Krebs Andreas, Ludwig Verena, Pfizer José, Dürner Gerd, Göbel Michael W
Institute of Organic Chemistry and Chemical Biology, Marie-Curie Strasse 11, 60439 Frankfurt/Main, Germany.
Chemistry. 2004 Jan 23;10(2):544-53. doi: 10.1002/chem.200305421.
We present two complementary methods for the stereoselective synthesis of non-natural alpha-amino acids with aromatic or heteroaromatic side chains. One approach is based on the chemical transformation of methionine, whereas the other applies the stereoselective Myers alkylation of glycine. The resulting product types differ in the linker length between glycine and the aromatic substituent. Since methionine and pseudoephedrine are available in both absolute configurations, R- or S-configured enantiopure amino acids with either C(2) or C(3) linkers can be obtained on gram scales. In each case the key step of the synthesis is hydroboration of the unsaturated building blocks 9 and 17, followed by palladium-catalyzed Suzuki cross-coupling with aryl halides. Attention must in certain cases be paid to the stereochemical integrity when basic Suzuki conditions are applied. Our initial difficulties are reported as well as the final "racemization-proof" procedures. The protecting groups chosen for the alpha-amino acids should be compatible with solid-phase peptide synthesis. This was confirmed by the successful synthesis of a series of tripeptides.
我们展示了两种用于立体选择性合成带有芳香族或杂芳香族侧链的非天然α-氨基酸的互补方法。一种方法基于甲硫氨酸的化学转化，而另一种方法则应用甘氨酸的立体选择性迈尔斯烷基化反应。所得产物类型在甘氨酸与芳香族取代基之间的连接链长度上有所不同。由于甲硫氨酸和伪麻黄碱两种对映体构型均有可得，因此可以以克级规模获得具有C(2)或C(3)连接链的R-或S-构型对映体纯氨基酸。在每种情况下，合成的关键步骤都是对不饱和结构单元9和17进行硼氢化反应，然后与芳基卤化物进行钯催化的铃木交叉偶联反应。在应用基本的铃木反应条件时，在某些情况下必须注意立体化学完整性。我们报告了最初遇到的困难以及最终的“防消旋”程序。为α-氨基酸选择的保护基团应与固相肽合成兼容。这通过一系列三肽的成功合成得到了证实。
