title: Investigation of the mechanism of racemization of litronesib in aqueous solution: unexpected base-catalyzed inversion of a fully substituted carbon chiral center.
abstract: Mitosis inhibitor (R)-litronesib (LY2523355) is a 1,3,4-thiadiazoline-bearing phenyl and N-(2-ethylamino)ethanesulfonamido-methyl substituents on tetrahedral C5. Chiral instability has been observed at pH 6 and above with the rate of racemization increasing with pH. A positively charged trigonal intermediate is inferred from the fact that p-methoxy substituent on the phenyl accelerated racemization, whereas a p-trifluoromethyl substituent had the opposite effect. Racemization is proposed to occur through a relay mechanism involving intramolecular deprotonation of the sulfonamide by the side chain amino group and attack of the sulfonamide anion on C5, cleaving the C5S bond, to form an aziridine; heterolytic dissociation of the aziridine yields an ylide. This pathway is supported by (1) a crystal structure providing evidence for a hydrogen bond between the sulfonamide NH and the amino group, (2) effects of substituents on the rate of racemization, and (3) computational studies. This racemization mechanism results from neighboring group effects in this densely functionalized molecule. Of particular novelty is the involvement of the side-chain secondary amino group, which overcomes the weak acidity of the sulfonamide by anchimeric assistance.
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285-3811. Electronic address: baertschi@lilly.com.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Baertschi
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285-3811.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Jansen
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285-3811.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Montgomery
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285-3811.
authors.forename: William K
authors.initials: WK
authors.lastname: Smith
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285-3811.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Draper
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285-3811.
authors.forename: David P
authors.initials: DP
authors.lastname: Myers
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285-3811.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Houghton
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285-3811.
authors.forename: V Scott
authors.initials: VS
authors.lastname: Sharp
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285-3811.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Guisbert
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285-3811.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhuang
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285-3811.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Watkins
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285-3811.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Stephenson
authors.affiliation: Vanderbilt University, Department of Chemistry, Nashville, Tennessee 37235.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Harris
mesh_terms: D001388:Aziridines / Q000737:chemistry; D002244:Carbon / Q000737:chemistry*; D002384:Catalysis; D004355:Drug Stability; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D015394:Molecular Structure; D012996:Solutions / Q000737:chemistry*; D013237:Stereoisomerism; D013449:Sulfonamides / Q000737:chemistry*; D013830:Thiadiazoles / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D001388:Aziridines; D012996:Solutions; D013449:Sulfonamides; D013830:Thiadiazoles; D014867:Water; C033132:aziridine; C000591843:litronesib; D002244:Carbon
keywords: chiral inversion; mechanism; neighboring group; racemization; relay ionization; ylide