Fused heterocyclics

Low methoxyl pectins

Tracer studies on the biosynthesis of threonine

<p>Cascade reactions, also referred to as domino reactions, have been widely used for the formation of carbon-carbon bonds. This type of reaction has the potential to circumvent protection and deprotection steps, shortening an overall synthetic process.</p><p>The Morita-Baylis-Hillman (MBH) reaction is a particularly notable example of an anionic domino reaction which provides straightforward access to &#946;'-hydroxy-&#945;,&#946;-unsaturated carbonyl compounds from aldehydes and &#945;,&#946;-unsaturated carbonyls. However, despite the importance of the Baylis-Hillman reaction, it is slow, reaction yields are quite low, and the process is not general, as it rarely works for &#946;-substituted &#945;,&#946;-unsaturated carbonyl species. Herein, we report an alternative approach to the preparation of MBH adducts employing an anti-selective direct aldol cascade reaction followed by oxidative elimination. This alternative process is rapid, efficient, and generally applicable, even to &#946;-substituted &#945;,&#946;-unsaturated compounds. </p><p>Progress toward the asymmetric total synthesis of apratoxin D is described. The key step of the synthesis is the asymmetric &#945;,&#945;-bisalkylation of chiral N-amino cyclic carbamate (ACC) hydrazones, a new methodology developed by our group. Herein we demonstrate the utility of this method for convergent total syntheses.</p> / Dissertation

<p>A number of 4-hydroxy amino acids have been synthesized via 1,3-dipolar cycloadditions of novel Z-nitrones and substituted olefins. Three achiral nitrones were synthesized in pursuit of a conformationally stable yet reactive Z-nitrone. The carboisopropoxynitrone was determined to be the best synthon in cycloadditions that favored a Z-nitrone oriented transition state. Solvent studies were performed for cycloaddition reactions and it was determined that polar solvents lead to "Z-derived" isoxazolidines whereas non-polar solvents primarily afford "E-derived" isoxazolidines. The incorporation of MgBr₂&middot;OEt,₂ to the reaction further enhanced the selectivity of the cycloaddition reaction in favor of "Z-derived" intermediates.</p><p> Chiral carboisopropoxynitrone derivatives were also realized and used in reactions with chiral olefins to afford optically active 4-hydroxy amino acids after several steps. (2R,4R) 4-hydroxyl-4-methylglutamic acid and (2R,4R) Monatin were both synthesized in high purity from corresponding olefins and the chiral carboisopropoxynitrone. Furthermore, the (2S,4S) enantiomers of both amino acids could be synthesized via enantiomers of the chiral nitrone and olefins.</p> / Dissertation

<p>This thesis deals with the development of syntheticmethodologies for the preparation of enantio- anddiastereomerically enriched nitrogen-containingheterocycles.</p><p>Asymmetric Lewis acid mediated Diels-Alder reactions with2H-azirines as dienophiles have been studied.Diastereoselective reactions with enantiomerically pureauxiliary-derived 2H-azirines afforded substituted bi- andtri-cyclic azaheterocycles comprising a fusedtetrahydropyridine–aziridine moiety in high yields andselectivities. It was found that the 8-phenylmenthol auxiliarywas superior to Oppolzer’s bornane-2,10-sultam in thesereactions. The influence of various Lewis acids on the reactionoutcome was probed and their presence was crucial forsuccessful reactions. The novel enantioselectiveaza-Diels-Alder reaction of benzyl- 2H-azirine-3-carboxylatewas investigated with a range of chiral Lewis acids andprovided the corresponding cycloadducts in moderate to lowyields and selectivities. The 2H-azirines were synthesized fromthe corresponding acrylates via the vinyl azides. An improvedand general procedure for thermolysis of vinyl azides into2Hazirines was developed.</p><p>Lewis acid mediated radical cyclizations of substitutedN-chloro-4-pentenyl- and 4- hexenylamines gave thecorresponding pyrrolidines in high yields and in moderate tohigh diastereoselectivities. The reactivity andstereoselectivity were found to be strongly influenced by thesubstituents on the alkenylamine. On the other hand, noapparent correlation between the different Lewis acids appliedand the obtained selectivities was observed. The relativestereochemistry of the cyclic products could be predicted usingthe Beckwith-Houk stereochemical model. The pyrrolidines wererearranged via aziridinium ions, which were ring-opened to thecorresponding piperidines. The efforts to developenantioselective radical cyclizations of cationic aminylradicals proved unsuccessful. Reaction conditions and chiralLewis acids were varied, yet, racemic product mixtures wereobtained. The N-chloro-N-alkenylamines were synthesized in goodyields.</p><p><b>Keywords:</b>diastereoselective, enantioselective,alkaloid, Lewis acid, chiral ligand, hetero-Diels-Alderreaction, 2H-azirine, aziridine, tetrahydropyridine, chiralauxiliary, vinyl azide, radical cyclization, cationic aminylradical, pyrrolidine, piperidine, aziridinium ion,N-chloro-N-alkenylamine.</p>

Heterocyclic alcohols were coupled with [pi]-nucleophiles in the presence of trimethylsilyl trifluoromethanesulfonate to provide a variety of substituted [beta]-heteroaryl propionates, including those with contiguous quaternary centers. This reaction also provided [beta]-heteroaryl propionates which were previously inaccessible by known methods by exploiting non-traditional Friedel Crafts reactivity. Good diastereoselectivity was also achieved when a chiral auxiliary was incorporated into the [pi]-nucleophile. Progress towards the synthesis of acutumine, an alkaloid possessing a densely functionalized aza-propellane core, two quaternary centers, and a neopentylic chlorine atom, was pursued. A variety of routes were employed, with some of the key steps explored including a Moore cyclization between dimethyl squarate and protected butyn-3-ols, a SmI₂ mediated ring opening of a densely functionalized dihydroisoquinoline ring, and a Stille reaction to install an key allyl functional handle. The thermodynamics behind the binding affinity of various ligands to the Src SH2 domain was also investigated. A series of four ligands were designed and enantioselectively synthesized in order to compare how differences in the conformations of the ligands affect the thermodynamics of binding. Namely, cyclopropanes were introduced into tetrapeptides to restrict the ligands to their binding conformations. The constricted ligands will then be compared to their appropriate flexible controls via the use of isothermal titration calorimetry (ITC) to determine the thermodynamics differences of binding between the two. / text

<p> Transition-metal catalyzed cross-coupling has, in many ways, revolutionized synthetic chemistry by providing streamlined syntheses using highly modular building blocks. Despite the widespread application of the Suzuki and Buchwald-Hartwig cross-coupling reactions, utilization of more contemporary cross-coupling protocols is narrower. Progress in applied research using transition- metal catalyzed reactions is often hampered by the necessity for unwieldy substrate syntheses. Seeking to tackle this problem, we have developed two novel C-C bond forming reactions in the context of the oxidative boron Heck reaction that converts simple starting materials into highly useful products which are directly applicable to many powerful synthetic protocols. </p><p> Firstly, an aerobic boron Heck reaction has been developed, which facilitates the conversion of feedstock olefins, namely, ethylene and propylene to styrenes and b-methylstyrenes using abundant (hetero)aryl boronic acids. The relevance to complex molecule synthesis is highlighted by a two-step synthesis of the pharmaceutical phenprocoumon. </p><p> Secondly, an aerobic boron Heck reaction of cyclobutene has been developed using abundant (hetero)aryl boronic acids. Instead of forming the classical Heck product (3-aryl-cyclobutene) a linear 1-aryl-1,3-diene is generated with complete chemo-, regio- and stereo-selectivity. 1-Aryl- 1,3-dienes have found myriad applications in modern transition-metal catalyzed cross-couplings however the substrates are often prepared by poorly efficient Wittig reactions. Both computational and mechanistic experimental data support a mechanism that proceeds by a classical Heck reaction followed by pericyclic ring opening mechanism for C-C bond cleavage. 1-Aryl-1,3,5-trienes were similarly prepared using alkenyl boronic acids.</p><p>

Benzopyrans and tetrahydroquinolines are motifs commonly found in natural products and pharmaceuticals. Each of these privileged scaffolds have a common benzomethane moiety. Iron (III) salts generate benzomethane intermediates from o-hydroxybenzyl alcohols or o-aminobenzyl alcohols under mild reaction conditions. These in situ generated intermediates can be trapped by olefins in a [4+2] cycloaddition reaction. Furthermore, isolation of unsymmetrical di- and triaryl methanes from a reaction with o-hydroxybenzyl alcohols and methyl eugenol demonstrate Friedel-Crafts reactivity with the benzomethane intermediates. In this work, a one-pot, multicomponent reaction with phenols, aldehydes, and olefins provide efficient access to benzopyrans. Iron (III) salts mediate the initial benzomethane formation in a Friedel-Crafts alkylation between a phenol and aldehyde. The in situ generated benzomethane is trapped with an olefin to afford a benzopyran with rearomatization as the thermodynamic driving force of the reaction. The reaction is tolerant of electron-rich phenols, aromatic, aliphatic, and heterocyclic aldehydes and electron-rich olefins. The synthesis of Psiguajadial F demonstrates the utility of the two-component methodology of o-hydroxybenzyl alcohols and olefins. Psiguajadial F is a meroterpenoid natural product isolated from Psidium guajava. To date 26 meroterpenoid natural products have been isolated from Myrtaceae L. many of which have demonstrated potent biological activity against cancer cell lines. The synthetic challenges in Psiguajadial F include a bicyclo[4.3.1]decane, two quaternary carbons, five rings, three contiguous stereocenters about the pyran B-ring and a trans-cyclobutane. The core B-ring of the natural product is assembled in a convergent step using a o-hydroxybenzyl alcohol and an olefin. The penultimate benzyl deprotection and diformylation steps completed the synthesis. In collaboration, a cell viability assay determined the cytotoxicity of the synthetic material against liver cancer cells. / 2020-11-07T00:00:00Z

The enantioselective total syntheses and absolute configuration assignments of (+)-ponapensin and (+)-elliptifoline have been achieved via enantioselective [3+2] photocycloaddition between 3-hydroxyflavone and methyl cinnamate. The resulting cyclopenta[b,c]benzopyran was reduced through a reagent-controlled, diastereoselective reduction. Amidation was accomplished through direct ester-amide exchange mediated by trimethylaluminum, and diastereoselective N-acyliminium cyclization was observed likely due to stereoelectronic stabilization of one face of the N-acyliminium. The total syntheses revealed the absolute configuration to be opposite of what was hypothesized. These observations led to an interesting biosynthetic hypothesis in which a kinetic resolution/parallel kinetic resolution may be taking place. Through testing this conjecture, an asymmetric transfer hydrogenation kinetic resolution methodology was developed and applied to the first enantioselective total syntheses of (+)-aglaiastatin and (-)-aglaroxin C. The total syntheses confirmed the absolute configuration of these metabolites, and the natural enantiomers were found to be the most biologically active. Chiral urea, thiourea, trifluoroethanols, and TADDOLs have been evaluated as catalysts in the asymmetric [3+2] photocycloaddition between 3-hydroxyflavone and methyl cinnamate. Chiral trifluoroethanols such as Pirkle's alcohol promoted [3+2] photocycloaddition between 3-hydroxyflavone and methyl cinnamate with enantioselectivities up to 40% ee with 20 mol% loading. These additives may be interacting with 3-hydroxyflavone through an excited state double proton transfer mechanism. The synthesis, unexpected light-driven di-epimerization, and biological evaluation of a novel rocaglate-derived β-lactone and β-lactone analogs have been achieved. In addition to in vitro inhibition of the serine hydrolases ABHD10 and ACOT1/2, the most potent β-lactone enantiomer was found to inhibit ABHD10 in PC3 cells, suggesting that derivatives of this β-lactone may serve as valuable chemical probes. The mechanism of the photochemical di-epimerization was investigated and may be occurring through photochemical electron transfer. Biotinylated rocaglate derivatives have been synthesized and evaluated in a streptavidin pull down assay to determine the molecular target of rocaglates. eIF4G was pulled down as the molecular target for one of the biotinylated analogs, but eIF4A was not pulled down by any of the biotinylated analogs.