The spectral data for idiospermine

Since this work was carried out in the early seventies the technology used reflects that era. The nmr spectrum was recorded on a Varian XL-100 spectrometer.

The nmr spectrum of idiospermine showed several characteristic features: twelve protons in the aromatic region; three one-proton doublets in the range δ 4.6 – δ 4.2; four three-proton singlets indicative of four N-Me groups; and three protons upfield at δ 1.30.

The nmr spectrum showed the following signals:

Doublet, 1H, δ 7.57 (J 6 Hz)
Multiplet, 11H, δ 7.35 – δ 6.20
Doublet, 1H, δ 4.64 (J 4.5 Hz)
Doublet, 1H, δ 4.31 (J 4.5 Hz)
Doublet, 1H, δ 4.19 (J 4.5 Hz)
Singlet, 3H, δ 3.56
Singlet, 3H, δ2.45
Singlet, 3H, δ2.40
Singlet, 3H, δ2.34
Multiplet, 10H, δ 3.46 – δ 2.04
Doublet, 2H, δ 1.30 (J 12.5 Hz)
Broad signal, 1H, δ 1.24

When the spectrum was run at 40 degrees C the one-proton signal at δ 1.24 had shifted to δ 1.30 and when the temperature was 60 degrees C it had shifted back to δ 1.24 while a one-proton doublet (J 4.5 Hz) moved out of the aromatic region upfield to δ 5.99 and the one-proton doublet at δ 4.64 became broader. When the spectrum was run at 70 degrees C the doublet which had moved out of the aromatic region had moved to δ 5.85 and had become broad, as did the doublet originally at δ 4.64 which moved to δ 4.56. These experiments suggested the presence of three N-H groups.

Exchange with deuterium oxide resulted in the disappearance of one of the signals in the range δ 7.35 - δ 6.20, and of the signals at δ 4.64 and δ 1.24; the doublets at δ 4.64 and δ 4.31 also collapsed to singlets. This confirms the presence of three N-H groups and two NH-CH-N residues of the type found in the calycanthaceous alkaloids.

The upfield signal at δ 1.30 has the characteristic position and appearance of the signal of the C3’-Heq proton in calycanthine. Chimonanthine type alkaloids do not show upfield signals in their nmr spectra (J.B Hendrickson, R. Göschke and R. Rees, Tetrahedron, vol 20 (1964), p565; E.S. Hall, F. McCapra and A.I. Scott, Tetrahedron, vol 23 (1967), p4131). The aliphatic region of the spectrum run at 70 degrees C was more clearly resolved; integration showed the presence due to four additional protons but, nevertheless, the spectrum closely resembled the corresponding region of the spectrum of calycanthine, but was doubled up. In particular, the doubling up of the triplet of doublets, which in calycanthine arises from C3-Hax and C3’’’-Hax, can be clearly seen. This doubling up of the signals for the protons of the ethylamine bridges of calycanthine must presumably be due to an unsymmetrical influence in the molecule.

If there is, in fact, a calycanthine moiety present, then the characteristic doublet of doublets (o- and m-coupling) for the upfield aromatic protons C8-H and C8’’-H would be expected to be visible in the spectrum of idiospermine. In fact, the spectrum shows a doublet at δ 6.26 (J 8.0 Hz) superimposed on a doublet of doublets (J 8.0 Hz, J 1.2 Hz) integrating for two protons. On the reasonable assumption that there is a calycanthine moiety present, then it follows that one aromatic ring has a 6-substituent to remove meta coupling.

Accepting this hypothesis, it remains to add to the calycanthine molecule at the C6 position the elements of a unit of N-methyltryptamine and one N-methyl group. The nature of this moiety emerged from a consideration of the uv data. The uv spectrum of idiospermine was different from those of the calycanthaceous alkaloids in several respects; in particular, there was an absorption at 302 nm of greatly enhance intensity (ε 32400) compared with an absorption at 310 nm (ε 5350) in the uv spectrum of calycanthine. This can be most satisfactorily understood if idiospermine contains a 2-arylindole residue.

The structure proposed for idiospermine satisfies the requirements of the nmr spectral data as follows: there are only two NH-CH-N protons as required; the aliphatic N-H probably resonates upfield; the three-proton singlet at δ 3.56 has a chemical shift which is very close to that for protons of the methyl group in N-methylindole (δ 3.60); the downfield proton in the aromatic region (δ 7.57) is suggestive of a proton at C7 of an indole nucleus.

The mass spectrum of idiospermine did not show the characteristic fragmentations of the calycanthaceous alkaloids (eg the loss of C3H8N from the ethylamine bridge of calycanthine). The base peak was at P-43, corresponding to the loss of C2H5N. This can be interpreted in terms of the presence of an N-methyltryptamine unit, giving rise to a McLafferty rearrangement.

Support for the tryptamine unit was obtained by examining the nmr spectrum with the presence of Eu(dpm)3. It was found that addition of 10-3M Eu(dpm)3 to a 4 x 10-3M chloroform solution of idiospermine caused a downfield shift of signals due to the tryptamine side chain leaving the calycanthine pattern more clearly visible.

The chemical constituents of Idiospermum australiense (Diels) S.T. Blake

This blog has been set up so that results of the study of the chemical constituents of Idiospermum australiense that we carried out at Sydney University in 1972 and 1973 may be more widely accessed. This blog is also a testimony to the pioneering work into natural product chemistry in Australia by the late Prof Ern Ritchie and the late Prof Wal Taylor who were my supervisors. Prof Taylor passed away just under a year ago and was working towards publishing the results of my study. In the event these results are not actually published in a recognized scientific journal then this blog makes available some the results that can otherwise be sourced from my thesis. It is well documented that in 1912 Diels described the tree as Calycanthus australiense Diels from a specimen collected in northern Queensland at Harvey Creek near the Russell River. Then in 1971 the plant was rediscovered in the Daintree area after a case of stock poisoning. T.S. Blake, a taxonomist with the Queensland herbarium, reclassified the plant into a new genus and family, Idiospermum australiense, Idiospermaceae.

This first post will briefly describe the results concerning the alkaloids found in the plant.
The bark, cotyledons, wood and leaves all yielded (+)-calycanthine
Bark: 0.1% calycanthine
Cotyledons: 0.05% calycanthine
Wood: 0.03% calycanthine
Leaves: 0.38% crude alkaloid fraction (calycanthine plus another alkaloid)

This result is significant in that it indicates that the plant is closely related to the calycanthaceae since according to Hegenauer, members of this family characteristically contain calycanthine type alkaloids (Hegnauer, R., Chemotaxonomie der Pflanzen, Band 3, p338 (Birkhauser Verlag: Basel 1964).

After exhaustive counter current separation of the alkaloid fraction from the leaves of the plant a new alkaloid, idiospermine (0.002%) was isolated.

Idiospermine (C34H40N6) can be viewed as a trimer of methyltryptamine plus an additional methyl group. From spectral data it was concluded that its structure is that of a calycanthine moiety linked via one of its para positions to the alpha position of methyltryptamine where the indole nitrogen has been methylated.

I moved on from chemistry in 1973 and I hope that in a future post I can obtain the assistance of a friend to post the actual chemical structures.

The uv spectrum displayed the presence of an alpha-aryl indole chromophore. Prof Taylor subsequently confirmed the structure via X-ray crystallography carried out by Prof Trevor Hambley of Sydney University.

Idiospermine is different from idiospermuline (extracted from the seeds of this plant) which is a chimonanthine analogue - Rujee K. Duke, Robin D. Allan, Graham A.R. Johnston, Kenneth N. Mewett and Ann D. Mitrovic, "Idiospermuline, a trimeric pyrrolidinoindoline alkaloid from the seed of Idiospermum australiense, Journal of Natural Products, vol 58 (no.8), 1995, pp1200-1208.

Idiospermine is, however, similar to idiospermamine B recently reported by Anthony R. Carroll, Gregory A. Feshner, Sandra Duffy and Vicky M. Avery at the 50th Annual Meeting of the American Society of Pharmocognosy held in Hawaii in June of 2009. This alkaloid was isolated from the bark of the plant and displays antimalarial, antitrypanosomal and cytoxic activities.

The structure of idiospermamine B ( C34H38N6) is that of a calycanthine moiety coupled at the beta position of methytryptamine followed by cyclisation (formation of a pyrrolidine ring). This work from researchers at Griffith University is about to be published in the very near future.

In 2001 Bremner published results into study of a Psychotria sp from Lombok, Indonesia - http://www.mdpi.com/1420-3049/6/2/117/pdf. He referred to an alkaloid with a molecular weight of 574. My guess is that this compund has the molecular formula ( C37H46N6). Bremner does not seem to have published a structure for this alkaloid but my guess is that it is a trimethylated compound from idiospermine.