Abstract

Abstract

Abstract

Resistenzeffekte beeinträchtigen zunehmend die Anwendung von Artemisinpräparaten gegen Malaria, sodass die Entwicklung von Derivaten oder verwandten cyclischen Peroxidstrukturen dringender wird. Eine Sequenz aus ¹O₂-En-Reaktion und nachfolgender Lewis-Säure-katalysierter Peroxacetalisierung bietet eine vielseitige Route zu neuen bicyclischen Peroxiden und Perorthoestern (siehe Schema).

Resistance effects to the antimalarial agent artemisinin and its derivatives spurs on the search for new compounds with related cyclic peroxide structures. A flexible route to new bicyclic peroxides and perorthoesters is provided by a sequence of ¹O₂ ene reaction and subsequent Lewis acid catalyzed peroxyacetalization.

The ene reaction of chiral allylic alcohols is applied as a tool for the investigation of intrapolymer effects by means of the stereoselectivity of the singlet-oxygen addition. The diastereo selectivity strongly depends on the structure of the polymer, the substrate loading degree and also on the degree of conversion demonstrating additional supramolecular effects evolving during the reaction. The efficiency and the stability of polymer-bound sensitizers were evaluated by the ene reaction of singlet oxygen with citronellol. The ene reaction with chiral ammonium salts of tiglic acid was conducted under solution phase conditions or in polystyrene beads under chiral contact ion-pair conditions. The products thus obtained precipitate during the photoreaction as ammonium salts. Moderate asymmetric induction was observed for this procedure for the first time.

Triplet 1,4-biradicals were generated by Norrish-Type-II hydrogen transfer from α-heteroatom-substituted β-branched butyrophenones 1–6 and detected by laser flash absorption measurements. For three oxy-substituted compounds 2–4 (R_α=OH, OCOMe, OCOOEt) comparable lifetimes were determined in acetonitrile (roughly 1.5 μs). In benzene, divergent trends were observed: for the hydroxy compound 2 a lower lifetime of 790 ns was determined, whereas for 3 and 4 the lifetimes increased to 4.9 μs. Photolyses of the α-amino-substituted compounds 1 and 6 resulted in transient species with significant lower lifetimes (for 1 160 ns in benzene and 450 ns in acetonitrile; for 6 <100 ns in both solvents). The mesyloxy substrate 5 undergoes rapid CO bond cleavage upon photolysis and no transient triplet species were detected. Computational (UB3 LYP/6–31G* and natural don orbital (NBO) analyses) results supported the assumption of a negative hyperconjugative interaction strongly stabilizing α-oxy-substituted over α-amino-substituted radicals.

Two reaction protocols are described which involve the use of polymer supports as reaction media for photooxygenation processes: 1) The use of polystyrene beads (PS) loaded with tetraphenyl- (TPP) or tetratolylporphyrin (TTP), swollen with the substrate in an appropriate organic solvent and subsequent irradiation under air. Products were isolated simply by dissolution in alcoholic solvents and filtration. 2) Covalently linked tetrastyrylporphyrin in polystyrene-divinylbenzene beads were synthesized by emulsifier-free emulsion polymerization and directly used for the photooxygenation protocol described above. The latter alternative allows also the use of less polar solvents for the extraction of the oxygenation products from the polymer beads. From the sensitizer loading degree, an optimal substrate/sensitizer molar ratio of 1,000–2,000 was determined and recyclization is possible for at least five times resulting in a minimum turnover number (with respect to the sensitizer TTP) of 5×10⁴ (after five cycles). Both approaches were applied to the ene reaction of singlet oxygen with citronellol (1), the regioisomeric pinenes 3 and 5, and the allylic alcohols 9a–c, respectively, as well as to the [4+2]-cycloadditions of singlet oxygen to sorbinol (7) and the chiral diene 11.

The synthesis of a variety of cyclic peptides from N-phthaloyl-protected di-, tri-, tetra-, and pentapeptides with different aminocarboxylic acid tethers by photodecarboxylation – initiated by intramolecular electron transfer – has been explored in aqueous media. The progress and the chemoselectivity of the follow-up processes after CO₂ extrusion were traced by the respective pH/time-profiles, as well as by the overall change in pH after completion of the reaction. The competition between cyclization and simple oxidative decarboxylation depends on spacer length and geometry, H-bonding interaction between the electron accepting phthalimide CO groups and amide H-atoms, as well as the geometric reorganization coupled with the radical combination step and the formation of the lactam rings. With progressing reaction, hydrolysis of the phthalimide chromophore becomes an increasingly important side reaction due to the constant increase in pH. The use of phosphate-buffered aqueous media consequently improved the cyclization yields. The ground-state interactions between amide groups and the terminal COO⁻ group with the imide CO groups were studied for the model system [N-(phthaloyl)glycyl]sarcosine (1) by NMR spectroscopy where the amide (E/Z)-equilibrium depends on the presence of carboxylate vs. free carboxylic acid, demonstrating the role of H-bonding and metal coordination.

Eines der interessantesten Phänomene des Lebens auf der Erde ist die Chiralität von Biomolekülen, deren Ursprung nach wie vor nicht geklärt ist. Eine der großen Herausforderungen, die mit diesem Phänomen verknüpft ist, ist die selektive und atomökonomische Synthese enantiomerenreiner Zielverbindungen aus nicht-chiralen Ausgangsverbindungen. In diesem Beitrag werden neue Entwicklungen auf dem Gebiet der asymmetrischen Photochemie und der Photochirogenese sowie der absoluten asymmetrischen Synthese beschrieben. Außerdem werden die möglichen Ursachen der Homochiralität auf der Erde sowie der Zusammenhang mit physikochemischen Parametern dargestellt.

One of the most interesting phenomena on Earth is the chirality of biomolecules, the origin of which remains unknown. A challenge arising from this phenomenon is the selective, atom-economic synthesis of enantiomerically pure target molecules from nonchiral starting materials. Herein, new developments in the field of asymmetric photochemistry and photochirogenesis are described with special emphasis on absolute asymmetric synthesis. In this context, the elucidation of the ultimate cause of homochirality phenomena on earth and the possible correlation with physicochemical parameters are also presented.

The intramolecular and intermolecular photoinduced electron transfer reactions of a series of mercaptoacetic acid and mercaptopropionic acid derivatives were investigated. In the intermolecular series, the phthalimidoalkylsulfanylalkylcarboxylates 1a−j and 2 were transformed into the tricyclic ring systems 3a−j and 4, respectively, with high regioselectivities. The mercaptoacetic acid and 2-mercaptopropionic acid derived substrates 1a−g and 2 readily cyclized in good to excellent yields (60−98%) but with low diastereoselectivities (except for 1d), whereas the corresponding 3-mercaptopropionic acid derived substrates 1h−j gave the corresponding tricyclic products 3h−j after prolonged irradiation, but with poor yields (11−20%). The intermolecular version − i.e., photodecarboxylative addition to N-methylphthalimide (5) as electron acceptor − was successful with mercaptoacetic acid, and 2-mercaptopropionic acid substrates 6a−c and the addition products 7a−c were obtained in high yields (57−90%). No addition, however, was observed with 3-(methylsulfanyl)propionic acid (6d). The regioselectivity of decarboxylation proceeded in a controlled manner for the mercaptosuccinic acid derivatives in both the intramolecular (with 8a−c) and the intermolecular (with 9) versions. Comparison between sulfur-activated and nonactivated species (13, 15) or irradiation of 1a under nonactivating conditions showed that the carboxylate anion in the position α to the electron-donating sulfur atom acts as a superior leaving group. This efficiency is drastically reduced for carboxylate anions in the β position. With the former substrates, the photochemical cyclization proceeds with high product yields. Quantum yield measurements for decomposition (Φ_d as a measure for cyclization) supported these observations. CV measurements indicated preorientation prior to electron transfer in the intramolecular pathway.

The multiplicity of the excited state controls the product distribution in the formation of endo/exo-oxetane 3 in the photocycloaddition of aldehydes 1 (R = Ph, Et, Me, iBu) with dihydrofuran 2 (Paternò–Büchi reaction). Whether the singlet or triplet channel dominates is strongly dependent on the temperature, which is therefore critical for the selectivity of the reaction.

Die Multiplizität des angeregten Zustandes kontrolliert die Produktverteilung bei der Bildung der endo/exo-Oxetane 3 durch Photocycloaddition von Aldehyden 1 (R=Ph, Et, Me, iBu) an 2,3-Dihydrofuran 2 (Paternò-Büchi-Reaktion). Ob dabei der Singulett- oder der Triplettkanal dominiert, hängt stark von der Temperatur ab, die sich damit als entscheidende Einflussgröße auf die Selektivität der Reaktion entpuppt.

The photooxygenation of 2,4-dimethyl-1,3-pentadiene (1) was investigated in seven polar and nonpolar solvents by oxygen-uptake measurements. The overall deactivation rate k_o ( = k_r + k_q) was additionally measured in chloroform solutions by singlet-oxygen (¹Δ_g) phosphorescence quenching which showed excellent agreement with the data from the detailed steady-state kinetics. The difference in solvent-polarity effects on the [4 + 2] cycloaddition (major path, leading to the endoperoxide 2) and ene reaction (minor path, leading to the allylic hydroperoxide 3) are explained by competition between a concerted and a perepoxide mechanism. In all solvents the physical quenching of singlet oxygen by 1 is at least as efficient as the chemical quenching. The reaction of the endoperoxide 2 and 3,3,6,6-tetramethyl-1,2-dioxene 9 with carbonyl compounds in the presence of TMSOTf resulting in the dihydrofuran 8 and the 1,2,4-trioxane 10, was also studied.

The twofold bridged sesquinorbornenes 2 and 6 were prepared using sequential [4 + 2] cycloadditions of benzoquinone with 1,5-dihydropentalenes 1 and 5. These syntheses were improved using dilution conditions or a more reactive substituted benzoquinone. Results from semiempirical and ab initio DFT calculations indicated remarkably high pyramidalization angles (ϕ = 46-47°) for the central C–C double-bond atoms. The chemical reactivity with triplet and singlet oxygen, dimethyldioxirane and N-methyl-1,2,4-triazoline-3,5-dione supports these structural assignments.