A hetero Diels–Alder approach to the synthesis of the first angucyclinone and angucycline 5-aza-analogues

A survey through the synthetic possibilities of pentalongin and its derivatives is presented. Pentalongin is the parent compound in the 3,4-dehydropyranonaphthoquinone series and is the active principle of the medicinal plant Pentas longiflora. Attention is paid to eight approaches towards these 3,4-dehydropyranonaphthoquinones. Synthetic methodologies for the corresponding nitrogen analogues are described, focusing on several natural products.

Section: Synthetic Approaches Towards 2-azaanthraquinonesmentioning

confidence: 99%

A Survey of Synthetic Routes towards the Pyranonaphthoquinone Antibiotic Pentalongin and Syntheses of the Corresponding Nitrogen Derivatives

Claessens¹,

Verniest²,

Jacobs³

et al. 2007

“…We report herein on a new and efficient synthesis of calothrixin B 3 which is inspired by our recent results obtained in the field of angucycline aza-analogues. 4 Based on these results, we thus believed that a hetero-Diels-Alder reaction between 3-bromo-9H-carbazole-1,4-dione (2) and 'push-pull' 2-aza-1,3-diene 3 would allow to assemble the core of the natural product in one single operation as depicted in Scheme 1. Following this strategy, the expected Diels-Alder adduct 4 could be used to access 1 after oxidation state adjustment and indole nitrogen protecting group removal.…”

mentioning

confidence: 95%

“…Since we already synthesised diene 3, 4 the first synthetic task was to prepare the bromo-activated dienophile 2 (Scheme 2). Toward this end, commercially available carbazole 5 was exposed to the action of DDQ in THF-H 2 O to form the 1,2,3,9-tetrahydro-carbazol-4-one (6), which was next protected under the form of a N-benzyl derivative 7.…”

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confidence: 99%

A Synthesis of Calothrixin B

Sissouma¹,

Collet²,

Guingant³

2004

A new short and efficient synthesis of calothrixin B is reported. The key reaction is a hetero-Diels-Alder reaction between 3-bromo-9H-carbazole-1,4-dione and a 'push-pull' 2-aza-1,3-diene.Calothrixin B (1) and its N-oxide derivative (calothrixin A) are natural products obtained in 1999 from the cell extracts of Calothrix cyanobacteria. 1 These metabolites display impressive in vitro cytotoxicity against HeLa cancer cells in the nanomolar range and also inhibit the growth of a chloroquine-resistant strain of the malaria parasite Plasmodium falciparum. 2 The calothrixins feature an amazing and unprecedented indolo[3,2-j]phenanthridine framework which, in addition to their remarkable biological activities, makes them interesting targets for synthetic organic chemists. We report herein on a new and efficient synthesis of calothrixin B 3 which is inspired by our recent results obtained in the field of angucycline aza-analogues. 4 Based on these results, we thus believed that a hetero-Diels-Alder reaction between 3-bromo-9H-carbazole-1,4-dione (2) and 'push-pull' 2-aza-1,3-diene 3 would allow to assemble the core of the natural product in one single operation as depicted in Scheme 1. Following this strategy, the expected Diels-Alder adduct 4 could be used to access 1 after oxidation state adjustment and indole nitrogen protecting group removal.Since we already synthesised diene 3, 4 the first synthetic task was to prepare the bromo-activated dienophile 2 (Scheme 2). Toward this end, commercially available carbazole 5 was exposed to the action of DDQ in THF-H 2 O to form the 1,2,3,9-tetrahydro-carbazol-4-one (6), which was next protected under the form of a N-benzyl derivative 7. Full aromatisation of 7 to give the 9-benzyl-9H-carbazol-4-ol (9a) could be accomplished in the presence of Pd/C in diphenyl ether at 250°C. However, a major drawback of this procedure was the concomitant formation of the N-debenzylated product 9b (ratio 1:1). Therefore, we came to favour a two-step procedure consisting of the formation of a-keto sulfoxide 8 (not isolated) followed by its easy aromatisation in THF at reflux. In these conditions, 9a could be cleanly accessed in 94% isolated yield. Conversion of 9a into 3-bromo-9H-carbazole-1,4-dione (2) was first attempted under the conditions of the Grunwell reaction, 5 e.g. treatment with an excess of NBS (4 equiv) in acetic acid. Although this protocol proved successful, compound 2 was accompanied by a product of over-bromination, 10, 6 from which it could be separated by column chromatography only with difficulty (60% isolated yield).Looking for a more convenient route to 2, which would avoid the formation of the undesirable 10, 9a was exposed to half an equivalent of NBS 7 to afford the 9-benzyl-3-bromo-9H-carbazol-4-ol (11) in 80% yield (based on reacting 9a). Its transformation into the desired 2 8 was subsequently accomplished by treatment with diacetoxyiodobenzene as shown in Scheme 3.With both diene 3 and dienophile 2 in hand, we were in a position to effect the key [4+2] cycloadditio...

“…In this respect, Guingant et al 7 have reported the synthesis of angucyclinone aza analogues by a method that involves cycloaddition reactions of 2-bromo-1,4-naphthoquinone derivatives with a push-pull heterodiene.…”

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confidence: 99%

“…3,4 The synthesis of aza congeners of the benz[a]anthraquinone chromophore of angucyclines and angucyclinones 5,6 has received relatively little attention despite the antitumor activity of several members of this family of antibiotics. In this respect, Guingant et al 7 have reported the synthesis of angucyclinone aza analogues by a method that involves cycloaddition reactions of 2-bromo-1,4-naphthoquinone derivatives with a push-pull heterodiene.…”

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confidence: 99%

Design and Synthesis of Angucyclinone 5-Aza Analogues

Valderrama¹,

González²,

Colonelli³

et al. 2006

A highly efficient one-pot procedure for the synthesis of phenanthridine-1,7,10-triones from acylbenzoquinones and cyclic enaminones is reported. The cycloaddition reactions of these quinones with 1-trimethylsilyloxybutadiene followed by hydrolysis and oxidative processes provide entry to a variety of angucyclinone 5-aza analogues.The substitution of a nitrogen atom for an aromatic CH group in anticancer drugs (e.g. ametantrone and 11-deoxydoxorubicin), 1,2 which provides active antitumor Nanalogues, has shown to be an effective strategy to design new potential antitumor compounds. These N-heterocyclic aromatic congeners could potentially retain the planar shape of the drug chromophore necessary for molecular recognition of the host. Furthermore, the basic and electron-withdrawing properties of the N-heterocycles seem to improve the affinity for the biological target and/or the cyclic redox mechanism. 3,4The synthesis of aza congeners of the benz[a]anthraquinone chromophore of angucyclines and angucyclinones 5,6 has received relatively little attention despite the antitumor activity of several members of this family of antibiotics. In this respect, Guingant et al. 7 have reported the synthesis of angucyclinone aza analogues by a method that involves cycloaddition reactions of 2-bromo-1,4-naphthoquinone derivatives with a push-pull heterodiene.As part of our continuous interest in the synthesis and biological evaluation of quinones 8 we have recently reported studies on azaanthraquinones. 8a The efficient and regioselective access to these compounds along with their promising antitumoral activities on several tumor cell lines encouraged us to extend our studies to the synthesis of aza analogues of benz[a]anthracene-1,7,12-trione, the skeleton of some angucyclines and angucyclinones.We now report our findings which show that phenanthridine-7,10-quinone derivatives can be efficiently obtained via an ionic [3+3] process from commercially available precursors. The applications of these quinones in the synthesis of benzo[j]phenanthridine-7,12-quinones through highly regiocontrolled [4p+2p]-cycloaddition reactions is also described.Based on recent results on the high-yield synthesis of a 5,8-dihydroxyisoquinoline derivative by reaction of acetylbenzoquinone 3b with methyl aminocrotonate, 8a we envisaged the construction of 7,10-dihydroxyphenanthridines by reaction of acyl-1,4-benzoquinones with cyclic enaminones. The following commercially available compounds were employed in this study: 2,5-dihydroxybenzaldehyde (1a), 2,5-dihydroxyacetophenone (1b), 3-amino-2-cyclohexen-1-one (2a), and 3-amino-5,5-dimethyl-2-cyclohexen-1-one (2b).Formylbenzoquinone 3a, prepared by oxidation of 1a with silver(I) oxide, 9 reacts with enaminone 2a at room temperature to give dihydroxyphenanthridine 4a in 87% yield. Similarly, acetylbenzoquinone 3b, prepared from 2,5-dihydroxyacetophenone (1b) and manganese dioxide, 10 was reacted with 2a in dichloromethane to yield dihydroxyphenanthridine 4b in 68% yield. Then, dihydroxyphenanthridines 4a...