Diterpenoid alkaloids synthesis

Waller and co-workers have used g.l.c.-mass spectrum combination in studies of diterpenoid alkaloid synthesis in Delphinium plants. 

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 ... 

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. 

Surveys of recent developments in the chemistry of C2o diterpenoid alkaloids,4 of the alkaloids of Consolida ambigua,5 and of the synthesis of diterpenoid alkaloids by thermolysis6 have appeared. 

Synthetic Studies directed toward the Diterpenoid Alkaloids.—In studies directed toward the synthesis of the C19 diterpenoid alkaloids, Chatterjee has reported45 the preparation of intermediate (150) by a very unusual synthetic sequence. 

Enmein was converted to 20-hydroxykaur-6-en-15a-pyranylether (382), which was oxidized with chromium trioxide in pyridine to afford the aldehyde 383. The latter was converted with hydroxylamine to the oxime 384. The nitrone 385 was prepared by treatment of 384 with bromine azide. Photolysis of 385 gave the desired compound 381 in 46% yield. This intermediate possesses several useful functionalities (e.g., carbinolamine ether linkage), which may be of interest for synthesis of C20-diterpenoid alkaloids after minor changes in this scheme. 

Meyer and co-workers reported (184) a simple synthesis of a tricyclic intermediate containing the ABE ring system. The sequence for the synthesis of 398 is outlined in Scheme 3. Compound 398 is of interest as an intermediate for synthesis of C20-diterpenoid alkaloids containing a substituent at the C-7 position, e.g., ajaconine, atidine, and spiradine. 

Five new diterpenoid alkaloids have been isolated from Aconitum species (Ranunculaceae) and five from Delphinium species (Ranunculaceae). Four new Anopterus (Escalloniaceae) bases have been identified. The most significant synthetic achievement has been the total synthesis of racemic chasmanine. A detailed review of the alkaloids of Delphinium staphisagria has appeared.1... 

Total Synthesis of Chasmanine.—Wiesner and his co-workers38,39 have accomplished a landmark in diterpenoid alkaloid chemistry in their completion of the total synthesis of racemic chasmanine (49), a hexacyclic base with six oxygen functionalities. The synthesis of the intermediate (50) was reviewed in the previous Report (Vol. 7, pp. 257—259). 

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. 

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. ... 

Syntheses Directed Toward Chasmanine.—Outstanding progress toward the total synthesis of the complex hexacyclic diterpenoid alkaloid chasmanine (46) has been reported. The pentacyclic intermediate (69) has been prepared, and, using a model system, the methodology for the conversion of this compound into chasmanine has been developed. These experiments employed many processes developed in the earlier synthetic work, and in a number of instances, considerable improvements in the methods have been made. 

A new synthesis of sempervirol has utilized the condensation " of j8-cyclocitral with 4-isopropyl-3-methoxybenzyl chloride to afford (108). Cyclization of the corresponding ketone gave the tricyclic system (109) which was converted into sempervirol. A novel rearrangement of the angularly fused cyclobutanone (110) to (111) forms the basis of a synthesis of potential intermediates for conversion into the diterpenoid alkaloids. 

Synthesis of Hesitine Diterpenoid Alkaloids. An efficient enantioselec-tive approach to the hesitine class of the C2o-diterpenoid alkaloids involves an intramolecular oxidopyridinium dipolar cycloaddition with a vinylic sulfone as the key transformation as depicted in Eq. 156.266 Once the sulfonyl group has played its role in the C-C bond formation, it is removed by a Na/Hg-promoted reductive desulfonylafion. 

The emphasis in work related to diterpenoid alkaloids has shifted from structure determination to partial and total synthesis. X-Ray crystallography played the major role in the structure work and in interpretation of unusual chemistry. However, some interesting new chemical and spectroscopic observations, and analyses of mass spectra, have been reported. 

The emphasis in C19 and C20 diterpenoid alkaloid research as evidenced by published accounts during the past year has shifted from synthesis to structure determination. Of particular interest are the reports of the isolation of two new C19 bases, acomonine and iliensine, having no C-1 oxygen function. The structures of delphisine and deoxydelcorine have been determined, and revisions of the structures earlier proposed for neoline, chasmanine, homochasmanine, and excelsine have appeared. The numbering systems for the lycoctonine, atisine, and veatchine skeletons are indicated in structures (A), (B), and (C), respectively. 

Over the last ten years Professor Wiesner and his co-workers at the University of New Brunswick have made important contributions to the synthesis of delphinine (31) and related diterpenoid alkaloids (147-150). 

Chapter 1. The Structure and Synthesis of Ci9-Diterpenoid Alkaloids S. William Pelletier and Naresh V. Mody... 

The Synthesis of the Denudatine Skeleton.—Wiesner and co-workers have successfully elaborated the carbon skeleton of denudatine (51) in studies designed to develop methods for the construction of the c/d ring systems of the diterpenoid alkaloids from aromatic intermediates such as (52) and (53). ... 

The Chemistry of Ringc.—The modification of ring c has centred on making available relays that are suitable for elaboration into more complex diterpenoids, the diterpenoid alkaloids, and triterpenoids. The unsaturated ketone (53) has proved to be a valuable relay for synthesis. It had been prepared previously from neoabietic acid, which is difficult to obtain pure. It has now been obtained from the levopimaric acid-formaldehyde adduct (50). Oxidation of the adduct with potassium permanganate not only formed the glycol but in an unusual step converted the cyclic ether into the (5-lactone (51). Dehydration, ozonolysis of the newly formed double bond, and then treatment of the keto-acetate (52) with chromous chloride afforded the a -unsaturated ketone (53). The last step involved hydrogenolysis, / -elimination. and decarboxylation. 

A New Synthesis of Chasmanine and 13-Desoxydelphonine. — Wiesner and co-workers have continued to effect improvements in the synthetic methods available for the construction of C19 diterpenoid alkaloids. They have reported a new synthesis which is ten steps shorter and considerably more efficient than the previous route (c/. this Report, 1978, Vol. 8, p. 229). These methods were developed using a model system, starting from compound (85). 

A new synthesis of the tetracyclic diterpenoid alkaloid intermediate (107), using an A B C approach, has been reported.Meyer and co-workers, in... 

Baillie LC, Batsanov A et al (1998) Synthesis of the A/E/F sections of conacraiitine, napelline and related diterpenoid alkaloids of the aconitine group. J Chem Soc Pericin Trans l(20) 3471-3478... 

Allenes have been added to many cyclic a,/8-unsaturated ketones to give methylenecyclobutane derivatives. The stereochemistry of such additions has been rationalized by Wiesner, who has used the method extensively in the synthesis of diterpenoid alkaloids. For example, the synthesis (Scheme 10) of talatisamine (39) involved the cycloaddition of allene to the enone (35) to give the photoadduct (36) which was converted into the masked aldol (37). Retro-aldol reaction followed by another aldol cyclization gave (38) which was converted into talatisamine (39). Intramolecular photocyclizations of appropriate allenic enones can also be expected to be synthetically useful. The formation of (41) from (40) in high yield is a promising reaction. A closely related process is the cyclization of (42) to (43) (Scheme 11). ... 

Peese KM, Gin DY. Efficient synthetic access to the hetisine C2o-diterpenoid alkaloids. A concise synthesis of nominine via oxidoisoquinolinium-l,3-dipolar and dienamine-... 

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