Techn. Universiẗat, Diss., 2003--Berlin.

Universiẗat, Diss., 2001--Jena.

Universiẗat, Diss., 2001--Marburg.

Universiẗat, Diss., 2004--Kiel.

Nitrogen-containing molecules are ubiquitous in both natural products and pharmaceutical drugs, thus an efficient method for the formation of these motifs is of great importance. Hydroamination, that is the addition of an N-H bond across an unsaturated carbon-carbon bond of an alkene or alkyne, stands out as a potential approach to obtain such molecules. To date, most research in this area relies on transition-metal catalysis to enable such reactivity. In efforts directed towards metal-free alternatives, we have developed a simple, metal-free hydroamination of alkenes using hydrazides. Further investigation into the corresponding reactivity of alkynes with hydrazides has provided access to novel azomethine imine products. In Chapter 2, expansion of the substrate scope with respect to the intramolecular hydroamination of alkenes using hydrazides, as well as studies directed towards elucidation of the mechanism of this reaction will be presented. The intramolecular hydroamination of alkynes using hydrazides and methods to access and isolate the azomethine imine products formed will be discussed in Chapter 3.

Thesis advisor: James P. Morken / This dissertation describes three methods towards the stereoselective synthesis of organoboronates, and their application towards pharmacological targets of interest. The first chapter describes the use of alkyl migrating groups and alkyl electrophiles in the synthesis of secondary boronic esters through a highly selective nickel-catalyzed three component conjunctive cross-coupling reaction. Products from this conjunctive cross-coupling reaction are then converted to two alkaloids through boron amination and annulation processes. The second chapter describes the platinum-catalyzed diastereoselective diboration of carbocyclic, heterocyclic, and bicyclic alkenes. This reaction proceeded under air and both a homogeneous and heterogeneous catalyst was employed. Application of this reaction towards synthesis of the nucleoside analog Aristeromycin is also described. The final chapter details the development of an inexpensive and easily synthesized chiral diazaborinine that provides stereoinduction across a wide range of concerted and stepwise cycloaddition processes, affording heterocyclic-boron containing products in high yield and selectivity. Transformations of resulting organoboronates are also described. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The Wittig reaction has constantly evolved during the last half-century and is one of the most strategic, reliable, widely-applicable carbon-carbon olefin bond forming processes available in organic synthesis. The reaction allows for olefination with complete positional selectivity, relatively high chemoselectivity and may be conducted in many cases with predictable stereocontrol. Triphenylphosphoranylides are ubiquitously employed and despite the myriad benefits these reagents bestow there are known disadvantages to their use—most prominently related to issues surrounding stereoselectivity and phosphine oxide removal which is notoriously problematic. Trialkylphosphoranylides, by contrast, undergo olefination in the presence of carbonyls with high (E)-stereoselectivity and the corresponding short chain trialkylphosphine oxides are water soluble. Previous work in our group has shown that semi-stabilised ylids of this type readily undergo olefination with a broad range of aldehydes under mild aqueous conditions. This aqueous Wittig reaction was then extended to the synthesis of substituted styrenes using aqueous formalin. In the search for ever milder conditions for the Wittig reaction we were also able to develop an organocatalytic Wittig reaction which was amenable to a bioorthogonal process. Thus, we were able to perform the first Wittig reaction in vivo by feeding the two reactants to Castylegia sepium. Alkenals (colloquially enals) are strategic intermediates in organic synthesis; their importance is growing each year due to the expanding breadth of iminium and vinylogous enamine organocatalysis. Unfortunately their preparation remains problematic requiring labour and reagent intensive multi-step sequences. A new pincolacetal-phosphonium salt (DualPhos) for the stereoselective two-carbon homologation of aldehydes has been developed which allows for the one-pot homologation of aldehydes to enals under aqueous and/or anhydrous conditions; its application to the total synthesis and stereochemical reassignment of phomolides G & H is discussed. / Thesis / Doctor of Philosophy (PhD)

No description available.

Thesis advisor: Amir H. Hoveyda / Chapter One: Stereoretentive Cross-Metathesis of Trisubstituted Olefins The development of stereoretentive olefin metathesis catalysts has solved a long-standing problem in the field, allowing for trisubstituted alkenes to be synthesized in high stereochemical purity and under kinetic control. E- as well as Z-isomers of trisubstituted alkenyl halides, nitriles, and allylic alcohols can be accessed through cross-metathesis of commercially available and easily accessible alkenes. Through the use of the same strategy, macrocyclic trisubstituted alkenes have been accessed in either isomeric form through stereoretentive ring-closing metathesis of the corresponding diene starting materials. Thus, for the first time, a wide range of E- and Z-trisubstituted alkenes can be obtained selectively through olefin metathesis, regardless of the underlying thermodynamic preferences. Chapter Two: Development of Catalytic Stereoretentive Cross-Metathesis of Trisubstituted Alkenyl Bromides We have introduced a general and widely applicable strategy for the synthesis of E- and Z-trisubstituted alkenyl bromides through cross-metathesis. The reaction is applicable to terminal, disubstituted, and trisubstituted olefins bearing a variety of functional groups including alkenes with α-, or β-branches. The requisite stereodefined cross-partners, E- and Z-2-bromo-2-butene are commercially available and can be synthesized with ease in one step from abundant starting materials. This represents a notable improvement over our previous approach, where the non-halogenated alkene starting material had to be prepared through cross-coupling in high stereochemical purity to ensure high stereoretention in the subsequent cross-metathesis. Catalysts derived from Mo monoaryloxide pyrrolide complexes, some of which are commercially available, are optimal for this transformation. The applicability of the approach is underscored through the formal synthesis of phomactin A with improved overall yield and step count. Chapter Three: Total Synthesis of Ambrein We have completed a total synthesis of ambrein, a terpenoid isolated from whale secretion, a much sought perfume ingredient. The approach involved joining two fragments through formation of the central trisubstituted alkene. Our route entailed a sequence of cross-metathesis of alkenyl bromides and cross-coupling, providing access to a previously difficult-to-access trisubstituted olefin with high efficiency and selectivity. One fragment was generated from a readily accessible enantiomerically enriched compound, sclareolide, and the other from inexpensive methylcyclohexenone. The stereogenic center of the latter was established through a NHC-Cu-catalyzed enantioselective allylic substitution, which was followed by differentiation of these alkenes through site-selective epoxidation. The total synthesis is more efficient and offers a more practical route to ambrein. Chapter Four: Stereoretentive Cross-Metathesis of Trisubstituted α,β-Unsaturated Carbonyl Compounds We have developed a strategy for the synthesis of Z- and E-Trisubstituted α,β-unsaturated carbonyl compounds through stereoretentive CM involving commercially available or easily accessible alkene substrates. The method is applicable to a variety of α,β-unsaturated esters, thioesters, and acyl fluorides. Furthermore, mono-, di-, and trisubstituted alkenes can be used as starting materials. Transformations may be carried out on gram scale and, in some cases, with commercially available Mo catalysts. The utility of the catalytic approach was highlighted through synthesis of previously accessed intermediates more directly and with improved efficiency. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Collagen is one of the most abundant human proteins. It exists as a right-handed superhelix called the triple helix. The triple helix consists of three left-handed polyproline type II (PPII helices) that intertwine around a common axis. Each PPII helix has the repeating peptide sequence (Gly–Xaa–Yaa)n with a high content of (2S)-proline (Pro) in the Xaa position (ca. 28%) and (2S,4R)-hydroxyproline (Hyp) in the Yaa position (ca. 38%). Unique to the prolyl amide is the ease of cis-trans isomerization. Since the triple helix necessitates that all peptide bonds be in the trans conformation, isomerization is the rate-limiting step in collagen folding. However, eliminating isomerization with a trans-locked alkene isostere destabilizes collagen-like peptides. Collagen is stabilized by electronic interactions, namely the n→π* interaction. Halo-alkene isosteres may be used to recapture these electronic interactions and stabilize a collagen-like peptide. An in-depth conformational analysis was conducted at the MP2/6-311+G(2d,p) level of theory to determine the viability of conformationally-locked halo-alkene isosteres. Fluoro-alkenes and chloro-alkenes were modeled at both the Gly–Pro and Pro–Pro (as a Pro–Hyp mimic) amide positions. Compared to the collagen crystal structure PDB ID: 1K6F, we found the fluoro-alkenes were closer geometric matches to both Gly–Pro and Pro–Pro than the corresponding chloro-alkenes. The chloro-alkene was predicted to have stronger n→π* interactions. The trans-locked proteo-alkene was also analyzed to understand why it destabilized the triple helix. We found that these models had other local minima close to the desired PPII geometry, likely leading to enhanced backbone flexibility. This deleterious flexibility was not predicted for either fluoro-alkene or chloro-alkene models. The conformationally-locked halo-alkene isostere Fmoc–Gly–Ψ[(Z)CF=C]-Pro–Hyp(tBu)–OH was designed and synthesized as a (Z)-fluoro-alkene Gly–Pro isostere. We used the chiral catalyst, L-Thr, for asymmetric aldol addition to cyclopentanone, which inadvertently enhanced the yield of the wrong enantiomer, in contrast with aldol addition to cyclohexanone. A Mg2+-promoted Horner-Wadsworth-Emmons reaction afforded the (Z)-fluoro-alkene over the (E)-fluoro-alkene in about a 2:1 ratio. The two diastereomers, Fmoc–Gly–Ψ[(Z)CF=C]-L-Pro–Hyp(tBu)–OH and Fmoc–Gly–Ψ[(Z)CF=C]-D-Pro–Hyp(tBu)–OH were separated by supercritical CO2 chromatography. The collagen-like peptides Ac–(Gly–Pro–Hyp)3–Gly–Ψ[(Z)CF=C]-L-Pro–Hyp–(Gly–Pro–Hyp)4–Gly–Gly–Tyr–NH2, Ac–(Gly–Pro–Hyp)3–Gly–Ψ[(Z)CF=C]-D-Pro–Hyp–(Gly–Pro–Hyp)4–Gly–Gly–Tyr–NH2, and the control peptide Ac–(Gly–Pro–Hyp)8–Gly–Gly–Tyr–NH2 were synthesized on solid-phase resin. The CD spectra of all three peptides showed the characteristic collagen triple-helix signature. The folding stability was determined by thermal melting (Tm). The peptide with the fluoro-alkene guest, Gly–Ψ[(Z)CF=C]-L-Pro–Hyp, was found to have a Tm value of 42.2 °C. The Tm of the control peptide was found to be 49.0 °C, a difference in stability of only ΔTm –6.8. Thus, the (Z)-fluoro-alkene as a Gly–Pro isostere forms a relatively stable triple helix. The peptide with the Gly–Ψ[(Z)CF=C]-D-Pro–Hyp guest was shown to have a linear relationship between ellipticity and temperature, indicating that a stable triple helix did not form. The enhanced stability of the (Z)-fluoro-alkene compared to the (E)-alkene Gly–Pro isostere (Tm = 28.3 °C) may be due to a stabilizing n→π* interaction, as determined by NMR deshielding of the 19F nucleus in the collagen-like peptide. In biological systems, isomerization of the prolyl amide is catalyzed by enzymes called PPIases. The PPIase Pin1 specifically catalyzes isomerization of the pSer–Pro sequence from the cis-conformation to the trans-conformation. Pin1 plays a crucial role in the G2→M transition of the cell cycle, implying the importance of cis-trans isomerization. The dipeptides H–Ser–Ψ[(Z)CH=C]-Pro–OH, H–Ser–Ψ[(E)CH=C]-Pro–OH and native H–Ser–Pro–OH were synthesized by literature methods, and activated for aminoacylation of tRNACUA for in vitro transcription-translation. Aminoacylation by chemical methods required the synthesis of a pdCpA dinucleotide. Formation of the dipeptide-dinucleotide complex was not completed because protection of the Ser side chain was problematic. On the other hand, conversion of the dipeptide into the 3,5-dinitrobenzyl ester conjugate allowed for enzymatic aminoacylation using the dFx flexizyme, an RNA enzyme. The native dipeptide was successfully coupled to tRNACUA and is ready for incorporation into a full-length Bora protein by in vitro transcription-translation. Both cis- and trans-locked alkene mimics have been converted to their respective 3,5-dinitrobenzyl ester conjugates. / Doctor of Philosophy / The proline amide (Xaa–Pro) in peptides and proteins is unique in that it allows for cis-trans isomerization. The triple-helix region of human collagen consists mostly of the repeating sequence (Gly–Pro–Hyp)n. Xaa–Pro amide-bond isomerization is rate-limiting for triple-helix formation. We eliminated isomerization at one position in a collagen-like peptide with a locked alkene mimic of Gly–Pro to attempt to stablize the triple-helix. Our computational results predicted that a fluoro-alkene Gly–Pro isostere would be a close geometric match for the native amide. Experimental results showed that a collagen-like peptide with a fluoro-alkene Gly–Pro isostere has an unfolding temperature that is 6.9 °C lower than the native control peptide. 19F NMR data of the collagen-like peptide shows a surprising deshielding of the fluorine nucleus, suggesting its participation in a stabilizing n→π* electronic interaction, similar to the native amide. Isomerization also plays a key role in proper cell division. We followed established methods to synthesize the cis- and trans-locked alkene mimics of Boc–Ser–Pro–OH and converted them into the 3,5-dinitrobenzyl ester conjugates. The 3,5-dinitrobenzyl ester is recognized by the dinitrobenzyl flexizyme (dFx) for enzymatic aminoacylation of tRNA. Once the alkene isosteres are aminoacylated, they will be incorporated into a full-length cell cycle regulatory protein called Bora to determine whether the cis- or trans-Pro state is necessary for healthy human mitosis, and which results in cancerous human mitosis.