Enantioselective synthesis of SM-130686 based on the development of asymmetric Cu(I)F catalysis to access 2-oxindoles containing a tetrasubstituted carbon.
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 ZnF(2). 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 alpha-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 alpha-keto amide 19, affording product 20 in 85% ee. The addition of ZnF(2) 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.
Tomita
Daisuke
D
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Yamatsugu
Kenzo
K
Kanai
Motomu
M
Shibasaki
Masakatsu
M
D002384:Catalysis; D003300:Copper / Q000737:chemistry; D005021:Ethylamines / Q000138:chemical synthesis*; D005459:Fluorides / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis*; D000078183:Oxindoles; D013237:Stereoisomerism
D005021:Ethylamines; D007211:Indoles; D000078183:Oxindoles; C443685:SM 130686; C022960:2-oxindole; D003300:Copper; D005459:Fluorides