Quinoline and Furoquinoline Alkaloids

3 Alkaloids from Anthranilic Acid 5.2.23.1 Quinoline and Furoquinoline Alkaloids 

Quinoline and furoquinoline alkaloids (57, 119) are widespread within the Rutaceae family. Many of these alkaloids have oxygen functions (hydroxy, methoxy, and methylenedioxy groups) at C-6, C-7, and/or C-8 of the quinoline ring. 

Simple quinoline alkaloids have been isolated from several genera - e.g., 4-methoxy-l-2-quinolone from Fagara boniensis, and edulitine from Casimiroa edulis. 

N-methyIplatydesminium salt, R=H, 67 pteleatinium salt,R=OH,68 O-methylbalfourodinium salt, R=OMe,69 

Related alkaloids have been obtained from other sources Lunasia amara, Ptelea trifoliata, Orixa japonica, Skimmia japonica, etc. 

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Cell suspension cultures of R. graveolens grown in the presence of 4-hydroxy-2-quinolone show increased amounts of quinoline and furoquinoline alkaloid production. For example, the concentration of dictamnine increased as long as 4-hydroxy-2-quinolone was present in the culture medium as soon as the quinolone was depleted, rapid transformation of dictamnine into 8-methoxy-dictamnine was observed. ... 

The Table summarizes recent isolation and structural elucidation work on quinoline and furoquinoline alkaloids of plant origin. The structure of folisine (4) from Haplophyllum foliosum was confirmed by synthesis. Heating the methiodide of dubinidine (11) yielded folisine. The alkaloid distribution in H. suaveolens was extensively examined in leaf, stem, fruit with seeds, and root kokusaginine (1 R = = OMe, R = H) was found to be the major component in all... 

Quinoline and Furoquinoline Alkaloids (Fig. 151). (Activated ) anthranilic acid reacts with (activated ) acetic acid to 2,4-dihydroxyquinoline. Probably 2-aminobenzoyl acetic acid, which is in a pH-dependent equilibrium with 2,4-dihydroxy quinoline, or an activated derivative of this compound is an intermediate. On the one hand 2,4-dihydroxy quinoline is transformed to echinorine. On the other hand it is a precursor of 3-prenylated chinoline alkaloids, isopropyl-dihydrofuroquinolines and furoquinolines. 

Boulanger D, Bailey BK, Steck W (1973) Formation of edulinine and furoquinoline alkaloids from quinoline derivatives by cell suspension cultures of Ruta graveolens. Phytochemistry 12 2399-2405... 

A number of furoquinoline alkaloids are available by taking advantage of in-between metalation of 2,4-dimethoxy quinoline derivatives, as established in model studies (Scheme 103). To illustrate, the trimethoxyquino-line 571, upon metalation and ethylene oxide quench, afforded the carbinol 572 which, upon mild hydrolysis, furnished the alkaloid dihydro-y-fagarine (573) together with the quinolone 574 (Scheme 172) (71T1351). 

A number of simple quinolines and quinolones have been isolated from various rutaceous plants, e.g., from angostura bark (Volume III, p. 80) and from Lunasia amara Blanco (Volume VII, p. 241 this chapter Section IV,A). The leaves of Haplophyllum dubium Eug. Kor (15, 16) contain dubamine (mp 96°-97°) which has been identified (17) as 2-(3,4-methylenedioxyphenyl)quinoline (I). Ruta graveolens L. contains, in addition to furoquinolines, the alkaloids graveoline (mp 205°) (18,19), and graveolinine (mp 115°-116°) (20), the latter (II) is also found in L. amara, and the former is the related l-methyl-4-quinolone (III). 

An introductory chapter on the furoquinoline alkaloids with excellent coverage and leading references to the literature has been published as part of a general volume on alkaloids.1 A detailed chromatographic analysis of quinoline alkaloids in liquid-liquid systems with buffered aqueous phase and a polarographic method for the determination of dubinidine from Haplophyllum foliosum have been reported.2 From a pH-R f relationship, the optimum conditions for extraction and chromatography were developed.20... 

Isolation and Detection Quinoline Alkaloids without 3-Substituents Furoquinoline Alkaloids 3-Prenylquinoline Alkaloids... 

Narasimhan et al. (194) instituted a new approach to the synthesis of furoquinoline alkaloids by introducing a C2 side chain into a preformed quinoline nucleus. Lithiation of 2,4-dimethoxyquinoline, 2,4,6-tri-methoxyquinoline, and 2,4,8-trimethoxyquinoline with n-butyllithium in ether and subsequent reaction with ethylene oxide furnished hydroxyethyl derivatives 237, which with 20% hydrochloric acid were converted into dihydrodictamnine (239), dihydropteleine (240), and dihydro-y-fagarine... 

The angular isomer 254 which was obtained previously (Volume VII, pp. 235, 237) was a minor product (5%) of the cyclization of aldehyde 247. Heating dictamnine with PPA at 180° resulted in partial conversion (20%) to the angular 2-quinoline, indicating that to obtain maximum yields of furoquinoline alkaloids in the aldehyde cyclization reaction temperature and reaction time must be carefully controlled. The mechanism of the dictamnine rearrangement may involve initial cleavage of the protonated vinyl ether 253 followed by formation of aldehyde 255 and cyclization to the more stable angular derivative (Scheme 20) (196). 

Non-hemiterpenoid Quinolines.—The three non-hemiterpenoid quinoline alkaloids reported this year are all 3-metho iyquinoline derivatives. Furoquinoline alkaloids had been isolated previously from Chloroxylon swietenia (East Indian satin wood), but now two new alkaloids, swietenidins A and B, have been obtained from the bark. Spectroscopic studies of swietenidin A and its monomethyl ether, and comparison of the data with those of the known 8-methoxy-iV-methyl-2-quinolone lunacridine, indicated that the alkaloid was the... 

Quinoline alkaloids with the furan moiety, such as kokusagine, dictamnine, and skimmianine, are called furoquinoline alkaloids, and it became apparent that a part of the furan moiety of these alkaloids was derived from... 

In the biosynthesis of the furoquinoline alkaloids, in order to form the five-membered ring, a ring closure procedure must occur and, as the biosynthetic precursor of these alkaloids, quinoline alkaloids with an epoxide moiety were considered [6]. Namely, in the biosynthesis of dictamnine, it was considered that the ring closure occurred on an unidentified precursor with an epoxide moiety to form platydesmine, which was converted into myrtopsine and finally dictamnine. Thus, quinoline alkaloids with an epoxide moiety in the side chain were considered to be important biosynthetic precursors of both the quinoline alkaloids with a C5 unit at the C-3 position, such as orixine and related alkaloids, and the furoquinoline alkaloids. Such biosynthetic precursors with an epoxide moiety were not isolated previously, probably because they might spontaneously cyclize. Finally, 2 R-preorixine, with an epoxide moiety in the side chain, and considered to be the direct biosynthetic precursor of orixine, was isolated from the... 

Another approach is the use of multicomponent reactions (MCRs) to rapidly and efficiently construct structurally complex and varied polycyclic natural product-like compounds (Figure 1.5). A number of synthetic transformations played a key role in the rapid assembly of such molecules including isocyanide-based reactions, aza- and non-aza [4+2] cycloadditions, [3+2] cycloadditions, and dansition-metal-catalyzed reactions. Using isocyanide-based MCRs, pyrrolopyridines exemplified by mappicine represent an atttactive library target for their biological activity. Furthermore, the furoquinoline alkaloid tecleabine represents a common quinoline alkaloid core similar to strnctnres fonnd in a polycyclic library. ... 

Anthranilic acid and acetate biosynthesize the simple quinoline alkaloids, which are then prenylated with mevalonic acid at the C-3 position to 3-prenyl-2-quinolone alkaloids (e.g., pterecortine from Ptelea trifoliata and orixine from Orixa japonica). 3-Prenyl-2-quinolone alkaloids are then cyclized to dihydrofuro-or dihydropyranoquinoline alkaloids. Hydroxylation at the C-3 position of dihy-drofuroquinoline alkaloids and subsequent loss of the isopropyl side chain produce the furoquinoline alkaloids (Fig. 5.2.8) dictamnine is a skeletal alkaloid and skimmianine is the most common alkaloid. 

The chemistry of thienoquinolines has been explored to a limited degree. Two types (378,379) will be described in this subsection. The pharmacological interest in thieno[2,3-Z>]quinoline (378) and derivatives thereof stems from their isosteric and isoelectronic resemblance to acridine furthermore, (378) constitutes the sulfur analog of furoquinoline (Section 3.17.2.1.5), which is the parent system of a number of alkaloids. Thieno[3,4-6]quinoline (379) is an o-quinonoidal heterocycle which is of interest both for theoretical reasons compared with its isoconjugate analogues and as a synthon in Diels-Alder reactions for the preparation of other condensed heterocycles. 

Introduction of the prenyl residue on to the quinoline skeleton can apparently occur with either a hydroxy- or a methoxy-group at C-4, for (167) and (168) are equally efficient precursors for dictamnine (172) and (174). Methylation of the oxygen function at C-2 as well, however, blocks further reaction, as seen in the isolation of inactive alkaloid after feeding [2,4- C2]-2,4-dimethoxyquinoline. The prenylquinolines (169) and (170) are also equally efficient precursors for dictamnine (172) and (174), and are thus presumably successive intermediates in furoquinoline biosynthesisit is known that the methyl group of (170) is retained in the genesis of skimmianine (173). ... 

The important first experiments on the biosynthesis of quinoline alkaloids were reported in Volume IX, Chapter 6. Extensive 14C and 3H tracer feeding experiments have now led to the elucidation of the main biosynthetic pathway to typical furoquinoline and hydroxyisopro-pyldihydrofuroquinoline alkaloids. In fact, the plan adopted for this chapter is based on the biosynthetic sequence. 

Addendum. A comprehensive review on the occurrence of alkaloids in the Rutaceae family has appeared. The broad spectrum of alkaloid types, including quinolines, furoquinolines, and acridones, may be appreciated from the list of species given in this review. 

Biosynthesis In plants the quinoline system can be formed by several different biogenetic routes (biochemical convergence). In the Cinchona alkaloids tryptophan acts as the precursor while simple quinolines, furoquinolines, and acridines originate from an-thranilic acid. The second biosynthetic parmer is often a hemiterpene (for furoquinolines) or an iridoid monoterpene (secologanin, see secoiridoids) for Cinchona alkaloids. 

Distribution of Pyrroloquinazoline Alkaloids Biological Activity Quinazolinocarboline Alkaloids Quinoline, Furoquinoline, Acridone, and 4-Quinoline Alkaloids... 

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. 

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