Of corydaline

Dehydrocorydaline, C22H2304lSk (Items 8,14, 31 list, pp. 170-2.) This alkaloid is formed by the gentle oxidation of corydaline.It is a yellowish crystalline powder, m.p. 112-3° (dec.) the hydrochloride, B. HCl. 4H2O, forms yellow leaflets hydriodide, B. HI. 2H2O, small yellow needles aurichloride, B. HAUCI4, red-brown needles, m.p. 219°. Like berberine,... 

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. 

The berberine relative (72) has been found to be a precursor of corydaline (68), acting to provide the hypothetical intermediate (73) for introduction of the C-methyl group. Curiously, the likely precursor, i.e. (69), for both (72) and (73) was not incorporated.20... 

C. Stereochemistry of Corydaline and Related Alkaloids 1. Relative Configuration... 

Advances in the chemistry of the corydaline type alkaloids since the last reporting have involved proposals for the relative and absolute configuration of ( + )-corydaline and related alkaloids. 

A knowledge of the stereochemistry of corydaline and mesocorydaline has permitted stereochemical assignments to be made to the other known 13-methyl-substituted tetrahydroprotoberberine alkaloids (105). 

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... 

Genesis of corydaline (98) along the protoberberine route requires labelling of C-5 and C-13 by [3- C]tyrosine and, in accord with this, one half of the tyrosine label incorporated into (98) was found to be at C-13." Clear support is thus provided by the above results for a pathway (Scheme 12) similar to that for the protoberberine alkaloids. (The illustrated pathway includes a plausible mechanism for the C-methylation reaction but neither the mechanism nor the point after reticuline at which methylation occurs has yet been established.)... 

Hydrochloride hydrate, C ,H,N04. HCI.H20, four-sided columns, mp 230-24[Pg.398]

According to Manske, the precursors of corydaline alkaloids (68) are already C-methylated on the benzylisoquinoline skeleton before ring C closure takes place (637). On the contrary, Blaschke reported that labeled reticuline (7f) is converted specifically into corydaline (68h) (638). The experiments have also shown that the radioactivity from [3-14C]tyrosine and from [methyl-14C]methionine is incorporated nonrandomly into predicted positions of corydaline and ochotensimine in Corydalis solida and C. ochotensis, respectively (639). The methyl group of methionine supplies the C-13 methyl group of corydaline and the exocyclic methylene group of... 

In the course of work leading to the elucidation of the structure of corydaline at the time that these researches were undertaken the structures of none of the protoberberines were known, and most of this work is of historical interest only. Had the later work on berberine and tetrahydro-palmatine been available the determination of the structure of corydaline would have been an easy task. That it contains the same nuclear structure is indicated by its ready oxidation to dehydrocorydaline. Unlike the reduction of palmatine which gives a single product, the dl-tetrahydro base, the reduction of dehydrocorydaline gives rise to a mixture of meso-and racemic corydaline (245). The mesocorydaline has been resolved by means of d-camphorsulfonic acid, but the d-base is not identical with d-corydaline. It is obvious therefore that corydaline contains two asymmetric carbons. 

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... 

Constitution. The empirical formula of thalictrifoline and its ready oxidation indicates that it is a methyl homologue of either canadine or sinactine, that is, corydaline in which two of the methoxyls are replaced by a methylenedioxy group. On oxidation with iodine in methanol it is transformed into a quaternary iodide, which on reduction with zinc and hydrochloric acid yields dZ-thalictrifoline, m.p. 151°, which was also obtained by reduction of the naturally occurring dehydrothalictrifoline chloride. Complete oxidation of thalictrifoline yielded m-hemipinic acid, and therefore its structure was written as LXV. This was confirmed by demethylenation to a dihydroxy base and methylation of the latter. The new base proved to be an optically active stereoisomer of corydaline, presumably that of mesocorydaline, and on racemization by iodine oxidation and subsequent reduction was converted into mesocorydaline. 

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). 

The biogenesis of ochotensimine has been studied in Corydalis ochotensis (Fumariaceae), and in conjunction with that of the tetrahydroprotoberberine alkaloid corydaline in C. solida. Both compounds are derived from two molecules of tyrosine and the 5-methyl group of methionine. The 5-methyl group of methionine supplies, among others, the C-13 methyl group of corydaline and the exocyclic methylene group of ochotensimine. (See also Sec. 19.4.)... 

The ultimate products of oxidation are therefore hemipinic acid (8 4-dimethoxyphthalic acid), wieiahemipinic acid (4 5-dimethoxy-phthalic acid) and pyridine-2 3 4 6-tetracarboxylic acid. The identity of the last-mentioned substance is doubtful, since it was produced by the oxidation of a supposed 2-methylpyridine-8 4 6-tricarboxylic acid. The latter has been synthesised by Lawson, Perkin and Robinson and shown to be different from Bobbie and Lauder s oxidation product. It was largely on the assumed position of the methyl group in this acid that Bobbie and Lauder based the position of the methyl group in their formula for corydaline. These observations establish the presence of one pyridine and two benzene rings in corydaline, and the study of corydilic and cory-daldine provided information as to the way in which these components are built into the molecule of corydaline. 

Dehydrocorydaline contains four methoxyl groups. On reduction it furnishes two stereoisomerides of corydaline, m.p. 135°, and m.p. 158-9° (163-4° vac.), Spath) the latter (wcsocorydaline) by crj stallisation of the d-camphorsulphonate can be partially separated into d- and 1-forms, the d-form of which is not identical with natmal corydaline. The second isomeridc, m.p. 135°, has not been resolved into optically active components, but from the sulphonic acid the Z-compoiicnt has been isolated by crystallisation of the brucine salt, and this is taken to indicate that the inactive corydaline, m.p. 135°, is dZ-corydaline. °... 

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