本論文分成兩個章節：第一章節再分成兩小節，第一小節主要探討將α-氰基丙烯酸酯如化合物 55 藉由與親二烯基進行 Diels-Alder 反應生成環化產物如 61及 63 。再運用萘化鋰試劑進行還原去氰取代反應引進各式各樣的親電子基如化合物 81, 84, 87及 108 ；因此可成功的將α-氰基丙烯酸酯當作丙烯酸酯具有立體空間擁擠的取代基或是具有多重取代基時之對等物以促進 Diels-Alder 化學反應。第二小節則是擴大第一小節還原去氰取代反應的應用性，藉由第一小節還原去氰取代反應所合成出來的化合物諸如 98 及 111以及經進一步還原反應所製備出的醇類化合物如 128 及 134 進行分子內環化反應合成出ㄧ系列具螺旋骨架的化合物如122, 131, 132, 136 及 138。
第二章節討論將前一章節所開發出的合成方法應用在天然物 (±)-(Z)-9-(Bromomethylene)-1,5,5-trimethylspiro[5,5]undeca-1,7-dien-3- one (140) 的合成工作上。首先使用具有四取代基的α-氰基丙烯酸酯 58 為親二烯基與反式-1,3-戊二烯進行 Diels-Alder 環化反應可ㄧ步建構出天然物中所需的三甲基，之後使用萘化鋰與 MVK 進行還原去氰1,4-加成反應製備出的化合物 100，再經由一連串的官能基轉換以及醛醇縮合反應建構出具天然物螺旋架構之化合物 164，之後再進行 Wittig reaction 合成出化合物 168。接下來只需進行 allylic oxidation 即可能完成天然物 (±)-(Z)-9-(bromomethylene)-1,5,5-
trimethylspiro[5,5]undeca-1,7-dien-3-one (140) 的全合成工作。

This thesis details the investigation into the development of a novel process for the construction of highly congested cyclohexenes, their utility in the generation of spiro motifs, and its application towards the total synthesis of natural product 140. Starting from □-cyanoacrylate 55 as a dienophile, the Diels-Alder reaction with isoprene and 2,3-dimethyl-1,3-butadiene gave cyclohexenes 61 and 63 respectively and individually. This cycloadduct was treated with lithium naphthalenide followed by an alkylating agent (e.g. 1,4-dibromobutane) or acylating agent (e.g. propionaldehyde) to furnish compounds 81 and 87 respectively. This was transformation was found to be generally applicable and also in a Michael addition fashion, allowing the access to a variety of highly substituted cyclohexenes (e.g. 84, 98, 100, 103, 106, 108, 111). In this way, □-cyanoacrylates have been demonstrated to be a highly versatile and functional dienophile equivalent to otherwise unreactive and highly congested acrylates in the Diels-Alder cycloaddition reaction. The cycloadducts obtained in the above study was found to be of further utility in the construction of spiro compounds. As such, the more remote acyl group on cycloadducts possessing 2 acyl groups (e.g. 103 and 106) could be selectively reduced to give the corresponding alcohols (128 and 134 respectively). Upon treatment with base, □-lactones were obtained (128 □ 131 and 132 and 134 □ 136). Additionally, the cycloadducts may be treated with base to promote an aldol condensation reaction to furnish cyclic ketones. For example, when cycloadduct 111 was treated with lithium hexamethyldisilazane, keto ester 122 was obtained.
Building upon the above studies, naturally occurring spiro ketone 140 was targeted for total synthesis. Starting from fully substituted acrylate 58, boron trichloride mediated Diels-Alder cycloaddition with trans-piperylene afforded a diastereomeric mixture of 73a and 73b, which was reductively alkylated by treatment with lithium naphthalenide followed by methyl vinyl ketone to afford keto ester 100. After protecting the methyl ketone present in 100 as the ketal (100 □ 161), the ethyl ester moiety was reduced with lithium aluminum hydride (161 □ 162). Alcohol 162 was then oxidized by treatment with pyridinium chlorochromate to give aldehyde 163 of which the protected methyl ketone was unmasked, giving ketone 160. Aldol condensation of compound 160 was then achieved under acidic conditions to yield spiro enone 164, the Wittig olefination of which then furnished bromide 168 with a E/Z ratio of 2:1. Towards the target molecule, it only remains to install the □,□-unsaturated ketone present in the natural product which is proposed to be achieved via treatment of bromide 168 with chromium trioxide. This investigation, along with the aforementioned 2 projects, is detailed in their entirety in this thesis.

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