Quinazolinone alkaloid

Known pyrrolo[2,l-/)]quinazoline and pyrido[2,l-/>]quinazolinone alkaloids are named and depicted in Table II. 

The chemistry of recently isolated naturally occurring quinazolinone alkaloids 06T9787. 

Bhattacharyya, j., and S. C. Pakrashi Carbon-13 NMR Analysis of Some 4-Quinazolinone Alkaloids and Related Compounds. Heterocycles 14, 1469 (1980). 

Kametani, T., C. V. Loc, T. Higa, M. Ihara, and K. Fukumoto Studies on the Syntheses of Heterocyclic Compounds. Part 724. Total Syntheses of the Quinazolinone Alkaloids Glycorine, Glomerine, Homoglomerine, Crysogine, and Euxylophoricines A and C. J. Chem. Soc. Perkin Trans. I 1977, 2347. 

Grieder and Thomas prepared a diverse library of natural product-like benzodiazepine-quinazolinone alkaloids similar to the family of circumdatins (Figure 11.72). Starting from benzodiazepinedione derivatives, the synthesis relied on a modified Eguchi protocol using a polymer-supported phosphine-mediated intramolecular aza-Wittig reaction in a key step of the reaction sequence. Following this route two sublibraries of tricyclic derivatives similar to the circumdatins D and E were prepared. 

The stmcturally related fused [2,l-b]quinazolinone alkaloids vasicinone 25, and its precursor deoxyvasicinone 26, are found in Biebersteinia multifida, Peganum harmala, and Adhatoda vasica that have anti-cancer, vasodilator (anti-hypertension), and bronchodilator (for treatment of asthma) properties. A solid-phase synthesis of vasicinone 25 and deoxyvasicinone 26 was reported by Reddy and colleagues in 2006 (Scheme 3.7). Resin-bound acid 21 was... 

Makino et al. described a pathway to quinazolinones utilizing a resin-bound amine, treatment of which with 2-methoxycarbonyl phenylisothiocyanate formed resin 147, which subsequently cydized in the presence of TFA to form the quina-zohnone core structure 151 [190]. Quinazoline alkaloids have been synthesized by cychzation of amidine intermediate 148 [191]. A two-step reaction on a sohd support involving cyclocondensation of ethyl oxalate 149 with benzamide and subsequent cleavage employing trimethylsilyl iodide also provided a quinazohne [192]. 

Ureas and thioureas react with IA (1 and 24) to form quinazolinediones (172)97,211 In this way the alkaloid glycosmicin (172 R1 = H, R = Me)190,211 was synthesized. Cyanamides and IA yield the 2-aminoquinazolinones 173212 with acylureas the quinazolinones 174 were produced213 216 (Scheme... 

Pursuing their efforts on the Niementowski reaction and its possibilities, Besson and coworkers have recently extended the family of fused quinazolinones which can be obtained via the microwave-assisted Niementowski reaction from the starting amidines (43). The authors described rapid and convenient access to pentacy-clic 6,7-dihydro-5a,7a,13,14-tetraazapentaphene-5,8-diones (44) structurally related to well studied terrestrial alkaloids (e.g. rutaecarpine and luotonine A) [50e]. The strong thermal effect, because of graphite-microwaves interaction, was particularly efficient in these reactions, in which the quinazolinone and the piperazine rings are fused. Only 10% by weight of graphite was used, in pressurized monomode reactors (Scheme 9.13). 

Chakraborty et al. (26) synthesized 1 by cyclization of the < -acyl-aminobenzamide 13 with diphosphorus pentoxide. Kametani et al. have developed a one-step synthesis of quinazolinone derivatives by condensation of sul-phinamide anhydrides generated from anthranilic acids and thionyl chloride with amides (27,28), imines (29,30), or thioamides (31). This reaction was applied to the synthesis of 1 (28,31,32), glycosminine (6) (28,31), glomerin (2) (27,31), homoglomerin (27), glycerine (3) (27), chrysogine (7) (27), and other quinazoline alkaloids (Scheme 1). 

The indole-containing alkaloid rutaecarpine 126 has been synthesised via cyclisation of a 2-indolyl radical onto the 2-position of a 4-quinazolinone (070BC103). The radical precursor 124 was prepared by N-alkylation of the 3-position of the 4-quinazolinone followed by bromination of the 2-position of the indole ring. Slow addition of BusSnH gave 15% of rutaecarpine 126 and 57% of the reduced product 125. 

Kametani and co-workers have applied their preparation of quinazolines from sulphinamide anhydrides cf. Vol. 8, p. 83) to the synthesis of the alkaloids glycorine (33 R = Me, R = H), glomerine (33 R = R = Me), and homo-glomerine (33 R = Me, R = Et). The reaction of the sulphinamide anhydride derived from anthranilic acid with O-benzyl-lactic acid amide furnished the quinazolinone [34 R = CH(OBz)Me], which was converted into the alkaloid crysogine [34 R = CH(OH)Me] by acid hydrolysis. 

Pakrashi, S. C., A. De, and S. Chattopadhyay Studies on 4-Quinazolinones Part I — Convenient Synthesis of Glycosminine and Arborine, the Alkaloids from Glycosmis arborea and Related 4-Quinazolinones. Indian J. Chem. 6, All (1968). 

Plugar, V. N., T. T. Gorovits, N. Tulyaganov, and Ya. V. Rashkes Transformations of 4-Quinazolinone Group Alkaloids in Animals. Khim. Prir. Soedin. 1977, 250 (Russ). 

Keywords Aza-Wittig reaction Quinazolinone annelation Quinazoline alkaloids -Microwave-assisted synthesis Solid-phase synthesis... 

Examples of quinazoline alkaloids synthesis by the quinazolinone aimela-... 

For synthesis of quinazoline derivatives, various coupling reactions have been utilized after synthesis of quinazoline-2,4(lH,3H)-diones via palladium-catalyzed oxidative coupling by Hirota et aL [187]. For example, synthesis of diarylquinazolines by iron-catalyzed cross-coupling reaction [188], and diamino quinazolinones by palladium-catalyzed amination [171] have been developed Synthetic applications to quinazoline alkaloids are given in Sect. 3. 

Quinazolinone annelation of the 0-protected chiral pyrolidinone 74 (derived from L-aspartic acid) forms pyrrolo[2,l-fc]quinazohn-9(lH)-one 75 subsequent desilylation affords (S)-(-)-vasicinone 10, which is identical with the natural /-product (Scheme 16) [212,213]. Asymmetric oxidation of de-oxyvasicinone 11 (via the imine enolate) with either (R)- or (S)-Davis ox-aziridine reagent (lO-camphorsulfonyloxaziridine) [214,215] provides a convenient route to both enantiomers, thus confirming the recently revised stereochemistry of natural vasicinone (Scheme 16) [212,213]. Recently another approaches to optically active pyrrolo[2,l-fo]quinazolinones 10 have been reported by Kamal et al. (lipase-catalyzed resolution) [56], and Argade et aL (asymmetric synthesis from (S)-acetoxysuccinic anhydride) [216]. One-pot synthesis of 11, and related alkaloids has been also developed by utilizing microwave irradiation by Liu et al. [217]. Biogenetically patterned short-step synthesis of pyrroloquinazolinone alkaloids is well established by On-aka [218], and for many other synthesis, see the references cited in these papers. 

A successful simple appHcation of the quinazolinone aimelation is the short step synthesis of rutecarpine 16, an indolopyridoquinazoline alkaloid of Evodia rutaecarpa, from 2,3,4,9-tetrahydro-lH-j8-carbolin-l-one 80 via 2-azidobenzoyl derivative 81 (Scheme 18) [222]. Even after Kametani s practical iminoketene/amides condensation synthesis [227,228], many other synthetic routes to 16 and related systems utilizing Fischer indole synthesis [223-225] or cyclocondensation [65,226,229,230], etc. have been developed among these syntheses, above quinazolinone annelation route is one of the most facile and concise one. Recently very concise Pd-assisted biaryl coupling route to 16 as well as to luotonin A (26) and B (27) has been developed by Harayama et al. [231,232] (see Sect. 3.5). 

The simple synthesis of antimycotic alkaloid tryptanthrin 17 via the quinazolinone annelation is summarized also in Scheme 18. Quinazolinone annelation of commercially available isatin 84 under the shown conditions gave 17 in 43% overall yield (Scheme 18) [222]. As the second route, oxindole 82 was annelated to indolo[2,l-fo]quinazolin-12(6ff)-one 83, which could be converted to 17 by air-oxidation but only in the modest yield [222]. Recently an efficient procedure for synthesis 17,16 and luotonin A (26), etc. has been reported using cyclocondensation of iminochloride and methylanthranylate, followed by further manipulations by Jahng et al. [229]. Several known attractive routes to 17 involves cyclocondensation of isatin with isatoic anhydride by Mitscher et al. [230], (Ru)3(CO)i2-catalyzed reductive J -heterocycUzation by Watanabe et al. [182,223]. 

---