Examination of the geminal acylation reaction and its application towards the synthesis of a steroid backbone

Melanson, Rhea Lise (2000) Examination of the geminal acylation reaction and its application towards the synthesis of a steroid backbone. Masters thesis, Memorial University of Newfoundland.

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Abstract

The geminal acylation reaction has been extensively studied in the Burnell research group. Acetals and ketones react with 1,2-bis((trimethylsilyl)oxy)cyclobutene (2) in the presence of a Lewis acid to give 2-substituted-1,3-diketones. Based on the knowledge that, on unsymmetrical diketones, the reaction occurs preferentially on the less sterically hindered center, competition studies were undertaken to investigate the outcome of the geminal acylation reaction on substrate mixtures. Not surprisingly, the less sterically hindered ketones of the mixtures were seen to yield the corresponding products in greater yields. Mixtures with higher concentrations of the hindered ketones still preferentially resulted in the formation of the products of the less hindered ketones. Substrate mixtures were selected to examine various other effects. It was found that β-substituents had a slight effect on the reaction, but not as great as an α-substituent. Cyclic ketones reacted faster than acyclic ones, with cyclohexanones reacting faster than cyclopentanones. Various nucleophiles were also examined, and it was found that 2 reacted faster than any other. -- Selection of an appropriate diketone to react in a geminal acylation reaction could, in theory, give a compound which would cyclize to a steroid in a synthetically efficient manner. The D-ring and the A-ring of the steroid could be formed by sequential geminal acylations using 1,2-bis((trimethylsilyl)oxy)cyclobutene (2) and 1,2-bis((trimethylsilyl)oxy)cyclopentene (55), respectively. The preparation of this diketone proceeded well and the first geminal acylation was performed in 95% yield. However, due to a shortage of time, the synthesis was not completed. -- Most of the work done in the past on the geminal acylation reaction has been with 1,2-bis((trimethylsilyl)oxy)cyclobutene (2). In the course of this work, novel compounds were prepared, mostly by the reaction of an acetal with 1,2-bis((trimethylsiiyl)oxy)cyclopentene(55).

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