Abstract
The objective of this thesis is to find a rapid and efficientsynthetic methodfor taxane and its biogenetic precursor -- seco-taxane. In the first section, we described the initialapproach for the taxane synthesis. The ring expansion ofbicyclo[3.3.0]octane to cyclooctane-ring and subsequently totaxane B,C ring and taxane A,B ring. However this approach wasunsucessful. Later, we efficiently and successfully synthesizedtaxane A-ring precursor, compound 219, with 53% yield. Thencompound 219 was subjected to Claisen rearrangement, reductionand Swern oxidation to form compound 243, a taxane A-ringanalogue, with 42% overall yield. In the second section,we described the utilization of compound 243 as startingmaterial in synthesis of taxane. Compound 243 on furtheralkylation, phenylselenyl cyclization, deprotection and Swernoxidation (4 steps) to yield a rigid compound 274 -- a taxaneprecursor. The alkylation of compound 243 resulted in twodiastereomers 268 and 269. Compound 269 hence formed can beconverted to 268 by Mitsunobu esterification and hydrolysis.Attempted intramolecular McMurry reductive cyclization oncompound 274 failed. Although the molecular model suggests thatthe two carbonyls can be close enough to undergo cyclization,NOE experiments on compound 274 at various temperature revealedthat the two carbonyl groups of compound 274 could be in closeproximity only at temperature above 60℃ which is much higherthan the McMurry coupling temperature. In the thirdsection, we described the use of compound 219 as startingmaterial in the synthesis of taxane and seco-taxane. Thecompound 219 was converted to 302 and 303 by a series oftransformations including three key reactions: (1)macrolactonization (2) Tebbe reaction and (3) Claisenrearrangement. We tried to lactonize 278, 287 and 283respectively to form 10-, 12-, and 14-member ring compounds,However only 283 underwent lactonization and afforded the14-member ring compound 282 in 75% yield. Compound 282 wasfinally converted to compounds 302 and 303 in three steps, bothhaving bicyclo[9.3.0]pentadecane backbone.摘要 本論文乃在研究 Taxane 及其生合成前驅物 seco-Taxane骨架之合成方法，其目的在於尋找一快速，而有效率的合成途徑。 在本研究之第一段部份，對於Taxane之合成策略進行初步的探討，即利用雙-五環擴環成八環來分別形成 Taxane [B,C] 環及[A,B] 環的策略，在這過程當中，我們成功而有效率的合成出A 環前驅物 219，產率 53%，接著將化合物 219 經 Claisen 重排，還原及 Swern氧化等 3步反應，得 A環類似物243 ，總產率 42% 。 第二段部份，利用 A環類似物 243，經過烷化、苯硒基環化、去保護及 Swern氧化等 4步反應，合成了我們所設計的鋼性結構的 Taxane 前驅物 274，在烷化反應當中得到了化合物268及 269兩個 diastereomers，其中化合物 269可經過Mitsunobu 酯化反應及水解反應將其 β-羥基轉變成 α-羥基而成為化合物 268此為合成化合物 274所須要的中間體，隨後嘗試將此鋼性的化合物 274進行八環的McMurry 還原偶合環化反應，但未成功，我們發現化合物 274之兩個羰基互相接近的溫度約在60℃以上，超出了一般 McMurry 偶合反應的溫度，因此，雖然利用分子模型設計出鋼性的化合物274 ，用意在於減少分子本身的亂度，卻仍無法克服反應時所須的能量障壁，而無法成環。 第三段部份利用A 環前驅物依序經過：去保護，保護，烷化，去保護，氧化，去保護，macrolactonization，保護， Tebbe反應， Claisen重排等九步反應，成功的合成出seco-Taxane 的骨架，這一段部份關鍵的幾個反應為 (1) macrolactonization，(2)Tebbe 反應以及 (3) Claisen重排反應，在進行 macrolactonization 中，分別嘗試了10個碳，12個碳及14個碳之環化反應，其中僅14個碳環化成功，形成了一個六圓環與十四圓環交錯的特殊結構- 化合物 282，利用此大環內脂化合物 282。經過三級醇的保護，再進行Tebbe 反應及Claisen 重排反應後，順利的合成含Bicyclo[9.3.1 ] pentadecane 的骨架的化合物 302及化合物 303。