Abstract
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.