The intramolecular asymmetric Pauson-Khand cyclization as a novel and general stereoselective route to benzindene prostacyclins: synthesis of UT-15 (treprostinil).
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)).
Moriarty
Robert M
RM
Department of Chemistry (M/C 111), University of Illinois at Chicago, Chicago, IL 60607, USA.
Rani
Neena
N
Enache
Livia A
LA
Rao
Munagala S
MS
Batra
Hitesh
H
Guo
Liang
L
Penmasta
Raju A
RA
Staszewski
James P
JP
Tuladhar
Sudersan M
SM
Prakash
Om
O
Crich
David
D
Hirtopeanu
Anca
A
Gilardi
Richard
R
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
D000473:Alkanes; D000480:Alkynes; D017646:Organosilicon Compounds; D044062:Prostaglandins I; D011464:Epoprostenol; C004544:naphtha; C427248:treprostinil