1.Asymmetric Synthesis of (+)-Valienamine2.Synthetic Studies toward (-)-Oseltamivir (Tamiflu)

• Main Authors: Shang-Ming Yeh, 葉上銘
• Other Authors: 楊圖信
• Format: Others
• Language: zh-TW
• Online Access: http://ndltd.ncl.edu.tw/handle/78651662736603242698

碩士 === 國立中興大學 === 化學系所 === 97 === In the first part, we report a 14-step asymmetric total synthesis of (+)-Valienamine from C2 symmetric L-(+)-tartaric acid. A new strategy toward enantiopure O-isopropylidene-protected valienamine evolved from controlled construction of a C2 symmetric O-isopropylidene-protected cyclohexenediol via ruthenium-catalyzed ring-closing metathesis of a C2 symmetric O-isopropylidene-protected octadienediol. Rigiocontrolled introduction of the hydroxymethyl unit via palladium-promoted carbonylation of enol triflate followed by stereocontrolled installation of the amino unit via a displacement of hydroxyl group with net inversion of configuration led efficiently to isopropylidene-protected valienamine. The requisite C2 symmetric octadienediol was readily prepared from the (+)-tartaric acid via a three-step protocol: (a) conventional one-pot elaboration of tartaric acid into O-isopropylidene-protected diamide, (b) coupling of diamide with vinylmagnesium bromide, and (c) stereocontrolled reduction of dienedione. The total asymmetric synthesis of (+)-Valienamine was thus realized in fourteen steps with an overall yield of 7.4%. In the second part, we turned our attention to the asymmetric synthesis of (+)-Oseltamivir (Tamiflu). To develop an efficient and practical route, we examined the use of L-(+)-tartaric acid as a cheap starting material. Treatment of the L-(+)-tartaric acid with 3,3-dimethoxypentane in the presence of acid resulted in efficient formation of the desired dimethyl 2,3-O-3-pentylidene tartrate 118 in 91% yield in one-pot. Reduction of 118 with DIBAL-H, followed by a highly diastereoselective divinylzinc addition to the insitu generated dialdehyde, produced the desired vinyl carbinol derivative 119 in 80% yield. Subsequent RCM using the second generation Grubbs’ catalyst afforded the corresponding cyclic diol. Gratifyingly, ring-closing metathesis of 119 with Grubbs’ second-generation catalyst followed by TFA-promoted isomerization of the in situ generated trans diol 120 and protection of diol with 3,3-dimethoxypenpane led to the desired C2-symmetric diacetonide 122. Selective reduction of the 2,3-O-3-pentylidene group with DIBAL-H in toluene provided a 62% yield of a 5:1 ratio of 123:124. Separation of these positional isomers followed by replacement of hydroxyl group with acetylamino and deprotection of the acetonide afforded diol 128. Controlled oxidation of the diol with Py/SO3/DMSO at 5℃ gave the desired enone 129 in 67% yield. Subsequent 1,4-addition of the azide nucleophile to electron deficient enone led to the undesired adduct resuting from an approach cis to the acetylamino group. Further efforts will direct toward elaboration of diol 128 into Tamiflu.