本論文內容共分為三個部分：第一及第二個部分乃是利用酯類烯醇基陰離子 (enolate) 進行新合環方法的開發；第三部分則是將我們開發出來的新方法應用於天然物9□-hydroxyageraphorone (179) 與 (1S, 3R, 4R)-calamenene-3,7-diol (189) 的合成研究。

第一部份：以市售的酯類化合物31，利用鋰化二異丙基胺 (LDA) 去質子化後，與本實驗室長年研究的□□氰基環烯酮32進行Michael加成反應，可順利得到加成化合物66。將化合物66利用鹵素交換以及碳酸鉀去質子化，便可順利合環得到具有酯基環己烷系統的化合物79與80。化合物79與80互為非鏡向異構物 (diastereomer)，利用X射線繞射可鑑定其中一個化合物之立體組態，另一個化合物利用差向異構化 (epimerize) 證明兩化合物之間的相互關係來推定立體組態。
第二部份：以化合物硫酚 (153)，經氯甲基化及鹵素交換合成化合物155。將乙醯乙酸甲酯 (156) 二次去質子化與化合物155反應可生成烷化化合物157。化合物157經由氧化及真空快速裂解即可合成Nazarov試劑159。利用DBU將化合物159去質子化後，與□□氰基環烯酮32進行double-Michael加成反應的研究。藉由double-Michael加成反應，可順利合成一系列具有□-酯基環己酮系統的化合物162。此類化合物亦可藉由X射線繞射鑑定產物或是產物衍生物來判斷其立體組態。
第三部份：以第二章合成的化合物170為基本骨架，利用碘化鈉與二甲氧基二乙醚 (diglyme) 除去酯基得到化合物201。將化合物201以三氟化硼選擇性保護得到化合物198後，以本實驗室長年研究的萘化鋰試劑 (Lithium Naphthlenide, L.N.) 進行還原去氰化反應，得到具有反式 (trans) 骨架的化合物203，在氯化鈰輔助下可順利加成異丙基得到化合物211，隨後利用順向脫去(syn-elimination) 脫去水分子可得化合物208。利用硼氫化反應並使用PCC氧化中間產物可得化合物219，此化合物在低溫下可被選擇性地還原酮基得到化合物220。化合物220再經過除去縮酮保護，保護羥基得到化合物221後，進行甲基化反應可合成化合物222。最後將化合物222進行溴化並進行脫去反應便完成天然物9□-hydroxyageraphorone (179) 的異構物化合物210。天然物 (1S, 3R, 4R)-calamenene-3,7-diol (189) 的合成研究可就藉由化合物208而來，利用簡單硼氫化反應合成化合物218後，依循上述步驟便可合成出 (1S, 3R, 4R)-calamenene-3,7-diol的前趨化合物231，並利用氯化銅與氯化鋰氯化化合物231可合成具有氯取代的化合物232，待尋找其他合適條件便可完成天然物 (1S, 3R, 4R)-calamenene-3,7-diol (189) 的全合成工作。

Two novel and highly effective annulative approaches to bicyclic carbacycles are described in Chapters 1 and 2 of this thesis. In Chapter 1, a tandem Michael addition and substitution reaction is employed. Secifically, the lithium enolate resulting from the treatment of ethyl 5-bromovalerate (31) with lithium diisopropylamide allowed to react with doubly activated □-cyano cycloalkenones to give cycloalkanones of the type exemplified by compound 66. Further treatment with potassium carbonate in the presence of sodium iodide allowed the preparation of highly substituted bicyclic systems exemplified by structures 79 and 80 bearing functionalities that are highly amenable towards further functional group manipulations. The structures of these diastereomers were readily arrived at unambiguously by the recrystallization of one followed by single crystal X-Ray crystallography. The remaining epimer was then inferred and confirmed by its conversion to the previously rigorously characterized epimer by treatment with sodium ethoxide.

The second chapter describes an alternative approach to the annulation process described above. As such, alkylation of thiophenol (153) with para-formaldehyde in the presence of hydrochloric acid gave chloride 154 which was treated with sodium iodide in acetone to effect a halide exchange to yield iodide 155. This was treated with the kinetic enolate of methyl acetoacetate to give □-ketoester 157, the sulfoxide analogue of which (i.e. 158) was subjected to pyrolytic conditions under reduced pressure to facilitate the desired syn-elimination process to afford enone 159. As expected, in the presence of a base (i.e. 1,8-diazabicyclo- [5.4.0]undec-7-ene (DBU)), exposure of individual □-cyanocyclo- alkenones exemplified by structure 32 with enone 159 led to the formation of, in one pot, bicyclic ketones represented by structure 162 via a sequential series of Michael addition reactions. As in the case above, these structurally interesting and useful bicyclic Michael adducts were unambiguously identified structurally by single crystal X-ray crystallography, among other spectroscopic methods.

The third chapter details the work demonstrating the above mentioned novel annulation process in a total synthesis study towards achieving the naturally occurring sesquiterpenes 9□-hydroxyageraphorone (179) and (1S,3R,4R)-calamenene-3,7-diol (189). Starting with ketone 170, arrived at from the coupling of enone 159 with 2-cyano-4-methyl- 2-cyclohexenone in the presence of DBU, nucleophilic decarboxylation with sodium iodide furnished diketone 201, the less hindered carbonyl of which was protected as the dioxolane to yield ketone 198. Reductive decyanation of ketone 198 led to trans-decalin 203 the carbonyl of which was subjected to a 1,2-addition process with isopropyl- magnesium chloride in the presence of cerium (III) chloride. The resulting alcohol 211 was transposed to alcohol 220 via a sequence of reactions involving dehydration, hydroboration, oxidation with pyridinium chlorochromate and reduction with sodium borohydride. Following the removal of the dioxolane protecting group and protection of the newly generated hydroxyl as the methoxymethyl ether, giving ketone 221, a regioselective methylation afforded ketone 222. Finally, the installation of the □,□- unsaturation was achieved via a bromination-dehydrobromination process to furnish the epimer of the natural product, 5-epi¬-9□-hydroxyageraphorone (210). In principle, a simple epimerization of the activated angular proton under basic conditions will allow the formation of the targeted natural product 179. Towards the second targeted naturally occurring sesquiterpene 189, starting from the hydroboration product 218, a similar sequence of events led to the generation of enone 231. In the presence of copper (II) chloride and lithium chloride, enone 231 was converted to advanced intermediate chloride 232. In principle, a simple dehydrochlorination of compound 232 will lead to the desired natural product 189. This process and the above mentioned epimerization will be investigated in the near future to bring this total synthesis endeavor to a successful conclusion. The details of these total synthesis studies and the above mentioned novel annulation processes are contained herein.

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