Catalytic asymmetric synthesis of tert-butanesulfinamide. Application to the asymmetric synthesis of amines
Catalytic asymmetric synthesis of tert-butanesulfinamide. Application to the asymmetric synthesis of amines
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DOI：
10.1021/ja972012z
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发表时间：
1997-10-15
影响因子：
15
通讯作者：
Ellman, JA
中科院分区：
文献类型：
--
作者：
Liu, GC;Cogan, DA;Ellman, JA
超过75%的药物和候选药物含有胺功能。尽管如此，胺的不对称合成（不包括r -氨基酸）远不如其他常见官能团的不对称合成发达。对甲苯磺酰胺及其对应的亚亚胺已成为不对称合成aziridines、r -和β-氨基酸以及r -支胺的焦点，研究非常有限。戴维斯是对甲苯亚胺研究的先驱，他证明了亚胺基是一种理想的助剂，因为它可以激活亚胺进行亲核加成，提供非对面层选择性，并且很容易通过温和的酸处理去除。在我们自己开发用于非对映选择性烯醇酸烷基化化学的n -酰基亚胺的努力中，5我们发现叔丁烷亚胺优于对甲苯亚胺，因为它的分子量更低，非对映选择性更强，6并且胺官能团的亲核性更强。遗憾的是，尚未报道制备光学纯叔丁烷磺酰胺的简便方法。本文报告了一种高度实用的两步法制备大量光学纯叔丁烷磺酰胺，关键步骤是催化不对称氧化叔丁基二硫化，这是一种非常便宜的起始材料（< 2美分/克）。我们进一步描述了叔丁烷磺酰胺在一般和权宜的不对称合成r支胺中的应用。我们设想叔丁烷磺酰胺可以由叔丁基叔丁烷乙硫代亚磺酸中间体衍生（1,eq 1）。尺度硫代亚磺酸盐的化学性质尚未得到广泛的研究，但有限的先例表明，金属酰胺和碳离子亲核试剂在对映体富集的硫代亚磺酸盐上分别发生立体特异性的加成，产生亚胺和亚砜的产物。制备亚硫代硫酸盐最方便的方法是催化不对称氧化叔丁基二硫化物，尽管以前的氧化方法对光学纯亚硫代硫酸盐的选择性令人失望。我们考虑了许多不同的氧化催化剂，但最吸引我们的是Bolm最近关于硫醚不对称氧化的报告。10所采用的钒催化剂具有很强的催化作用（催化剂含量低至0.01%），并且与廉价的化学计量氧化剂过氧化氢相容。唯一的缺点是一般适度报道的对映选择性（53-70%的硫醚和85%的ee - 2-苯基- 1,3 -二硫烷）。我们首先利用Bolm报道的一般反应条件，在室温下以CH2Cl2为溶剂，在2%催化剂负载下探索了许多不同的配体。所选配体的数据见表1。芳基环5位的位阻效应并不重要，但电子效应对催化剂的周转和选择性都起着至关重要的作用（表1）。电子因子和空间因子对芳基环3位取代基都很重要（条目5-8）。最后，立体效应在R3中发挥重要作用，叔丁基比其他取代基具有更高的选择性。在这些研究的基础上，将3,5 -二叔丁基水杨醛与叔亮醇缩合制备最佳配体，这两种配体都是市售的（条目1和12，表1）。溶剂对催化剂的选择性也有很大的影响。特别是，虽然1,2 -二氯乙烷具有与CH2Cl2相当的选择性…
Greater than 75% of drugs and drug candidates incorporate amine functionality. 1 Nonetheless, the asymmetric synthesis of amines, 2 excluding R-amino acids, is much less developed than the asymmetric synthesis of other common functional groups. p-Toluenesulfinamide and the corresponding sulfinimines have become the focus of increasing attention for the asymmetric synthesis of aziridines, R-and β-amino acids, and, in very limited studies, R-branched amines. 3, 4 Davis, who pioneered efforts on the study of p-toluenesulfinimines, demonstrated that the sulfinyl group serves as an ideal auxiliary because it activates the imine for nucleophilic addition, provides diastereofacial selectivity, and is easy to remove simply by treatment with mild acid. In our own efforts to develop N-acylsulfinamides for diastereoselective enolate alkylation chemistry, 5 we found tert-butanesulfinamide to be superior to p-toluenesulfinamide due to the lower molecular weight, enhanced diastereofacial selectivity, 6 and enhanced nucleophilicity of the amine functionality. Unfortunately, expedient methods have not been reported for the preparation of optically pure tert-butanesulfinamide. 6 Herein we report a highly practical two-step procedure to prepare large quantities of optically pure tert-butanesulfinamide with the key step being the catalytic asymmetric oxidation of tert-butyl disulfide, which serves as an extremely inexpensive starting material (< 2 cents/g). We further describe the utility of tert-butanesulfinamide for the general and expedient asymmetric synthesis of R-branched amines. We envisaged that tert-butanesulfinamide could be derived from a tert-butyl tert-butanethiosulfinate intermediate (1, eq 1). The chemistry of scalemic thiosulfinates has not been explored extensively, but limited precedent did indicate that addition of metal amides7 and carbanion8 nucleophiles to enantioenriched thiosulfinates occurs stereospecifically to provide sulfinamide and sulfoxide products, respectively. The most expedient method for the preparation of the thiosulfinate would be catalytic asymmetric oxidation of tert-butyl disulfide, although previous oxidative approaches toward optically pure thiosulfinates have resulted in disappointing selectivities. 9 We considered a number of different oxidation catalysts but were most attracted to a recent report by Bolm on the asymmetric oxidation of thioethers. 10 The vanadium catalysts employed are highly catalytic (as little as 0.01% catalyst) and are compatible with the inexpensive stoichiometric oxidant hydrogen peroxide. The only detraction was the generally modest reported enantioselectivities (53-70% for thioethers and 85% ee for 2-phenyl-1, 3-dithiane).We first explored a number of different ligands at 2% catalyst loading using the general reaction conditions reported by Bolm, room temperature with CH2Cl2 as the solvent. Data for selected ligands are provided in Table 1. Steric effects at the 5-position of the aryl ring are not important, but electronic effects play a critical role in both catalyst turnover and selectivity (entries 1-4, Table 1). Both electronic and steric factors were found to be important for substituents at the 3-position of the aryl ring (entries 5-8). Finally, steric effects play an important role at R3, with the tert-butyl group providing significantly higher selectivity than other substituents. On the basis of these studies, the optimal ligand is prepared by condensation of 3, 5-di-tert-butylsalicylaldehyde with tert-leucinol, both of which are commercially available (entries 1 and 12, Table 1). Solvent was also found to have a dramatic effect upon catalyst selectivity. In particular, while 1, 2-dichloroethane provides comparable selectivities to CH2Cl2 …