Concise asymmetric total synthesis of scyphostatin, a potent inhibitor of neutral sphingomyelinase.
The concise asymmetric total synthesis of scyphostatin has been achieved by condensation of the optically active cyclohexane unit, prepared from the commercially available 1,4-cyclohexadiene by our own method, and the side chain, prepared by the method developed by Hoye and Tennakoon (T. R. Hoye, M. A. Tennakoon, Org. Lett. 2000, 2, 1481-1483). The modification of the epoxy cyclohexenone unit was achieved in a late stage of the total synthesis, and deprotection of the primary alcohol was conducted in the final step. During the synthesis several key reactions were attained: 1) intramolecular bromoetherification of the cyclohexadiene acetal; 2) stereoselective introduction of the tertiary alcohol, 3) deprotection of the acetal function to the aldehyde by combination with silyl triflate/2,4,6-collidine and the one-pot synthesis of the disilyl aldehyde compounds, with different types of silyl groups, from the dihydroxy acetal compounds; and 4) facile deprotection of the 2,4-dimethoxyphenylmethyl ((2,4)DMPM) protecting group of the primary alcohol.
Fujioka
Hiromichi
H
Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, 565-0871, Japan. fujioka@phs.osaka-u.ac.jp
Sawama
Yoshinari
Y
Kotoku
Naoyuki
N
Ohnaka
Takuya
T
Okitsu
Takashi
T
Murata
Nobutaka
N
Kubo
Ozora
O
Li
Ruichuan
R
Kita
Yasuyuki
Y
D000080:Acetals / Q000138:chemical synthesis / Q000737:chemistry; D000438:Alcohols / Q000737:chemistry; D000447:Aldehydes / Q000737:chemistry; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D053138:Cyclohexenes / Q000138:chemical synthesis / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006900:Hydroxylation; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism
D000080:Acetals; D000438:Alcohols; D000447:Aldehydes; D000577:Amides; D053138:Cyclohexenes; D004791:Enzyme Inhibitors; D011753:Pyrones; C121123:scyphostatin; C052568:cyclohexene; D013108:Sphingomyelin Phosphodiesterase; D009584:Nitrogen; C059033:1,1-dimethoxyethane