Thesis (Ph. D.)--University of Illinois, 1917. / Vita.

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Thesis (Ph. D.)--University of Wisconsin--Madison, 1957. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 66-68).

Thesis (PH. D.)--University of Illinois. / "Biographical": 1 p. at end.

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

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A broadly based approach has been undertaken to the development and use of camphor derivatives as chiral auxiliaries in asymmetric synthesis – an approach which has embraced synthetic, mechanistic and computational studies. The unambiguous characterization of mono- and dihydroxy-derivatives, obtained by reduction of chiral camphor ether dimers, has been achieved through detailed one- and two-dimensional NMR spectroscopic analysis. The resulting data has been used to establish both the regio- and stereochemistry of the hydroxyl groups. A camphor-derived cyclic iminolactone has been shown to provide a convenient platform for the synthesis of chiral α-amino acids, stereoselective monoalkylation of the iminolactone affording a range of products in yields of 52 - 65 % with up to 85 % d.e. The attempted development of chiral bifunctional Morita-Baylis-Hillman substrates has revealed an unexpected equilibration between isomeric bornane 2,3-diol monoacrylates via acid-catalysed intramolecular transesterification. A detailed [superscript 1]H NMR-based kinetic study of the rearrangement in various media and at various temperatures has permitted the determination of the kinetic and thermodynamic parameters. A computational study at the DFT level has been used to explore the potential energy surfaces of the acid-catalysed and uncatalysed transesterification of the monoacrylate esters. The theoretical data supports the involvement of cyclic intermediates and has provided a rational basis for predicting the favoured reaction pathways. Novel camphor-derived phenyl sulfonate esters and N-adamantylsulfonamides have been synthesised for use as chiral auxiliaries in the Morita-Baylis-Hillman reaction. Modeling at the Molecular Mechanics level has provided useful insights into possible conformational constraints and an adamantyl sulfonate auxiliary has been successfully used in the stereoselective synthesis of a range of products, generally in excellent yield and with up to 95 % d.e.

The investigation has been focussed largely on the chemistry and stereo-directing potential of camphor-derived compounds. The major regioisomer produced on partial hydrolysis of N-benzylcamphorimide was identified, by one- and two-dimensional NMR and X-ray crystallography, as (+)-(1S,3R)-(N-enzylcarbamoyl)-2,3,3-trimethylcyclopentanecarboxylic acid, the methyl ester of which was shown to undergo an unexpected intramolecular rearrangement during LAH reduction to afford (1S,3R)-Nbenzyl-3-hydroxymethyl-2,2,3-trimethylcyclopentane carboxamide. Several tartrate- and camphor-derived diols have been investigated as chiral auxiliaries in various asymmetric reactions of corresponding acetals of α,β-unsaturated aldehydes. MCPBA epoxidation of the tartrate-derived acetals afforded epoxy acetals in 4-12% diastereomeric excess. The camphor-derived acetals were obtained solely as the exosubstituted diastereomers, the stereochemistry being confirmed by two-dimensional NMR spectroscopy and X-ray crystallography. Simmons-Smith cyclopropanation of these camphor-derived acetals afforded cyclopropyl products with diastereoselectivities of 4% d.e. for the bornane-2,10-diol acetal and 46->99% d.e. for the bomane-2,3-diol acetals. In order to increase diastereofacial selectivity, a camphor-derived diol having a bulky substituent at C-10 was prepared, viz., phenyl 2,3-dihydroxybomane-10sulfonate, and α,β-unsaturated acetals of this diol were shown to undergo Simmons-Smith cyclopropanation with complete topological control (>99% d.e.), the diastereoselectivities being conveniently determined by ¹H and ¹³C NMR spectroscopy. Computer modelling, with the software package HYPERCHEM®, was used to explore the stereochemical aspects of the Simmons-Smith cyclopropanation, and hydrolysis of one of the cyclopropyl acetals has permitted the diastereoselective bias to be confirmed. (+)-Pinane-2,3-diol was also investigated as a chiral auxiliary in the Simmons-Smith reactions of α,β-unsaturated aldehydes, and moderate diastereoselectivities (20-30% d.e.) were observed. In a series of exploratory studies, the Diels-Alder reaction of the 2,3-dihydroxybomane-10-sulfonate acetal of trans-cinnamaldehyde with cyclopentadiene afforded a single cycloadduct, while OSO₄ dihydroxylation, MCPBA oxidation and alkylation of chiral acetals produced from both bomane-2,3-diol and phenyl 2,3-dihydroxybomane-10-sulfonate were less selective.