Four amidic bisbenzylisoquinolines have been isolated from Cyclea atjehensis. These are (-)-curicycleatjenine [1], (-)-curicycleatjine [2], (-)-isocuricycleatjenine [3], and (-)-isocuricycleatjine [4]. ¹H-nmr spectroscopy at 500 MHz in CDCl₃ solution can clearly differentiate between the two geometric isomers for each of the four alkaloids. Cyclea species (Menispermaceae) are found in southeastern Asia, and Cyclea atjehensis Forman, the plant of particular interest in the present study, is available in Thailand. We have found that C. atjehensis is rich in bisbenzylisoquinolines of the head-to-tail curine type (8-12', 11-7'). Four of these alkaloids were actually obtained, and it is interesting to note that all four possess a methylenedioxy group—an unusual substituent among the bisbenzylisoquinolines in general (1-3) as well as an N-acetyl function. The four alkaloids could be clearly divided into subgroups based upon their absolute configuration. The first subgroup included the non-phenolic (-)-curicycleatjenine [1] and the phenolic (-)-curicycleatjine [2], which possess the 1S, 1'R configuration. The second subgroup consists of the non-phenolic (-)-isocuricycleatjenine [3] and the phenolic (-)-isocuricycleatjine [4] which incorporate the 1R, 1'R configuration. Alkaloids 1 and 3 present nearly identical mass spectra, with a strong molecular ion at m/z 634 (C₃₈H₃₈N₂O₇), and a base peak at m/z 189 corresponding to rings A and B of the molecules. Other important peaks were found at m/z 340 and 295 due to facile cleavage of the doubly benzylic bonds and corresponded to rings C, A', and B' and rings A, B, and C', respectively. Similarly, phenolic alkaloids 2 and 4 showed closely related mass spectral patterns with a very strong molecular ion at m/z 620, which was also the base peak in 4. The molecular ion was flanked by an equally strong [M - 1]⁺ ion, m/z 619, which was the base peak in the spectrum of 2. The fact that the molecular ions were 14 daltons less than those for alkaloids 1 and 3 pointed to the presence of a phenolic function in lieu of a methoxyl group. Additionally, because the strong m/z 340 peak in the spectra of alkaloids 1 and 3 is replaced by a peak at m/z 326 in 2 and 4, it was logical to conclude that the phenolic function in 2 and 4 was located on ring C or A'. Buttressing this argument was the fact that the m/z 295 and 189 peaks observed in the spectra of 1 and 3, which are descriptive of the top half of the dimers, were also present in the spectra of 2 and 4 with the same intensities. The ¹H-nmr spectra at 500 MHz in CDCl₃ revealed that two isomeric species were present in solution in each instance due to geometric isomerism about the amidic bond. The two isomeric species could be clearly distinguished and were present in each instance in a ratio of ca. 3.5:1. Furthermore, through nmr nOe measurements, it was possible to define the geometric isomerism in each case. The ¹H-nmr spectrum of the major isomer for (-)-curicycleatjenine is summarized around expression 1a, and that for the minor isomer around 1b. The protons of the methylenedioxy group resonate as two close doublets at δ 5.86 and 5.91 in species 1a and at δ 5.88 and 5.91 in 1b. The two methoxyl singlets were at δ 3.68 and 3.95 in one instance and at δ 3.71 and 3.95 in the other. The N-methyl signal remained constant at δ 2.31, and the H-1 broad doublet was evident at δ 4.20 for 1a and at δ 4.16 for 1b, while the two N-acetyl singlets were appreciably different, appearing at δ 2.13 in 1a and at 2.25 in 1b. The non-equivalence of the two acetyl signals is a reflection of the prevailing geometrical isomerism. This difference is also emphasized by the chemical shifts of H-1'. This proton appears as a doublet of doublets centered at δ 5.05 for the major isomer 1a and at δ 4.45 for 1b. A small but significant difference was also noted for the shifts for H-10' and H-14' with signals at δ 6.11 and 7.25 for 1a and δ 6.18 and 7.05 for 1b. A complete nmr nOe study (see Experimental) confirmed each of the above assignments. In particular, irradiation of the N-acetyl singlet of 1a (δ 2.13) led to an enhancement of the H-3' signals (δ 3.42 and 3.90) with no effect upon the H-1' signal (δ 5.05). On the other hand, irradiation of the 1b N-acetyl (δ 2.25) produced an enhancement of the H-1' signal (δ 4.45), while H-3' was unaffected. The nmr spectrum of the phenolic (-)-curicycleatjine [2] showed the obvious lack of a methoxyl singlet near δ 3.70, which led us to place the phenolic hydroxyl function at C-12. Species 2a was the major isomer, and 2b was the minor. It will be noted that for both isomers the signals for H-8' are shifted further downfield by about 0.3 ppm in relation to the corresponding signals for 1a and 1b. As expected, O-methylation of 2 led to (-)-curicycleatjenine [1]. Our second subgroup, consisting of (-)-isocuricycleatjenine [3] and (-)-isocuricycleatjine [4], again showed the same type of geometric isomerism in the nmr spectra with the a isomers predominating. Differences in chemical shifts, parallel to those mentioned in the cases of 1a and 1b above, could be observed between 3a and 3b and also between 4a and 4b. The H-1 signal was now more upfield, appearing at δ 3.64 for 3a and at δ 3.60 for 3b. Additionally, H-14 was shifted downfield to δ 7.23 for 3a and 7.33 for 3b. Again, as in compounds 1 and 2, a complete nmr nOe analysis served to confirm the assignments of the chemical shifts. The nmr spectrum of the phenolic (-)-isocuricycleatjine [4] indicated the lack of a C-12 methoxyl. There was also a downfield shift of H-8', which is near δ 6.00 as compared to around δ 5.56 in 3. CH₂N₂ O-methylation of 4 furnished (-)-isocuricycleatjenine [3]. Some differences in specific rotations could be observed between our four alkaloids, and we had to resort to sodium in liquid NH₃ cleavage to establish the absolute configurations. Reduction of (-)-curicycleatjenine [1] supplied a complex mixture of products from which small yields of (-)-N-acetylcoclaurine [5] and (+)-N-methyl-7-hydroxy-12-methoxytetrahydrobenzylisoquinoline [6] were obtained. Alternatively, reduction of (-)-isocuricycleatjenine [3] led to a mixture from which we could identify (-)-N-acetylcoclaurine [5] and (-)-N-methyl-7-hydroxy-12-methoxytetrahydrobenzylisoquinoline which is enantiomeric with 6. It follows that (-)-curicycleatjenine [1] and by extension (-)-curicycleatjine [2] partake of the 1S, 1'R configuration, while (-)-isocuricycleatjenine [3] and (-)-isocuricycleatjine [4] belong to the 1R, 1'R series. It is interesting to note that, just like alkaloids 1-4, the cleavage product (-)-N-acetylcoclaurine [5] exists in CHCl₃ solution as two isomers, 5a and 5b, in a ratio of approximately 7:3, which can be readily differentiated by nmr spectroscopy (4).