Enantioselective Synthesis of SM-130686 Based on the Development of Asymmetric Cu(I)F Catalysis To Access 2-Oxindoles Containing a Tetrasubstituted Carbon

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• 作者：Daisuke Tomita ; Kenzo Yamatsugu ; Motomu Kanai ; Masakatsu Shibasaki
• 刊名：Journal of the American Chemical Society
• 出版年：2009
• 出版时间：May 27, 2009
• 年：2009
• 卷：131
• 期：20
• 页码：6946-6948
• 全文大小：167K
• 年卷期：v.131,no.20(May 27, 2009)
• ISSN：1520-5126

文摘

Two different catalytic enantioselective approaches to 3-aryl- and 3-alkenyl-3-hydroxy-2-oxindoles have been developed. First, enantioselective arylation and alkenylation reactions of isatins using aryltrimethoxysilanes and alkenyltrimethoxysilanes as nucleophiles can be catalyzed by a complex of CuF with structurally tuned Taniaphos (6) in the presence of a catalytic amount of ZnF₂. Despite the wide substrate scope, this intermolecular reaction was not applicable to a catalytic enantioselective synthesis of SM-130686 (1), a highly potent, orally active growth hormone secretagogue containing a sterically congested chiral tetrasubstituted carbon. Therefore, we developed an intramolecular catalytic enantioselective arylation of α-keto amides, taking advantage of the robustness of arylboronate reagents under multiple synthetic conversions and silica gel column chromatography purification. A complex of CuF with Ph−BPE (12) catalyzed the enantioselective arylation of α-keto amide 19, affording product 20 in 85% ee. The addition of ZnF₂ to this intramolecular reaction was not necessary. The first enantioselective synthesis of SM-130686 was achieved using this catalytic methodology. Because 2-oxyindoles are a versatile motif for biologically active compounds, the two types of Cu-catalyzed asymmetric reactions developed here will be useful for the synthesis of other natural products and pharmaceutical leads.