16: rutaecarpine 17: tryptanthrin

16: rutaecarpine 17: tryptanthrin

sclerotigenin >/-Bu

O R3

21: R1 = H, R2 = (S)-indol-3-ylmethylen glyantrypine 22: R1 = (S)-Me, R2 = (S)-indol-3-ylmethylen fumiquinazoline F 23: R1 = (R)-Me, R2 = (S)-indol-3-ylmethylene fumiquinazoline G

24: R = Me alantrypinoine 25: R = CH2OH serantrypinone

26: R = H luotonin A 27: R = OH luotonin B 28: R = OMe luotonin E

Chinese medicine Wu-Chu-Yu and interesting pharmacological properties of 16 have been found [66]. The indolopyridoquinazoline skeleton has been found also in various sources as the congeners such as 1,2-dihydroxy [67], 2-methoxy [68], 3-hydroxy [69], 7-hydroxy [70], and 7,8-dihydroxy rutae-carpines, etc. [71]. Indolo[2,1-b]quinazoline-6,12-dione known as the antibiotic tryptanthrin (17) has also a long history [72], and it was isolated from various sources [73] including Strobilanthes Crusia O. Kuntze, used as a traditional remedy for dermatophytic infection such as athlete's foot in Okinawa [74], and yet new interesting biological activities such as inhibition of HGF (hepatocyte growth factor) production have been found [75].

The structural diversity of fungal quinazolines has been broadened with the discovery of asperlicin (20) along with asperlicins B, C, D, and E, produced by Aspergillus alliaceus, which is a potent cholecystokinin (CCK) antagonists [76-79]. A series of new quinazoline alkaloids fused with ben-zodiazepinone were also isolated from a fungus culture of Penicillium sp., wherein benzomalvin A (18) is prototypical member [80,81]. The simplest sclerotigenin (19) was recently isolated from organic extracts of sclero-tia of Penecillium sclerotigenum (NRRIL,3461) [82], and many other ben-zodiazepinoquinazoline alkaloids such as circumdatin A-G were also isolated from the fungus Aspergillus ochraceus [83-85]. The quinazoline alkaloid hinckdentine A isolated from the marine bryozoan Hincksinoflustra denticulate collected from the eastern coast of Tasmania contains a novel hexahydroazepino[4',5':2,3]indolo[1,2-c]quinazoline ring system providing a challenging synthetic target [86]. A group of quinazoline alkaloids involving the pyrazino[2,1-b]quinazoline-3,6-dione substructure was found also in fungal metabolites. For example, the simplest member glyantrypine (21) was isolated from Aspergillus clavatus [87]. Fumiquinazolines A-E, F (22) and G (23) were isolated from a strain of Aspergillus fumigatus found in Pseudolabrus marine fish [88,89]. Fumiquinazolines H and I were isolated from a fungus (Acremonium sp.) [90]. Fiscalines A-C were also isolated from Neosartorya fischeri [91,92]. Novel spiro-type pyrazinoquinazolines such as spiroquinazoline from Aspergillus flavipes [93], alantrypinone (24) [94], and serantrypinone (25) [95], both from Penicillium thymicola were isolated. N-Acetylardeemin [96] having the pyrazinoquinazoline substructure isolated from Aspergillus fischeri is known as one of the most potent MDR (multi-drug resistance) inhibitor [97,98]. These alkaloids often exhibit very interesting biological properties and have drawn considerable interest of synthetic chemists as discussed in Sect. 3. Several new pyrroloquinazolinoquinoline alkaloids luotonin A (26), B (27), and E (28), etc. featuring a unique structure with a quinoline and a quinazoline fused together have been isolated from the aerial parts of Peganum nigellastrum (Zygophyllaceae) [99,100]. Among them 26 has triggered considerable synthetic works due to its biological activity such as topoisomerase I inhibitor [101] like antitumor camp-

tothecin [102] and has been reviewed recently [29]. Details are given in Sect. 3.5.

Studies on quinazoline compounds and quinazoline natural products have a long history as above, however, remarkable progress of synthetic methodology applicable to synthesis of quinazoline alkaloids and related molecules has been attained during the last decade. In this review article, the topical synthetic methodologies such as, for examples, iminophosphorane mediated synthesis (aza-Wittig methodology), use of organometallic reagents, microwave assisted synthesis, and solid phase synthesis, etc. will be discussed retrospectively in Sect. 2. Some selected examples of quinazoline alkaloids synthesis by these methodologies will be discussed in Sect. 3. On the other hand, quinazoline skeleton has been utilized very elaborately for the designing of unique aziridination reagent [103,104], quinazolinap ligands to use as the asymmetric catalyst [105], heterocalixarenes [106] and electroluminescent devices [107], etc., however, these topics are not discussed in this article due to limitations of space.

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