Practical synthesis of chiral emopamil left hand as a bioactive motif.
An asymmetric synthesis of (2S)-2-(2-isopropyl)-5-hydroxy-2-phenylpentanenitrile (emopamil left hand, 2) has been completed by use of the MAD (methyl aluminum bis(4-methyl-2,6-di-tert-butylphenoxide)-induced rearrangement of a chiral epoxyalcohol as the key reaction. The stereochemistry of the chiral quaternary center was confirmed by transformation of 2 to (S)-noremopamil. This method requires minimal purification procedures and affords high chemical and optical yields. Acid-catalyzed isomerization of an allylaldehyde and retro-aldol type racemization at the quaternary carbon of a nitrile-alcohol were encountered.
Kimura
Teiji
T
Tsukuba Research Laboratories, Eisai Company, Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 3002635, Japan. t2-kimura@hhc.eisai.co.jp
Yamamoto
Noboru
N
Suzuki
Yuichi
Y
Kawano
Koki
K
Norimine
Yoshihiko
Y
Ito
Koichi
K
Nagato
Satoshi
S
Iimura
Yoichi
Y
Yonaga
Masahiro
M
D002384:Catalysis; D002625:Chemistry, Organic / Q000379:methods; D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry; D013237:Stereoisomerism; D014700:Verapamil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
C471005:2-(2-isopropyl)-5-hydroxy-2-phenylpentanenitrile; D009942:Organometallic Compounds; C471006:methyl aluminum bis(4-methyl-2,6-di-tert-butylphenoxide); C471007:noremopamil; D014700:Verapamil; C052752:emopamil