Hydrastinic acid

The intermediate products (I) and (II) lose water, forming hydrohydrastinine and oxyhydrastinine respectively. Alkaline permanganate converts oxyhydrastinine into hydrastinic acid (III), C HgOgN, needles, m.p. 164° this in turn is oxidised by dilute nitric acid to hydrastic acid methylimide (IV), CJ0H7O4N, m.p. 227-8°, which, when warmed with potassium hydroxide solution, furnishes methylamine and hydrastic acid (V). 

Constitution. Hydrastine contains two methoxyl groups and a methylenedioxy-group, and behaves as a tertiary base. The first insight into the inner structure of the base was obtained when Freund and Will showed that with dilute nitric acid it undergoes hydrolytic oxidation, yielding opianic acid and a new base hydrastinine, CiiHigOgN. This reaction is analogous with the similar hydrolytic oxidation of narcotine (p. 201) to opianic acid and cotarnine and hydrastinine is allied to cotarnine and can be prepared from it. 

This represents hydrastine as a seeondary amine and a free acid, though the alkaloid reacts with alkyl iodides on the whole as a tertiary amine and forms salts with alkalis rather as a lactone than as a free acid. These and other considerations led Freund and Rosenberg to suggest the alternative formula (IV), based on Roser s formula for narcotine (p. 204). 

Bicuculline, C2oHi,06N. (Items 1, 9, 10, 13, 14, 18, 20, 23-26, 34, 35, 38 list, p. 169). This alkaloid exists in two forms, m.p. 177° and m.p. 196°, and has [a], ° + 130- 5° (CHCI3). The hydrochloride has m.p. 259° (dec.) and from the methiodide, W-methylbicuculline, plates, m.p. 246°, has been prepared. Bicuculline contains no methoxyl groups it behaves as a lactone and is convertible by alkalis into bicucine, which is possibly the corresponding hydroxy-aeid (see below). It simulates hydrastine in its reactions and differs from that base by CH, indicating that a methylene-dioxy group replaces two methoxyl groups, and this view is supported by comparison of the products of oxidative hydrolysis of the two alkaloids. Both yield hydrastinine (p. 163) as the basic product, but while hydrastine provides as the second product, opianic acid,... 

Hordenine (Anhaline), 154, 155, 161, 633 Hunnernanrtia fuTrumoefolia, 173 hunnemannine, 173, 302 Hydrangea umbeUata, 781 Hydrastal hydrastic acid, 164, 165 Hydrastine, 162, 209, 210, 328 constitution, 163 formula, 166-7... 

O-acetylophiocarpine (381) with ethyl chloroformate afforded the C-8—N cleaved urethane 382 in quantitative yield. Sequential treatment of 382 with silver nitrate, PCC, sodium hydroxide, and p-toluenesulfonic acid in ethanol furnished acetal 384, which was reduced with lithium aluminum hydride followed by hydrolysis to afford the hemiacetal 385. Oxidation of 385 with PCC provided (+ )-a-hydrastine (369). Similar treatment of O-acetylepi-ophiocarpine (386) afforded ( )-/J-hydrastine (368) however, in this case, C—N bond cleavage of 386 with ethyl chloroformate proceeded without regioselectivity. 

A series of N-substituted narceine amides (Section III,D,1) was prepared from 101 under the action of primary amines (100). Acid-catalyzed dehydration transformed these amides to corresponding imides (ene lactams) of the ( )-narceine imide (117) type (100). Similar transformations were performed in the hydrastine series (101). JV-Methylhydrastine (98) when treated with dilute ammonium hydroxide gave hydroxy lactam 127, which was dehydrated to (Z)-fumaridine (113) (5). Sodium borohydride was able to reduce the stilbene double bond in 98 to produce saturated lactone 132 (5). 

Gentry EJ, Jampani HB, Keshavarz-Shokri A, Morton MD, Velde DV, Telikepalli H, Mitscher LA, Shawar R, Humble D, Baker W. (1998) Antitubercular natural products Berberine from the roots of commercial Hydrastis canadensis powder. Isolation of inactive 8-oxotetrahydrothalifen-dine, canadine, beta-hydrastine, and two new quinic acid esters, hycandinic acid esters-1 and -2. J Nat Prod 61 1187-1193. 

Berberine has been converted into a mixture of a- and /3-hydrastines, in the proportions 1 2 oxidation with potassium ferricyanide produced dimeric oxy-bisberberine, which with methanolic hydrochloric acid yielded the betaine (91). Hydration of this, followed by N-methylation, yielded the keto-ester (92), which gave a- and /3-hydrastines on reduction with sodium borohydride and subsequent hydrolysis.100 The photo-oxidation of tetrahydroberberine methiodide to allo-cryptopine has been reported.101... 

Like other acid chlorides and cyanogen bromide, vinyl chloroformate brings about fission of benzylic and allylic amines e.g. hydrastine is converted into the enol lactone (145).169 Normorphine and norcodeine give substituted thioureas (146) with alkyl isothiocyanates.170... 

Hydrastine has been prepared by the hydrogenolysis of the 1-phenyl-l/f-5-tetrazolyl ether of (—)-a-narcotoline,154 and in the racemic form by the reductive cyclization of the quaternary salt of the keto-acid (53) that is obtained from oxidoberberine (51) as described above.133 The lactone (80), prepared by the dye-sensitized photo-oxidation of oxidonorcoralyne followed by reduction with sodium borohydride and from 6 -acetylpapaveraldine by oxidation with hypo-bromite followed by reduction, has been TV-methylated and reduced with sodium borohydride to an isomer of cordrastine.133 Cordrastine itself has been synthesized by the electrolytic reduction of a mixture of the iminium salt (81) and bromomeconine (82), a process that has been shown to be of general applicability to the synthesis of alkaloids of this group.155... 

Homoaporphins, 201 Homobenzoqulnones, 339 Homogeranic acid, 295 Homopropargylic alcohols, 279-280 Humulene-4,5-epoxide, 64 Hunsdiecker reaction, 293 Hydrastine, 214, 215 Hydrazides, 429 Hydrazine, 236-237, 351... 

The identification of hydrastine (75, 78, 239), particularly by means of fluorescence (230, 233, 240), by UV-spectra (59, 60), and by IR-spectra (64), has been reported. The quantitative determination of hydrastine can be achieved by titration with perchloric acid (120), by fluorescence... 

The treatment of 3,4-dehydro-9-hydroxylaudanosine (18) with 2% acetic acid on the steam bath yields veratric aldehyde and hydroxylaudanosine, whereas the treatment of narco tine diol (19 R = OMe) and hydrastine diol (19 R = H) with acetic acid and tin(ii) chloride yields the reduced anhydro-compounds (20 R = OMe and H). The oxidation of narcotine with mercury(n) acetate and EDTA affords tarconine methyl ether (21), meconine, and opianic acid. ... 

Hydrastine has been prepared from the aldehydo-acid (53 R = H) by... 

The interesting conversion of nornarceine (181) into the rhoeadine analogues (187) and (188) has been carried out as shown in Scheme 9. Nornarceine (181), obtained from (— )-a-narcotine, was heated in base to afford the enamine (182) which readily cyclized in dilute acetic acid to the y-lactone (183). Upon standing, (183) was oxidized to the ketone (184). Lithium borohydride reduction led to the c/.s-acid (185). The derived ds-fused lactone (186) was then reduced to the hemi-acetal (187) which upon O-methylation with trimethyl orthoformate gave (188). The structure of the methiodide salt of (187) was confirmed by an X-ray analysis. The phthalideisoquinoline alkaloid (— )-bicuculline (189) was then converted into naturally occurring (+ )-rhoeadine (190) by an analogous route. Since (— )-bicuculline was obtained from (—)-)3-hydrastine, whose synthesis had been reported in 1950, this transformation represents the first total synthesis of a rhoeadine alkaloid. ... 

The correct empirical formula, C21H21O6N, was proposed byEijkman (30) and by Freund and Will (31) following earlier ones by Mahla (32) and Power (33). Oxidative fission yields opianic acid (31, 34, 35) and a new base, hydrastinine, CuHiaOsN, m.p. 116-117°, but, unlike narcotine, hydrastine does not suffer hydrolysis when heated with water or dilute sulfuric acid at 200° (36) and is not cleaved by reducing agents such as zinc or tin and hydrochloric acid or sodium amalgam (35). 

Oxidative Fission of Hydrastine (37). Hydrastine (1 g.) is dissolved in a mixture of nitric acid (sp. gr. 1.42) (2 ml.) and water (8 ml.) and the solution maintained at 75° for 20 min. To the cold solution a strong aqueous solution of potassium hydroxide is added until strongly alkaline when hydrastinine (0.4 g.) separates in the crystalline condition. It may be recrystallized from dry ether. 

Narcotine and hydrastine yield sparingly soluble precipitates with a number of inorganic complex acids, such as silicotungstic (199-206), phosphotungstic (199), ferro- and ferricyanic (207-210), chloroplatinic (92, 211-214), and many others including double compounds with heavy metals (213, 215-218). Many color reactions have been observed, but a large number of these depend upon some tjipe of condensation with one of the fission products, and few if any are exclusively diagnostic or specific (160, 167, 219-224). 

A stereospecific conversion of berberine into ( )-/3-hydrastine has been reported. Photolytic oxidation of oxyberberine yields the lactol (123), the N-methyl quaternary salt of which can be reduced with sodium borohydride to give racemic jS-hydrastine in 95% yield. Both phthalide-isoquinolines (e.g. adlumine) and spirobenzylisoquinolines e.g. corydaine) have been synthesized from /3-phenethylamines and methylenedioxyphthalide carboxylic acid (124). Several ethers of narcotoline have been prepared and converted into derivatives of nornarceine. The biotransformation of narcotine in rats has been examined and di-O-desmethylnarcotine, cotarnine, hydrocotarnine, oxocotarnine, and O-demethylmeconine have been isolated from urine. " Bicuculline, which has... 

A stereospecific conversion of berberine to j8-hydrastine has been achieved through the intermediacy of 8,13-dioxo-14-hydroxycanadine <45). Treatment of this colorless compound with 25% aqueous sulfuric acid produces instantly the deep violet color characteristic of dioxoimmonium salt formation. Upon... 

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