Corydaline synthesis

C alkylation was used in the corydaline synthesis 194). LukeS and Dedek 195) obtained on methylation of l-methyl-2-ethylidenepyrrolidine a C-alkylation product, i.e., l-methyl-2-isopropyl-/l -pyrroline (106). Alkylation of the same enamine with ethyl bromoacetate was the first synthetic step in the preparation of D,L-pseudoheliotridane 196). 

Special Reactions of Papaverine. Papaverine undergoes a number of reactions, which are of interest as providing methods of synthesis for other alkaloids, of which examples will be found under laudanosine, laudanine, laudanidine, codamine (pp. 187-195), berberine (p. 331), corydaline (p. 284), and glaucine (p. 311). 

These methods were applied to a synthesis of corydaline (469) (231), tetrahydrocorysamine (470) (235), and corybulbine (471) (236) (Scheme 95). Rather mild 13-methylation was developed by treatment of dihydroberberine (90) with 30% formaldehyde in 10% acetic acid (237,238). However, this method cannot be applied to an introduction of other C-13 substituents because aldehydes other than formaldehyde do no react. 

A-Acyliminium ions are versatile intermediates for synthesis of nitrogenous compounds, particularly alkaloids [154]. The conjugate system is very electrophilic such that it can be intercepted by various donors including carbonyl compounds and jt-systems. In comparison with a,p-unsaturated ketones the replacement of the a-carbon with a nitrogen atom accentuates the reactivity of these species. Ingenious applications of the JV-acyliminium ions include service to synthesis of corydaline [155], lycoramine [156], quebrachamine [157], and ajmaline [158], to name a very few. 

Several 13-unsubstituted and 13-methyl-berbine alkaloids have been synthesised by reacting homophthalic anhydride with 3,4-dihydroisoquinolines followed by a sequence of reaction. Synthesis of (+) corydaline (57) involves the following steps... 

Furthermore, the following compounds were synthetically prepared racemic cheilanthifoline (58c) (47), kikemanine (58d) (129), canadine (58e), berberine (59a) (590, 614), tetrahydropalmatine (58g) (475), sinac-tine (58h), cavidine (68d) (616,617), nandinine (58i) (590, 614, 615), capaurine (58p) (618), capaurimine (58o) (128, 618a), xylopinine (60c) (610, 615, 619), O-methylcaseanadine (62b) (70, 620), thalictricavine (68b), and corydaline (68h) (615). Xylopinine (60c) and some other alkaloids were synthesized by benzoylation of 1-alkyl-3,4-dihydroisoquinolines followed by photocyclization. This method provides a useful route to the synthesis of other protoberberine alkaloids (619). It is also applicable to the synthesis of cularine (51) and spirobenzyltetrahydroisoquinoline alkaloids (188). Xylopinine was also synthesized from the corresponding enamide under benzyne reaction conditions (615). Kametani etal. summarized their findings on the synthesis of these alkaloids and described the formation of protoberberines by debenzylation and photolysis of tetrahydroisoquinolines (622, 623). The total stereospecific synthesis of racemic ophiocarpine (70a) from the 3,4-dihydroisoquinoline derivative by Mannich cyclization was also described (624). 

The indolizidinedione derivatives (322), easily available from l-alkyl-3,4-dihydroisoquinolines and oxalyl chloride, react with arynes to give 13-substituted 8-oxo-protoberberines (323), probably through the mechanism outlined in Scheme 73. This chemistry has been exploited in the total synthesis of the alkaloid (+ )-corydaline <86JOC278i>. 

Synthesis. The first synthetic evidence for the structure of corydaline was provided by Koepfli and Perkin (255), who condensed /8-veratryl-ethylamine with 3,4-dimethoxy-a-methylhomophthalic anhydride to yield the amide LIX. The action of phosphoryl chloride on the methyl ester of LIX yielded the isoquinoline, probably LX, but formulated with... 

The synthesis of corydaline itself was accomplished by Spath and Ktuta... 

Since in most naturai protOberberines C13 has no substituent, or at most a methyl or methoxyl group (Refs. 2, 17), it is of interest to be able to avoid the arylation of C13 observed in 21. Fortunately, this is achieved by the presence of a methyl group at the corresponding position in the pyrrolinedione, which has enabled us to carry out total synthesis of corydaline (22)- 3,4-dimethoxybenzyne (22d) reacts regioselectively with the pyrrolinedione 29b to give a 32% yield of the adduct 34a. which reduction with lithium aluminium hydride and sodium borohydride converts into corydaline (Scheme 11)(Ref. 16). 

---