Corydalic acid methyl ester

As a part of the total synthesis of (+ )-corydalic acid methyl ester (12), a reaction of a cyclic enolate with an imine has been applied. The 2-toluamide enolate 9, which in this case is substituted at the methyl group, adds stereospecifically to imine 10, affording mainly tram-iso-quinolone 11 with a d.r. (transjds) > 95 525. 

The stereochemistry of corydalic acid methyl ester (8) was confirmed by correlation with the Hofmann degradation product of mesotetrahydro-... 

The Hofmann degradation product 252 used for a synthesis of corynoline (254) was again a useful starting material for ( )-corydalic acid methyl ester (8). It was reduced with sodium cyanoborohydride to the trans derivative 10 as a major product, which was converted to 8 via acetal 268 and aldehyde 269 (143). 

The 6,7-secoberbine alkaloids contain the four following natural products corydalic acid methyl ester (55), corydamine (56), N-formylcorydamine (57), and hypecumine (58). These bases, called 3-arylisoquinolines, were described by Shamma and Moniot (2) as a separate class of isoquinoline alkaloids. Santavy (7) classified them among benzophenanthridines. It seems, however, that they may be considered as biosynthetic intermediates between the protoberberines on the one hand and the benzophenanthridines on the other. 

Three of the alkaloids (55-57) were isolated from Corydalis incisa (63-65) and two (57, 58) from Hypecoum procumbens (66), where they coexist with the parent protoberberines. They are formed in plants by an oxidative C-6—N bond cleavage, possibly through an aldehyde intermediate 61. This assumption was supported by in vivo experiments in which ( )-tetrahydrocorysamine-8,/4-/2 (59) and (+ )-tetrahydrocoptisine-8,74-/2 (60) were fed to Corydalis incisa (67) to produce corydalic acid methyl ester-8-/ (55) along with corydamine-8-f (58) and corydalic acid methyl ester-8-/ (55) with corynoline-8-/ (62), a benzophenantridine alkaloid, respectively (Scheme 14). 

In Table IV some physical data and spectral characteristics of 6,7-secoberbines are listed. Only methyl corydalate (55) is optically active. Formula 55 presents the spatial structure of this compound, deduced by Nonaka et al. (65) and confirmed by Cushman et al. by both correlation with (+)-mesotetrahydrocorysamine (72) (<5S) and total synthesis (69). It is difficult to find common characteristic features in both the mass and H-NMR spectra of these alkaloids because they differ significantly from each other in their structures. On one hand, corydalic acid methyl ester (55) incorporates a saturated nitrogen heterocycle, while the three aromatic bases (56-58) differ in the character of the side chain nitrogen. For example, in mass fragmentation, ions of the following structures may be ascribed to the most intensive bands in the spectrum of 55 ... 

Several transformations of 6,7-secoberbine alkaloids to their parent congeners were conducted. Corydalic acid methyl ester (55) was converted to (+)-mesotetrahydrocorysamine (72) (65) (Scheme 18), and corydamine (56) was transformed to tetrahydrocoptisine (39) 64) (Scheme 19). 

Corydalic acid methyl ester lateral lithiation2... 

Corydalic acid methyl ester 11, isolated from Corydalis incisa, is derived from a proposed biosynthetic intermediate in the route to the tetrahydroprotoberberine alkaloids. The 1,2,3,4-tetrasubstituted ring of 11 demands control by an ortholithiation strategy, and the synthetic route proposed by Clark and Jahangir2 employs a lateral lithiation of 12 and addition to an imine as the key disconnection at the centre of the molecule. 

Similarly 7,8-methylenedioxy-4-methylhomophthalic anhydride has been converted to ( ) corydalic acid methyl ester... 

Corydalis incisa Corydalic acid methyl ester (163) 279... 

Radioactive tetrahydrocorysamine (68) was found to label corynoline (71), acetylcorynoline (72), and corydalic acid methyl ester (74) specifically, and radioactive tetrahydrocoptisine (67) specifically labelled the same alkaloids plus corydamine (73) corynoline (71) was not incorporated into (74). These results are consistent with the pathway outlined in Scheme 4, in which (69) and (70) are logical intermediates. Their intermediacy is further supported by the observation that (75), labelled as shown, gave radioactive corynoline (71) in which the residual tritium label was located at C-6. 

Styrene 4, prepared by Hofmann degradation of the methiodide of synthetic 3, upon hydroboration and basic oxidation, gave rise to an alcohol identical to 1. The stereochemical assignment for corydalic acid methyl ester was based on rates of methiodide formation, the 13-methyl group shift in the PMR, and the absence of Bohlmann bands in the IR spectrum of the protoberberinoid derivative 3 derived from the natural product (see Scheme 22.1). 

By feeding to Corydalis incisa ( )-tetrahydrocoptisine labeled with tritium at C-8 and C-14, it has been demonstrated that this tetrahydroprotoberberine can be converted to corynoline, corydalic acid methyl ester, and corydamine. Additionally, tetrahydrocorysamine acts as a precursor for corynoline and corydalic acid methyl ester by oxidative fission of the C-6 to N-7 bond (Scheme 22.3). ... 

Corydalic acid methyl ester, which incorporates a tetrahydroisoquinoline unit, shows peaks due to the expected retro-Diels-Alder fragmentation, loss of the carbomethoxy group, and interaction of the ester and amine functions (Scheme llA) ... 

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