A Formal Vinyl Sulfonyl Nazarov Cyclization Accesses 9-(tosylmethyl)-2,3,4,4a-tetrahydro-1H-fluorenes

During the course of a proposed route to synthesize ladderane lipids, a novel one-pot 4π electrocyclic ring opening followed by a Nazarov-type 4π electrocyclization reaction was discovered. The reaction was studied further due to its potential as a method for accessing the privileged tetrahydrofluorene scaffold and the opportunities for further functionalization provided by the allyl sulfone moiety. Optimized conditions for the transformation involved refluxing model substrate 7-phenyl-8-tosylbicyclo[4.2.0]oct-6-ene in 1,2-dichloroethane for 3 h to generate intermediate (E)-1-((2-(cyclohex-1-en-1-yl)-2-phenylvinyl)sulfonyl)-4-methylbenzene. Upon cooling to room temperature, addition of 1.2 equiv iron(III) chloride promotes cyclization to furnish 9-(tosylmethyl)-2,3,4,4a-tetrahydro-1H-fluorene after 10 h in 78% yield. In order to determine the effect electronics may have on the transformation, functionality was introduced onto the phenyl ring. While no noticeable effect was observed on the electrocyclic ring opening step, the nature of the substituents significantly affected the quantity of promoter required for the cyclization step. Although a superstoichiometric amount of iron(III) chloride and heat was required with an electron withdrawing substituent on the aryl ring, electron donating substituents lowered the activation barrier to cyclization – necessitating only catalytic amounts of iron(III) chloride at room temperature. This transformation represents the first report of a Nazarov cyclization with a vinyl sulfone on the central carbon

Exploring Enantioselective and Multicomponent One-Pot Reactions Utilizing Alkynes as Linchpins Toward Biologically Active Molecules

Robust synthetic methodology to make complex small molecules that are of biological importance is a highly investigated area. Utilizing fundamental bond-making reactions, like the Diels-Alder reaction and the Nazarov cyclization, in new efficient one-pot methodologies can help to expand the scope of reactions available to make such molecules. Using proprochiral and high energy starting materials like alkynes can afford reactive intermediates that can then undergo further transformations in one pot. The Diels-Alder (DA) reaction is a powerful synthetic tool that organic chemists have relied on for forming six-membered rings with good predictability for nearly a century. While there have been many reports of novel DA reactions and DA reactions in total syntheses, a void still exists in fully utilizing alkynyl dienophiles. There are very few enantioselective DA reactions that utilize alkynyl dienophiles, and none to date that utilize oxygen functionalized dienes. Herein we report a new BINOL-Al-Cl catalyst preparation that is robust enough to catalyze such a reaction with great success both in terms of yield and enantiomeric ratios. The products, 1,4-cyclohexadienes, have two regiochemically different alkenes, which can serve as functional handles that can be further elaborated to furnish molecules of biological interest. While expanding the scope of the enantioselective alkyne DA, alkynyl aldehydes were found to undergo a Hetero-Diels-Alder (HDA) reaction when reacted with oxygen functionalized dienes in the presence of aluminum Lewis acids. There is only one report for the development of an enantioselective HDA reaction utilizing an alkynyl aldehyde. Due to the highly reactive 1,4-cyclohexadiene produced by an alkyne DA reaction, this intermediate is poised to undergo a second, tandem DA reaction. From this tandem DA, a cis-decalin is produced. There are many biologically active terpenoids that contain the cis-decalin structural motif. This two-fold DA reaction proved to be a good method for rapid generation of cis-decalin molecules possessing biological activity. The highly reactive 1,4-cyclohexadiene intermediate formed from an alkyne DA reaction also proved to be poised to undergo a tandem Nazarov cyclization (NC). The reported tandem DA/NC is a reliable way to rapidly generate a library of [6-5-6] tricyclic molecules. In this report one compound contains a nitrogen-containing ring, which opens the door to utilizing heteroatom-containing starting materials. Using indole substituted alkynyl ketones in this reaction would produce even larger [6-5-5-6] tetracyclic molecules. Such polycyclic, heteroatom containing molecules are of high interest due to their abundance not only in nature, but in their use as pharmaceutical drugs

Development of New Domino Reactions of Alkylidene Meldrum’s Acids Involving Friedel-Crafts Chemistry and Catalytic Conjugate Allylation of Alkylidene Meldrum’s Acids

Alkylidene Meldrum’s acids are very reactive acceptors in conjugate additions, and are known to be significantly more electrophilic than other α,β-unsaturated carbonyl electrophiles. They also offer advantages in terms of ease of preparation, purification and storage. Despite this, they are relatively underused in organic synthesis, and have been treated as something of a curiousity in the literature. The goal of my research was to demonstrate the utility of these molecules in new reactions that are not readily available to other electrophiles. To facilitate this work, new conditions for the Knoevenagel condensation of aldehydes with Meldrum’s acid were developed. This allowed access to a broader range of monosubstituted alkylidenes than was previously possible from any single method. In a reaction that exploits the acylating ability of Meldrum’s acid, a domino addition of phenols to alkylidene Meldrum’s acids was developed. Here, Yb(OTf)3 catalyzed the addition of a phenol to the alkylidene as well as acylation through activation of the electrophile. The unique properties of these acceptors permitted synthesis of 3,4-dihydrocoumarins and coumarins through C-alkylation/O-acylation, and also 4-chromanones and chromones through O-alkylation/C-acylation. The predictable and general reversal of chemoselectivity is dependent on the number of substituents on the alkylidene. The same properties that make alkylidene Meldrum’s acids strong electrophiles also make them excellent dienophiles. A one-pot Diels-Alder/Friedel-Crafts process was used as an entry into the 6-5-6-tricyclic skeleton of a family of natural products that have been of interest in our group. The modular nature of the reaction allowed structural variation at nearly every position around both 6-membered rings. An attempted extension of this work into the synthesis of ergot alkaloids provided insight into the factors affecting Friedel-Crafts acylation of 4-substituted indoles. These results provided a highly regioselective entry into 4,5-fused indole ring systems. The electrophilicity of alkylidene Meldrum’s acids was combined with Lewis acid activation for development of a mild conjugate allylation reaction. The use of allyltriphenyltin as nucleophile for addition to monosubstituted alkylidenes avoided many of the practical disadvantages of working with trialkylstannanes. By employing such a relatively weak allylating agent, functional group compatibility was maximized to include groups susceptible to nucleophilic allylation. Additions to chiral, non-racemic alkylidenes were highly diastereoselective. It was also shown that functionalized all-carbon quaternary stereocentres can be formed by this process

Efficient synthesis of biologically active small molecules

Pancratistatin and narciclasine are natural products isolated from Pancratium litorale1 and Narcissus poeticus2 respectively. Pancratistatin and Narciclasine have been shown to possess potent antitumour activity3 however they have never been widely exploited due to their limited availability from natural sources.4 Pancratistatin and narciclasine both contain a dihydroisoquinolinone framework. The work described in this thesis explores synthetic routes relating to this dihydroisoquinolinone framework, as well as comparable tetrahydroisoquinolines. An initial proposed synthetic route involved the synthesis of the dihydroisoquinolinone framework via the corresponding indanone. Indanones have also been shown to possess potential antitumour activity.5 A range of lactam and indanone analogues were synthesised and a selection were tested for biological activity against cancer cell lines. The most biologically active lactam analogue synthesised was lactam 170. Lactam 170 was synthesised via two steps from commercially available starting materials in an overall 51 % yield and was tested in the HT29 colon cancer cell line to give an IC50 value of 9 μM. Indanone 177 is an analogue of natural product indanocine and was synthesised via two steps in an overall 49 % yield. Analogue 177 was tested in the 60 cell line screen by the National Cancer Institute (NCI) to give a mean GI50 value of 1.29 μM and is currently under consideration for further testing. This thesis describes the synthesis and biological testing of the aforementioned compounds as well as an array of analogues.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Efficient synthesis of biologically active small molecules

Pancratistatin and narciclasine are natural products isolated from Pancratium litorale1 and Narcissus poeticus2 respectively. Pancratistatin and Narciclasine have been shown to possess potent antitumour activity3 however they have never been widely exploited due to their limited availability from natural sources.4 Pancratistatin and narciclasine both contain a dihydroisoquinolinone framework. The work described in this thesis explores synthetic routes relating to this dihydroisoquinolinone framework, as well as comparable tetrahydroisoquinolines. An initial proposed synthetic route involved the synthesis of the dihydroisoquinolinone framework via the corresponding indanone. Indanones have also been shown to possess potential antitumour activity.5 A range of lactam and indanone analogues were synthesised and a selection were tested for biological activity against cancer cell lines. The most biologically active lactam analogue synthesised was lactam 170. Lactam 170 was synthesised via two steps from commercially available starting materials in an overall 51 % yield and was tested in the HT29 colon cancer cell line to give an IC50 value of 9 μM. Indanone 177 is an analogue of natural product indanocine and was synthesised via two steps in an overall 49 % yield. Analogue 177 was tested in the 60 cell line screen by the National Cancer Institute (NCI) to give a mean GI50 value of 1.29 μM and is currently under consideration for further testing. This thesis describes the synthesis and biological testing of the aforementioned compounds as well as an array of analogues.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Synthesis of Taiwaniaquinoids via Nazarov Triflation

A unified approach toward the taiwaniaquinoids that has yielded four natural products is described. A new variant of the Nazarov reaction with concomitant formation of an enol triflate serves as one of the key steps, considerably shortening the synthetic scheme and providing a general entry into this class of bioactive natural products