Alkaloids quinazoline

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.  

Peganine has two nitrogen atoms and its monoacidity is due to the formation of a cyclic amidinium cation. The Schopf-Oechler scheme for the synthesis of peganine from o-aminobenzaldehyde and 

Maeholan, Collection Czechoslov. Chem. Commun. 24, 550 (1959) L. Skmsky, Z. Naturforsch. 14B, 474 (1959). 

7-amino-a-hydroxybutyraldehyde under physiological conditions has been repeated and d -peganine was isolated in 39% over-all yield. 

The structure of febrifugine (the famous Chan San alkaloid known since 200 b.c.) has been completely elucidated, but that of the isomer isofebrifugine which occurs with it is still in some doubt. All evidence points to the semiketal structure (52) and, although it is readily converted to febrifugine, it does not react with ketonic reagents. 

Quinazoline Alkaloids.— The biosynthesis of vasicine (=peganine) (163) has been investigated in Adhatoda vasica (Acanthaceae) and Peganum harmala (Zygo-phyllaceae). In both plants the anthranoyl portion is known to derive from anthranilic acid [the reported incorporation of tryptophan (0.017 %) suggested as via anthranilic acid seems of questionable significance]. The remaining atoms of vasicine, however, appear to arise by different pathways in the two plants. 

In contrast, the biosynthesis of vasicine (163) in A. vasica does not involve ornithine and its congeners. However, [3- C]aspartic acid (as 164) was incorporated with heavy labelling of C-2 of vasicine [4- C]aspartic acid was only randomly incorporated.Aspartic acid appears then to provide a C2 unit (for C-1 and C-2). The origin of the other C2 unit (C-3 and C-10) has been tested using [1- C]- and [2- C]-acetate, [3- C]pyruvate, and [2- C]glycine. In 

Groger, S. Johne, and K. Mothes, Abhandl. Deut. Akad. Wiss. Berlin Kl. Chem. Geol. Biol., 1966, 581 S. Johne and D. Groger, Z. PflanzenphysioL, 1969, 61, 353. 

4-Amino-2-hydroxy[4- C]butyric acid (the corresponding aldehyde has been condensed with o-aminobenzaldehyde to give vasicine 4-hydroxy-[2- C]glutamic acid (found with vasicine in Linaria yw/garis ), N-methyl-anthranilic acid, and N-formylanthranilic acid have been tested as vasicine precursors in A. vasica, without success. 

In addition to vasicine (163), P. harmala produces vasicinone (165) and deoxy-vasicinone (166). Attempts to observe either the interconversion or order of biosynthesis of these three alkaloids have been unsuccessful.  

Quinazoline alkaloids contain more than 100 compounds. They have been isolated from animal and plant sources. The plant family Rutaceae is especially rich in these alkaloids. Typical quinazoline alkaloids include, for example, arborine, glomerin, homoglomerin, glycerine, glycosminine, febrifugine and 

Quinazoline alkaloids are known as biologically active compounds. Arborine inhibits the peripheral action of acetylcholine and induces a fall in blood pressure. Febrifugine is an anti-malarial agent and vasicine acts as a uterine stimulant. Glomerin and homoglomerin are alkaloids of the defensive system in some organisms (e.g., in the glomerid millipede). 

The investigation of the constituents of Glycosmis arborea continues cf. Vol. 9, p. 85 Vol. 10, p. 80) with the isolation of the new alkaloid glycophymoline (17) the structure was established by spectroscopy and by its formation by methylation of glycophymine (18).20 

The antibiotic tryptanthrin (21), originally isolated from a micro-organism 

Vascine and some of its analogues have been synthesized from o-aminobenzal-dehydes and 4-amino-2-hydroxybutanal,23 and a series of arborine derivatives has also been prepared.24 

Reagents i, AC2O, pyridine, HCl, reflux ii, aq. NaOH iii, CH2N2 

The Kametani synthesis of quinazoline alkaloids (c/. Vol. 8, p. 83) has been improved by allowing sulphinamide anhydrides to react with thioamides arborine (41), glycosminine (40), and glomerine (42) were prepared in this way in good yield. Arborine (41) and glycorine (43) have been synthesized by the reaction of ethylurethane and phosphorus pentoxide with N-methyl-phenylacetanilide and with N-methylformanilide, respectively.  

Arborine (41) and glycorine (43) have been isolated from Glycosmis biloc-ularis, and Peganum nigellastrum is a new source of the tricyclic alkaloids d/-vasicine (peganine), vasicinone, and desoxyvasicinone.  

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Quinazoline alkaloids are found in at least six botanical families of which the Rutaceae are the most important in this respect. Thus, arborine was isolated from Glycosmis arborea in 1952 and in the following year appeared its structure (990) and synthesis by thermal cyclization of the phenylacetyl derivative (989) of (V-methylanthranilamide (53JCS3337>. The same plant material yields three related alkaloids, glycosmicine (991), glycorine (992) and glycosminine (993) (63T1011>. 

Quinazoline, 1,2,3,4-tetrahydro-synthesis, 3, 108, 124 Quinazoline, 5,6,7,8-tetrahydro-synthesis, 3, 116 Quinazoline alkaloids occurrence, 3, 148 Quinazolinecarbonitriles hydrolysisj 3, 83 Quinazoline-2-carbonitriles reactions... 

Eguchi S (2006) Quinazoline Alkaloids and Related Chemistry. 6 113-156 Erd lyi M (2006) Solid-Phase Methods for the Microwave-Assisted Synthesis of Heterocycles. 1 79-128... 

In the construction of C=N bond-containing compounds, such as nitrogen heterocycles, the aza-Wittig methodology has received increased attention as the method of choice [7]. Thus, an easy access to optically active (-)-vasicinone (7-15), a pyr-rolo[2,l-fc]quinazoline alkaloid which is used in indigenous medicine [8], was... 

It should be also noted that, in a very recent publication, Liu and coworkers were successful in applying microwave radiation within their domino approach towards the synthesis of pyrrolo[2,l-fc]quinazoline alkaloids such as deoxyvasicinone, 8-hy-droxydeoxyvasicinone, mackinazolinone and isaindigotone, which exhibit a promising broad spectrum of biological activities. In the case of isaindigotone, the authors were able to extend their strategy to a three-component procedure, which comprises the domino conversion of anthranilic acids and Boc-protected amino acids into the tricyclic core skeleton [43]. 

The pharmacologically important tryptanthrine, a quinazoline alkaloid, is known for its antimycotic activity and is used against skin infections. This alkaloid is obtained from isatin (260) and o-azidobenzoyl chloride (261), as shown in Scheme 96. The adduct formed is cyclized via a Staudinger and an aza-Wittig reaction to afford tryptanthrine (262) (92H153). 

Figure 59. Structural development of quinazoline alkaloid vasicine.

Bacterial metabolites include novel alkaloids, peptides, and macrocyclic lactams. The most unusual metabolites from dmoflagellate are polyethers, both linear and macrolides. The latter were also found abundantly in brown seaweeds (Chart 7.6.FA/PO). Filamentous fimgi have afforded new isoindole and quinazoline alkaloids, as well as new-skeleton steroids (Chart 7.6.A/P/I). 

A quinazoline alkaloid skeleton has been synthesized by means of the Rh-catalyzed cyclohydrocarbonylation of diaminoalkenes. The reaction of 2-(A -allylaminomethyl)aniline 55 gave quinazoline 59 in excellent yield through the highly linear-selective hydroformylation of 55 to aldehyde 56, followed by the sequential formations of hemiaminal 57 and iminium ion 58 as intermediates and then the subsequent intramolecular amine addition (Scheme In the same manner, the reaction of A -allyl-2-aminomethylaniline 60 afforded 61 in 96% yield. ... 

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