title: Telescoped Process to Manufacture 6,6,6-Trifluorofucose via Diastereoselective Transfer Hydrogenation: Scalable Access to an Inhibitor of Fucosylation Utilized in Monoclonal Antibody Production.
abstract: 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.
authors.affiliation: Pivotal Drug Substance Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Michal M
authors.initials: MM
authors.lastname: Achmatowicz
authors.affiliation: Discovery Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: John G
authors.initials: JG
authors.lastname: Allen
authors.affiliation: Pivotal Drug Substance Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Bio
authors.affiliation: Discovery Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.affiliation: Pivotal Drug Substance Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Borths
authors.affiliation: Pivotal Drug Substance Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: John T
authors.initials: JT
authors.lastname: Colyer
authors.affiliation: Pivotal Drug Substance Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Crockett
authors.affiliation: Pivotal Drug Substance Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Tsang-Lin
authors.initials: TL
authors.lastname: Hwang
authors.affiliation: Syncom BV, Kadijk 3, Groningen 9747 AT, The Netherlands.
authors.forename: Jan N
authors.initials: JN
authors.lastname: Koek
authors.affiliation: Attribute Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Osgood
authors.affiliation: Pivotal Drug Substance Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Roberts
authors.affiliation: Attribute Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Swietlow
authors.affiliation: Pivotal Drug Substance Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Oliver R
authors.initials: OR
authors.lastname: Thiel
authors.affiliation: Pivotal Drug Substance Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Seb
authors.initials: S
authors.lastname: Caille
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry*; D000920:Antibody-Dependent Cell Cytotoxicity; D002384:Catalysis; D003460:Crystallization; D005643:Fucose / Q000031:analogs & derivatives* / Q000737:chemistry*; D006865:Hydrogenation; D007074:Immunoglobulin G / Q000737:chemistry; D010084:Oxidation-Reduction; D012428:Ruthenium; D013237:Stereoisomerism
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D005643:Fucose; D012428:Ruthenium