title: Facile entry to an efficient and practical enantioselective synthesis of a polycyclic cholesteryl ester transfer protein inhibitor.
abstract: An efficient enantioselective synthesis of the chiral polycyclic cholesteryl ester transfer protein (CETP) inhibitor 1 has been developed. The synthesis was rendered practical for large scale via the development of a modified Hantzsch-type reaction to prepare the sterically hindered pyridine ring, enantioselective hydrogenation of hindered ketone 6 utilizing novel BIBOP-amino-pyridine derived Ru complex, efficient ICl promoted lactone formation, and a BF3 mediated hydrogenation process for diastereoselective lactol reduction. This efficient route was successfully scaled to produce multikilogram quantities of challenging CETP drug candidate 1.
authors.affiliation: Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc. , 900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877, United States.
authors.forename: Zhengxu S
authors.initials: ZS
authors.lastname: Han
authors.forename: Yibo
authors.initials: Y
authors.lastname: Xu
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Fandrick
authors.forename: Sonia
authors.initials: S
authors.lastname: Rodriguez
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Qu
authors.forename: Nina C
authors.initials: NC
authors.lastname: Gonnella
authors.forename: Sanjit
authors.initials: S
authors.lastname: Sanyal
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Reeves
authors.forename: Shengli
authors.initials: S
authors.lastname: Ma
authors.forename: Nelu
authors.initials: N
authors.lastname: Grinberg
authors.forename: Nizar
authors.initials: N
authors.lastname: Haddad
authors.forename: Dhileep
authors.initials: D
authors.lastname: Krishnamurthy
authors.forename: Jinhua J
authors.initials: JJ
authors.lastname: Song
authors.forename: Nathan K
authors.initials: NK
authors.lastname: Yee
authors.forename: Waldemar
authors.initials: W
authors.lastname: Pfrengle
authors.forename: Markus
authors.initials: M
authors.lastname: Ostermeier
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schnaubelt
authors.forename: Zeno
authors.initials: Z
authors.lastname: Leuter
authors.forename: Sonja
authors.initials: S
authors.lastname: Steigmiller
authors.forename: Jürgen
authors.initials: J
authors.lastname: Däubler
authors.forename: Emanuel
authors.initials: E
authors.lastname: Stehle
authors.forename: Lukas
authors.initials: L
authors.lastname: Neumann
authors.forename: Thomas
authors.initials: T
authors.lastname: Trieselmann
authors.forename: Patrick
authors.initials: P
authors.lastname: Tielmann
authors.forename: Annette
authors.initials: A
authors.lastname: Buba
authors.forename: Rainer
authors.initials: R
authors.lastname: Hamm
authors.forename: Gunter
authors.initials: G
authors.lastname: Koch
authors.forename: Svenja
authors.initials: S
authors.lastname: Renner
authors.forename: Juan R
authors.initials: JR
authors.lastname: Dehli
authors.forename: Florian
authors.initials: F
authors.lastname: Schmelcher
authors.forename: Christian
authors.initials: C
authors.lastname: Stange
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mack
authors.forename: Rainer
authors.initials: R
authors.lastname: Soyka
authors.forename: Chris H
authors.initials: CH
authors.lastname: Senanayake
mesh_terms: D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D006865:Hydrogenation; D008968:Molecular Conformation; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D011725:Pyridines