昂贵（例如，来自Aldrich的PhB（OH）2 $225.00摩尔/升）。更实用和通用的方法将从芳基溴开始开始，其中许多是可商购的且便宜的（比较来自Aldrich的PhBr 2.50摩尔/升）。然而，没有报道成功地催化不对称芳基加成到醛，开始与芳基溴。[12本文中，我们公开了一种一锅法，其从芳基溴化物开始，用于原位生成芳基锌中间体，并将其催化不对称加成到醛上，以得到高度对映体富集的二芳基甲醇和苄醇。我们选择检查由Nugent [14，15]开发的氨基醇配体MIB在商业ZnPh 2对2-萘甲醛的不对称加成中[Eq.①]。我们高兴地发现，苯基化反应在甲苯中进行，对映选择性为94%（表1，条目1）。不幸的是，苯基锂与ZnCl 2在甲苯中的金属转移是不成功的，因为ZnCl 2在这种介质中的不溶性。相反，已知醚溶剂促进金属转移反应。然而，在乙醚中的不对称加成得到低的对映选择性（60%;表1，条目2）。为了平衡金属转移所需的乙醚的溶剂化性质和甲苯的低极性，我们研究了叔丁基甲基醚（tBuOMe）。市售ZnPh 2、（NH 4）-MIB和2-萘甲醛在tBuOMe中的反应混合物提供88%ee的产物（表1，条目3）。tBuOMe和己烷（1：3）的溶剂系统表现出大致相同的性质。
The catalytic asymmetric addition of aryl groups to aldehydes has generated an enormous amount of attention.[1] The resulting diarylmethanols are important constituents of biologically active compounds, such as clemastine,[2] orphenadrine,[3, 4] neobenodine,[3, 4] chloropheniramine,[5, 6] cizolirtine,[7] and carbinoxamine.[8] Although the majority of enantioselective aldehyde arylation reactions rely on the use of costly diphenylzinc ($55–75 gÀ1), important advances in the use of other aryl transfer reagents, such as arylboronic acids [9, 10] and Ph2Si (OMe) 2,[11] have been reported. Although a limited number of aryl boronic acids are commercially available, they are quite expensive as well (eg, PhB (OH) 2 $225.00 molÀ1 from Aldrich). A more practical and versatile method would begin with aryl bromides, many of which are commercially available and inexpensive (compare PhBr $2.50 molÀ1 from Aldrich). There are no reports, however, of successful catalytic asymmetric aryl additions to aldehydes that begin with aryl bromides.[12, 13] Herein, we disclose a onepot method that begins with aryl bromides for the in situ generation of aryl zinc intermediates and their catalytic asymmetric addition to aldehydes to afford highly enantioenriched diarylmethanols and benzylic alcohols. We chose to examine the amino alcohol ligand MIB developed by Nugent [14, 15] in the asymmetric addition of commercial ZnPh2 to 2-naphthylaldehyde [Eq.(1)]. We were pleased to find that phenylation proceeded in toluene with 94% enantioselectivity (Table1, entry1). Unfortunately, transmetalation of phenyllithium with ZnCl2 in toluene was unsuccessful because of the insolubility of ZnCl2 in this medium. In contrast, ethereal solvents are known to promote transmetalation reactions. The asymmetric addition in diethyl ether, however, gave a low enantioselectivity (60%; Table 1, entry 2). In an attempt to balance both the solvating properties of diethyl ether, needed for the transmetalation, and the low polarity of toluene, we examined tert-butyl methyl ether (tBuOMe). A reaction mixture of commercial ZnPh2,(À)-MIB, and 2-naphthylaldehyde in tBuOMe furnished the product in 88% ee (Table 1, entry 3). A solvent system of tBuOMe and hexanes (1: 3) exhibited about the same