The Cularines

The phenolic base cularicine has been prepared by a synthesis which closely parallels the original synthesis of cularine. However, variations in the scheme were introduced to accommodate the sensitivity of the required phenol protecting group to Lewis acid.  

The diphenyl ether 1 was converted to the morpholinamide 2, which after cyclization to the enamine 3 and hydrolysis furnished the tricyclic ketone 4. Interestingly, in the modified Pomeranz-Fritsch cyclization step, one of a pair of ethoxyl rather than hydroxyl racemates was isolated. Catalytic hydrogenolysis and reductive iV-methylation completed the synthesis shown below  

Oxidation of isocularine derivatives with a variety of oxidants to obtain 1,2-dehydro analogs led instead to ring-B aromatic cc-oxo products.  

---

There are several reports of tetrahydroisoquinolines with a fused furan ring that could be argued (for the sake of the classification used in this collection) as an oxidative attack by the a-hydrogen of the 1-benzyl onto the 8-HO substituent, in a manner similar to the formation of a seven-membered ether ring seen in the cularines. It can also be seen as a similar oxidative attack from an a-hydroxy group (a commonly encountered benzyl substituent) on the 8-hydrogen position. The first of these two mechanisms (illustrated above) is used in this collection. 

To our knowledge the biological effects of the alkaloids of the cularine group have not been studied. 

A similar analysis of the cularine portion of cancentrine resulted in the tentative assignment of the remaining aromatic carbon atoms (36). The signals at 194.0, 160.1, and 104.3 ppm were assigned to C-l, C-25, and C-24, respectively. The assignment of the oxygenated carbon atoms can at best be considered tentative. 

Alkaloids of the cularine group have always been assumed to be derived by internal oxidative coupling of a diphenolic base or triphenolic base of general structure (89, R=Me or H) though no such base was known until the isolation of crassifoline (89, R=Me) from Corydalis olavioulata (G. Blaschke and G. Scriba, Z.Naturforsch., 1983, 38C, 370) and from Saraooapnos crassifolia (J.M. Boente et al., Tetrahedron Letters, 1983, 2303),... 

A possible mode of biogenesis of alkaloids of the cularine type has been simulated by the oxidation of l-(4-hydroxy-3-methoxybenzyl)-8-hydroxy-6,7-dimethoxy-2-methyltetrahydroisoquinoline to the dienone (164), and rearrangement of this... 

The mass spectra (Section II, D) indicated that the phenolic function was located in the cularine half of the molecule, whereas a comparison of the NMR spectra of cancentrine (1) and its 0-acetate (3) indicated that there is a proton para to a phenolic hydroxyl group (6) and hence the latter must be placed at C-20. This assignment was confirmed by observed nuclear Overhauser effects (NOE) of 25, 25, and 24%, respectively, in three aromatic signals when the methoxyl resonances of cancentrine were saturated in turn. Such a result is possible only if each of the three methoxyl groups is vicinal to an aromatic proton. Since the location of the substituents on the aromatic rings was known from the X-ray structure of 7 this result unambiguously places the hydroxyl group at C-20 (3). 

The spectra of the 0-methyl ether 2 and the 0-acetate 3 are similar and show shifts in the m/e 350 and m/e 363 ions expected from methyla-tion and acetylation, respectively. This evidence placed the hydroxyl group in the cularine moiety of the molecule as only these ions were affected. The 0-acetate has a pronounced tendency to eliminate ketene so that its spectrum has all the peaks associated with cancentrine itself as well as ions 42 mass units greater in those ions involving the cularine half. 

Dehydrocancentrine-B, a cherry-red alkaloid isolated from the same source, had the same functional groups as cancentrine (NMR, IR). However, its IR spectrum indicated the presence of an additional double bond in agreement with the molecular formula (C36H32N2O7) obtained by high-resolution mass spectrometry (HRMS). The mass spectrum was very similar to that of cancentrine with the exception that ions from the cularine half of the molecule appeared two mass units lower. Thus there were ions at m/e 361 (C21H15NO5) and m/e 348 (C20H14NO5) arising from fissions a + b and a -l- c, respectively (Scheme 1). This indicated that the extra double bond was in the cularine part of the molecule and must be located at the only available position, namely, C-31—C-32 (12). The NMR spectrum supported the location of the double bond in this position by the presence of a fourth AB system one half of which was visible at S 6.25 (Jab = 7.0 Hz). The location of the substituents and the relative stereochemistry of the alkaloid were shown to be identical with those... 

The cularine alkaloids appear to occur only in the genera Corydalis and Dicentra. 

Cularines.—Ferricyanide oxidation of the tetrahydrobenzylisoquinoline (50) gave the cularine analogues (51) and (52) in 2.5% and 5% yield respectively. ( + )-Cularine was then obtained from (51) by O-methylation. Analogous... 

Bisbenzylisoquinoline Alkaloids by Marshall Kulka The Cularine Alkaloids by R. H. F. Manske. a-Naphthaphenanthridine Alkaloids BY R. H. F. Manske The Erythrophleum Alkaloids by G. Dalma. The Aconitum and Delphinium Alkaloids by E. S. Stern... 

Almost all of the studied plants have been found to contain protoberberines, protopines, and phthalideisoquinolines. The occurrence of aporphines and ben-zophenanthridines is frequent. The secoberbines have been isolated from C. incisa and C. ochotensis. The cularines, which are characteristic of some plants of the genus Corydalis, are also found in the genera Dicentra and Sarcocapnos. 

Since the isolation of the first cularine alkaloid, more than 40 years ago, two reviews in Vols. 4 and 10 of this treatise (7, 2) and chapters in the books of Shamma 3a, 3b) and Kametani 4a, 4b) have dealt with four representative alkaloids of the cularine group. In the last decade, more than 25 other alkaloids have been isolated and characterized, including several with modified structures and different oxidation states. This group of alkaloids is regularly reviewed in the Specialist Reports of the Chemical Society (Alkaloid Series) (5). A complete listing of cularine alkaloids was published in 1984 6). It is now accepted that the dibenzoxepine skeleton is the characteristic structure of cularine alkaloids, although these may have evolved from several well-differentiated biogenic routes. The cularine-morphine dimer cancentrine and its derivatives have been excluded from this chapter as there have been no reports since the last review in Vol. 14 of this treatise (7). 

The cularine group is the largest representative class and presently consists of 14 alkaloids. Alkaloids of this group, with three oxygenated substitutents at... 

---