Asymmetric synthesis of an N-acylpyrrolidine for inhibition of HCV polymerase.
A practical asymmetric synthesis of a highly substituted N-acylpyrrolidine on multi-kilogram scale is described. The key step in the construction of the three stereocenters is a [3+2] cycloaddition of methyl acrylate and an imino ester prepared from l-leucine t-butyl ester hydrochloride and 2-thiazolecarboxaldehyde. The cycloaddition features novel asymmetric catalysis via a complex of silver acetate and a cinchona alkaloid, particularly hydroquinine, with complete diastereomeric control and up to 87% enantiomeric control. The alkaloid serves as a ligand as well as a base for the formation of the azomethine ylide or 1,3-dipole. Experiments have shown that the hydroxyl group of hydroquinine is a critical element for the enantioselectivities observed. The cycloaddition methodology is also applicable to methylvinyl ketone, providing access to either alpha- or beta-epimers of 4-acetylpyrrolidine depending on the reaction conditions utilized. The synthesis also highlights an efficient N-acylation, selective O- versus N-methylation, and a unique ester reduction with NaBH4-MeOH catalyzed by NaB(OAc)3H that not only achieves excellent chemoselectivity but also avoids formation of the undesired but thermodynamically favored epimer. The highly functionalized target is synthesized in seven linear steps from l-leucine t-butyl ester hydrochloride with all three isolated intermediates being highly crystalline.
Agbodjan
Armel A
AA
Chemical Development, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
Cooley
Bob E
BE
Copley
Royston C B
RC
Corfield
John A
JA
Flanagan
Roy C
RC
Glover
Bobby N
BN
Guidetti
Rossella
R
Haigh
David
D
Howes
Peter D
PD
Jackson
Mary M
MM
Matsuoka
Richard T
RT
Medhurst
Katrina J
KJ
Millar
Alan
A
Sharp
Matthew J
MJ
Slater
Martin J
MJ
Toczko
Jennifer F
JF
Xie
Shiping
S
D000179:Acrylates / Q000737:chemistry; D000215:Acylation; D000470:Alkaloids / Q000737:chemistry; D018360:Crystallography, X-Ray; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016174:Hepacivirus / Q000201:enzymology*; D007097:Imines / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012834:Silver / Q000737:chemistry; D012997:Solvents; D013237:Stereoisomerism
D000179:Acrylates; D000470:Alkaloids; D007097:Imines; D011759:Pyrrolidines; D012997:Solvents; D012834:Silver; D012321:DNA-Directed RNA Polymerases; C032519:pyrrolidine; C035956:methyl acrylate