The present review offers an overview of the current approaches for the photochemical and photocatalytic generation of reactive intermediates and their application in the formation of carbon–carbon bonds. Valuable synthetic targets are accessible, including arylation processes, formation of both carbo- and heterocycles, alpha- and beta-functionalization of carbonyls, and addition reactions onto double and triple bonds. According to the recent advancements in the field of visible/solar light catalysis, a significant part of the literature reported herein involves radical ions and radicals as key intermediates, with particular attention to the most recent examples. Synthetic application of carbenes, biradicals/radical pairs and carbocations have been also reported.

Carbon-Carbon Bond Forming Reactions via Photogenerated Intermediates.

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.

Photochemical reactions as key steps in natural product synthesis

Chemistry and Biology of Mycotoxins and Related Fungal Metabolites

Many fungi, lichens, and bacteria produce xanthones (derivatives of 9H-xanthen-9-one, “xanthone” from the Greek “xanthos”, for “yellow”) as secondary metabolites. Xanthones are typically polysubstituted and occur as either fully aromatized, dihydro-, tetrahydro-, or, more rarely, hexahydro-derivatives. This family of compounds appeals to medicinal chemists because of their pronounced biological activity within a notably broad spectrum of disease states, a result of their interaction with a correspondingly diverse range of target biomolecules. This has led to the description of xanthones as “privileged structures”.(1) Historically, the total synthesis of the natural products has mostly been limited to fully aromatized targets. Syntheses of the more challenging partially saturated xanthones have less frequently been reported, although the development in recent times of novel and reliable methods for the construction of the (polysubstituted) unsaturated xanthone core holds promise for future endeavors. In particular, the fascinating structural and biological properties of xanthone dimers and heterodimers may excite the synthetic or natural product chemist.

Xanthones from Fungi, Lichens, and Bacteria: The Natural Products and Their Synthesis

Xanthones from fungi, lichens, and bacteria : the natural products and their synthesis

The total synthesis of bikaverin (1b) is described, from everninic acid (5) and 3,5-dihydrobenzoic acid (6). Dieckmann condensation of methyl 2-acetyl-3,5-bis(benzyloxy)phenylacetate (14), synthesised from (6), followed by treatment with protected everninic acid chloride (9) gave 1,3-bisbenzyloxy-6,8-bis(2-benzyloxy-4-methoxy-6-methylbenzoyloxy)naphthalene (16). Photoinduced Fries rearrangement of (16) afforded 1,3-bis(benzyloxy)-7-(2-benzyloxy-4-methoxy-6-methylbenzoyl)-6-(2-benzyloxy-4-methoxy-6-methylbenzoyloxy)-8-hydroxynaphthalene (23). Ring closure of (23) with tetramethylammonium hydroxide in pyridine gave the angular benzoxanthene, 1,3-bis(benzyloxy-6-hydroxy)-10-methoxy-8-methylbenzo[c]xanthen-7-one (25), which was oxidized with potassium dichromate to give the orthoquinone, 1,3-bis(benzyloxy)-10-methoxy-8-methylbenzo[c]-xanthen-5,6,7-trione (28). By a novel type of rearrangement, (28) was transformed into the linear benzoxanthen, 8,10-bis(benzyloxy)-3-methoxy-1-methylbenzo[b]xanthen-6,11,12-trione (29) by treatment with silica gel. Oxidation and debenzylation of (29) with manganese dioxide in concentrated H2SO4 gave norbikaverin (1a).

Synthesis of bikaverin

The synthesis of 1, 3-dimethoxyfluoren-9-ones (7a-f) from ethyl 2-aryl-4, 6-dihydroxybenzoates (4a-d), prepared by the reaction of diketene with ethyl 3-aryl-3-oxopropionates (3a-d), is described. Reaction of diketene with 3a-d in the presence of sodium hydride in tetrahydrofuran gave 4a-d. Methylation of 4a-d with methyl iodide, followed by treatment with alcoholic sodium hydroxide, gave 2-aryl-4, 6-dimethoxybenzoic acids (6a-d). Cyclization of 6a-d with trifluoroacetic anhydride gave 7a-f.

Studies on Ketene and Its Derivatives. CX. Synthesis of 1,3-Dimethoxyfluoren-9-ones

The synthesis of naturally occurring anthracene-9, 10-diones (12a-c) from ethyl 2-benzyl-4, 6-dihydroxybenzoates (7a-d), prepared by the reaction of diketene with ethyl 4-aryl-3-oxobutanoates (6a-d), is described. Reaction of diketene with 6a-d in the presence of sodium hydride in tetrahydrofuran gave 7a-d. Treatment of 7a-d with methyl iodide in the presence of potassium carbonate, followed by ethanolic sodium hydroxide, gave 2-benzyl-4, 6-dimethoxybenzoic acids (9a-d). Cyclization of 9a-d with trifluoroacetic acid-trifluoroacetic anhydride gave anthrone derivatives (10a-d) which, without purification, were oxidized with chromium trioxide to give the anthracene-9, 10-diones (11a-d). Selective demethylation of 11a-c with boron tribromide gave 12a-c.

Studies on ketene and its derivatives. CIX. Synthesis of naturally occurring anthracene-9,10-diones.

Total synthesis of bikaverin involving the novel rearrangement of an ortho-quinone to a para-quinone

Methylation of bikaverin (Ib) with diazomethane afforded monomethylbikaverin (Ic). Reductive acetylation of Ia, b, c with acetic anhydride and sodium acetate in the presence of zinc powder gave rise to benzoxanthene derivatives (IIc, d, e), respectively. Ib was hydrolyzed with aqueous sodium hydroxide to give everninic acid (III) and orcinol (IV). However, hydrolysis of Ic with alcoholic potassium hydroxide gave rise to cyclopentenoxanthene derivative (V). Ozonolysis of Ic gave xanthone derivative (XI).

Jun Nakano

Papers

Synthesis of bikaverin

Studies on Ketene and Its Derivatives. CX. Synthesis of 1,3-Dimethoxyfluoren-9-ones

Studies on ketene and its derivatives. CIX. Synthesis of naturally occurring anthracene-9,10-diones.

Total synthesis of bikaverin involving the novel rearrangement of an ortho-quinone to a para-quinone

Chemical Reactions of Bikaverin