Thorsten Bach

Photochemical Reactions as Key Steps in Natural Product Synthesis

Photochemical reactions contribute in a significant way to the existing repertoire of carbon-carbon bond-forming reactions by allowing access to exceptional molecular structures that cannot be obtained by conventional means. In this Review, the most important photochemical transformations that have been employed in natural product synthesis are presented. Selected total syntheses are discussed as examples, with particular attention given to the photochemical key step and its stereoselectivity. The structural relationship between the photochemically generated molecule and the natural product is shown, and, where necessary, the consecutive reactions in the synthesis are illustrated and classified.

Catalytic enantioselective reactions driven by photoinduced electron transfer.

Photoinduced electron transfer is an essential step in the conversion of solar energy into chemical energy in photosystems I and II (ref. 1), and is also frequently used by chemists to build complex molecules from simple precursors. During this process, light absorption generates molecules in excited electronic states that are susceptible to accepting or donating electrons. But although the excited states are straightforward to generate, their short lifetimes makes it challenging to control electron transfer and subsequent product formation—particularly if enantiopure products are desired. Control strategies developed so far use hydrogen bonding, to embed photochemical substrates in chiral environments and to render photochemical reactions enantioselective through the use of rigid chiral complexing agents. To go beyond such stoichiometric chiral information transmission, catalytic turnover is required. Here we present a catalytic photoinduced electron transfer reaction that proceeds with considerable turnover and high enantioselectivity. By using an electron accepting chiral organocatalyst that enforces a chiral environment on the substrate through hydrogen bonding, we obtain the product in significant enantiomeric excess (up to 70%) and in yields reaching 64%. This performance suggests that photochemical routes to chiral compounds may find use in general asymmetric synthesis.

Pd(II)-Catalyzed Regioselective 2-Alkylation of Indoles via a Norbornene-Mediated C–H Activation: Mechanism and Applications

A palladium-catalyzed direct 2-alkylation reaction of free N-H indoles was developed based on a norbornene-mediated regioselective cascade C-H activation. The detailed reaction mechanism was investigated by NMR spectroscopic analyses, characterization of the key intermediate, deuterium labeling experiments, and kinetic studies. The results indicate that a catalytic cycle operates, in which an N-norbornene type palladacycle is formed as the key intermediate. Oxidative addition of alkyl bromide to the Pd(II) center in this intermediate is the rate-determining step of the reaction. The synthetic utility of this indole 2-alkylation method was demonstrated by its application in natural product total synthesis. A new and general strategy to synthesize Aspidosperma alkaloids was established employing the indole 2-alkylation reaction as the key step, and two structurally different Aspidosperma alkaloids, aspidospermidine and goniomitine, were synthesized in concise routes.

Enantioselective Catalysis of Photochemical Reactions

The nature of the excited state renders the development of chiral catalysts for enantioselective photochemical reactions a considerable challenge. The absorption of a 400 nm photon corresponds to an energy uptake of approximately 300 kJ mol(-1) . Given the large distance to the ground state, innovative concepts are required to open reaction pathways that selectively lead to a single enantiomer of the desired product. This Review outlines the two major concepts of homogenously catalyzed enantioselective processes. The first part deals with chiral photocatalysts, which intervene in the photochemical key step and induce an asymmetric induction in this step. In the second part, reactions are presented in which the photochemical excitation is mediated by an achiral photocatalyst and the transfer of chirality is ensured by a second chiral catalyst (dual catalysis).

Palladium-Catalyzed Direct 2-Alkylation of Indoles by Norbornene-Mediated Regioselective Cascade C–H Activation

A palladium-catalyzed direct 2-alkylation reaction of free N-H indoles has been developed. This reaction relies on a norbornene-mediated cascade C-H activation process at the indole ring, which features high regioselectivity and excellent functional group tolerance. The reaction represents the first example for a generally applicable, direct C-H alkylation of indole at the 2-position.

Recent Advances in the Synthesis of Cyclobutanes by Olefin [2 + 2] Photocycloaddition Reactions

The [2 + 2] photocycloaddition is undisputedly the most important and most frequently used photochemical reaction. In this review, it is attempted to cover all recent aspects of [2 + 2] photocycloaddition chemistry with an emphasis on synthetically relevant, regio-, and stereoselective reactions. The review aims to comprehensively discuss relevant work, which was done in the field in the last 20 years (i.e., from 1995 to 2015). Organization of the data follows a subdivision according to mechanism and substrate classes. Cu(I) and PET (photoinduced electron transfer) catalysis are treated separately in sections 2 and 4, whereas the vast majority of photocycloaddition reactions which occur by direct excitation or sensitization are divided within section 3 into individual subsections according to the photochemically excited olefin.

Enantioselective Lewis Acid Catalysis of Intramolecular Enone [2+2] Photocycloaddition Reactions

[2+2] Asymmetrically Catalysts in thermal reactions operate by lowering energy barriers of bound substrates, and thereby increasing the proportion of reagents that can proceed to products at a given temperature. In photochemical reactions, light provides the energy to surmount the barrier. It is therefore challenging to alter selectivity through catalysis, because the catalyst may not be bound when a given reagent absorbs the light. Brimioulle and Bach (p. 840) surmounted this problem in the light-induced intramolecular [2+2] cycloaddition of enones by using a catalyst that shifted the absorption wavelength of the bound substrate. The light was thus predominantly absorbed by substrate-catalyst complexes, enabling asymmetric induction by the catalyst to provide enantiomerically enriched products. A catalyst attains selectivity in a photochemical reaction by shifting the absorption wavelength of its complexed substrate. Asymmetric catalysis of photochemical cycloadditions has been limited by the challenge of suppressing the unselective background reaction. Here, we report that the high cross-section ππ* transition of 5,6-dihydro-4-pyridones, a versatile class of enone substrates, undergoes a >50 nanometer (nm) bathochromic absorption shift upon Lewis acid coordination. Based on this observation, enantioselective intramolecular [2+2] photocycloaddition reactions (82 to 90% enantiomeric excess) were achieved with these substrates using 0.5 equivalents of a chiral Lewis acid upon irradiation at a wavelength of 366 nm. One of the products was applied as a key intermediate in the total synthesis of (+)-lupinine and the formal synthesis of (+)-thermopsine. Several enones show similar bathochromic shifts in the presence of a Lewis acid, indicating that chiral Lewis acid catalysis may be a general approach toward enantioselective enone [2+2] photocycloadditions.

Enantioselective intramolecular (2+2)-photocycloaddition reactions of 4-substituted quinolones catalyzed by a chiral sensitizer with a hydrogen-bonding motif

Six 2-quinolones, which bear a terminal alkene linked by a three- or four-membered tether to carbon atom C4 of the quinolone, were synthesized and subjected to an intramolecular [2 + 2]-photocycloaddition. The reaction delivered the respective products in high yields (78-99%) and with good regioselectivity in favor of the straight isomer. If conducted in the presence of a chiral hydrogen-bonding template (2.5 equiv) at low temperature in toluene as the solvent, the reaction proceeded enantioselectively (83-94% ee). An organocatalytic reaction was achieved when employing a chiral hydrogen-bonding template with an attached sensitizing unit (benzophenone or xanthone). The xanthone-based organocatalyst proved to be superior as compared to the respective benzophenone. Closer inspection revealed that the reaction of 4-(pent-4-enyloxy)quinolone leading to a six-membered ring, annelated to the cyclobutane, was less enantioselective (up to 41% ee with 30 mol % catalyst) than the reaction of 4-(but-3-enyloxy)quinolone leading to a five-membered ring (90% ee with 5 mol % and 94% ee with 20 mol % catalyst). Photophysical data (emission spectra, laser flash photolysis experiments) proved that the latter photocycloaddition was significantly faster, supporting the idea that the dissociation of the substrate from the catalyst prior to the photocycloaddition is responsible for the decreased enantioselectivity. Under optimized conditions, employing 10 mol % of the xanthone-based organocatalyst at -25 °C in trifluorotoluene as the solvent, three of the other four substrates gave the intramolecular [2 + 2]-photocycloaddition products with high enantioselectivities (72-87% ee). In all catalyzed reactions, the yields based on conversion were moderate to good (40-93%).

A Chiral Thioxanthone as an Organocatalyst for Enantioselective [2+2] Photocycloaddition Reactions Induced by Visible Light†

Thioxanthone 1, which was synthesized in a concise fashion from methyl thiosalicylate, exhibits a significant absorption in the visible light region. It allows for an efficient enantioselective catalysis of intramolecular [2+2] photocycloaddition reactions presumably by triplet energy transfer.

Light-Driven Enantioselective Organocatalysis†

In recent years, organocatalysis has emerged as an important area of modern catalysis that complements metal catalysis and enzyme catalysis. Many chiral compounds that could not be prepared previously in enantiomerically pure form by other transformations, or which were only obtained in tedious reaction sequences, were made accessible by organocatalytic reactions. Nonetheless, there are still many product classes that are not available by conventional enantioselective organocatalysis. Any reaction pathway requiring photochemical but not thermal activation is inherently impossible to be catalyzed by a classical organocatalyst unless the process of photochemical activation and catalysis are separated. Processes in which light energy serves as direct driving force for enantioselective bond formation require the design of chiral organocatalysts to harvest light and allow sensitization of the substrate by energy or electron transfer. 5] After initial success in this area employing a catalytic photoinduced electron transfer (up to 70 % ee with 30 mol% catalyst), herein we present a chiral organocatalyst that combines a significant rate acceleration by triplet energy transfer with high enantioselectivities. In the studied test reaction (Scheme 1), a yield of 90 % and an enantioselectivity of 92% ee were achieved with only 10 mol% of this catalyst. The intramolecular [2+2] photocycloaddition of quinolone 1, first described by Kaneko et al., leads to two regioisomeric products: the predominant straight product 2, and the crossed product 3. This particular transformation was selected as test reaction, because it delivers a cycloaddition product by a rapid five-membered ring closure, and because it had already been shown by Krische et al. that a sensitization of this reaction is possible by a chiral benzophenone (19% ee with 25 mol% catalyst). The latter result provided hope that a catalytic reaction course might be feasible with the benzophenone 4 described earlier. The