Total synthesis of (-)-neplanocin a by using lithium thiolate-initiated Michael-aldol tandem cyclization reaction.
(-)-Neplanocin A (1), S-adenosylhomocystein hydrolase inhibitor, was synthesized. The characteristic of this synthesis is a stereoselective construction of five-membered ring of neplanocin A by intramolecular aldol reaction of the lithium enolate that was generated by conjugate addition of lithium thiolate. TBS-protected chiral omega-oxo-alpha,beta-unsaturated ester 16, which was prepared from D-mannitol, was treated with 1.2 equiv of lithium benzylthiolate in THF at -20 degrees C to give three separable cyclization products in good yields and stereoselectivity. After conversions of protective groups, the benzylsulfanyl part of 21 was removed by oxidation to sulfoxide and subsequent thermal elimination to give the requisite double bond. Through the functional group transformations of 30, total synthesis of (-)-neplanocin A (1) was accomplished.
Ono
M
M
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
Nishimura
K
K
Tsubouchi
H
H
Nagaoka
Y
Y
Tomioka
K
K
D000241:Adenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D043383:Adenosylhomocysteinase; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006867:Hydrolases / Q000037:antagonists & inhibitors; D018020:Lithium Compounds / Q000737:chemistry; D008353:Mannitol / Q000737:chemistry; D008698:Mesylates / Q000737:chemistry
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D018020:Lithium Compounds; D008698:Mesylates; D008353:Mannitol; C035617:phenylmethanesulfonic acid; C031096:neplanocin A; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine