Abstract
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.