title: The intramolecular asymmetric Pauson-Khand cyclization as a novel and general stereoselective route to benzindene prostacyclins: synthesis of UT-15 (treprostinil).
abstract: A general and novel solution to the synthesis of biologically important stable analogues of prostacyclin PGI(2), namely benzindene prostacyclins, has been achieved via the stereoselective intramolecular Pauson-Khand cyclization (PKC). This work illustrates for the first time the synthetic utility and reliability of the asymmetric PKC route for synthesis and subsequent manufacture of a complex drug substance on a multikilogram scale. The synthetic route surmounts issues of individual step stereoselectivity and scalability. The key step in the synthesis involves efficient stereoselection effected in the PKC of a benzoenyne under the agency of the benzylic OTBDMS group, which serves as a temporary stereodirecting group that is conveniently removed via benzylic hydrogenolysis concomitantly with the catalytic hydrogenation of the enone PKC product. Thus the benzylic chiral center dictates the subsequent stereochemistry of the stereogenic centers at three carbon atoms (C(3a), C(9a), and C(1)).
authors.affiliation: Department of Chemistry (M/C 111), University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Moriarty
authors.forename: Neena
authors.initials: N
authors.lastname: Rani
authors.forename: Livia A
authors.initials: LA
authors.lastname: Enache
authors.forename: Munagala S
authors.initials: MS
authors.lastname: Rao
authors.forename: Hitesh
authors.initials: H
authors.lastname: Batra
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.forename: Raju A
authors.initials: RA
authors.lastname: Penmasta
authors.forename: James P
authors.initials: JP
authors.lastname: Staszewski
authors.forename: Sudersan M
authors.initials: SM
authors.lastname: Tuladhar
authors.forename: Om
authors.initials: O
authors.lastname: Prakash
authors.forename: David
authors.initials: D
authors.lastname: Crich
authors.forename: Anca
authors.initials: A
authors.lastname: Hirtopeanu
authors.forename: Richard
authors.initials: R
authors.lastname: Gilardi
mesh_terms: D000473:Alkanes / Q000737:chemistry; D000480:Alkynes / Q000737:chemistry; D018360:Crystallography, X-Ray; D003500:Cyclization; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D006865:Hydrogenation; D015394:Molecular Structure; D017646:Organosilicon Compounds / Q000737:chemistry; D044062:Prostaglandins I / Q000138:chemical synthesis*; D013237:Stereoisomerism
chemical_list: D000473:Alkanes; D000480:Alkynes; D017646:Organosilicon Compounds; D044062:Prostaglandins I; D011464:Epoprostenol; C004544:naphtha; C427248:treprostinil