Quinazoline group alkaloids

A convenient synthesis of quinazolines has been reported, and has been applied to the synthesis of representative alkaloids of the quinazoline group (Scheme 5).27 The procedure depends on the formation of sulphinamide anhydrides (23) from the reaction of anthranilic acids with thionyl chloride and the generation in situ of the iminoketens (24). Addition of the latter to the imine (25) or to 2-piperidone, for example, afforded alkaloid (27). Arborine (26) was prepared similarly from N-methylanthranilic acid application of the method to the synthesis of rutecarpine is described in Chapter 11. 

There are several alkaloids in the structure of which are both quinazoline and indole nuclei. Evodiamine (1001 R = H) and rutaecarpine (1002) were both isolated from the seeds of Evodia rutaecarpa about 1916 and synthesized in 1927. They were found subsequently to occur also in Xanthoxylum rhetsa, which in addition yielded rhetsinine (1001 R = OH) (59T(7)257). The plant Hortia arborea afforded two more related alkaloids, hor-tiacine and hortiamine, each characterized by a methoxy group in the benzene ring of the indole portion (60JA5187). 

Under the heading Alkaloids of Undetermined Constitution, have been included bases about which a good deal of information is available, though they cannot yet be allocated to sturctural groups, either because sufficient, definite information is not available, or because such data are available only about one or two members of an extensive series found in one plant or one genus. The Diehroa bases are probably quinazolines. Of the Erythrophloeum alkaloids some might be placed in the group of... 

Alkaloids containing a quinazoline nucleus form a small but important group of natural products and have been isolated from a number of different families in the plant kingdom. The quinazoline alkaloids are of the four types (48), (49), (50), and (51). The structures of arborine, peganine, febrifugine, rutaecarpine, and evodi-amine have been elucidated by degradation and synthesis and are described in recent reviews on quinazoline alkaloids. ... 

Two new quinazoline alkaloids of unusual structure were obtained from the seed husks of Zanthoxylum arborescens.12 Infrared, H n.m.r., and mass spectroscopy showed that the major alkaloid was a quinazolone containing a phenethyl substituent. The 13C n.m.r. spectrum indicated that an iV-methyl rather than an O- methyl group was present, but the spectroscopic studies did not distinguish between structures (19 R = H) and (20 R = H). The alkaloid was shown to be the iV-phenethyl derivative (20 R = H) by synthesis (Scheme 4), and a minor... 

The methodology was successfully extended to a one-pot total synthesis of complex heterocyclic systems such as pyrazino [2,1-b] quinazolines 79, encountered in nature as alkaloids 80-82 (Scheme 50) [125]. To assemble the pyrazino[2,l-fo]quinazoline core, N-Boc protected amino acid 76 was employed instead of carboxylic acid 72 (Scheme 49) in the synthesis of the corresponding intermediate benzoxazinones 77. The subsequent reaction with an amine moiety of another amino acid ester 78 was accompanied by concomitant cleavage of the N-Boc protecting group and diketopiperazine-like cyclization (for the one-pot deprotection-cyclization reaction of N-Boc dipeptide esters to afford 2,5-piperazinedione under microwave dielectric heating, see [128]) to afford the target heterocycle 79. Hence, the total... 

A considerable number of new quinoline and acridone alkaloids has been identified and the recognition of two new groups of dimeric quinolinone alkaloids is of particular interest. There has been little activity in the quinazoline alkaloid area and this section is omitted this year. 

Febrifugine is the first alkaloid to be isolated from a member of the Saxifragaceae, and it is the first known alkaloid outside the cinchona group to possess marked antimalarial activity. Its quinazoline structure is of particular interest in view of the recorded antimalarial activity of some synthetic quinazolines (49). A number of synthetic analogues of XXXII have been prepared and tested as antimalarials (51). 

Dreyer and Brenner 62) isolated two new quinazoline alkaloids from seed husks of Zanthoxylum arborescens. The major compound, C17H16N2O2 exhibits a blue fluorescence on TLC. In the H-nmr spectrum the downfield aromatic quartet at 8 8.12 (J = 7.1 Hz) and a one-proton triplet at 8 7.8 (J = 7 Hz), each further split (J = 1 Hz) suggest the presence of four adjacent aromatic protons on an ortho-substituted benzene ring. The aromatic quartet farthest downfield at 8 8.12 indicates the presence of a / r/-related carbonyl group. Two two-proton multiplets (8 2.93—4.40) are consistent with the presence of a 2-phenylethyl system. Other nmr data, in light of the mass spectrum, suggest the presence of an N-methylanthranilic acid system. These characteristics could be assembled in two different ways, leading to structures (7) (Chart 1) and (31). C-spectroscopy and synthesis from N-methylisatoic anhydride and 2-phenylethylamine finally allowed elucidation of the structure. The synthetic product, l-methyl-3-(2 -phenylethyl)-lH,3H-quinazolin-2,4-dione (7) was identical with the alkaloid. 

In the biosynthetic pathway of the alkaloids derived from anthranilic acid, the carbon atom corresponding to the carboxyl carbonyl group is included in the resulting alkaloids, except for those alkaloids with the phen-azine skeleton. The main groups of alkaloids derived from anthranilic acid are classified as quinoline, acridone, and quinazoline alkaloids. These alkaloids are typically isolated from rutaceous plants, except for febrifugine and related alkaloids, which possess the quinazoline skeleton these are isolated from plants of the Saxifragaceae family. 

Vasicine was also isolated from the seeds of Peganum harmala (Zygophyl-laceae) [2] consequendy, the same alkaloid is also known as peganine. Two groups reported the total synthesis of d/-vasicine (peganine) [3,4]. The related quinazoline alkaloids, vasicinone and desoxyvasicinone, were also isolated from P. harmala [5]. 

In addition to the relatively simple anthranilic-derived metabolites mentioned above, several distinctive types of alkaloids are derived from this amino acid. Most of these are associated with the Rutaceae and related families of the Rutales. Among these groups of alkaloids are the quinazoline, pyrroloquinazoline, quinazolinocarboline, quinoline, furoquinoline, and acridone types. 

About 60 simple quinazoline alkaloids have been isolated from several plant families, microorganisms, and animals (Groger, 1980). Arborine (5), from leaves of Glycosmis species (Rutaceae), is an example of this group of alkaloids (Fig. 31.3) (Johne, 1986). 

Several groups of quinazoline alkaloids involving pyrazino[2,l-fo]quinazoline-3,6-dione substructure are found in fungal metabolites. These include glyantrypine (21) [87], fumiquinazolines A-E, F (22), G (23) [88,89], H and I [90], and fiscalines A-C [91,92]. Novel spiro-type pyrazinoquina-... 

Quinazoline alkaloids a group of about 30 alkaloids, which occur in higher plants (in families taxono-mically very distant from one another), animals and bacteria. They are derived biosyntfaetically from an-thranilic add. The simplest representative of the Q.a. is Glomerine (see) which is a very rare animal Q.a. Of the plant Q.a., Febiifugine (see) has some significance. In the wide sense, tetrodotoxin fi-om the puffer... 

In this chapter, some of the latest developments in the groups of natural products collectively known as the quinolin/one, quinazolin/one, and acridone alkaloids are presented. Emphasis is placed on their biogenesis, biological activities, and... 

The biosynthesis of the main groups of quinoline, acridone, and quinazoline alkaloids is established. However, a great deal of more detailed work remains to be done. The topics included here have been selected to stimulated further experimental biosynthetic research in the area. 

Two quinazoline alkaloids were also isolated and characterized in the study reported by AfiyatuUov and coworkers (see also Section 7.3.3) [54]. For the first, 92 (R = -H), correlations were observed from 14-methine and 18-vinyl protons to the N2 resonating at 128.5 ppm, while the H7 resonance correlated to the N5 quinazoline nitrogen. In the case of the second homolog, 93 R = -OH, only a correlation from the hydroxyl group to the quinazoline N5 resonance at 208.3 ppm was reported by the authors. 

---