Diels-Alder reactions of 3-furylamines in organic and aqueous solvents

Various 5-methyl-3-aminofurans have been shown to undergo facile Diels-Alder reactions with methyl acrylate in aqueous media. Reactions proceeded with exclusive regiochemistry, and enamine cycloadducts were readily hydrolyzed to afford 7-oxabicyclo[2.2.1]heptanones in high yields

Studies toward the synthesis of salvinorin A

Salvinorin A [(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(acetyloxy)-2-(3-furanyl)-dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naptho[2,1-c]pyran-7-carboxylic acid methyl ester] is a trans-neoclerodane diterpene from the leaves of the hallucinogenic Mexican sage Salvia divinorum and has been identified as the principal psychoactive component in this plant of traditional spiritual importance. Salvinorin A is the most potent naturally occurring hallucinogen found so far and is reported to act selectively as a ƒÛ-opioid receptor agonist. Synthetic modification of the natural product has contributed to a number of proposed pharmacophores to identify the key structural features necessary for biological activity and a direct strategy for the asymmetric synthesis of the natural product is desirable since it allows access to a more diverse range of analogues. An ambitious retrosynthetic study of salvinorin A indicated the C(3)-heterosubstituted furan as an appropriate starting material for a Diels-Alder approach towards the ketone ring of the natural product. An expedient and high yielding methodology for the preparation of 3-furylamines is described, allowing the flexible introduction of alkyl substituents in the C(5) position. Optically pure ephedrine isomers have been explored as chiral amine auxiliaries and have been successfully attached as 3-furylamine substituents using the general methodology described. The 3-furylamines are electron rich dienes that are highly reactive towards Diels-Alder cycloaddition reactions with methyl acrylate. Diastereoisomers of the 7-oxanorbornane species methyl 1-methyl-5-oxo-7-oxa-bicyclo[2.2.1]heptane-2-carboxylate were prepared as new compounds from the hydrolysis of Diels-Alder cycloadducts and are functionalised bicyclic intermediates to access the ketone of the natural product. Diels-Alder reactions between the non-racemic (2S)-ephedrine-derived furans and methyl acrylate gave spiro-oxazolidine adducts that underwent hydrolysis to give the desired ketone. X-ray crystallography data for the derivatised cycloadduct established diastereoselectivity in favor of the (1S,4S)-enantiomer, as desired for the asymmetric natural product synthesis. A procedure for the ether cleavage of methyl 1-methyl-5-oxo-7-oxa-bicyclo[2.2.1]heptane-2-carboxylate was required to access the convergent precursor methyl 5-acetoxy-2-methyl-4-oxocyclohex-2-enecarboxylate. Successful C-O cleavage was achieved using Lewis-acid catalysis with BBr3 followed by mixing with the hindered base 2,4,6-collidine to yield methyl 5-hydroxy-2-methyl-4-oxocyclohex-2-enecarboxylate albeit only at high dilution. Acetylation proceeded in excellent yield in the same reaction vessel to give methyl 1-methyl-5-oxo-7-oxa-bicyclo[2.2.1]heptane-2-carboxylate in excellent yield. The devised synthetic pathway is shown to successfully construct the ketone ring of salvinorin A and stereoselectivity for the (1S,4S)-enantiomer can be achieved using the ephedrine derived furans as desired for the asymmetric natural product synthesis. The ƒÔ-lactone ring 6-(furan-3-yl)-5,6-dihydro-4-methyl-3-vinylpyran-2-one was derived from rudimentary precursors as a convergent reagent to introduce the lactone ring of salvinorin A. A short synthesis for the racemic compound is described starting from the aldol reaction between 3-furaldehyde and acetone to give the 3-furfurol, 4-(furan-3-yl)-4-hydroxybutan-2-one in quantitative yield. The 3-furfurol was reacted to form the ƒÑ-bromovinyl ester, 1-(furan-3-yl)-3-oxobutyl 2-bromobut-3-enoate using a deconjugation/esterification protocol with 2-bromobut-3-enoyl chloride. Intramolecular ring closure to the ƒÔ-lactone was achieved using a Reformatsky reaction and dehydration under acidic conditions yielded the racemic convergent precursor 6-(furan-3-yl)-5,6-dihydro-4-methyl-3-vinylpyran-2-one in high yield. A possible strategy for joining the ketone and lactone fragments for the total synthesis of salvinorin A is proposed

Studies towards the synthesis of Salvinorin A

Salvinorin A 1, a psychoactive neoclerodane diterpenoid from the Mexican sage S. divinorum, has gained interest as a selective kappa-opioid receptor agonist. Non-racemic 3-furylamines 9a and 9b have been prepared from (+)-pseudoephedrine and (-)-ephedrine for application in the stereoselective synthesis of the ketone ring of 1. Diels-Alder reaction of 9b with methyl acrylate in aqueous media, followed by selective ether bridge cleavage, has allowed access to the cyclohexenone 17 with preservation of stereochemistry at C2. A model route to the lactone ring has also been achieved through a one-pot deconjugation/esterification procedure of 2-bromocrotonyl chloride 20 to the furyl alcohol 19 followed by Reformatski-mediated ring closure

Studies towards the synthesis of fibronectin-based peptidomimetics

Fibronectin (FN) protein was discovered in the early 1970s by Richard Hynes. Since then this large, multidomain glycoprotein present in the extracellular matrix and in body fluids has been intensively research, and has been found to play a fundamental role in cell adhesion, cell migration, cell survival, angiogenesis, and other important biological processes. In recent years the interest in FN has risen; the novel FN isoform, termed Migration Stimulating Factor (MSF) has been cloned and characterized, and new results documenting the involvement of FN and MSF in wound healing, cancer progression and bacterial metastasis have been presented. The recent findings have shown that MSF’s bioactivities (e.g. stimulation of cell motility, hyaluronan synthesis and angiogenesis) are mediated by the highly conserved amino acid motif Ile-Gly-Asp (IGD), and are mimicked by small synthetic peptides containing this sequence. The aim of this project was to design and synthesize first generation non-peptidic compounds which could mimic the biological activity of MSF (i.e. IGD peptidomimetics). The second part of this thesis describes the role of FN in bacterial pathogenesis. Staphylococcus aureus is commonly present in the nose and on the skin of one third of all people, and is normally harmless at these sites. However, the microorganism possesses the ability to enter the body, invade cells and cause infection. The mechanism for S. aureus adhesion to, and invasion of, human cells has been extensively studied. It is now postulated that bacterial invasion is mediated by FN, that acts as a bridge between bacterial proteins adhesins and integrin receptors present on the cell surfaces. The biologically active motif, by which FN mediates its adhesion to bacterium, has not been unambiguously identified. However, the preliminary, unpublished studies point towards a short terapeptide sequence, Gly-Arg-Ile-Ser (GRIS), which is highly conserved within FN. We proposed to elucidate the role of the native GRIS motif by synthesising a small, nonpeptidic molecule, which could mimic its biological properties and activities

New functionalised 3-hydroxypyridines

This thesis is concerned with the synthesis and reactions of functionalised 3- liydroxypyridines, in particular 2-aryl- and 2-heteroary 1-3-liydroxypyridines by non- coupling methodology, from furan precursors. Chapter 1 reviews the synthesis and reactions of 3-hydroxypyridines. Chapter 2 describes the synthesis of 2-acylfurans via differing methods, which include acylation of the furan nucleus, Grignard reactions of furaldehydes and, most notably, reaction of lithiofurans with reagents containing a nitrile component. Chapter 3 concerns reaction of acylfurans with ammonia at high pressure and temperature to produce 3-hydroxypyridines. We have found that this ring expansion is able to withstand many differing substituents including bromine. Further development of the pyridine ring system involves reaction of the ring atoms or substituents, including protection of the hydroxy group. This ring expansion was used in the development of a novel azabenzotriazole starting from a simple furan compound, and this is reported in Chapter 4.The methodology described in this thesis is versatile and has allowed access to a range of novel pyridine derivatives in synthetically useful quantities which should be of interest in many areas of organic chemistry

Novel synthesis of highly functionalised furans and investigation into a cope rearrangement of furylvinylcyclopropanes

Furans are important heteroaromatic units that occur as subunits in various complex natural products, biologically active compounds and pharmaceuticals. Due to their pharmacophoric properties they find widespread application e.g. in the drug discovery process. In contrast to the classical condensation based-methods and metal-mediated approaches, organocatalytic methods for construction of furan have been relatively unexplored. The opening chapter details investigation undertaken into furan formation methodology developed within the Clark group. It was determined that the choice of the acid species was vital for proton transfer to ensure clean and effective conversion of the substrates into the desired furans. Studies were carried out using a chiral acid in an attempt to deliver the furan product in an enantioselective manner. Since the formation of a new stereocentre is achieved in this process, we investigated the potential development of a diastereoselective reaction using substrates bearing an existing stereocentre. The original organocatalytic furan synthesis using THT and ynenedione with nucleophiles was successfully expanded by designing a substrate with a tethered nucleophile that initiates a second cyclization to form polycyclic systems. Cyclohepta[b]furans are an important class of organic compounds found in many natural products, pharmaceuticals, bioactive compounds and functional materials. The development of efficient routes for their formation is therefore of great interest to the synthetic chemist. The second chapter details research undertaken towards a new methodology for the construction of cyclohepta[b]furans. Starting from a simple linear ynenedione the cascade reaction affords furans containing a fused bicyclic system which rearrange to cycloheptadienes. Since it has been observed that the cyclisation and rearrangement occurred successfully it was hypothesised that it may be possible to carry out furan formation followed by Cope rearrangement in a one-pot fashion without isolation of the furan intermediate