Development of an Asymmetric Synthesis of a Chiral Quaternary FLAP Inhibitor

• Published in: Journal of organic chemistry Vol. 80; no. 3; pp. 1651 - 1660
• Main Authors: Fandrick, Keith R, Mulder, Jason A, Patel, Nitinchandra D, Gao, Joe, Konrad, Michael, Archer, Elizabeth, Buono, Frederic G, Duran, Adil, Schmid, Rolf, Daeubler, Juergen, Desrosiers, Jean-Nicolas, Zeng, Xingzhong, Rodriguez, Sonia, Ma, Shengli, Qu, Bo, Li, Zhibin, Fandrick, Daniel R, Grinberg, Nelu, Lee, Heewon, Bosanac, Todd, Takahashi, Hidenori, Chen, Zhidong, Bartolozzi, Alessandra, Nemoto, Peter, Busacca, Carl A, Song, Jinhua J, Yee, Nathan K, Mahaney, Paige E, Senanayake, Chris H
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 06.02.2015; Amer Chemical Soc
• Subjects: 5-Lipoxygenase-Activating Protein Inhibitors - chemical synthesis; 5-Lipoxygenase-Activating Protein Inhibitors - chemistry; Boron Compounds - chemistry; Carbamates - chemistry; Catalysis; Chemistry; Chemistry, Organic; Molecular Structure; Physical Sciences; Science & Technology; Stereoisomerism; TERTIARY BORONIC ESTERS; SECONDARY ALCOHOLS; CROSS-COUPLING REACTIONS; PRACTICAL SYNTHESIS; REAGENTS; ENANTIOSELECTIVE SYNTHESIS; CONVERSION; CONSTRUCTION; TRANSFER HYDROGENATION; STEREOGENIC CENTERS
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo502550h

A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor.