Catalytic asymmetric total synthesis of (+)-lactacystin.
Total synthesis of (+)-lactacystin, a potent and selective proteasome inhibitor, was accomplished using a catalytic enantioselective Strecker reaction of a ketoimine as the initial key step. An enone-derived N-phosphinoyl ketoimine 7 was selected as a stable masked alpha-hydroxy ketoimine analogue. Excellent enantioselectivity (98% ee) and practical catalyst activity were produced under the optimized catalyst preparation method using 2.5 mol % Gd{N(SiMe3)2}3 as a metal source and 3.8 mol % D-glucose-derived ligand 8. This reaction was conducted on a 5 g scale. The chiral tetrasubstituted C-5 carbon efficiently controlled the stereochemistry of the other three chiral centers of lactacystin. Chelation-controlled Meerwein-type reduction of ketone 5 using i-PrMgBr (originally reported by Kang in a related substrate) selectively produced the desired secondary alcohol at the C-9 position. The C-6 hydroxy and C-7 methyl groups were introduced via a silyl conjugate addition followed by the Tamao oxidation and Donohoe methylation, respectively, in a highly stereoselective manner. A practical amount of enantiomerically pure clasto-lactacystin beta-lactone (2), the biologically active form of (+)-lactacystin, can be synthesized using this route. clasto-Lactacystin beta-lactone (2) was converted to (+)-lactacystin following the reported procedure.
Fukuda
Nobuhisa
N
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
Sasaki
Kazuki
K
Sastry
T V R S
TV
Kanai
Motomu
M
Shibasaki
Masakatsu
M
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D002384:Catalysis; D007097:Imines / Q000737:chemistry; D007783:Lactones / Q000737:chemistry; D015394:Molecular Structure; D013237:Stereoisomerism
D007097:Imines; D007783:Lactones; C067713:lactacystin; D000111:Acetylcysteine