Journal
TETRAHEDRON
Volume 74, Issue 38, Pages 5069-5084Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tet.2018.04.005
Keywords
Catalytic asymmetric reduction; NaBH4; Co complex; Fluspidine; sigma 1 receptor antagonist
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology (Japan) [25E07B212, 22750088, 24510112, 24106713]
- Advanced Catalytic Transformation Program for Carbon Utilization (ACT-C) from Japan Science and Technology Agency (JST)
- Grants-in-Aid for Scientific Research [24106713, 22750088, 24510112] Funding Source: KAKEN
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Asymmetric NaBH4 reduction catalyzed by the Co(II) complex of a chiral diamidine-type sp(2)N ligand, Naph-diPIM-dioxo-iPr, was successfully applied to 3-silyloxycinnamate substrates without over-reduction, giving quantitatively 3-silyloxy-3-arylpropionates with an enantiomer ratio of up to 99:1. The high utility was confirmed on a 30-g scale using 0.1 mol% catalyst. Both Z and E substrates could be converted to a single enantiomeric product by changing the ligand chirality. The relationship between the ZIE stereochemistry and the absolute configuration of the 1,4-reduction product provided important information about the mechanism underlying enantioface selection. Combination of the asymmetric catalysis with two other key steps, Suzuki coupling with an N-protected tetrahydropyridine boronic acid derivative and intramolecular bromo etherification, realized an efficient synthetic route to both enan-tiomers of fluspidine. The new strategy permits the introduction of substituents on the two aryl groups and piperidine ring, allowing for structural variations toward the development of higher performance sigma 1 receptor antagonists. (C) 2018 The Authors. Published by Elsevier Ltd.
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