Concise synthesis of quinazoline alkaloids, luotonins A and B, and rutaecarpine

Alkyl, aryl, heteroaryl and acyl radicals have been cyclised onto the 2-position of 3H-quinazolin-4-one. The side chains containing the radical precursors were attached to the nitrogen atom in the 3-position. The cyclisations take place by aromatic homolytic substitution hence retain the aromaticity of the 3H-quinazolin-4-one ring. The highest yields were obtained using hexamethylditin to facilitate cyclisation rather than reduction without cyclisation. The alkaloids deoxyvasicinone 2, mackinazolinone 3, tryptanthrin 4, luotonin A 5 and rutaecarpine 8 were synthesised by radical cyclisation onto 3H-quinazolin-4-one.The 3H-quinazolin-4-one ring system is important to the biological activity of both naturally occurring alkaloids, biosynthesised from anthranilic acid, and pharmaceuticals. The alkaloids include vasicinone 1 and deoxyvasicinone 2, 1 mackinazolinone 3, 2 tryptanthrin 4, 3 luotonins A 5, B 6 and E 7 4 and rutaecarpine 8. 5 3H-Quinazolin-4-one alkaloids have been recently reviewed. 6 All the 3H-quinazolin-4-one natural products have interesting biological activity and have therefore been extensively investigated for useful pharmaceutical activity. The 3H-quinazolin-4-one ring is regarded as a 'privileged structure' in combinatorial synthesis. 7 These are structures which represent molecules that are capable of binding at multiple sites with high affinity and facilitate more rapid discovery of useful medicinally active compounds. 7Our study involved the development of protocols involving radical cyclisation for the synthesis of polycyclic 3H-quinazolin-3-ones (Scheme 1). The protocols have also been used for the synthesis of novel polycyclic quinazolinones including the natural Department of Chemistry, Loughborough University, Loughborough, Leics, UK LE11 3TU. E-mail: g.w.weaver@lboro.ac.uk; Fax: 44(0) 1509 223925; Tel: 44(0) All of the above cyclisations are 'oxidative' i.e. the intermediate p-radicals are not reduced by triorganometal hydrides [e.g. tributyltin hydyride (Bu 3 SnH)] as normally observed for these reagents. The cyclisations proceed by aromatic homolytic substitution with abstraction of hydrogen in a rearomatisation process. Aromatic homolytic substitution has been recently reviewed 27 and the mechanism of Bu 3 SnH mediated 'oxidative' cyclisation elaborated. 28 The pyrimidin-4-one ring of the quinazolin-4-ones has some aromaticity and therefore aromatic homolytic substitution could be predicted, and was observed in our studies, as shown in Scheme 1 (9 to 11 via the p-radical 10). However, the lower aromaticity could favour reductive cyclisation in which the intermediate p-radical 10 is intercepted by reagents such as Bu 3 SnH. Our prediction that radical cyclisation onto the quinazolin-4-one ring would be 'oxidative' was supported by the 'oxidative' radical cyclisation onto related ring systems, e.g. pyrimidine-2,4-diones, 23,24This journal is

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“…The data for rutaecarpine were the same as those in the literature. 41 The data for 39 were the same as obtained in the previous synthesis.…”

Section: Cyclisation Of 3-[(2-bromoquinolin-3-yl)methyl]-4(3h)-quinazmentioning

confidence: 99%

Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin

et al. 2007

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“…In 2004, Harayama and coworkers reported an intramolecular C-H arylation between two heteroarenes (Scheme 16.30) [65]. The coupling precursor 146, which was synthesized by N-alkylation of 4-quinazolinone with 2-bromo-3-(bromomethyl)quinoline, was cyclized using catalytic Pd(OAc) 2 and PPh 3 to give luotonin A in 66% yield.…”

Section: Luotonin B (Intramolecular C-h Arylation Of Quinazoline)mentioning

confidence: 99%

Synthesis of Natural Products and Pharmaceuticals via Catalytic CH Functionalization

Yamaguchi¹,

Amaike²,

Itami³

2016

Transition Metal‐Catalyzed Heterocycle Synthesis via CH Activation

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“…[38] In einer Arbeit von 2004 berichteten Harayama et al über eine intramolekulare C-H-Arylierung zwischen zwei Heteroarenen (Schema 11). [39] Die Kupplungsvorstufe 35, die durch N-Alkylierung von 4-Chinazolinon mit 2-Brom-3-(brommethyl)chinolin synthetisiert wurde, cyclisierte in Gegenwart eines Palladiumkatalysators zu Luotonin A (36), das in 66 % Ausbeute erhalten wurde. Dieser Naturstoff wurde anschließend in zwei Stufen zu Luotonin B (37) hydroxyliert.…”

Section: C-c-bindungsbildung Durchunclassified

Funktionalisierung von C‐H‐Bindungen: neue Synthesemethoden für Naturstoffe und Pharmazeutika

2012

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Die direkte Funktionalisierung von C‐H‐Bindungen in organischen Molekülen hat sich in jüngster Zeit zu einer wirksamen und idealen Methode entwickelt, mit der Kohlenstoff‐Kohlenstoff‐ und Kohlenstoff‐Heteroatom‐Bindungen geknüpft werden können. Der Aufsatz gibt einen Überblick über die Strategien, die durch Funktionalisierung von C‐H‐Bindungen eine rasche Synthese von biologisch aktiven Verbindungen wie Naturstoffen und pharmazeutischen Zielsubstanzen ermöglichen.

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Concise synthesis of quinazoline alkaloids, luotonins A and B, and rutaecarpine

Cited by 68 publications

References 53 publications

Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin

Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin

Synthesis of Natural Products and Pharmaceuticals via Catalytic CH Functionalization

Funktionalisierung von C‐H‐Bindungen: neue Synthesemethoden für Naturstoffe und Pharmazeutika

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