A highly efficient asymmetric synthesis of vernakalant.
A novel synthesis of vernakalant is described. Using inexpensive and readily available reagents, the key transformations involve (1) an efficient zinc-amine-promoted etherification, (2) a highly stereoselective enzyme-catalyzed dynamic asymmetric transamination to set up the two contiguous chiral centers in the cyclohexane ring, and (3) a pyrrolidine ring formation via alkyl-B(OH)2-catalyzed amidation and subsequent imide reduction.
Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
John
J
Limanto
Eric R
ER
Ashley
Jingjun
J
Yin
Gregory L
GL
Beutner
Brendan T
BT
Grau
Amude M
AM
Kassim
Mary M
MM
Kim
Artis
A
Klapars
Zhijian
Z
Liu
Hallena R
HR
Strotman
Matthew D
MD
Truppo
D000586:Amination; D000588:Amines / Q000737:chemistry; D000840:Anisoles / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D002712:Chlorides / Q000737:chemistry; D003510:Cyclohexanes; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D017967:Zinc Compounds / Q000737:chemistry
D000588:Amines; D000840:Anisoles; D002712:Chlorides; D003510:Cyclohexanes; D011759:Pyrrolidines; D017967:Zinc Compounds; C506365:Cyclohexane; C016837:zinc chloride; C524581:vernakalant