Telescoped Process to Manufacture 6,6,6-Trifluorofucose via Diastereoselective Transfer Hydrogenation: Scalable Access to an Inhibitor of Fucosylation Utilized in Monoclonal Antibody Production

• Published in: Journal of organic chemistry Vol. 81; no. 11; pp. 4736 - 4743
• Main Authors: Achmatowicz, Michal M, Allen, John G, Bio, Matthew M, Bartberger, Michael D, Borths, Christopher J, Colyer, John T, Crockett, Richard D, Hwang, Tsang-Lin, Koek, Jan. N, Osgood, Stephen A, Roberts, Scott W, Swietlow, Aleksander, Thiel, Oliver R, Caille, Seb
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 03.06.2016; Amer Chemical Soc
• Subjects: Antibodies, Monoclonal - chemistry; Antibody-Dependent Cell Cytotoxicity; Catalysis; Chemistry; Chemistry, Organic; Crystallization; Fucose - analogs & derivatives; Fucose - chemistry; Hydrogenation; Immunoglobulin G - chemistry; Oxidation-Reduction; Physical Sciences; Ruthenium; Science & Technology; Stereoisomerism; KETONES; (TRIFLUOROMETHYL)TRIMETHYLSILANE; ASYMMETRIC TRANSFER HYDROGENATION; TRIFLUOROMETHYLATION
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.6b00646

IgG1 monoclonal antibodies with reduced glycan fucosylation have been shown to improve antibody-dependent cellular cytotoxicity (ADCC) by allowing more effective binding of the Fc region of these proteins to T cells receptors. Increased in vivo efficacy in animal models and oncology clinical trials has been associated with the enhanced ADCC provided by these engineered mAbs. 6,6,6-Trifluorofucose (1) is a new inhibitor of fucosylation that has been demonstrated to allow the preparation of IgG1 monoclonal antibodies with lower fucosylation levels and thus improve the ADCC of these proteins. A new process has been developed to support the preparation of 1 on large-scale for wide mAb manufacture applications. The target fucosylation inhibitor (1) was synthesized from readily available d-arabinose in 11% overall yield and >99.5/0.5 dr (diastereomeric ratio). The heavily telescoped process includes seven steps, two crystallizations as purification handles, and no chromatography. The key transformation of the sequence involves the diastereoselective preparation of the desired trifluoromethyl-bearing alcohol in >9/1 dr from a trimethylsilylketal intermediate via a ruthenium-catalyzed tandem ketal hydrolysis–transfer hydrogenation process.