Dendrobines synthesis

Cationic olefin cyclization as a key step led to the shortest racemic dendrobine synthesis reported so far (163, 164). Livinghouse et al. used an intramolecular acylnitrilium attack on a preformed methylcyclopentene moiety to construct the quaternary center and a reductive radical cyclization as second key step in a convergent synthesis to construct the fully substituted skeleton of dendrobine. A few additional steps led then to dendrobine (82). In most of the syntheses following Livinghouse efforts the intention was less focused on strategy (economy) of the synthesis of dendrobine (82) than on demonstrating the versatility of the (newly developed) key step. 

After the intense use of concerted reactions for natural product synthesis, the related metal-catalyzed cyclizations gained ground in the 1980s and 1990s. Several authors demonstrated the effectiveness of these reaction types for the synthesis of dendrobine (82). Takano et al. and Zard et al. used the Pauson-Khand reaction as a key step for their EPC-synthesis efforts (144,165,166). Mori et al. relied on the more stable zirkonacycle in a related key step (167-169), while Trost et al. employed a palladium-catalyzed alkylation as well as a palladium-catalyzed ene reaction as key steps (170). Takano s efforts ended with the tricyclic skeleton of dendrobine, whereas Mori and Trost finished their formal EPC-syntheses with intermediates of Kende s and Roush s racemic S3mtheses, respectively. Both completed dendrobine synthesis would have necessitated more than 20 steps. 

The first synthesis using an intramolecular Diels-Alder reaction (IMDA) as key step was Borch s intended (zh)-dendrobine synthesis, which culminated in the synthesis of ( )-4-ep/-dendrobine (193) (153,154). 

In a short known reaction sequence, enal 250 was obtained from commercially available material 184). With methylamine and magnesium sulfate imine 251 was formed and combined with acyl chloride 252 185) (>4 steps). The use of low temperatures for this acylation led exclusively to the less substituted dienamide 253. The desired basic skeleton of dendrobine 254 was obtained by cyclizing 253 at 180°C in an acceptable 50% yield, Adduct 254 was accompanied by small amounts of the exo-adduct. Epoxidation led exclusively to exo-epoxide 255, which by means of trimethylsilyltriflate was converted into the allylic silyl ether. Acid treatment liberated the hydroxy group and subsequent oxidation of alcohol 256 led to enone 163, an intermediate of Inubushi s dendrobine synthesis and thus concluded this formal synthesis. The intermediate 163 was obtained from commercially not available materials in seven steps in 22.5% overall yield. To reach ( )-dendrobine according to Inubushi et al. would afford six additional steps, reducing the overall yield to 0.4% without including the preparation of the starting materials from commercially available compounds. 

In a continuation of his work on dendrobine synthesis, Roush132 has found that the intramolecular Diels-Alder reaction of the diene-ester (265) gives predominantly the bicyclic compound (266). This was an unexpected result because... 

Bicyclic compounds of structure (4) are needed for the synthesis of the alkaloid dendrobine. What is the starting material for a Diels-Alder synthesis of (4) Stereochemistry is obviously vital here. 

Roush gives an analysis of how he came to choose (4) as an intermediate and how it was developed into dendrobine. Another synthesis of dendrobine... 

During the course of a short and efficient total synthesis of (-) -dendrobine (3-76), an alkaloid which exhibits antipyretic and hypotensive activities [37], a new domino radical sequence has been exploited by Cassayre and Zard which involves the cycli-... 

Cycloaddition reactions of furans are still widely used as key steps in the construction of complex molecules including natural products. As an example, the intramolecular Diels-Alder cycloaddition of 2-amido substituted furans provides a useful tool for the synthesis of fused, nitrogen-containing poly-heterocycles. Thus, thermolysis of 3-substituted amidofuran produces tricyclic indolinone 39 as a 2 1 mixture of diastereomers via amidofuran cycloaddition-rearrangement methodology, which serves as a key intermediate in the total synthesis of ( )-dendrobine, a major component of the Chinese ornamental orchid Dendrobium nobile . 

Dendritic polymers, fullerene, 12 252 Dendritic salt, 22 805 Dendritic siloxanes, synthesis of, 22 554 Dendrobine, 2 102... 

Introduction of a quaternary carbon center is readily achieved by PKR. Takano and Zard independently employed this methodology for the synthesis of (—)-dendrobin (Equation (44)). ... 

Dendrobium Alkaloids.—A third synthesis of shihunine, the principal base of several Dendrobium spp., has been reported. It involves allowing the dilithio-anion (12) to react with l-methyl-2-pyrrolidone (13), to yield ( )-shihunine (14) in 23% yield.11 Full experimental details pertaining to a synthesis of ( )-dendrobine, reported briefly earlier, have been described.12... 

Dendrobium Alkaloids. —An earlier reported synthetic route to (+)-dendrobine has been improved by the development of a superior synthesis of the perhydroindenone intermediate that is involved.13... 

A one-pot PKR-hydrogenation sequence was the key step in a non-racemic synthesis of (-)-dendrobine (222) published recently. Starting from (+)-trans-... 

Scheme 63 The synthesis of (-)-dendrobine using a PKR/hydrogenation combination as the key step. Partial hydrogenolysis was observed when optimizing reaction conditions...

Mp MS IR H-NMR [c(]d partial synthesis starting with dendrobine (82) synthesis... 

Scheme 11) 81). Mubironine C (99) showed an additional methoxy group and no y-lactone signals. Its structure was proven by its identity with methanolyzed dendrobine. Since all three alkaloids were connected with dendrobine (82) by synthesis, their absolute configuration is in accord with that of dendrobine (82). 

A-Methyldendrobinium chloride (84) was the first quaternary picrotoxane alkaloid isolated and characterized by Inubushi 114). The next dendrobinium salt isolated was A-isopentenyldendrobinium chloride (85) 81). Its structure was determined by pyrolysis to dendrobine (82). The configuration of its quaternary nitrogen was determined by synthesis 81). 

When Porter and Coscia published their reviews (2, 3) no total synthesis of a picrotoxane had come forth. Even the partial syntheses were not well developed, as mubironine A (97), an oxidation product of dendrobine (82), was not known as natural product at that time. The same is true for nordendrobine, the demethylation product of dendrobine (82), now known as mubironine B (98). Partial syntheses in the 1970s were made to determine the structure or absolute configuration of new picrotoxanes and are described earlier in this chapter. 

Eight years after the structure elucidation of dendrobine (82) was completed, two total syntheses of this highly crowded tetracyclic compound with its seven stereogenic centers were published. To date, seven total syntheses and five formal syntheses have been reported. Those synthesis efforts nicely reflect trends in total synthesis over the last decades, which shall be demonstrated by the stereoselective construction of the quaternary center, a formidable task even today. 

Due to the more complex structures of most sesquiterpene picrotoxanes compared with the dendrobines, fewer syntheses have been reported. Their structures with up to nine stereogenic centers were too complex to be used as test molecules for newly developed reactions. Three of the syntheses reported beginning with 1979 followed new strategies (two picrotoxinin syntheses and one coriamyrtin synthesis). The other syntheses of picrotoxinin (1), picrotin (2), coriamyrtin (9), tutin (11), corianin (21), methyl picrotoxate (42), and asteromurin A (22) were extensions either of successful dendrobine syntheses or partial syntheses. Remarkably, with one exception, all the syntheses are EPC-syntheses. 

Inubushi announced the successful synthesis of dendrobine (82) in a short communication in the same year as Yamada et al. (147). In 1974, a full description of these efforts followed (148). 

Kende s elegant racemic synthesis is still one of the shortest total synthesis of dendrobine (82), although no less than eight syntheses and four additional synthesis attempts followed (151). As Yamada in his first attempt, Kende et al. started with cheap, commercially available thymol, which was converted via thymoquinone and Thiele-Winter-acetoxylation into the known l,2,4-triacetoxy-3-isopropyl-6-methylbenzene (168) (Scheme 17) (178). 

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