Quinol Alkaloids

Electrophilic aromatic substitution of 5-hydroxy-2,4-dimethoxy-3-methylaniline by reaction with the iron complex salts affords the corresponding aryl-substituted tricarbonyliron-cyclohexadiene complexes. O-Acetylation followed by iron-mediated arylamine cydization with concomitant aromatization provides the substituted carbazole derivatives. Oxidation using cerium(IV) ammonium nitrate (CAN) leads to the carbazole-l,4-quinones. Addition of methyllithium at low temperature occurs preferentially at C-1, representing the more reactive carbonyl group, and thus provides in only five steps carbazomycin G (46 % overall yield) and carbazomycin H (7 % overall yield). 

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Scheme 3 Carbazole-l,4-quinone and carbazole-l,4-quinol alkaloids...

The carbazole-1,4-quinol alkaloids are also accessible by the iron-mediated arylamine cyclization (Scheme 14). Electrophilic substitution reaction of the arylamine 24 with the complex salts 6a and 6b affords the iron complexes 25. Protection to the acetates 26 and oxidative cyclization with very active manganese dioxide leads to the carbazoles 27, which are oxidized to the carbazole-... 

Hydroxylation at C-5 or C-l3 has also been successfully achieved by lead tetraacetate oxidation, which was extensively studied in connection with isoquinoline alkaloids by Umezawa s group. (+)-Govanine (96) and (+)-discretine (97) were oxidized with lead tetraacetate in acetic acid to afford 5-acetoxy products 100,101, and 102 via p-quinol acetates (e.g., 99) (Scheme 23)... 

In 1988, Nakamura et al. reported the isolation of carbazomycins G (269) and H (270) from the culture broth of Streptoverticillium ehimense. These alkaloids have a structurally unique carbazole-l,4-quinol framework and were obtained from Nature in racemic form. Carbazomycin G showed moderate antifungal activity against... 

From the residue that remained after the isolation of macrorine, isomacrorine, and macrorungine, a fourth alkaloid could be isolated. This was called normacrorine (174). The structure (119) was deduced mainly from IR and NMR spectra and confirmed by synthesis. This synthesis makes use of the method of Clemo for the preparation of pyridylimidazoles. The oxime of 2-acetylquinoline (123) was converted, via the /vtoluenesulfonyl ester, to 2-potassium thiocyanate gave 4-quinol-2-yl-2-mercaptoimidazole... 

Carbazomycin G and H have been isolated from Streptoverticillium ehimense [38]. In nature carbazomycin G occurs as a racemic mixture and the same is assumed for carbazomycin H. Garbazomycin G was reported to show antifungal activity. The two compounds share a unique structure, namely the carbazole-l,4-quinol moiety. Starting from the appropriate iron complex salt, iron-mediated arylamine cydization provides a simple route to both alkaloids (Scheme 15.10) [39]. 

Hydro-quinol, 1-4-Di-hydroxy Benzene.—The third isomeric dihydroxy benzene, viz., the para compound, i-4-di-hydroxy benzene, is known as hydro-quino or hydro-quinone. The latter name is derived from its relation to quinone (p. 636) from which it is obtained on reduction and which it yields on oxidation. Both hydro-quinol and quinone derive their names from the fact that they are obtained by the oxidation of quinic acid, an acid derived from the alkaloid quinine. The phenol is found in various plants or may be obtained from them by the hydrolysis of glucosides present, e.g., arbutin, which is a glucoside hydrolyzing into glucose and hydro-quinol. 

The structure of maculosidine as 6,8-dimethoxydictamnine has been confirmed. Hydrogenolysis, followed by acid hydrolysis, gave 6,8-dimethoxy-3-ethyl-4-hydroxy-2-quinolone, identical with a synthetic specimen (104). The alkaloid has been synthesized (105) by the method of Tuppy and Bohm. Maculine (6,7-methylenedioxydictamnine) has been synthesized by Ohta and Mori (106, 107) by a modification of Grundon s method (108). 3,4-Methylenedioxyaniline was condensed with ethyl 2-benzyloxyethylmalonate and the resulting 4-hydroxy-2-quinol-... 

Since many isoquinoline alkaloids incorporate a guiacol moiety, we first tried to oxidize the most accessible 6-methoxy- and 7-methoxy-l,2,3,4-tetrahydroisoquinolinols (types A and B) with LTA. Later, tetrahydro-isoquinolinols of type C were also used. In spite of Wessely s statement (16) that LTA oxidation of both vanillin and isovanillin affords the corresponding o-quinol acetates, for a while we were able to obtain not the o-quinol acetate 2 from corypalline (1) but the p-quinol acetate 3 (17). At the outset of our study (IS), LTA oxidation of isocorypalline (4) gave no isolable o-quinol acetate 5, 4-acetoxyisocorypalline (6) being isolated instead. 

Recently, Gozler et al. (123) proposed the stereostructure 1,4-ci s-l,2,3,4-tetrahydro-4,6-dihydroxy-7-methoxy-l-(3,4-dimethoxyben-zyl)-2-methylisoquinoline (446) for (-l-)-roemecarine. However, the stereostructure was revised to 449 based on the synthesis of 446 (124). Namely, two epimeric acetates, ( )-l,4-(ij- and ( )-l,4-/r zi.v-4-acetoxy-l,2,3,4-tetrahydro-6-hydroxy-7-methoxy-1 -(3,4-dimethoxybenzyl)-2-methyliso -quinolines (447 and 448), previously prepared via a thermal isomerization of the corresponding o-quinol acetates (19), were used for synthesis of ( )-roemecarine and its epimer (Scheme 60). Hydrolysis of 447 and 448 with 5% methanolic potassium hydroxide proceeded with retention of the configuration at C-4 to give the authentic ( )-1,4-c/.v- and ( )-i,4-tran.s-diols 446 and 449. As a result, structure 446 was inconsistent with natural roemecarine on the basis of H-NMR spectral comparison, while 449 was identical with the alkaloid with respect to spectroscopic data. 

Treatment of the quinol acetates derived from 5-, 6-, or 7-hydroxytetra-hydroisoquinolines with lead tetraacetate (LTA) in acid gives different types of alkaloids. LTA oxidation of 7-hydroxy bases 82b,c,f,g in acetic... 

The oxidation of alkaloids of this group with a variety of reagents has been studied in detail. With lead (IV) acetate phenolic tetrahydroberberines are oxidised to quinol acetates in the same way as benzylisoquinolines. Govanine (181, R =Me, R =H) is converted in this way into the dienone (182) and this is transformed by acetic anhydride and sulphuric acid into ace-toxyacetylgovanine (183, R =Me, R =R =Ac), which on hydrolysis in methanol gives (183, R =R =Me, R =H) and its C-5 epimer. 

The total syntheses of the less common alkaloids cassamedine (35f) (427) and N-methylovigerine (25n) (458), and of some nornucipherine derivatives were also achieved (459). Thaliporphine (24g), domesticine (241), and glaucine (24h), can be synthesized via the p-quinol acetate route (415, 460, 461) (Scheme 11). 

Scheme 11. Synthesis of the aporphine alkaloids (24) via the p-quinol acetate route (413).

Fig. 6.20 Aurachin RE a tuberculosis (TB) drug, and oxidative modification of menaquinone by M tuberculosis CYP128A1. a Aurachin RE an alkaloid antibiotic with anti-TB activity through its inhibition of menaquinone biosynthesis (enzyme MenA) [339], R. erythropolis RauA (CYP1050A1) catalyzes the N-hydroxylation of an aurachin intermediate to produee the aetive auraehin RE compound [337], b Dihydromenaquinone MK9, the major quinol electron carrier in Mtb respiration, is likely...

The same year, Canesi s group reported an asymmetric s5mthesis of the levoro-tatory enantiomer of the Amaryllidaceae alkaloid fortucine [105]. The L-tyrosine-derived phenol 163 was treated with DIB in HFIP to induce an oxo-spirocyclization into the para-quinolic lactone 164, which was treated with methanolic KOH to mediate both the opening of the lactone unit and an aza-Michael addition of the amide onto the cyclohexa-2,5-dienone moiety in high yield and stereoselectivity. The resulting aza-bicyclic intermediate 165 was then converted in 11 steps into (-)-fortucine (Fig. 41). This first asymmetric synthesis of fortucine led to the correction of the absolute configuration of the natural (+)-fortucine [105]. 

The first total syntheses of the marine bromotyrosine-derived alkaloid subereamollines A and B were also described by Ley s group in 2011 [119]. Access to the spirocyclohexadienylisoxazoline core of the targets was ensured by a DIB-mediated oxo-spirocyclization of the phenolic oxime methyl ester 205, followed by a diastereoselective ketone reduction of the resulting orf/io-quinol 206 (Fig. 51). The methyl ester 207 was then converted in two steps into rac-subereamolline A or B. Both racemates were then separated into their respective enantiomers by chiral HPLC [119]. 

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