Abstract
The research projects described in this thesis are involved in the fields of synthetic organic chemistry methodology development and the total synthesis of an antineoplastic agent. In the first area, the use of the reductive alkylation protocol of nitriles previously developed in this laboratory towards the generation of structural motifs not readily attained via conventional methodologies is discussed. Specifically, starting with compounds 26 and 55, reductive decyanation as achieved by treatment with lithium naphthalenide followed by the addition of methyl iodide (26□34) or n-butyl iodide (55□64) yielded the desired tetrasubstituted methylene product. Interestingly, when thiophene 55 was subjected to the same process but trapping with benzaldehyde, the predicted product was not isolated. Instead, substituted thiophenes 75a and 75b as well as ring opened thioether 58 resulted. In addition to this, the use of malononitrile derivative 90 in the Diels-Alder cycloaddition reaction was explored. Reacting dienophile 90 with 2-methyl-1,3-butadiene allowed for the facile formation of highly substituted cyclohexene 98. Upon reductive acylation of this with lithium naphthalenide followed by benzaldehyde, alcohol 107 was obtained, the hydroxyl of which was readily converted to the methyl ether. Subsequent reductive decyanation of this intermediate with lithium naphthalenide resulted in an overall E2 elimination process to yield cyclohexene 108. Likewise, reductive decyanation of 98 followed by trapping of the ensuing anion with oxygen and reduction of the resulting endoperoxide gave tertiary alcohol 113, base treatment of which allowed for the isolation of cyclohexenone 120. Overall, dienophile 90 has been demonstrated as a versatile reagent in the Diels-Alder cycloaddition process, effectively functioning as, in the first case, an 1,3-disubstituted allene equivalent and, in the latter case, monosubstituted ketene equivalent. In the total synthesis area, the total synthesis of D-501036, a recently discovered highly potent 126 antineoplastic agent is detailed. Suzuki coupling of boronic acid 134 and iodoselenophene 128 gave the expected aldehyde 139. The aldehyde functionality of compound 139 was protected and the resulted intermediate was converted readily to boronic acid 141. This was followed by a second Suzuki coupling reaction with iodide 128, the product of which was readily converted to the target molecule.