Thesis (Ph.D.)--University of Wyoming, 2008. / Title from PDF title page (viewed on August 3, 2009). Includes bibliographical references (p. 125-129).

Thesis (Ph. D.)--University of Chicago, Dept. of Chemistry. / Includes bibliographical references. Also available on the Internet.

Thesis (M.S.)--Virginia Polytechnic Institute and State University, 1993. / Vita. Abstract. Includes bibliographical references (leaves 152-155). Also available via the Internet.

Thesis (docteur ès sciences)--Université de Genève. / "Thèse No 2144." Includes bibliographical references (p. [136-139]).

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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.

This thesis is divided into two chapters. Chapter I describes the synthesis of several novel chiral oxazolines and investigations of their utility in asymmetric synthesis. Oxazoline 58, prepared from L-PhenyIaIanine, and oxazolines 75, 76, 77 and 83 prepared from L-tyrosine, were subjected to a deprotonation-aIkyIation sequence. The diastereomeric excess of the alkylated oxazoline possessing the S-configuration at the α-chiral carbon was only modest (20-23%) as determined by ¹H nmr spectroscopy. The expected increase in diastereoselectivity, due to steric and chelation effects, with the modified oxazolines 23, 23, 12, and 83 was not observed. The second chapter deals with various aspects of the chemistry of organosiIicon compounds. Our attempts to develop a silicon-based protecting group for alcohols and amines met with only limited success. SuIfonyichloride 98, prepared from 4-chIorotoIuene, was converted to several sulfonates 99 and sulfonamides 100. The proposed deprotectlon by a fluoride-Induced fragmentation process does appear to proceed through a sulfene Intermediate. However, the success of the deprotection appears to be dependent on an anhydrous source of fluoride ion, the absence of internal proton sources, and stabilized leaving groups. A proposed deoxygenation method involving fIuorIde-induced fragmentation of siIanecarboxyIic esters was not successful. Treatment of esters 148 and 157 did not give any of the desired deoxygenation products octane and ⍜-nitrotoIuene, respectively, but Instead gave quantitative yields of 1-octanol and ⍜-nitrobenzyl alcohol. A general and convenient method of preparing siIanecarboxyIic acids has been developed. Ozonolysis of bissiIyIacetyIenes 139 in dichIoromethane at -24°C gives either the symmetric silyisiIanecarboxyIates 140 or siIanecarboxyIic acids 132 directly in cases where the sllyigroup is not sterically hindered. Silyisi IanecarboxyIates 140 are then readily converted by acid-catalyzed hydrolysis or methanolysls to siIanecarboxyIic acids. The kinetics of the thermal rearrangement of several siIanecarboxyIic esters in ⍜-dichIorobenzene to give the corresponding siloxanes were studied by monitoring the progress of the reactions by ¹H nmr spectroscopy. These first-order rearrangements are characterized by large free energies of activation of about 32 kcal/mole at 120°C. The thermolysis of siIanecarboxyIic acids has been determined to proceed by a different pathway to give only the corresponding silylformates. Acid-catalyzed alcoholysis of silylsiIanecarboxyIates and silylcarboxylates has been found to proceed by a silyI-oxygen cleavage mechanism. Kinetic studies showed that the acid-catalyzed hydrolysis of t-butyldImethyIsiIyI phenyIacetate is an overall third-order reaction. Only the Aal² mechanism is consistent with the results of both the chemical and kinetic studies. This result represents the first demonstration of carboxylic ester hydrolysis proceeding by the Aal² mechanism. [Formula Omitted] / Science, Faculty of / Chemistry, Department of / Graduate

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