Delgado Oscar, Müller H Martin, Bach Thorsten
Lehrstuhl für Organische Chemie 1, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
Chemistry. 2008;14(8):2322-39. doi: 10.1002/chem.200701823.
The potent antibiotic thiazolylpeptide GE2270 A was synthesized starting from N-tert-butyloxycarbonyl protected valine in a longest linear sequence of 20 steps and with an overall yield of 4.8 %. Key strategy was the assembly of the 2,3,6-trisubstituted pyridine core by consecutive cross-coupling reactions starting from 2,6-dibromo-3-iodopyridine. The complete Southern fragment was installed by Negishi cross-coupling of 3-zincated 2,6-dibromopyridine at the terminal 2-iodothiazole of a trithiazole (87 %). The substituent at C-6 representing the Northern part of the molecule was introduced in form of the truncated tert-butyl 2-bromothiazole-4-carboxylate after metalation to a zinc reagent by another Negishi cross-coupling (48 %). Decisive step of the whole sequence was the macrocyclization to a 29-membered macrolactam, which was conducted as an intramolecular Stille cross-coupling occurring at C-2 of the pyridine core and providing the desired product in 75 % yield. The required stannane was obtained by amide bond formation (87 %) between a complex dithiazole fragment representing the Eastern part of GE2270 A and a 3,6-disubstituted 2-bromopyridine. Final steps included attachment of a serine-proline amide dipeptide to the Northern part of the molecule (65 %), formation of the oxazoline ring and silyl ether deprotection (55 % overall).
强效抗生素噻唑基肽GE2270 A是从N-叔丁氧羰基保护的缬氨酸开始合成的，最长线性序列为20步，总产率为4.8%。关键策略是从2,6-二溴-3-碘吡啶开始，通过连续的交叉偶联反应组装2,3,6-三取代吡啶核心。通过3-锌化的2,6-二溴吡啶与三噻唑末端的2-碘噻唑进行Negishi交叉偶联，安装完整的Southern片段（87%）。通过另一次Negishi交叉偶联（48%），将代表分子Northern部分的C-6位取代基以截短的叔丁基2-溴噻唑-4-羧酸酯的形式引入，该酯在金属化形成锌试剂后引入。整个序列的决定性步骤是大环化形成一个29元大环内酰胺，这是通过吡啶核心C-2位发生的分子内Stille交叉偶联进行的，产率为75%。所需的锡烷是通过代表GE2270 A东部部分的复杂二噻唑片段与3,6-二取代的2-溴吡啶之间形成酰胺键（87%）获得的。最后步骤包括将丝氨酸-脯氨酸酰胺二肽连接到分子的Northern部分（65%）、形成恶唑啉环和脱除硅醚保护基（总产率55%）。
