進年來有關於發展便利且具有立體選擇性的環化反應是有機化學家相當重視的一個議題，尤其是在天然物化學中，具有烯環己烷 (methylenecyclohexane) 結構的天然物在自然界中相當普遍，因此開發一個能有效率建立烯環己烷結構的方法是很重要的。最近本實驗室發現一特殊的環化反應可以快速的建立烯環己烷骨架，我們使用一系列的a-氰基環烯酮化合物進行1,4-加成反應來引進1-戊烯的支鏈，接著再將所得之ω-烯-α-氰基環酮化合物利用等當量醋酸鈀試劑來進行反應，可成功的合成各式烯環己烷化合物，產率為81-36%，除此之外，此環化反應也可以催化量的醋酸鈀試劑 (0.25 eq.) 搭配醋酸酮試劑 (1.5 eq.) 為輔助氧化劑來進行。
接著我們也應用此環化反應來進行天然物 (+)-δ-selinene (123) 及 (+)-10-epijunenol (124) 的合成研究，以市售的l-menthone (147) 為起始物，經甲醛基化及鹼性條件的重排反應製備化合物146，再經1,4-加成反應可合成化合物145，以醋酸鈀試劑進行烯環己烷環化反應及L.N.試劑進行還原去氰反應可以合成烯酮化合物144，化合物144為天然物neoacolamone (126) 的C-7 epimer異構物，最後以LAH對化合物144進行還原反應及在酸性環境下進行脫水反應可完成 (+)-δ-selinene (123) 的合成，對於10-epijunenol (124) 的合成研究，以LAH對化合物152進行還原反應雖然沒有順利得到目標物，但我們合成了其C-6 epimer 異構物，即化合物154。
除此之外，我們也利用本實驗室已開發之Pd(OAc)2輔助之α-酯基酮環化反應為關鍵步驟，有效率的完成了 (±)-acutifolone A (161) 的全合成，對於 (±)-acutifolone A (161) 的合成工作，我們以市售的4-甲基環己酮182為起始物，利用甲氧羰基化反應 (carbomethoxylation) 、 phenylselenenylation-氧化脫去法以及Michael加成反應來合成化合物180a，再利用Pd(OAc)2輔助之環化反應及氫化反應來建構一重要中間產物174 ，化合物174與TMSCl及Et3N作用形成矽烯醇醚中間體後，以Pd(OAc)2進行氧化反應可生成化合物191，接著以vinylmagnesium bromide及CuI進行 Michael加成反應引進乙烯基生成化合物192，再以Pd(OAc)2輔助之氧化反應來建立共軛二烯官能基即完成了消旋天然物 (±)-acutifolone A (161) 的全合成，總計共經過了14個反應步驟，總產率為14.5%。

Cyclic motifs containing a methylene appendage such as methylenecyclopentane and methylenecyclohexane systems are found in high abundance in naturally occurring compounds, the construction of which typically is a rather involved process. Recently, we developed an annulative approach towards these structurally attractive motifs involving, in the case of methylenecyclopetanes, a highly facile 1,4-addition of 4-pentenylmagnesium bromide to 2-cyano-2-cycloalkenones followed by a Pd(II)-mediated cyclization of the resulting w-unsaturated a-cyano ketones with concomitant formation of an exocyclic double bond. This 2-step process was found to provide the desired methylenecyclohexanes in good overall yield and further investigation led to the delineation of a process which was catalytic with regards to the expensive palladium reagent.
The utility of the annulative process towards the methylenecyclohexane system was demonstrated in the asymmetric total synthesis of the natural product (+)-δ-selinene (123) as well as a project directed towards the asymmetric total synthesis of (+)-10-epijunenol (124). Starting from commercially available l-menthone (147), the requisite a-nitrile was installed via a well precedented 3-step process to yield 146. Conjugate addition of 4-pentenylmagnesium bromide (146à145) followed by the Pd(II) mediated annulation furnished ketone 152. Compound 152 was then treated with lithium naphthalenide to remove the angular nitrile with concomitant transpositioning of the exocyclic olefin to the fully substituted endocyclic position, resulting in the formation of enone 144, the C-6 antipode of neoacolamone (126), a naturally occurring compound. Continuing on towards (+)-d-selinene (123), ketone 144 was reduced with lithium aluminum hydride (144à153) and dehydrated under acidic conditions to achieve the total synthesis of (+)-δ-selinene (123). Towards 10-epijunenol (124), it’s C-7 antipode was synthesized via the reduction of ketone 152, an advanced intermediate generated using a synthetic route similar to that described above with some variations
To demonstrate the generality of the abovementioned methodology towards methylenecycloalkanes, the total synthesis of natural product (±)-acutifolone A (192) was also achieved in an efficient manner using the above detailed annulative approach w-unsaturated a-ester ketone 180a as the key step. Starting from commercially available 4-methylcyclohexane (182), ketone 180a was generated via carbomethoxylation, phenylselenenylation followed by oxidative elimination, and Michael addition to afford compound 180a. Pd(II)-mediated cyclization of comound 180a gave the expected methylenecyclopentyl intermediate which was hydrogenated to furnish key itermediate 174. An a,b-unsaturation was installed onto compound 174 via oxidation of its silyl enol ether analogue to furnish enone 191. Michael reaction of compound 191 was then achieved by vinyl magnesium bromide and CuI to afford compound 192, which was oxidized by treatment with Pd(OAc)2 to afford the (±)-acutifolone in racemic form.

目 錄
中文摘要 -------------------------------------------- I
英文摘要 -------------------------------------------- II
謝誌 -------------------------------------------- III
縮寫對照表 -------------------------------- IV
目錄 -------------------------------------------- VI
第一章 醋酸鈀催化ω-不飽合a-氰基酮環化反應 -------- 02
第一節 緒論 ----------------------------------- 02
第二節 研究構想 ------------------------------------ 14
第三節 結果與討論 ----------------------------------- 15
1.3.1 α-氰基環酮之製備 -------------------------- 15
1.3.2 α-氰環烯酮的製備 --------------------------- 18
1.3.3 ω-烯-α-氰基環酮化合物的製備 ------------------ 21
1.3.4 烯環己烷化合物的合成 -------------------------- 26
1.3.5 α-氰基環酮化合物89、90、94、96環化反應的研究 37
1.3.6 還原去氰烷化反應研究 ------------------------ 45
第四節 結論 ------------------------------------ 52
第五節 實驗部份 ------------------------------------ 53
1.5.1 一般實驗方法 ------------------------------------ 53
1.5.2 實驗步驟及光譜資料 --------------------------- 55
第二章 (+)-δ-selinene的合成研究 ------------------ 101
第一節 緒論 ------------------------------------101
第二節 研究構想 --------------------------------- 108
第三節 結果與討論 -----------------------------------109
2.3.1 α-氰基酮化合物146的製備 ------------------ 109
2.3.2 ω-烯-α-氰基環酮化合物145的合成 ------------------ 110
2.3.3 以醋酸鈀催化的成環反應來合成化合物151 --------- 112
2.3.4 利用L.N.試劑進行還原去氰反應來合成化合物144 113
2.3.5 (+)-δ-selinene (123) 的合成 ----------------- 116
2.3.5 10-epijunenol (124) 的合成研究 ----------------- 118
第四節 結論 ------------------------------------ 120
第五節 實驗部份 ------------------------------------ 123
2.5.1 一般實驗方法 ------------------------------------ 123
2.5.2實驗步驟及光譜資料 --------------------------- 123
第三章 (±)-Acutifolone A的全合成研究 ------------------ 135
第一節 緒論 ------------------------------------ 135
第二節 研究構想 ------------------------------------ 140
第三節 結果與討論 ------------------------------------ 143
3.3.1 α-酯基酮化合物185的合成 ------------------ 143
3.3.2 α-酯基酮化合物180a的合成 ------------------ 145
3.3.3 環外雙鍵化合物187和環內雙鍵化合物188的合成 147
3.3.4 中間產物174的合成 --------------------------- 150
3.3.5 利用hydrazone衍生物190來鑑定化合物174的相對立體化學 -------------------------------------------- 153
3.3.6 (±)-Acutifolone A (161) 的合成 --------- 155
3.3.7 (±)-Acutifolone A (161) 的NMR光譜比對 --------- 160
3.3.8 Bisacutifolone C (165) 的合成研究 --------- 163
3.3.9 具光學活性之天然物 (+)-acutifolone A (161) 的合成設計 -------------------------------------------- 164
第四節 結論 ------------------------------------ 166
第五節 實驗部份 ------------------------------------ 168
3.5.1 一般實驗方法 ------------------------------------ 168
3.5.2實驗步驟及光譜資料 --------------------------- 168
參考文獻 -------------------------------------------- 181
附錄 一 X-ray圖譜數據 --------------------------- 189
附錄 二 化合物之1H NMR, 13C NMR, DEPT及NOE光譜圖 -------------------------------------------- 195

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