title: Zinc catalyzed and mediated asymmetric propargylation of trifluoromethyl ketones with a propargyl boronate.
abstract: The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the N-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist BI 653048. A mechanism for the boron-zinc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones.
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./PO BOX 368, Ridgefield, Connecticut 06877-0368, USA. daniel.fandrick@boehringer-ingelheim.com
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Fandrick
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Reeves
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Bakonyi
authors.forename: Prasanth R
authors.initials: PR
authors.lastname: Nyalapatla
authors.forename: Zhulin
authors.initials: Z
authors.lastname: Tan
authors.forename: Oliver
authors.initials: O
authors.lastname: Niemeier
authors.forename: Deniz
authors.initials: D
authors.lastname: Akalay
authors.forename: Keith R
authors.initials: KR
authors.lastname: Fandrick
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wohlleben
authors.forename: Swetlana
authors.initials: S
authors.lastname: Ollenberger
authors.forename: Jinhua J
authors.initials: JJ
authors.lastname: Song
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Sun
authors.forename: Bo
authors.initials: B
authors.lastname: Qu
authors.forename: Nizar
authors.initials: N
authors.lastname: Haddad
authors.forename: Sanjit
authors.initials: S
authors.lastname: Sanyal
authors.forename: Sherry
authors.initials: S
authors.lastname: Shen
authors.forename: Shengli
authors.initials: S
authors.lastname: Ma
authors.forename: Denis
authors.initials: D
authors.lastname: Byrne
authors.forename: Ashish
authors.initials: A
authors.lastname: Chitroda
authors.forename: Victor
authors.initials: V
authors.lastname: Fuchs
authors.forename: Bikshandarkoil A
authors.initials: BA
authors.lastname: Narayanan
authors.forename: Nelu
authors.initials: N
authors.lastname: Grinberg
authors.forename: Heewon
authors.initials: H
authors.lastname: Lee
authors.forename: Nathan
authors.initials: N
authors.lastname: Yee
authors.forename: Michael
authors.initials: M
authors.lastname: Brenner
authors.forename: Chris H
authors.initials: CH
authors.lastname: Senanayake
mesh_terms: D001897:Boronic Acids / Q000737:chemistry*; D002384:Catalysis; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry*; D015394:Molecular Structure; D010293:Pargyline / Q000031:analogs & derivatives* / Q000737:chemistry*; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry*; D013237:Stereoisomerism; D015032:Zinc / Q000737:chemistry*
chemical_list: D001897:Boronic Acids; D006845:Hydrocarbons, Fluorinated; D007659:Ketones; D011392:Proline; D010293:Pargyline; D015032:Zinc