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The cyclopentyl compounds 113,114, and 115 and their enantiomers ent-113, ent-114 and ent-115 represent valuable chiral building blocks for the synthesis of steroids and triterpenoids. These compounds are readily available in chiral form from the Grob type cleavage of (+)-9,10-dibromocamphor (120) or (-)-9,10-dibromocamphor (ent-120) respectively. The hydroxyacid 114 was transformed into the bicyclic ester 153 in a series of seven steps, the key step of which was the intramolecular Friedel-Crafts acylation of the methylene diacid 161. The ester 153 is considered to be a valuable steroidal CD synthon, incorporating functionality for introduction of both the A and B rings and a C(20) sidechain. It was demonstrated that it was possible to alkylate the ketal 169 stereospecifically and convert the product to the enone 168 in which the steroidal C(20) centre has been established with the natural R configuration. In a second approach to steroidal precursors, the hydroxydiene 299 was prepared in six steps from the bromoester 115. The enantiomer of 299, (ent-299) represents a potentially useful intermediate in the intramolecular Diels-Alder route to A-aromatic steroids such as estrone (3), and would be readily available from ent-115. The bromoester ent-115 and (+)-5,6-dehydrocamphor (223) were combined in a synthesis of the tetracyclic hydroxyenone 252, the key step of which was the anionic oxy-Cope rearrangement of the 5,6-dehydrocamphor derivative 241. The structure 252 is considered to represent the basic tetracyclic skeleton of euphane and apo-euphane triterpenoids, and posesses suitable functionality for incorporation of methyl groups at C(10) and C(8) (apo-euphane) or C(14) (euphane), as well as oxygen substituents at those centres at which it is commonly found in the triterpenoids. Finally, a mechanistic investigation of the rearrangement of 2-methylenebornane (314) to 4-methylisobornyl acetate (315) is described. The methyl region of the ¹H NMR spectrum of 4-methylcamphor (308), derived from 314, was unambiguously assigned by a series of NMR experiments and used to trace the fate of deuterium when 2-(dideuteriomethylene)bornane (323) and 8-deuterio-2-methylenebornane (324) were subjected to the rearrangement conditions. [formulas omitted] / Science, Faculty of / Chemistry, Department of / Graduate

This thesis, entitled "The use of camphor in sesquiter-penoid synthesis", consists of three chapters. Chapter One describes the conversion of (+)-8-bromocamphor (42) into a chiral dimethyl-acetal enolsilyl ether (105) that undergoes facile TiCl₄₋ promoted intramolecular cyclisation to provide tricyclic intermediates (195a,b), which after a series of functional group interconversions and the introduction of the gem-dimethyl group, leads to the first enantiospecific total synthesis of (+)-longiborneol (59) (ca. 13% in 21 steps from ( + )-camphor (26)). Oxidation of (+)-longiborneol (59) provides (+)-longicamphor (83), which was converted into (+)-longi-isoborneol (89) by reduction. Subsequent treatment with of (+)-longiisoborneol (89) with MsCl, 4-DMAP, and pyridine, reveals (+)-longifolene (61) (ca. 52% in 3 steps from (59)). Two other major attempts were also carried out prior to the successful synthesis of (59) and (61). Triene acetates (103a,b) were synthesised (ca. 8% in 10 steps from (+)-camphor (26)), but failed to undergo the intramolecular Diels-Alder reaction. In addition, (+)-campherenone (151) was also prepared (ca. 28% in 9 steps from (+)-camphor (26)), and both (151) and its derivatives (170), and (104) undergo SnCl₄-promoted intermolecular tertiary ∝-alkylation reaction to provide dimers (169a,b). Chapter Two describes two synthetic approaches to albene (221) which involves an intramolecular ene reaction, or an intramolecular free radical cyclisation reaction. A new enantiospecific synthesis route to (+)-β-santalene (259) (ca. 78% in 2 steps from (+)-campherenone (151)) is illustrated, however, (+)-β-santalene failed to undergo the intramolecular ene reaction to provide olefin (261). In addition, bromo-olefin (260) is also prepared (ca. 59% in 14 steps from (+)-camphor (26)), but cyclises in a 6-exo-trig mode in the intramolecular free radical cyclisation reaction to provide methyl ether (331). Chapter Three describes an evaluation of the potential use of (+)-5,6-dehydrocamphor (323) as a chiral synthon in the synthesis of the A,B ring system (cf. 329) of several classes of terpenoid. (+)-5,6-dehydrocamphor (323) was prepared from (-)-endo-3-bromocamphor (41) in two steps, and which is then converted to bicyclic enones (368a,b, 369a,b, 376a,b) by a sequence in which the key reaction was an anionic oxy-Cope rearrangement. Bicyclic enones (368a,b) were converted to tricyclic ketals (385a,b), but attempts to convert this compound to an angularly methylated intermediate (434) were unsuccessful. Furthermore, 1,5-dienols (409a,b), synthesised from (323) in ca. 50% yield, failed to undergo an anionic oxy-Cope rearrangement to provide bicyclic ketones (410a,b). Alternative ways of constructing an angular methyl group into the C(10) position in bicyclic enones (369a,b, or 376a,b) are currently being investigated in our laboratory. In addition, bicyclic ketones (373a,b) could serve as key intermediates in an enantiospecific synthesis of spirodysin (421), and indirectly to the synthesis of furodysin (422), and furodysinin (423). [Formula Omitted] / Science, Faculty of / Chemistry, Department of / Graduate

Camphor has been functionalised at the C(5), C(6), C(8) and C(9) positions by procedures previously developed and the corresponding derivatives have subsequently been utilised as key intermediates in mono- and sesquiterpenoid syntheses. The monoterpenoid analogues of the plant growth-promotor (-)-cis-sativenediol and the growth-inhibitor (-)-helminthosporal, (-)-5-exo, 6-exo-dihydroxycamphene and (+)-1,4-diformyl-2,3,3-trimethylcyclopentene respectively, have been prepared from (-)-camphor by a synthetic route involving the 'remote oxidation' of (+)-isobornyl acetate to a mixture of 5- and 6-oxoisobornyl acetates. The trans-diol (-)-5-endo, 6-exo-dihydroxycamphene was also obtained during this study. The synthetic monoterpenoids and their enantiomers were found to be devoid of growth-promoting or growth-inhibiting properties on two varieties of rice (Oryza sativa). The 'remote oxidation' technique has also been applied to the synthesis of nojigiku alcohol [(+)-6-exo-hydroxycamphene], a metabolite of Chrysanthemum japonense, from (+)-camphor. The structure, absolute configuration, and physical constants of this monoterpenoid alcohol and its derivatives have thus been established. (+)-9-Bromocamphor was used as a starting material for two unsuccessful synthetic approaches to the trisnorsesquiterpenoid albene, a metabolite of plants of the genera Petasites albus (L.) Gearth and Adenostyles alliariae (G.) Kern. One of these routes was based on the proposal that epi-β- santalene, a natural sesquiterpenoid which had previously been synthesised in our laboratory, could be a biosynthetic precursor of albene. However, during these investigations the original structure of albene was revised and a third synthetic route to this compound using (+)-8-bromocamphor as starting material was therefore studied. (+)-8-Bromocamphor has also been utilised as the starting material in a synthetic approach to clausantalene, a sesquiterpenoid isolated from Clausena indica 0liv. (Rutaceae). A synthesis of dehydroclausantalene and epidehydroclausantalene T_9-hydroxy-9-(3' -methyl-V -butenyl )camphenes] has been accomplished but the regio- and stereoselective hydration of these two compounds to clausantalene and its epimer respectively is still under investigation. / Science, Faculty of / Chemistry, Department of / Graduate

The two British Columbia nudibranchs Cadiina luteomarginata and Acanthadoris nanaimoensis have sweet fragrances. The possible importance of odours in the interactions of marine organisms initially aroused our chemical curiosity. The results of our research concerning the structural investigation of seven terpenoids obtained from the organic extracts of these two opisthobranch molluscs is presented in this thesis. Five of the molecules isolated from luteomarginata have been identified as furodysin (53), furodysinin (54), microcionin-2 (55), albicanyl acetate (51) and albicanol (52). A sixth molecule, luteone (57) which gives the sweet fragrance to C. luteomarginata has been partially characterized . A crystalline derivative of this methyl ketone has been submitted for X-ray diffraction analysis. The sweet fragrance of A. nanaimoensis has been related to the presence of a sesquiterpenoid (existing as two constitutional isomers, in a 5:1 ratio). Three hypothetical structures based on spectral analysis, chemical reactions and biosynthetic reasoning are proposed. The biological origin of the seven terpenoids has also been investigated and is discussed in this thesis. / Science, Faculty of / Chemistry, Department of / Graduate

In the first part of this thesis an intramolecular alkylation study involving 4a-(3-chloropropy1)-4,4a,5,6,7,8— hexahydro-2-(3H) -napthalenone (77a) , 4 a- ( 3-iodopropy 1) - 4,4a,5,6,7, 8,-hexahydro-2(3H)-napthalenone(77b) and 4a-(mesylate methyl)— 4,4a,5,6,7,8,hexahydro-2(3H)-napthalenone(95) is described. Bicyclic a, ^-unsaturated ketones (77a), (77b) and (95) were prepared and their cyclizations via intramolecular alkylation under a variety of reaction conditions was investigated. In the case of ketone (77a) high selectivity for a or d'-alkyla-tion was achieved by varying certain reaction parameters. The reaction parameters studied were solvent, base, complexing agent and leaving group. The action of potassium t-butoxide in t-butyl alcohol on octalone (77a) afforded ketone (90) as the major product and ketone (91) as the minor product. A change in the solvent system to a 60/40 mixture of THF/t-BuOH combined with the addition of 18-crown-6 afforded selectively ketone (90). The action of potassium t-butoxide in t-butyl alcohol on octalone (77b) however, afforded the ketone (91) exclusively. Exclusive formation of ketone (91) was also achieved by the action of lithium diisopropylamide in THF on ketone (77a). At no time was ketone (92) detected. Bicyclic ketone (95) having a mesylate methyl group at the angular position was subjected to a number of reaction conditions. The position of alkylation was found to be dependent on solvent and the presence of 18-crown-6. The action of lithium t-butoxide or potassium t-butoxide in t-butyl alcohol or THF on ketone (95) afforded exclusively ketone (66). The ketone (95) in HMPA, with or without 18-crown-6, however afforded ketone (104) as the major product and ketone (66) as the minor product. Ketone (103) was not detected. In the second part of this thesis a 15-step synthesis of (±) isolongifolene (114) from 4a-(carbomethoxy)-4a,4,5,6,7,8— hexahydro-2-(3H) -napthalenone (97) is described. Alkylation with methyl iodide of (97) afforded the dimethylated octalone (146). Octalone (146) was transformed into octalone (147) via a Wittig reaction using methylenetriphenylphosphorane. Diene (147) was hydroborated using disiamylborane in THF and the resultant mixture of alcohols (148) and (149) was acetylated with acetic anhydride and pyridine to afford acetates (153) and (154). The latter mixture was allylically oxidized by the action of N— bromosuccinimide in dioxane in the presence of light to yield keto acetates (155) and (156). Decarbomethoxylation of the keto acetates followed by ketalization of resultant mixture afforded ketal acetate (160). Lithium aluminum hydride reduction of (160) followed by tosylation of the resultant alcohol (161) afforded ketal tosylate (162). Acid hydrolysis of (162) followed by intramolecular alkylation of the resultant keto tosylate (163) afforded the tricyclic octalone (165). Dehydro-genation of the latter using DDQ yielded dienone (166) which when treated with lithium dimethylcuprate in ether afforded octalone (167). Treatment of (167) with pyridinium hydrobromide perbromide followed by dehydrobromination of the resultant crude bromide (168) afforded the cross conjugated ketone (169). The latter was converted into octalone (124) via a methyl cuprate reaction. Octalone (124) was not converted into (±) isolongifolene since this transformation had already been reported. Dienone (166) was converted into α, β-unsaturated keto nitrile (172) by the action of diethyl aluminum cyanide on the former. This transformation was to eventually provide an entry into the zizaane class of sesquiterpenoids. / Science, Faculty of / Chemistry, Department of / Graduate

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