Of -laudanosine

The constitution of laudanosine was determined by Pictet and Athanasescu/ who prepared it by reducing papaverine methochloride with tin and hydrochloric acid and deracemising the dZ-laudanosine (iV-methyltetrahydropapaverine) so obtained, by fractional crystallisation of the quinate. Laudanosine must, therefore, be represented by formula... 

A complete synthesis of laudanosine was effected by Pictet and Finkelstein by the condensation of omoveratrylamine (I) with homo-veratroyl chloride (II), giving omoveratroyl omoveratrylamine, which with phosphoric oxide undergoes cyclisation to 3 4-dihydropapaverine (III), which was converted into the methochloride and reduced to laudanosine (IV). 

The first postulate may be illustrated by the still unrealised conversion of laudanosine into glaucine by oxidation, resulting in the loss of one atom of hydrogen from each aromatic nucleus and union of these as shown by the dotted line. 

Gawley and coworkers showed that oxazolines can be used in place of formamidines for asymmetric alkylations of tetrahydroisoquinolines. A number of substituted oxazolines were evaluated as chiral auxiliaries, and one derived from valinol was found to be optimal. Interestingly, the same enantiomer of valinol affords the opposite enantiomers of the substituted tetrahydroisoquinoline when incorporated into formamidine or oxazoline auxiliaries. An example is shown in Scheme 58, as applied to a synthesis of laudanosine and the morphinan 9-7 -0-methylflavinantine. ° ... 

Laudanosine (6,7,3, 4 -tetramethoxy-1 -benzyltetrahydroisoquinoline) was isolated for the first time by Hesse (371) from opium. Intravenous administration of this substance to rabbits reduced the intraocular pressure (372). The whole effect manifested itself by motor restlessness, convulsions, disorders in coordination of movements, salivation, etc., which indicated an involvement of the extrapyramidal system and the mesencephalon. The effect produced by synthetic racemic laudanosine on rabbits was similar to that of the (+) form, but it was more toxic (373). The pharmacological properties of laudanosine have also been described (374). 

Another methods for the electrochemical formation of the active carbanion is the cathodic reduction of iminium salts. When an iminium salt is reduced in the presence of a suitable alkylating agent, an alkyl group is introduced to the carbon atom of the imine. Some isoquinoline and indole type alkaloids are synthesized by using this substitution method as exemplified bellow by the synthesis of laudanosine 51 37>. 

The benzylisoquinoline alkaloids are widely distributed in nature and are intermediates in the biosynthesis of alkaloids of this family (2, 3). It is not surprising therefore that several groups (6, 7, 15, 23) have examined their spectra. Among the alkaloids that have been studied are reticuline (26) (7), norlaudanosine (27) (7), laudanosine (28) (6, 15), and the cis- and trans-N-oxides of laudanosine, 29 and 30, respectively (7). The chemical shifts of laudanosine are recorded in Table IV and the structures of the alkaloids may be found in Fig. 4. 

The assignments of the 13C chemical shifts of laudanosine were first made by Wenkert et al. (6) and confirmed later (15). It is now apparent that compounds 2 and 3 (14) and 3,4-dimethoxyphenethylamine (6, 15) serve as satisfactory models of the isoquinoline and benzyl moieties, respectively. The substitution of a 3,4-dimethoxybenzyl group at C-l of 3, as in laudanosine (28), caused changes to occur in the chemical shifts of the aliphatic carbon atoms of the tetrahydroisoquinoline moiety analogous to those of the compounds with substituents at C-l listed in Table II (C-l, +7.9 C-3, —6.2 C-4, —3.5 NCH3, —3.6). The chemical shift changes between 27 and 28... 

The 13C spectrum of cularine (34) (Fig. 6, Table VI), has been reported by Wenkert et al. (6). The chemical shifts of the aliphatic carbon atoms were assigned by comparison with those of laudanosine (28) and follow also from those of the simple isoquinolines (Section II). In the aromatic region the resonances of the pair of protonated carbon atoms at C-5 and C-6 were differentiated from those at C-2 and C-5 by the observation of... 

Microbiological transformation of laudanosine by the micro-organism Cunninghamella blakesleeana is accomplished by selective demethylation, to give i/f-codamine (19).29 Isoquinoline alkaloids that can be selectively halogenated can readily be converted into hydroxy-compounds by lithiation of the bromo-... 

Bromolaudanosine, on treatment with potassamide or sodamide in liquid ammonia, yields the dibenzo[ >,g]indolizinium salt (21), the reaction presumably proceeding through the aryne, together with aminolaudanosine and the indoline (22) and the indole (23).32 Photolysis of laudanosine methiodide yields the base (24 R = Me) in methanol and (24 R = H) in water. The latter, on heating with... 

Methods of purification38 and estimation39,40 of papaverine and of estimation of ethaverine41 have been described and the stereochemistry of the quaternization of laudanosine has been studied.42 The effects of papaverine on cerebral circulation of... 

Laudanosine metabolism may be reduced in liver disease (52), and in renal insufficiency higher plasma concentrations and an apparently delayed elimination of laudanosine have been reported (53). Prolonged infusion of atracurium in intensive care (for 38-219 hours) led to slowly increasing plasma laudanosine concentrations, which appeared to plateau after 2-3 days (54). The maximum plasma laudanosine concentrations in six patients were 1.9-5 pg/ml. There was no evidence of cerebral excitation. Nevertheless, caution is urged in patients with severe hepatic dysfunction (55,56), particularly if associated with renal insufficiency, when repeated bolus doses or an infusion of atracurium are given over a prolonged period. 

Hennis PJ, Fahey MR, Canfell PC, Shi WZ, MiUer RD. Pharmacology of laudanosine in dogs. Anesthesiology 1984 61 A305. 

Fahey MR, Canfell PC, Taboada T, Hosobuchi Y, Miller RD. Cerebrospinal fluid concentrations of laudanosine after administration of atracurium. Br J Anaesth 1990 64(l) 105-6. 

On the basis of comparison of the physical constants of 0,0-dimethylphellodendrine methine with those of laudanosine methylmethine (LXXII) (mp 94°-95° hydrobromide, mp 209.5°-211°), these bases were supposed by Tomita and Kunitomo (68) to be identical. Thus phellodendrine was represented by the isoquinoline structure LXXIII. 

Alkaloid isolations are summarized in Table 5. Photolysis of laudanosine hydrochloride (33) or laudanosine metho-salts in hydroxylic media yields cleavage... 

Another interesting finding is that electrolytic oxidation of laudanosine (15b) in TFA affords a 17% yield of glaucine (20) the presumed intermediate again being a morphinandienone. ... 

Sodium thiophenoxide appears to be the best reagent for the selective demethyla-tion of quaternary ammonium salts." 2-Butanone is used as solvent. The reaction involves Sn2 attack by the phenoxide anion on the N-methyl group. An example is the demethylation of ( )-laudanosine methochloride to laudanosine. A limitation... 

Attempts have been made to realize experimentally the conversion of laudanosine-type bases to bases of the aporphine and morphine series, so far without success. In an attempt to convert laudanosoline [xtx] to norglaucine [x ] it was discovered that the former is very readily oxidized to intractable materials, but that oxidation with chloranil [5-6] or tetrabromo-o-benzoquinone [7] affords, not the expected norglaucine, but 2 3 11 12-tetrahydro-8-methyldibenzotetrahydropyrrocolinium ohloride [xxi]. Protosinomenine [i] has been synthesized in two ways [3, 8], but the conditions required for the conversion of this base to sinomenine [iv] have not yet been realized and their discovery must be largely fortuitous [6],... 

Bisquaternary salts of laudanosine with itself and with other tetrahydroisoquinolines and long chain dihalides have been prepared as potential neuromuscular blocking agents of the same type as tubocurarine. The most widely studied of such salts is atracurium (44) (R. Hughes and D.J. Chappie, Brit.J.Anaesth., 1981, 31 J.B. Stenlake et al., Eur.J. 

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