[A novel and practical synthesis of (+)-biotin via Fukuyama coupling reaction].
(+)-Biotin (1) was synthesized from readily accessible L-aspartic acid (4). The contiguous asymmetric centers at C-3a and C-6a were formed through a diastereoselective aldol reaction of N-Cbz-3-amino-4-butanolide 5 to provide trans-disubstituted lactone 6 with high stereoselectivity (trans/cis = 12:1). The imidazolidin-2-one moiety of 1 was constructed by a stereoselective Hofmann rearrangement of beta-substituted asparagine derivative 7 to provide cyclic urea 8. This reaction proceeds with complete retention of stereochemistry. Removal of the protective groups of 8 and subsequent dibenzylation and thionation provided thiolactone 2. The installation of the C-4 side chain of 1 was performed through a Pd/C-catalyzed coupling reaction of 2 with ethoxycarbonylbutylzinc iodide 14a (Fukuyama coupling reaction), which permitted the synthesis of 1 from 2 under industrially applicable mild conditions in three steps.
Shimizu
Toshiaki
T
CMC Research Laboratory, Tanabe Seiyaku Co. Ltd., 3-16-89 Kashima, Yodogawa-ku, Osaka 532-8505, Japan. t-simizu@tanabe.co.jp
D001224:Aspartic Acid; D001710:Biotin / Q000138:chemical synthesis*; D002244:Carbon; D002384:Catalysis; D002625:Chemistry, Organic; D007783:Lactones; D007854:Lead; D009532:Nickel; D055601:Organic Chemistry Phenomena; D013237:Stereoisomerism
D007783:Lactones; D007854:Lead; D001224:Aspartic Acid; D001710:Biotin; D002244:Carbon; D009532:Nickel