Kinetic resolution of 1,2-diols through highly site- and enantioselective catalytic silylation
Kinetic resolution of 1,2-diols through highly site- and enantioselective catalytic silylation
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DOI：
10.1002/anie.200703650
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Snapper, Marc L.
中科院分区：
文献类型：
--
作者：
Zhao, Yu;Mitra, Aurpon W.;Snapper, Marc L.
1，2-二醇是多种生物活性分子的组分;因此，以高对映体纯度容易获得这类结构单元是一个重要的目标。[1]特别需要提供通过不对称二羟基化[2]（例如，来自顺式烯烃的顺式-1，2-二醇产物）[2，3]不可用的二醇并且提供有区别的羟基的催化方案。我们开发了一种通过催化不对称硅烷化反应动力学拆分三类无环1，2-二醇的有效方法[4]。[5，6]手性1，2-二醇的对映选择性甲硅烷基化比相关的内消旋异构体的对映选择性甲硅烷基化更复杂[5]，并且需要来自手性催化剂的更高的精确度。如预期的，有效的动力学拆分必须涉及与底物的一种对映体的优选反应（a！B@ ent-a！ent-b;方案1）。然而，这类转化需要一个额外的关键属性：硅烷化必须以高位点选择性进行[7]（a！B@ a！ent-c;方案1）。因此，1，2-二醇的动力学拆分不仅仅是挑战催化剂促进一种对映异构体的优先甲硅烷基化的能力;它说明了催化剂可以区分两个羟基位点的程度-RS和RL之间的尺寸差异越小（方案1），催化剂需要的区分越多。我们从研究rac-2a的动力学拆分开始（表1）。催化剂1是一种小分子（MW= 308.5 g molecular-1），最近被鉴定为有效促进内消旋二醇的对映选择性甲硅烷基化[5]，其引发不对称甲硅烷基化。在48 ℃下获得中等选择性（表1，条目1; krel= 5）。在较低的反应温度下，选择性增加（表1，条目1-4），并且在1050 ℃下，催化拆分进行，krel= 35（表1，条目4）。在所有情况下，没有检测到由更受阻的甲醇的反应衍生的甲硅烷基醚（通过GLC分析< 2%）。[8]进一步的研究使我们能够建立纯化后提供96%ee和44%产率的2a的条件（参见表2，条目1）。[10]另外值得一提的几点：1）反应以高位点选择性进行;在大多数情况下，很少（表2条目4和5中分别为3%和2%）或不产生异构甲硅烷基醚4（表2条目1-3和6中< 2%）。仅用带有羧酸酯的底物（表2，条目7和8）形成14%的异构体4（参见下文的进一步讨论）。2)作为高位点选择性的结果，以有用的产率获得未反应的二醇和甲硅烷基醚。在表2所示的条件下，设计用于最大未反应底物对映体纯度，顺式-1，2-二醇以30-48%的产率和87至> 98%ee回收。3）表2中的选择性（97：3位点选择性; krel= 29），
1, 2-Diols are components of a variety of biologically active molecules; facile access to this class of building blocks in high enantiomeric purity is thus an important objective.[1] Catalytic protocols delivering diols that are not available through asymmetric dihydroxylation [2](eg, syn-1, 2-diol products from cis alkenes)[2, 3] and which furnish differentiated hydroxy groups are particularly desirable. We have developed an efficient method for kinetic resolution [4] of three classes of acyclic 1, 2-diols through catalytic asymmetric silylation.[5, 6] Enantioselective silylation of a chiral 1, 2-diol is more complex than that of the related meso isomers [5] and necessitates a higher degree of precision from the chiral catalyst. An effective kinetic resolution, as expected, must involve preferable reaction with one enantiomer of the substrate (rate of a! b@ ent-a! ent-b; Scheme 1). This class of transformations, however, demands an additional and critical attribute: it is imperative that silylations proceed with high site selectivity [7](rate of a! b@ a! ent-c; Scheme 1). Kinetic resolution of a 1, 2-diol, therefore, does more than challenge a catalyst s ability to promote preferential silylation of one enantiomer; it illustrates the extent to which a catalyst can differentiate between two hydroxy sites—the smaller the difference in size between RS and RL (Scheme 1), the more discriminating the catalyst needs to be. We began by studying the kinetic resolution of rac-2a (Table 1). Catalyst 1, a small molecule (MW= 308.5 g molÀ1) that was recently identified to be effective in promoting enantioselective silylations of meso diols,[5] initiates asymmetric silylation. Moderate selectivity is obtained at 48C (Table 1, entry 1; krel= 5). At lower reaction temperatures, selectivity increases (Table 1, entries 1–4), and, at À508C, catalytic resolution proceeds with krel= 35 (Table 1, entry 4). In all cases, the silyl ether derived from reaction of the more hindered carbinol is not detected (< 2% by GLC analysis).[8] Further investigations allowed us to establish conditions that provide 2a in 96% ee and 44% yield after purification (see Table 2, entry 1).A variety of syn-1, 2-diols can be catalytically resolved (Table 2); selectivities are usually at useful levels (krel> 10).[10] Several additional points merit mention: 1) Reactions proceed with high site selectivity; in most cases, little (3% and 2% in Table 2, entries 4 and 5, respectively) or none of the isomeric silyl ether 4 is generated (< 2% in Table 2, entries 1–3, and 6). Only with substrates bearing a carboxylic ester (Table 2, entries 7 and 8) is 14% of isomer 4 formed (see below for further discussion). 2) As a result of high site selectivities, unreacted diols and silyl ethers are obtained in useful yields. Under the conditions shown in Table 2, designed for maximal unreacted substrate enantiomeric purity, syn-1, 2-diols are recovered in 30–48% yield and in 87 to> 98% ee. 3) The selectivity (97: 3 site selectivity; krel= 29) in Table 2,