Diterpenoid alkaloids structure

Sultankhodzhaev MN et al. (2005) Tyrosinase inhibition studies of diterpenoid alkaloids and their derivatives structure-activity relationships. Nat Prod Res 19(5) 517-522... 

Diterpenoid Alkaloids.—The structure and synthesis of the diterpenoid alkaloids have been reviewed. The subject is also covered in detail in the Specialist Periodical Report on the Alkaloids. A number of new alkaloids with the ent-kaurene skeleton have been isolated from Anopterus glandulosus and A. macleayanus. The structure of the major alkaloid anopterine (104) was assigned ... 

Structure determination of the diterpenoid alkaloids (C20) has been a challenging task because of the diverse skeleta of these alkaloids. During the period ( 1962-1972), many of the structures were determined by X-ray crystal structure determination. The development of high resolution NMR and Mass spectral instruments has facilitated the structure elucidation and determination of the stereochemistry of the diterpenoid alkaloids. The structures of more than 240 naturally occurring diterpenoid alkaloids have been determined in the past twenty five years making use of, 3C NMR studies. 

The present catalogue provides proton and/or carbon-13 NMR chemical shift assignments and physical constants for many of the naturally occurring diterpenoid alkaloids and their derivatives. The literature search is not intended to be exhaustive. It is hoped that the 13C NMR data bank will serve as a useful guide for determining the structures of newly isolated alkaloids. 

Diterpenoid Alkaloid Natural Occurrence (N) Derivative (D) Structure Type X-Ray H c... 

The chemistry of the diterpenoid alkaloids, rather than their structure elucidation by physical methods, has attracted more interest during the year covered by this Report. While several new alkaloids have been reported, most of the research on these polycyclic, polyfunctional bases has involved chemical conversions and synthetic methods. Most notably, Wiesner s group at New Brunswick, Canada, has reported a fourth-generation synthesis of the delphinine-type alkaloids. That this marvel of synthetic engineering accomplishes the stated goals1 of a highly efficient, fully regio- and stereo-specific synthesis of these complex natural products is abundantly clear. 

Alkaloids of Delphinium dictyocarpum DC.—Dictysine [C21H33N03 m.pt 184—186°C] has been assigned structure (37) on the basis of chemical and spectroscopic studies.25" An unpublished X-ray analysis256 demonstrates that (37) is incorrect and that the structure should be as shown in (37a). Derivatives of dictysine (38)—(42) are shown here as the corrected structures. This alkaloid was isolated from the epigeal parts of Delphinium dictyocarpum DC.26 On acetylation of dictysine with acetyl chloride, the triacetate (38) and the two diacetates, (39) and (40), were obtained. The reaction of dictysine with one molar equivalent of periodic acid for three hours gave the a-hydroxy-ketone (41), while treatment with excess periodic acid for three days yielded the aldehyde carboxylic acid (42). These structures were supported by mass-spectral, i.r., and XH and 13C n.m.r. analyses. This is the first example of a C20 diterpenoid alkaloid which contains hydroxyl groups at C-16 and C-17. 

The diterpenoid alkaloids, isolated mainly from Aconitum and Delphinium species (Ranunculaceae), have been of great interest since the early 1800s because of their pharmacological properties. Extracts of Aconitum species were used in ancient times for treatment of gout, hypertension, neuralgia, rheumatism, and even toothache. Extracts have also been used as arrow poisons. Some Delphinium species are extremely toxic and constitute a serious threat to livestock in the western United States and Canada. Delphinium extracts also manifest insecticidal properties. In the last 30 to 40 years, interest in the diterpenoid alkaloids has increased because of the complex structures and interesting chemistry involved. 

Included in this chapter is a catalog of all known C20-diterpenoid alkaloids showing the correct structures, physical properties, plant sources, and key references. Previously published books (19 21) and recent reviews (15-16) have reported incorrect structures for several well-known C20-diterpenoid alkaloids. This catalog should be very useful for it presents in a single place important structural information on the C20-diterpenoid alkaloids that has been scattered through hundreds of papers and dozens of review articles. 

Vakognavine is the first example of an N, C-19-seco-diterpenoid alkaloid reported and an interesting alkaloid for biogenetic speculation. The authors (116) suggested that the C-19 aldehyde may be a plausible alternate to the pseudokobusine structure as an intermediate in the biosynthesis of the modified atisine-type skeletons such as hetisine. The C-19 hydroxyl of vakognavine hydriodide (119) is reminiscent of the oxazolidine oxygen of isoatisine. 

In 1964 Molodozhnikov and co-workers (137) reported the isolation of several diterpenoid alkaloids from the shrub Spiraea japonica L. fil. of the Roseaceae family. Later Goto and co-workers (138) examined alkaloids of the same plant (Japanese name Shimotsuke ) and isolated 10 new alkaloids. The structures of 3 of these, spiradine A (152), spiradine B (153), and spiradine C (154) have been determined by chemical correlations coupled with a single-crystal X-ray analysis (139) of spiradine A methiodide (155). 

In 1974, Japanese chemists (134) demonstrated the utility of 13C-NMR spectroscopy in the field of C20-diterpenoid alkaloids. They determined the structures of miyaconine (145) and apomiyaconine (147), two rearrangement products of miyaconitine, by the aid of 13C-NMR spectroscopy. 

The 13C-NMR spectra of these compounds were analyzed to identify and distinguish skeletal features of the atisine and veatchine-type alkaloids for use in the structure elucidation of new C20-diterpenoid alkaloids. 

The structures of two new C20-diterpenoid alkaloids designated as ovatine (6) and lindheimerine (7), isolated from G. ovata var. lindheimeri, have been elucidated (33) with the help of13C-NMR spectroscopy. Similarly, the structure of dihydroajaconine (81) was also established (S3) with this technique. 

Interest in the chemistry of diterpenoid alkaloids has continued, as shown by the volume of publication during the past year. In spite of the increased reliance on physical methods of structure determination, especially on X-ray crystallography and 13C n.m.r. spectroscopy, interesting chemical transformations of these complex bases have been reported. 

In addition to several newly reported diterpenoid alkaloids, the structures of some forty alkaloids have been revised on the basis of recent work. The structures presented in this Report have been revised from those reported in the literature to reflect these recent corrections. The level of efforts directed toward the synthesis of diterpenoid alkaloids was substantially reduced this year, with only a description of the synthesis of napelline by Professor Wiesner s group appearing. No reports of new work on the Daphniphyllum diterpenoid alkaloids were available to our laboratories. 

Structure Revisions and General Studies Revision of the Structures of Thirty-seven Lycoctonine-related Diterpenoid Alkaloids.—Lycoctonine was assigned structure (1) on the basis of an X-ray crystallographic analysis of (2) in 1956.4 Since that time, the structures of most of the lycoctonine-type alkaloids have been based on correlations with lycoctonine. 

Revisions Based on 13C N.M.R. Analysis.—The revision of the structures of five C19 diterpenoid alkaloids on the basis of the 13C n.m.r. spectral data has been reported.8,9 Yunusov and co-workers,10 relying predominantly on mass-spectral data, had proposed structure (43) for acomonine (C2jH41N07), isolated from the roots of Aconitum monticola. Based partially on chemical correlations with acomonine, they later assigned structures to iliensine (44) (Cj NO,)11 and 14-dehydroiliensine (45),12 isolated from Delphinium biternatum. These were the first reported C19 diterpenoid alkaloids lacking an oxygen function at C-l. 

Alkaloids of Aconitum yesoense Nakai.—Sakai and co-workers42 have reported the isolation and elucidation of the structure of three new C19 diterpenoid alkaloids from Aconitum yesoense Nakai. These minor bases, ezochasmanine, ezo-chasmaconitine, and anisoezochasmaconitine, were isolated together with pseudo-kobusine (92), chasmanine (59), and jesaconitine (93). Ezochasmanine (94) (C25H41N07 m.pt 115—118 °C) formed a mixture of the monoacetate (95) and the diacetate (96) when treated with acetic anhydride in pyridine. The reaction of... 

Alkaloids of Delphinium carolinianum Walt.—Delcaroline (C25N41N08 amorphous m.pt of perchlorate is 160—162 °C) was the major alkaloid isolated from whole plants of D. carolinianum Walt., which is native to the south-eastern United States.50 The known bases ajaconine (103) and browniine (7) were also isolated from these plants. Acetylation of delcaroline with acetic anhydride in pyridine gave the monoacetate (104). The structure (22) for delcaroline was assigned primarily on the basis of comparison of the 13C n.m.r. spectra of (22), its monoacetate (104), browniine (7), and dictyocarpine (8). Thus delcaroline, with a hydroxyl group at C-10 and a methoxymethylene group at C-4, represents a novel substitution pattern among the known C19 diterpenoid alkaloids. 

Research on diterpenoid alkaloids published during the past year has continued to expand the body of structural and synthetic information available on these complex plant bases. The structures of ten new alkaloids from Aconitum and Delphinium species, including seven new bisditerpenoid alkaloids, have been reported. Tlie most significant progress in methods of structure elucidation has been the very successful applications of n.m.r. to the study of complex diterpenoid alkaloids. The New Bruns wick group under Professor Karel Wiesner has continued its progress toward the syntheses of the Ci9-aconitine-type alkaloids. An historical account of the synthesis of talatisamine (1), the first synthesis of a hexacyclic aconite alkaloid, has been published. This work was reviewed in a previous Report. ... 

Diterpenoid Alkaloids.— The alkaloids of Delphinium staphisagria include some bisditerpenoid alkaloids such as staphidine, staphinine, and staphimine. The full paper has appeared on the structure and stereochemistry of delphisine, neoline, chasmanine, and homochasmanine. The application of n.m.r. measurements to these alkaloids has led to the revision of the structure of the alkaloid A from D. bicolor... 

Chapter 2 by Giovanni Appendino provides a fascinating treatment of Taxine, a collective name referring to a mixture of diterpenoid alkaloids from the yew tree (genus Taxus). Taxine is responsible for the toxic properties of the yew tree that has been documented in historical and fictional literature, from Julius Caesar to Shakespeare, and from Agatha Christie to T. S. Eliot. The chapter treats the history, isolation techniques, structure elucidation, chemistry, and pharmacology of Taxine. 

This technique is of paramount importance in structural studies in this area, and is used extensively. The chief types are proton and carbon-13 nmr spectroscopy, which will be dealt with separately. A lengthy review chapter on the application of nmr-spectroscopy to Ci9-diterpenoid alkaloids is noteworthy (Pelletier et al., op. ait.-, see also idem, in "The Alkaloids. Chemistry and Physiology," ed. R. H. F. Manske and R. G. A. Rodrigo, Vol. XVII, Chapter 1, Academic Press, New York, 1979). 

In the following table an attempt has been made to list all diterpenoid alkaloids isolated since 1977. The references relate in most cases to their isolation, purification, and structure determination. For work on known alkaloids, especially structural revision, the review sources listed at the beginning of the chapter should be consulted. Blank spaces in the table signify that the appropriate properties have not been recorded. Only alkaloids for which a reasonably substantiated structure has been advanced are included. Entries marked with an asterisk may be artefacts. The literature has been covered up to the end of 1985, and some 1986 references have been included. The alkaloids have been arranged in order of natural source. 

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