Photocatalytic Transformations of Electron-Deficient Alkenes.

PhD Theses.Alkenes are excellent platform chemicals that can undergo various transformations to generate valuable compounds with a range of industrial applications. In recent years, photocatalysis has been increasingly applied in organic synthesis as a unique way of generating radical intermediates that are otherwise not easily accessible. While alkene activation by single electron transfer (SET) oxidation have been studied extensively for photocatalytic hydrofunctionalizations, examples involving SET reduction to the anionic radical species is scarce and the methods are limited by a narrow scope. Unless highly reducing systems were employed, photoreduction of less-activated alkenes bearing one electron-withdrawing group has not been reported to date. Thus, there is a need for new strategies to perform reductive transformations of simple alkenes. As an alternative to these methods that require either highly oxidizing or reducing conditions, we hypothesized that a different alkene activation strategy could be developed by exploiting hydrogen atom transfer (HAT) chemistry. Our developed photoreduction strategy (Chapter 2) is applicable to over 20 substrates including methyl cinnamate derivatives and other synthetically useful alkenes. Through experimental and computational studies, we have confirmed that the transformation is enabled by an unprecedented hydrogen atom transfer from the oxidized Hantzsch ester to the alkene substrates. The findings from our investigation have driven us to explore other photocatalytic transformations of electron-deficient alkenes. A systematic study was carried out towards developing E to Z isomerization strategies that rely on substrate activation, omitting the need of pre-functionalization (Chapter 3). The last part of this thesis describes our α-selective hydroaminoalkylation protocol for accessing beta-amino acids from a variety of methyl cinnamate and aniline analogues (Chapter 4). This methodology has been successfully applied to styrenes, proving its versatility to generate functionalized amines in a single step

Total Synthesis of Tiacumicin A. Total Synthesis, Relay Synthesis, and Degradation Studies of Fidaxomicin (Tiacumicin B, Lipiarmycin A3)

The commercial macrolide antibiotic fidaxomicin was synthesized in a highly convergent manner. Salient features of this synthesis include a β-selective noviosylation, a β-selective rhamnosylation, a ring-closing metathesis, a Suzuki coupling, and a vinylogous Mukaiyama aldol reaction. Careful choice of protecting groups and fine-tuning of the glycosylation reactions led to the first total synthesis of fidaxomicin. In addition, a relay synthesis of fidaxomicin was established, which gives access to a conveniently protected intermediate from the natural material for derivatization. The first total synthesis of a related congener, tiacumicin A, is presented

Efficient reduction of electron-deficient alkenes enabled by a photoinduced hydrogen atom transfer

Direct hydrogen atom transfer from a photoredox-generated Hantzsch ester radical cation to electron-deficient alkenes has enabled the development of an efficient formal hydrogenation under mild, operationally simple conditions. The HAT-driven mechanism is supported by experimental and computational studies. The reaction is applied to a variety of cinnamate derivatives and related structures, irrespective of the presence of electron-donating or electron-withdrawing substituents in the aromatic ring and with good functional group compatibility

Letter: A photocatalytic regioselective direct hydroaminoalkylation of aryl-substituted alkenes with amines

A photocatalytic method for the α-selective hydroaminoalkylation of cinnamate esters has been developed. The reaction involves the regioselective addition of α-aminoalkyl radicals generated from aniline derivatives or aliphatic amines to the α-position of unsaturated esters. The scope of aromatic alkenes was extended to styrenes undergoing hydroaminoalkylation with anti-Markovnikov selectivity, which confirms the importance of the aromatic group at the β-position. Simple scale-up is demonstrated under continuous flow conditions, highlighting the practicality of the method

Stereoselective Arene-Forming Aldol Condensation: Catalyst-Controlled Synthesis of Axially Chiral Compounds

The fundamental role that aldol chemistry adopts in various disciplines, such as stereoselective catalysis or the biosynthesis of aromatic polyketides, illustrates its exceptional versatility. On the one hand, numerous aldol addition reactions reliably transfer the stereochemical information from catalysts into various valuable products. On the other hand, countless aromatic polyketide natural products are produced by an ingenious biosynthetic machinery based on arene-forming aldol condensations. With the aim of complementing aldol methodology that controls stereocenter configuration, we recently combined these two tenets by investigating small-molecule-catalyzed aldol condensation reactions that stereoselectively form diverse axially chiral compounds through the construction of a new aromatic ring

A novel biomimetic synthesis of resorcylic acid lactones; via macrolactonization and transannular aromatization

Resorcylic acid lactones (RALs) are biologically active polyketide natural products with typically a large macrocyclic ring fused to a resorcylic unit.i This thesis outlines novel biomimetic syntheses of such natural products utilizing intramolecular capture of acylketenes for macrolactonization and subsequent transannular aromatization to form resorcylic cores in a one-pot procedure. This strategy is sufficiently concise for analogue synthesis and therefore has potential use for pharmaceutical applications. One of the RAL family, namely (S)-zearalenone (5), was successfully synthesized following our developed strategy. The key acylketene precursor 3 was prepared in eight steps from norbonene 1 via alkene 2 in excellent E/Z selectivity. Thermolysis of 3 provided macrocycle 4 by retro-Diel-Alder fragmentation which in turn underwent ketal deprotection and transannular aromatization to give the natural product 5 in high yields.ii [Molecular structure diagrams appear here. To view, please open pdf attachment] Following the successful synthesis of (S)-zearalenone (5), this methodology was applied to a more complex target, LL-Z1640-2 (9). The synthesis of diketo-dioxinone 7 was achieved via Weinreb amide 6 in eight steps. The key transformations included selective Lindlars reduction of alkyne 6 and the incorporation of keto-dioxinone unit 10 by dianion chemistry. Upon heating a hydroxy-keto-dioxinone 7, macrocyclic triketo-ester was generated which smoothly aromatized to afford resorcylate 8 in a one-pot procedure. Further three steps of manipulation on resorcylate 8 furnished TAK-kinase inhibitor 9.iii [Molecular structure diagrams appear here. To view, please open pdf attachment] Extensive studies have been carried out towards the racemic synthesis of dimeric dihydroisocoumarin, known as tragoponol (16). Our aim included the use of inter- and intra-molecular ketene trapping which would be followed by two separate aromatizations to construct its dilactone structure. The left hand side resorcylate unit rac-14 was synthesized in seven steps starting from commercially available β-keto-ester 11 through a ketene trapping and an aromatization sequence utilizing diketo-dioxinone rac-12 and alcohol rac-13. The incorporation of keto-dioxinone unit was achieved by C-acylation of dilithium enolate derived from keto-dioxinone 10 with Weinreb amide rac-14 to give diketo-dioxinone rac-15 in high yield. [Molecular structure diagrams appear here. To view, please open pdf attachment] The final part of this thesis describes the studies carried out on a recently isolated RAL called paecilomycin B (21). A unique tetrahydropyran unit within the macrocyle is one of its attractive structural features. The key precursors 18 were successfully synthesized in five steps from alcohol 17. The introduction of four stereogenic centres was controlled by a diastereoselective aldol reaction, a CBS-reduction, and a directed epoxidation of an allylic alcohol. [Molecular structure diagrams appear here. To view, please open pdf attachment] (i) Schirmer, A.; Kennedy, J.; Murli, S.; Reid, R.; Santi, D. V. PNAS, 2006, 103, 4234. (ii) Miyatake-Ondozabal, H.; Barrett, A. G. M. Tetrahedron 2010, 66, 6331. (iii) Miyatake-Ondozabal, H.; Barrett, A. G. M. Org. Lett. 2010, 12, 5573

Total synthesis of the protected aglycon of fidaxomicin (Tiacumicin B, Lipiarmycin A3)

Fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is a novel macrocyclic antibiotic that is used in hospitals for the treatment of Clostridium difficile infections. This natural product has also been shown to have excellent bactericidal activity against multidrug-resistant Mycobacterium tuberculosis. In spite of its attractive biological activity, no total synthesis has been reported to date. The enantioselective synthesis of the central 18-membered macrolactone is reported herein. The key reactions include ring-closing metathesis between a terminal olefin and a dienoate moiety for macrocyclization, a vinylogous Mukaiyama aldol reaction, and a Stille coupling reaction of sterically demanding substrates. The retrosynthesis involves three medium-sized fragments, thus leading to a flexible yet convergent synthetic route

Efficient Reduction of Electron-Deficient Alkenes Enabled by a Photoinduced Hydrogen Atom Transfer

Direct hydrogen atom transfer from a photoredox-generated Hantzsch ester radical cation to electron-deficient alkenes has enabled thedevelopment of an efficient formal hydrogenation under mild, operationally simple conditions. The HAT-driven mechanism, key to circumventthe problems associated with the low electron affinity of alkenes, is supported by experimental and computational studies. The reaction is appliedto a variety of cinnamate derivatives and related structures, irrespective of the presence of electron-donating or electron-withdrawingsubstituents in the aromatic ring and with good functional group compatibility