Gregory Dake

This dissertation presents research work on hetero-Diels-Alder reactions using 2-diphenylphosphoryloxy-1,3-butadienes and imines for the construction of six-membered nitrogen heterocycles. Chapter 1 provides an overview of hetero-Diels-Alder reactions that primarily focuses on imines and enol-based dienes. Chapter 2 describes hetero-Diels-Alder reactions between 2-diphenylphosphoryloxy-1,3-butadienes and imines under the promotion of iron(III) chloride. Twelve examples of 2-diphenylphosphoryloxy-1,3-butadienes were synthesized, and eighteen cycloaddition products were constructed in 30–91% isolated yields. Relative configurations of products formed in diastereomeric mixtures were analyzed by 2-dimensional NMR spectroscopy, and the diastereomeric ratios ranged from 2:1 to >20:1. The utility of the enol phosphate functionality was demonstrated in manipulations of the cycloaddition products in transition metal catalyzed cross-coupling reactions. Chapter 3 describes the multicomponent hetero-Diels-Alder reactions using dienes from Chapter 2, amines, and aldehydes through in situ generation of iminium species under the promotion of boron trifluoride diethyl etherate. The reactions were carried in non-distilled dichloromethane without the use of inert atmosphere. Thirty-one examples of cycloaddition products were presented with a diverse scope of aromatic aldehydes, aliphatic aldehydes, N-sulfonyl amines, and N-carbamoyl amines. Chapter 4 describes a sequence of cycloaddition–cross-coupling–oxidation reactions to construct functionalized pyridines. The N-Fmoc substituted cycloaddition products were subjected to Pd(0)-catalyzed Kumada coupling reactions with varied Grignard coupling partners. The Fmoc protecting group in the cross-coupling products was deprotected using piperidine. A subsequent addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone oxidized the heterocyclic ring to an aromatic pyridine structure. Twenty examples of disubstituted pyridines and one example of trisubstituted pyridine were constructed in 17–88% yields over two synthetic steps. Twelve examples of fluorescent 4-biphenylpyridines were constructed and could potentially be applied in light-luminating materials. Their wavelengths of maximum emission lied in the range of 349–389 nm.

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This thesis describes work attempting to synthesize and derivatize marine natural products. Chapter 1 outlines a brief history of natural products chemistry. It explains why modern medicines are commonly derived from natural sources using historical examples. It also explains why natural products chemists have turned to organisms in the oceans for exploration into new and unique molecular frameworks and biological activities.Chapter 2 describes the work done towards total synthesis of the marine natural product cladoniamide G. The successful approach involves coupling a halogenated 2,2-bisindole with an unsymmetric, tricarbonyl electrophile. It also describes work towards synthesis of analogues, including attempts to glycosylate the natural product.Chapter 3 is the first chapter that discusses work towards total synthesis of a second marine natural product, nahuoic acid A. This chapter focuses on synthesis of a linear cycloaddition precursor that resembles an intermediate in the presumed biosynthetic pathway. The work in this chapter culminates in attempts at a Diels-Alder reaction to form a cis-decalin system.Chapter 4 also focuses on work towards total synthesis of nahuoic acid A. However, the work in this chapter uses a Diels-Alder reaction to form a cis-decalin system early, and then focuses on the challenges of functionalizing the decalin. Four general approaches to functionalization are investigated: conjugate additions, nucleophilic substitutions, sigmatropic rearrangements, and metal catalyzed cycloisomerizations.

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This thesis outlines the polymerization and novel reactivity of enantiomerically pure compounds featuring the relatively uncommon phosphaalkene moiety. Chapter 1 introduces the chemistry of the phosphaalkene (Ar-P=CR₂) structural fragment. This motif is compared and contrasted to the established chemistry of C=N and C=C groups. Similarities and differences are highlighted by an examination of: (a) phosphaalkene synthesis, (b) phosphaalkene polymerization and (c) phosphaalkene-metal coordination.Chapter 2 details the addition reactions of MeM (M = MgBr, Li) nucleophiles to enantiomerically pure phosphaalkene-oxazoline 1.10a [PhAk-Ox, MesP=CPh(CMe₂Ox)]. Of note, the reaction of MeMgBr and PhAk-Ox is highly diastereoselective and affords a new P-chiral phosphine oxazoline ligand. Chapters 3 and 4 report the free radical initiated homo- and co-polymerizations (with styrene) of enantiomerically pure phosphaalkene-oxazolines 1.10a (Chapter 3) and 4.1a [MesP=CPh(3-C₆H₄Ox), Chapter 4]. The coordination of rhodium(I) to copolymers of 1.10a and styrene permits the isolation of novel macromolecular complexes. Additionally, polymers of 4.1a display unique spectroscopic signatures that permit the direct assignment of styrene-phosphaalkene linkages in the polymer backbone. Chapters 5 and 6 highlight the coordination chemistry of phosphaalkenes. Chapter 5 discusses the syntheses of κ³(PNN)-copper(I) complexes featuring enantiomerically pure pyridine-bridged phosphaalkene-oxazoline 5.1a [ArP=CPh(2-C₅H₃N-6-Ox)]. Chapter 6 explores the insertion of the P=C functional group into Pd–R bonds, permitting the synthesis of novel phosphapalladacyclopropanes (6.1a-b) and palladium(II) complexes featuring 1,2-dihydropyridinato donors (6.3 and 6.4). Chapter 7 provides perspective for the work contained within this thesis.

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This dissertation presents investigations on the synthesis of polyoxygenated tetrahydroxanthone ring systems. Chapter 1 provides a brief overview of the family of naturally occurring compounds called xanthones. The classification, isolation, biological properties and the synthetic approaches to this family of compounds is included. Because the work of this dissertation was inspired by the tetrahydroxanthone unit embedded in simaomicin α (1.1), a detailed review of the synthetic methods available to access tetrahydroxanthone units is presented.Chapter 2 describes eight synthetic approaches that were investigated to construct substituted tetrahydroxanthones. A stereospecific intramolecular [3+2] dipolar cycloaddition of nitrile oxides resulted in the synthesis of novel fused tetracyclic isoxazolines, tetracyclic isoxazoles, and aminotetrahydroxanthones. An intramolecular hydroacylation promoted by N-heterocyclic carbenes produced substituted tetrahydroxanthones and hexahydroxanthones.Chapter 3 describes the successful synthesis of polyoxygenated tetrahydroxanthones through a 4-dimethyl- aminopyridine-promoted cycloisomerization of o-alkynoylphenol derivatives. It is proposed that the cycloi- somerization is initiated by the 1,4-addition of DMAP, followed by either a Morita-Baylis-Hillman-type aldol reaction, or deprotonation of the phenol. However, the actual mechanism remains unknown. The cycloisomerization of o-alkynoylphenol derivatives was useful in the synthesis of 1,4,5-trioxygenated or 1,5- dioxygenated tetrahydroxanthones with variable substituents at position 7. The diastereoselectivity of the reaction modestly favoured the trans-isomer.

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This dissertation presents investigations of enamides as π-nucleophiles within the context of electrophilic platinum(II) and gold(I) salt catalyzed cycloisomerization reactions.Chapter 1 provides a brief overview of electrophilic metal salt catalyzed cycloisomerization reactions with a primary focus on platinum, gold, and silver salts.Chapter 2 describes the first total synthesis of Lycopodium alkaloid (+)-fawcettidine (2.5), completed in sixteen synthetic operations from (R)-(+)-pulegone (2.56). The feature reaction in the sequence was a platinum(II)-catalyzed annulation of highly functionalized bicyclic enamide 2.124 to give tricycle 2.125. This annulation reaction installed the quaternary stereocenter, placed the double bond of the enamine in the correct position, and formed an exocyclic alkene which was amenable to further manipulation. A thiolate anion addition to an enone and a Ramberg-Backlund reaction were other noteworthy steps for the completion of the synthesis of (+)-fawcettidine.Chapter 3 describes the platinum(II)- and gold(I)-catalyzed cyclorearrangement of 1,2,3,4-tetrahydropyridine derivatives containing an aromatic substituted alkyne moiety tethered at the 3-position of the ring. The reactions proceeded by a tandem cycloisomerization/Friedel-Crafts addition process resulting from an initial 6-endo-dig cyclization, forming nitrogen-containing tetracyclic scaffolds featuring a quaternary carbon center. The 5-exo-dig mode of cyclization was observed to be a minor pathway. Platinum(II)-catalyzed cycloisomerization reactions formed the products in 51-98% yield. Gold(I)-catalyzed cycloisomerization reactions were lower yielding. An unexpected azocine derivative was observed when an enamide substrate was treated with 20 mol% of silverhexafluoroantimonate(V).Chapter 4 describes the platinum(II)- and gold(I)-catalyzed cycloisomerization/Friedel-Crafts tandem process of acyclic enamine derivatives featuring 1-arylalkynes. Four tricyclic products were observed: two products were formed by initial 6-endo-dig (major pathway) or 5-exo-dig (minor pathway) cyclization. The alkene of the 6-endo product frequently isomerized under the reaction conditions to form a 1-aza-substituted indene derivative, and the 5-exo product often eliminated to form substituted naphthalene derivatives. Catalysis with a platinum(II) salt, a gold(I) species derived from the mixture of triphenylphosphine gold(I) chloride and silver hexafluoroantimonate(V), or [(2-biphenyl-bis-tbutylphosphine)Au(I)・NCCH₃]⁺SbF₆⁺⁻(1.70) gave mixtures of products in 21-100% yield. Gold(I) catalyst 1.70 was the most effective of the catalysts tested.

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This thesis outlines the design, synthesis and utilization of phosphaalkene-based ligandsfor asymmetric catalysis.Transition metal catalysis studies that utilize achiral phosphaalkene-based ligands arereviewed in Chapter 1. In addition, the synthesis and reactivity of phosphaalkenes are brieflyintroduced in this chapter.The reactivity of a palladium(II) phosphaalkene complex [MesP=CPh(2-py)⋅PdCl₂]bearing the smaller P-Mes substituent compared to the traditional Mes* is described in Chapter2. This complex was found to be a competent catalyst for the Overman–Claisen rearrangementwith yields ranging from 33% to 91%.In Chapter 3, a modular route to a set of chiral phosphaalkene–oxazoline [PhAk–Ox,R′P=CR′′(C(i-Pr-Ox)R₂)] proligands is described. The synthetic route starts from a chiral poolmaterial (L-valine) and generates the P=C bond by a phospha-Peterson reaction. The electronicand steric properties of the proligands (R′, R′′ and R) were modified using this synthetic route.MesP=CPh(C(i-Pr-Ox)Me₂) was thermally polymerized to generate poly(methylenephosphine).The investigation of the coordination chemistry of PhAk–Ox proligands is described inChapter 4. Rhodium(I) and iridium(I) PhAk–Ox complexes were characterized by X-raycrystallography and NMR spectroscopy. Rhodium(I) PhAk–Ox complexes were found to beactive in the asymmetric allylic alkylation of ethyl (1-phenylallyl) carbonate with dimethylmalonate as a nucleophile. The optimal conditions generated products in 37% yield and 66% ee.The investigations of PhAk–Ox ligands in palladium(0) catalyzed allylic alkylation of1,3-diphenylpropenyl acetate using malonate type nucleophiles are reported in Chapter 5. Thestructural modification of the ligand through the incorporation of a gem-dimethyl group [MesP=CPh(C(4-i-Pr-5-Me₂-Ox)Me₂)] was needed to optimize yields (73–95%) andenantioselectivities (79–92%). Ring-closing metathesis processes were used to generateenantioenriched carbocycles.To conclude, the results presented in this dissertation represent the highest reportedenantioselectivities for a reaction utilizing a phosphaalkene-based ligand. These results alsoserve as a proof of concept that phosphaalkene ligands can be used in asymmetric catalysis.

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