Marco Ciufolini


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Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - Nov 2020)
Aza-spirocyclic compounds via oxidative amidation of phenols: application on the studies towards the synthesis of himandrine and the total synthesis of Erythrina alkaloids (2018)

This thesis illustrates two application of the oxidative amidation of phenols in the synthesisof natural products.The first part focuses on an approach to himandrine via a tandem oxidative cyclizationof a phenolic dienylsulfonamide / intramolecular Diels-Alder reaction / epimerization sequencethat produces a substituted trans-fused decalone. This material exhibits three of thefive rings present in the natural product, but it is made in racemic form. Efforts to preparesaid trans-decalone in enantioenriched form are also outlined. The strategy that was exploredin that respect relies on a Rh(I)-mediated diastereoselective 1,4-addition of an arylboronicacid to a conjugated ester derived from L-serine.The second part of this dissertation describes the total synthesis of two Erythrinaalkaloids, (+)-3-demethoxyerythratidinone and (+)-erysotramidine, via the oxidativecyclization of a phenolic oxazoline. A key step of the synthesis involves the desymmetrizationof a dienone through a highly diastereoselective, intermolecular 1,4-addition of the alcoholrevealed upon unraveling of the oxazoline. This allows the creation of the aza-spirocentercharacteristic of this class of alkaloids with the correct configuration. The degree ofstereocontrol achieved in the course of such operations is essentially perfect (nodiastereomeric side products detectable). This synthesis also introduces improvedtechniques to effect a crucial eliminative Curtius-Schmidt rearrangement.

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Chiral hypervalent iodine mediated enantioselective oxidative dearomatization of naphthols (2017)

This dissertation investigates and describes the hypervalent iodine mediated dearomatization of naphthols, thereby yielding diversity of spiro-heterocyclic compounds in both racemic and chiral form. The first part of this thesis discloses the synthesis of racemic spiropyrrolidines and spirolactams via oxidative amidation of corresponding naphtholic sulfonamides, employing DIB as the oxidant. Enantioselective variant of the same have been demonstrated by using in situ generated chiral hypervalent iodine to provide chiral spiropyrrolidines. A noteworthy side reaction discovered in the course of these studies is the asymmetric oxidative addition of meta-chlorobenzoic acid to the naphtholic sulfonamides. The resulting acyloxylated adducts were formed with a greater degree of asymmetric induction compared to spiropyrrolidines in the same reaction mixture. Based on the results obtained from optimization study and substrate scope, plausible mechanistic insights of both cyclization and acyloxylation reactions have been provided. The second part of this thesis unravels the spiroetherification of naphtholic alcohols, thereby yielding spiroethers both in racemic and chiral form. Chiral hypervalent iodine reagents generated in situ provided a range of spiroethers with excellent ee’s and high yields. These chiral oxidants have been evaluated for kinetic resolution of naphtholic primary alcohols bearing stereogenic center at β-position in the side chain.

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Extending the boundaries of diaryliodonium reagents: expressing I-nucleophilicity of aryl iodides and metal-free preparation of sulfonium salts (2016)

Diaryliodonium salts are a well-established class of hypervalent iodine reagents and act as aryl group transfer agents towards nucleophiles. This work established the possibility of metathesis between diaryliodonium triflates and various iodoarenes. In an effort to further understand the factors that govern this process, λ³-iodanes containing 2-thienyl moieties were prepared. As a result, aryl iodides unable to undergo metatesis previously were found to be suitable nucleophiles as the metathesis favors diaryliodonium species where more nucleofugal aryl iodides, such as 2-iodothiophene, are expelled during the course of the reaction. In addition, we showed that copper catalysis was not necessary for the arylation of sulfides, selenides and tellurides. Indeed, thermal reactions between the chalcogenides and diaryliodonium triflates afforded the corresponding triarylchalcogenium salts in good yields. This is particularly significant for the preparation of the triaryltelluronium species, as only limited protocols for their preparation were known.

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Formal total synthesis of (?)-tetrodotoxin (2016)

This dissertation details a formal total synthesis of (±)-tetrodotoxin, a potent sodium channel blocker, based on a transformation developed in these laboratories: the bimolecular oxidative amidation of phenols. The present route leads to the Du Bois intermediate in 27 steps from a commercial starting material. Because the Du Bois intermediate can be elaborated to tetrodotoxin in 4 steps, this work constitutes a formal synthesis of the natural product in 31 steps. This is competitive with the best known alternatives. A structural revision of the Sato tetrodotoxin intermediate is also provided. Finally, an even more concise avenue to a new bis-lactonic precursor of the natural product is described, and potential enantioselective routes to tetrodotoxin are discussed.

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Applications of hypervalent iodine reagents in organic synthesis: the development of iodonium metathesis reaction and effort towards himandrine (2015)

This thesis discloses two different applications of hypervalent iodine(III) reagents in organic synthesis. In the first part, a novel reactivity of diaryliodonium triflates towards aryl iodides will be discussed. The new mode of reactivity allows various diaryliodonium triflates to be accessed, simply by heating a mixture of electron deficient diaryliodonium triflate with a moderately electron rich aryliodide. In the second part of the thesis, the use of (diacetoxyiodo) benzene in oxidative amidation in the context of total synthesis will be made.

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A synthetic approach to quinocarcin and cyanocycline A: the Ugi reaction of complex amino acids (2012)

This dissertation describes synthetic efforts towards the natural products quinocarcin and cyanocycline A. Our approach capitalizes on the Ugi reaction of a complex pyroglutamol-derived aminoacid. This ambitious strategy first required the synthesis of the aminoacid, which required considerable development; ultimately the route was optimized to become practical and consistently high-yielding. Ugi condensation reactions using this material were successful, providing advanced precursors of the target molecules.

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Development of oxidative methodologies and application toward tetrodotoxin core (2011)

This thesis covers a novel approach to tetrodotoxin that relies on the oxidative amidation of a phenol and intramolecular nitrile oxide cycloaddition to install a β-hydroxynitrile unit among the key steps. These transformations, and others contained herein, effectively set the tetrasubstituted C-8a stereocenter, as well C-4a formyl equivalent and C-5, C-7 and C-8 hydroxyl groups. Novel reaction types were developed in the course of this work, including a new method for the oxidation of oximes to nitrile oxides using hypervalent iodine reagents. Additionally, I identified a tandem reaction sequence, involving the dearomatization of a phenol, followed by [3+2]-dipolarcycloaddition, the first of its kind. This tandem sequence proved a powerful tool for the rapid construction of multicyclic compounds from structurally simpler starting materials. These studies resulted in advanced intermediates which contained much of the structure of the tetrodotoxin core.

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Methodology for natural product synthesis : sordarin, himandrine and lepadiformine (2010)

Fungal infection, of small concern in healthy individuals, can become problematic in immunosuppressed patients with illnesses such as AIDS, and the search for substances that exert antifungal action by new mechanisms continues. A noteworthy group of potent antimycotic natural products known as the sordarins meet this criterion. In order to investigate the effect of various functional and skeletal changes to sordarin on anti-pathogenic activity, we have devised practical, expeditious, and efficient routes to analogs of the natural product. The bioactivity of the new compounds against various pathogenic fungi was evaluated. This research constitutes the first half of my doctoral dissertation.The second half of my work centers on the development of a practical method for the oxidative amidation of phenols. This reaction achieves the conversion of phenols into spirocyclic (sulfon)amido-dienones. The new methodology forms the centerpiece of envisioned syntheses of (±)-himandrine and (-)-lepadiformines. Himandrine, isolated from the bark of Galbulimima belgraveana, displays anticholinergic activity and is thus of potential interest for the treatment of a number of human ailments. Our himandrine skeleton synthesis centered on a tandem oxidative amidation and Diels-Alder reaction, using three different approaches. The alkaloid (-)-lepadiformines displays potency as a potassium channel blocker. Our synthetic study towards this substance utilizes the oxidative cyclization of a phenolic sulfonamide as the key step. The resulting dienone is then desymmetrized through a stereoselective Michael addition leading to an enantiopure tricyclic intermediate, to which hydrocarbon side chain was appended in high yield. Further elaboration will lead to the natural product.

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Total synthesis of micrococcin P1 (2009)

This thesis describes the total synthesis of the thiopeptide antibiotic micrococcin P1.It unambiguously elucidates its structure, which has been subject to controversy for over thirty years. The centerpiece of the route to the target molecule is a facile one-pot construction of the central thiazole/pyridine cluster developed in our laboratory. This highlyconvergent route entails a delicate Michael addition to yield a Hantzsch dihydropyridine intermediate, which undergoes further oxidation to the fully aromatised heterocycle. The synthesis was completed by the coupling of this core with a highly-modified sensitive peptide chain. The modular nature of the synthesis can also accommodate modifications forSAR studies, contributing thereby to the fields of medicinal chemistry, pharmacology, and microbiology. At a purely chemical level, we remain confident that this work will serve as a valuable guide in the elaboration of other members of the thiopeptide family.

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Master's Student Supervision (2010 - 2018)
Oxidative cyclization of phenolic N-acyl sulfonamides (2017)

The oxidative activation of appropriately substituted phenols with a hypervalent iodine reagent, in the presence of suitable nitrogen nucleophiles, results in formation of 2- or 4-amidodienones. The process is described as the oxidative amidation of phenols. The dienones thus produced are useful building blocks for the synthesis of alkaloids. The nitrogen nucleophile may be an oxazoline, a sulfonamide or phosphoramide (intramolecular reactions), or a nitrile (bimolecular reaction), but not a carboxamide. This is because carboxamides express Onucleophilicity toward oxidatively activated phenols, resulting in formation of iminolactones, which are readily hydrolyzed to lactones upon workup.This present thesis describes efforts to extend oxidative amidation chemistry to carboxamides. The behavior of phenolic N-acyl sulfonamides was thus explored. The product obtained upon oxidative cyclization of these substrates proved to be dependent upon their structure. In many cases, N-sulfonyl iminolactones were thus obtained. These heretofore undocumented products proved to be surprisingly stable and resistant to hydrolysis.

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Efforts Towards the Total Synthesis of Nosiheptide (2015)

This thesis described here aims to achieve the total synthesis of nosiheptide, a representative member of the so-called E-series of thiopeptide antibiotic. Our group has established various techniques for the assembly of their complex molecular framework, and demonstrated the total syntheses of two D-series thiopeptide antibiotics. However, there is no precedent total synthesis of compound belonging to E-series. The part of the reason is that the presence of an additional 3-OH substituent not only adds significant synthetic complications, but also bars the use of the previously established technology. The present work details the assembly of the pyridine-thiazole cluster of E-series thiopeptide substance through a modified Hantzsch reaction that delivers the complete pyridine segment in a triply convergent fashion. Optimization studies related to this pyridine formation have further enhanced the conciseness and simplicity of the method. This chemistry thus developed can be applied to medicinal chemistry investigations in thiopeptide antibiotic field; an endeavor that will possibly unveil valuable new antibiotics.

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5-N,C-Disubstituted cyclopentadienes for facially selective Diels-Alder reactions (2011)

This thesis describes research on the Diels-Alder facial selectivities of 5-N,C-disubstituted cyclopentadienes. Two novel chiral cyclopentadienes were created, both display facial selectivity in Diels-Alder reactions. Moreover, the two cyclopentadienes display opposing facial selectivities, and thus allow tunable control of faciality. The results obtained in the course of these studies have important implications for ongoing synthetic efforts in our laboratory.

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Synthetic studies towards homotyrosinol sulfonamide derivatives via Heck-Mizoroki coupling reactions (2010)

Homotyrosine, as a nonproteinogenic α-amino acid, is present as a component of diverse natural products that have important biological activities. Therefore, homotyrosine and its derivatives are important precursors for the total synthesis of some natural products. However, up to now, there was no report concerning a reliable synthetic route towards the synthesis of homotyrosine or its derivatives in a preparative scale.In this thesis, a robust method was developed for the preparation of homotyrosinol derivatives and related intermediates through a Mizoroki-Heck coupling reaction between an aryl iodide and appropriate amino acid-derived olefins in the presence of N-phenylurea as the ligand. In addition, a preparative scale protocol for the oxidative cyclization of the homotyrosinol sulfonamide derivative was established. These results are essential for various synthetic efforts towards more complicated natural products ongoing in our laboratory.

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Total Synthesis of Thiocillin I (2010)

This thesis describes the first total synthesis of Thiocillin I, a thiopeptide antibiotic that is structurally similar to Micrococcin P1. Our group has recently completed the first total synthesis of the latter natural product. In that connection, new methodology had to be devised for the assembly of the central pyridine-thiazole cluster of the molecule. The present work details the development of a considerably more efficient "second generation approach" to that crucial molecular subunit. The new technique relies upon a three-component condensation to form the pyridine core with the full complement of thiazoles already in place. This transformation is recognized as a variant of the Bohlmann-Rahtz reaction that has heretofore eluded the synthetic community. Minor modification of this chemistry is likely to facilitate the synthesis of several other thiopeptide antibiotics, naturally occurring or otherwise. This presages the advent of technology for the conduct of medicinal chemistry studies of thiopeptide substances and promises to lead to new generations of chemotherapeutic resources.

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