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National Chung Hsing University Institutional Repository - NCHUIR > 理學院 > 化學系所 > 依資料類型分類 > 碩博士論文 >  1.不對稱合成(+)-Valienamine 2.探索(-)-Oseltamivir (Tamiflu)的合成途徑

Please use this identifier to cite or link to this item: http://nchuir.lib.nchu.edu.tw/handle/309270000/94365

標題: 1.不對稱合成(+)-Valienamine 2.探索(-)-Oseltamivir (Tamiflu)的合成途徑
1.Asymmetric Synthesis of (+)-Valienamine 2.Synthetic Studies toward (-)-Oseltamivir (Tamiflu)
作者: 葉上銘
Yeh, Shang-Ming
Contributors: 楊圖信
中興大學
關鍵字: (+)-Valienamine;(-)-Oseltamivir;Tamiflu
不對稱合成;克流感
日期: 2009
Issue Date: 2012-08-31 13:37:11 (UTC+8)
Publisher: 化學系所
摘要: (一) 不對稱合成 (+)-Valienamine
我們利用C2對稱的L-(+)-tartaric acid為起始物,經由14步不對稱全合成(+)-Valienamine。在本研究中,我們在酸催化下利用DMP (2,2-dimethoxypropane)將具C2對稱之L-(+)-tartaric acid轉化成酯類,接著加入morpholine一鍋化將起始物轉化為O-isopropylidene-protected diamide,再以vinylmagnesium bromide與diamide進行偶合反應得到不飽和酮類,藉著Luche reduction還原得到具立體選擇性之dienediol。最後再利用Grubbs’ catalyst 2nd進行RCM(Ring-closing metathesis),即可得到C2對稱之環己烯雙醇主架構。由於環己烯雙醇為C2對稱,我們可以利用鈀(Pd)金屬進行有位向選擇性的carbonylation進而引進hydroxymethyl group。之後藉由立體控制將羥基置換成胺基得到isopropylidene-protected valienamine。最後再進行去保護及上保護,即可利用14步全合成(+)-Valienamine pentaacetate 26,總產率為7.4%。
(二) 探索 (-)-Oseltamivir (Tamiflu)的合成途徑
我們嘗試利用便宜的L-(+)-tartaric acid作為起始物,發展有效率及實用的路徑進行(-)-Oseltamivir的合成研究。在酸催化下以3,3-dimethoxypentane一鍋化將L-(+)-tartaric acid衍化成2,3-O-3-pentylidene tartrate 118,接著以一鍋化反應利用DIBAL-H將118還原成dialdehyde,接著再加入divinylzinc進行高非鏡像選擇性的加成,得到allylic alcohol。接著利用Grubbs’ catalyst 2nd進行RCM (Ring-closing metathesis)、TFA (Trifluoroacetic acid)催化下誘導trans fused-acetonide轉移到相鄰碳上之氫氧基,形成cis fused-acetonide,最後再加入3,3-dimethoxypentane將另一邊之cis fused-diol上保護,經一鍋化反應得到C2對稱之diacetonide。利用DIBAL-H對2,3-O-3-pentylidene group進行有位向選擇性的還原反應可得到123:124的比例為5:1。分離異構物之後將二級醇衍化為acetylamino group並去保護acetonide得到diol 128。利用Py/SO3/DMSO氧化diol得到不飽和酮類129。隨後利用azide對環己烯酮進行1,4-addition得到非預期的azide和acetylamino group為同向之產物。我們希望由不同的diol進行氧化,再引進氮原子,進而合成(-)-Oseltamivir。
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.
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