Diterpenoid Total Synthesis

Synthetic endeavours have continued in the diterpenoid series. The cyclization of geranylgeranic acid chloride to derivatives of cembrene, and their conversion into cembrene itself, have been described. Some further extensions of the route to macrocyclic diterpenoids based on the intramolecular cyclization of epoxysulphides and the subsequent modification of the macrocylic product have been described.  

A stereoselective total synthesis of the antifungal mould metabolite ( )-LL-Z1271a (165) from the readily available Wieland-Miescher diketone, via the keto-lactone (164), has been described. A synthesis of grindelic acid (167) from the unsaturated 7-toluene-p-sulphonate (166) utilized an intramolecular solvolysis of the toluene-p-sulphonate to construct the 9—13 ether bridge. 

An alternative synthesis of the tricyclic intermediate (168), together with the elaboration of C-4 with the configuration of both podocarpic and dehydroabietic acids, has been reported. In a stereoselective total synthesis of ( )-callitrisic acid and ( )-podocarpic acid, the C-4 stereochemistry was established by reductive methylation of the enol-ether (169). 

In an A B — C approach to diterpenoid total synthesis, the Michael addition of t-butyl j8-keto-esters to the unsaturated aldehyde (170) formed a key step. 

Isogai, A. Suzuki, S. Tamura, S. Murakoshi, Y. Ohashi, and Y. Susuda, Agric. and Biol. Chem. (Japan), 1976, 40, 2305. 

Biomimetic cyclization of polyenes as routes to diterpenoids continues to be explored. The brominative cyclization of geranyl-linalool afforded160 the 3-bromo-manoyl oxide and the boron trifluoride-catalysed cyclization of the diepoxide of p-homogeranylanisole gave 13-methoxy-A-homo-4a-oxopodocarpatrienol.161 Some further synthetic studies of anhydroverticillol have been reported.162 

A number of bicyclic diterpenoids have insect anti-feedant properties and consequently the synthesis of intermediates such as (93) in this series has attracted 

The synthesis of perhydrophenanthrenes related to tri- and tetra-cyclic diterpenoids has continued to be an active area.167 Compound (94) has been synthesized as a possible intermediate for the synthesis of cafestanone.168 A synthetic approach to diterpenoids with an abnormal trans-syn ab ring junction [e.g. (95)] has been described.169 The syntheses of 13-methoxypodocarpatrien-19,20-dioic acid170 and the ll-hydroxyabieta-2,8,11,13-tetraen-l-one,171 isomeric with shonanol, have been described. 

The biological activity of the diterpenoids of the aphidicolin-stemodin series makes these compounds attractive targets. The total synthesis of stemodin (96) has been described.172 The key spiro-centre at C-9 was constructed by the internal aldol condensation of the keto-aldehyde (97) to afford (98). Several stereoselective syntheses of aphidicolin have been reported with different solutions to the problem 

The gibberellin plant hormones continue to attract synthetic attention. The total synthesis of gibberellin A4 (101) by a more efficient route has been reported,176 and a major achievement has been the total synthesis of gibberellin Ax (102) and 

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Mori, K. Matsui, M. Diterpenoid total synthesis. XIII. Taxodione, a quinone methide tumor inhibitor. Tetrahedron 1970, 26, 3467-3473. 

Yajima, A., Mori, K. Diterpenoid total synthesis. XXXII. Synthesis and absolute configuration of (-)-phytocassane D, a diterpene phytoalexin isolated from the rice plant, Oryza sativa. Eur. J. Org. Chem. 2000,4079-4091. 

Paquette, L. A., Backhaus, D., Braun, R. Direct asymmetric entry into the cytotoxic 8,9-secokaurene diterpenoids. Total synthesis of (-)-0-methylshikoccin and (+)-0-(methylepoxy)shikoccin. J.Am. Chem. Soc. 1996,118,11990-11991. 

Mori, K. and Koga, Y. (1991) Diterpenoid total synthesis. XXIX. Synthesis of ( )-14-deoxy-stypoldione, an analog of the marine natural product stypoldione. Liebigs Ann. Chem., 769-774. 

Mori, K., and M. Matsui Diterpenoid Total Synthesis-VIII ( )-Kaur-16-en-19-oic Acid, ( )-Kaur-16-en-19-ol, ( )-Monogynol, and Some Oxygenated Kauranes. Tetrahedron 24, 3095 (1968). 

Total synthesis of taxoids, diterpenoids with 0-heterocyclic fragments 97H(46)727. 

In 2011, Hartwig and coworkers reported the total synthesis of taiwaniaquinol B (55, Scheme 11.9), a member of a family of diterpenoids that are derived from the abietane skeleton [36]. A key aspect of the Hartwig synthesis of taiwaniaquinol B was the use of the iridium-catalyzed borylation reaction to accomplish the C(5) functionalization of resorcinol derivative 53. This regioselectivity for the overall bromination is complementary to that which would be obtained using a standard electrophilic aromatic substitution (EAS) reaction. In the transformation of 53 to 54, a sterically controlled borylation was first accomplished, which was then followed by treatment of the boronic ester intermediate with cupric bromide to... 

Since the discovery of the high anticancer activity of taxol, much attention has been drawn to its asymmetric synthesis. The total synthesis stood for more than 20 years as a challenge for organic chemists. The compound taxoids are diterpenoids isolated from Taxus species and have a highly oxidized tricyclic carbon framework consisting of a central eight-membered and two peripheral six-membered rings (see Fig. 7-2).21... 

Anionic oxy-Cope rearrangement was also employed for the enantioselective total synthesis of compounds related to marine metabolites (equation 230)305 307, as well as for the preparation of diterpenoide vinigrol (equation 231)308 and cerorubenic acid-in... 

It has been shown" that isomerization of the exocyclic allylic system of the five-membered ring D of kaurenols depends on the orientation of the C(15) hydroxyl group. The total synthesis of methyl atis-16-en-19-oate, a tetracyclic diterpenoid possessing a bicyclo[2.2.2]octane skeleton, has been accomplished" using a homoallyl-homoallyl radical rearrangement process of methyl 12-hydroxykaur-16-en-19-oate monothioimid-azolide (280) as the pivotal step. Two plausible mechanisms have been presented" ... 

Resiniferatoxin (RTX) is a daphnane diterpenoid contained in the irritant latex of some succulent African Euphorbias. Its total synthesis has been described as a 40 step asymmetric synthesis (Wender et al., 1997 see below), but for clinical use RTX isolated from Euphorbia resinifera. 

METHODOLOGY VALIDATION AND STRUCTURE CORRECTION BY TOTAL SYNTHESIS THE CASE OF THE CLERODANE DITERPENOID, SACACARIN... 

Miyaoka H, Shida H, Yamada N, Mitome H, Yamada Y (2002) Total Synthesis of Marine Diterpenoid Kalihinene X. Tetrahedron Lett 43 2227... 

In the total synthesis of nalanthalide, the crucial coupling of the 7-pyrone moiety with the diterpenoid core was achieved by lithium halogen exchange of 3-bromo-2-methoxy-5,6-dimethyl-4/7-pyran-4-one 353 and addition of the resulting 3-lithio-7-pyrone 354 to aldehyde 355 to produce 356 in an impressive 87% yield (Scheme 53) <2005OL3745, 2006TL3251>. 

Quantitative conversion in refluxing xylene of the p-peroxide 84 is the final step in the total synthesis of the diterpenoide /h.v-epoxide stemolide (Sch. 52) [91]. 

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). 

Characteristic to some important cembrane diterpenoids, such as isocembrene, cembrene, cembrene C, and sarcophytol A, is a 1,3-diene unit in the macrocyclic skeleton. In continuation of our ongoing project on the total synthesis of cembrane-type diterpenoids, we intended to explore a novel macrocyclization method to... 

Thus, an efficient and convergent total synthesis of ( )-isocembrene has been accomplished in seven steps from the known geranylacetone through an intramolecular Stille cross-coupling reaction. The strategy is of great potential for the divergent synthesis of complex cembrane-type diterpenoids such as cembrene-C and sarcophytols. 

There have been a number of novel diterpenoid structures described during the year. The diterpenoids must now rival the sesquiterpenoids in their variety of skeleta. The absolute configuration of clerodin has now been revised with consequent ramifications in the configuration assigned to a number of other diterpenoids. Another notable advance during the year has been the total synthesis of gibberellic acid. 

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