A facile method for the transformation of N-(tert-butoxycarbonyl) α-amino acids to N-unprotected α-amino methyl esters
A facile method for the transformation of N-(tert-butoxycarbonyl) α-amino acids to N-unprotected α-amino methyl esters
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DOI：
10.1021/jo990311w
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发表时间：
1999-12-10
影响因子：
3.6
通讯作者：
Vite, GD
中科院分区：
文献类型：
--
作者：
Chen, BC;Skoumbourdis, AP;Vite, GD
甲基N-无保护R-氨基酯是有机合成中的重要中间体。1它们可以方便地通过相应的游离R-氨基酸在甲醇中使用气态HCl、1aSOCl2、1b或TMSCl进行Fisher类型的酯化反应来制备。1C此外，已经开发了越来越多的方法来制备具有已经被Boc基团保护的R-氮原子的R-氨基酸。2-7例如，N-Bocβ-氨基醇、2个N-Boc苄胺、3个N-Boc呋喃胺、4和N-Boc烯丙胺5的氧化直接得到N-Boc R-氨基酸。N-Boc R-氨基-R，β-不饱和羧酸的还原也得到N-Boc R-氨基酸。6因此，开发一种方法直接将N-Boc R-氨基酸转化为N-不受保护的R-氨基酸甲酯，而不需要事先解除N-Boc基团的保护和分离游离的R-氨基酸中间体是非常重要的。以前，N-Boc R-氨基酸甲酯的转化分两步进行：(I)在碱1d-f，10的存在下，用重氮甲烷1d，8，9或碘甲烷生成羧酸的酯；(Ii)用诸如盐酸，1e-g，11-三氟乙酸，1d，12或三氟化硼之类的酸去保护生成的酯的N-Boc基团。13虽然总收率通常令人满意，但由于重氮甲烷的安全性问题以及在碘甲烷情况下的竞争N-甲基化，这种方法受到限制，特别是对于大规模制备。14 Rosenberg和他的同事在脚注中报道了用甲醇盐酸处理N-Boc-O-甲基酪氨酸，但没有实验细节或产率，得到了O-甲基酪氨酸甲酯盐酸盐。15MeOH/TMSCl是一种以羧酸为原料制备甲酯的简便体系。16与传统的甲醇中的HCl气态相比，使用TMSCl进行酯化反应更具优势，不仅因为它的使用和测量更方便，而且还因为它起到了除水剂的作用，使酯化反应更快、更清洁。理论上，在羧酸与TMSCl/MeOH的酯化反应中，至少生成1当量的HCl。我们设想，如果使用N-Boc R-氨基酸，这种原位产生的HCl可能会影响N-Boc基团的去保护。因此，L-N-Boc-苯丙氨酸在甲醇中与TMSCl在室温下反应2 h，得到19%的产物--苯丙氨酸甲酯(4，M+H)180，此外还有两个中间峰，通过反相高效液相色谱和LC/MS分析，起始物质完全消失。主峰移动慢于4或1，是N-Boc-苯丙氨酸甲酯(2，62%，M+H)280，而最快的洗脱峰是N-Boc脱保护中间体苯丙氨酸(3，19%)。进一步搅拌后，2和3分别经N-Boc脱保护和酯化反应得到4，且前者的反应速度快于后者。经过一夜的搅拌，去掉溶剂并用乙醚结晶，以94%的收率得到了所需的产物L-苯丙氨酸甲酯盐酸盐(方案1和表1，条目1)。重要的是，没有外消旋发生在
Methyl N-unprotected R-amino esters are important intermediates in organic synthesis. 1 They can be conveniently prepared by a Fisher-type esterification of the corresponding free R-amino acids in methanol using gaseous HCl, 1a SOCl2, 1b or TMSCl. 1c In addition, an increasing number of methods have been developed for the preparation of R-amino acids with the R-nitrogen atom already protected by a Boc group. 2-7 For example, oxidations of N-Boc β-amino alcohols, 2 N-Boc benzylamines, 3 N-Boc furfurylamines, 4 and N-Boc allylamines5 afford directly N-Boc R-amino acids. Reduction of N-Boc R-amino-R, β-unsaturated carboxylic acids also gives N-Boc R-amino acids. 6 It is therefore of importance to develop a method for the direct transformation of N-Boc R-amino acids to methyl N-unprotected R-amino esters without prior deprotection of the N-Boc group and isolation of the free R-amino acid intermediate. Previously, the transformation of N-Boc R-amino acids to methyl N-unprotected R-amino esters was carried out in two steps:(i) ester formation of the carboxylic acid using diazomethane1d, 8, 9 or iodomethane in the presence of a base1d-f, 10 and (ii) deprotection of the N-Boc group of the resulting ester with an acid such as hydrochloric acid, 1e-g, 11 trifluoroacetic acid, 1d, 12 or boron trifluoride. 13 Although the overall yields are usually satisfactory, this method is limited, especially for large scale preparation, as a result of the safety concern with diazomethane and the competitive N-methylation in the case of iodomethane. 14 Treatment of N-Boc-O-methyl tyrosine with methanolic HCl was reported by Rosenberg and coworkers in a footnote without experimental details or yield to give O-methyl tyrosine methyl ester hydrochloride. 15MeOH/TMSCl is a facile system for the preparation of methyl esters from carboxylic acids. 16 Compared to the conventional gaseous HCl in methanol used for esterification, use of TMSCl is more advantageous not only because it is more convenient to use and measure but also because it acts as a water scavenger so that the esterification is faster and cleaner. In theory, at least 1 equiv of HCl is generated in the esterification of carboxylic acid with TMSCl/MeOH. We envisioned that this HCl generated in situ may affect the deprotection of the N-Boc group if an N-Boc R-amino acid is used. Thus, treatment of L-N-Boc-phenylalanine in methanol with TMSCl at room temperature for 2 h gave 19% of the desired product, phenylalanine methyl ester (4, M+ H) 180), in addition to two intermediate peaks and complete disappearance of the starting material by reverse-phase HPLC and LC/MS. The major peak, moving more slowly than 4 or 1, was N-Boc-phenylalanine methyl ester (2, 62%, M+ H) 280), whereas the fastest eluting peak was the N-Boc deprotection intermediate phenylalanine (3, 19%). Upon further stirring, both 2 and 3 underwent N-Boc deprotection and esterification, respectively, to give 4, with the former reaction being faster than the latter. After stirring overnight, the desired product, L-phenylalanine methyl ester hydrochloride (4), was obtained in 94% yield by removing the solvent and crystallizing the product with ether (Scheme 1 and Table 1, entry 1). Importantly, no racemization took place in