Tricyclic natural products synthesis

Benzocyclobutenediones are of interest on their own as well as for their usefulness as versatile intermediates. The synthesis of adriamycin analogs has been attempted and the syntheses of the similar tricyclic natural products islandicin 180 and digitopurpurone 181 (Scheme 45) are examples of this approach (77JOC2371). 

Cyclopentenones. A recent synthesis of (+)-albene (5), a tricyclic natural product, from the Diels-Alder adduct (1) of cyclopentadiene and 2,3-dimethylmaleic anhydride required transformation of a succinic anhydride group to a cyclopehtenone (4). This was accomplished via a protected keto aldehyde 3 in four steps as formulated in 51% overall yield.1... 

Another interesting example of the use of microwave irradiation in generating interesting building blocks for natural product synthesis, was reported by A.G. Falliset al. [175] regarding the synthesis of the functionalized tricycle [9,3,1,0 ]pentadecene system of Taxanes, the core skeleton that can be found in Taxol (Fig. 8). Taxol has elicited considerable interest [176-178] due... 

The formation of /3-hydroxyselenides through the reaction of a selenium-stabilized carbanion with carbonyl compounds has been extensively used also in the context of natural product synthesis. The phenylselenoalkyllithium compound 115 was reacted with aldehyde 116 to afford /3-hydroxyselenide 117. In a radical cyclization cascade the tricyclic molecule 118 was generated in good yields and subsequent transformations led to the synthesis of pentalenene 119 (Scheme 28).1 9 Also other natural products like zizaene and khusimone have been synthesized via a similar route.200... 

Although most of the work with Rh-mediated intramolecular C-H insertion has focussed on five-membered ring construction, the first application to natural product synthesis, by Cane, involved establishment of a six-membered ring. Thus, on exposure to Rh2(OAc>4, diazoketone 2 was cyclized to the tricyclic lactone 3 [2. This product had previously been transformed by Paquette into pentalenolactone E (4) [3]. 

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. 

Aldol condensations of more complex aldehydes are often sufficiently slow to allow successful alkylation reactions. There are numerous examples of aldehyde enolate methylations in the field of natural product synthesis. As shown in Scheme 29, the methylation of a tricyclic aldehyde, which was employed in the synthesis of ( )-rimuene, provides an illustrative case. As expected for an exocyclic enolate intermediate such as (61), the methyl group was introduced equatorial to the six-membered ring with a high degree of stereoselectivity. a-Alkylated aldehydes may be prepared efficiently by alkylations of enamines, Schiff base anions, hydrazone anions and other methods. A discussion of this methodology is provided in Section 1.1.5. 

After the initial observation by the Beecham group, the first detailed exploration of rhodium-mediated intramolecular C—H insertion in natural product synthesis was by Cane (Scheme 5). Starting from the symmetrical bicyclooctanone (131), he elaborated the corresponding diazo ester (132). Rhodium-mediated methine insertion to give (133> then proceeded smoothly. The tricyclic lactone (133) so produced had already been converted, by Paquette, to pentalenolactone E (134). In the same article (not... 

From the viewpoint of natural products synthesis, retro-aldol condensation of the elec-trosynthesized tricyclic compounds 181 and 182 provided the selective formation of trans-hydroazulene 183 and triquinane 184 in good yields, respectively (Scheme 37). Herein, the selective attack of a methoxy anion to the /3-diketone is due to the stereochemistry of the aryl group introduced to the C6-position. 

Resolution of an Af-acetylaminocyclopentene carboxylate shown in Scheme 2.34 was used to access optically pure starting material for the synthesis of carbocyclic nucleoside analogs with promising antiviral activity [241]. The bulky tricyclic monoester was required for natural product synthesis [242]. 

More highly substituted aromatics have also been studied in the course of natural product synthesis. For example, rhodium(II) mandelate-catalyzed cyclization of diazoketone 41 produces the ring expanded product 42, which on hydrogenations furnishes the tricyclic lactone 43. ... 

Krafft and co-workers used olefin metathesis to prepare several inside-outside medium-size rings as scaffolds for natural products synthesis. Reaction of bicyclic lactone 267 with 10 mol % of 4 in refluxing dicholormethane gave the corresponding tricyclic lactone 269 in 88% yield after only two hours. 

A l,2,3,4-tetrahydro-/ -carboline, which consists of a tricyclic indole, is an attractive drug template due to its potential antioxidative activity [1-7], Carboline derivatives are also useful as intermediates for natural product synthesis [8-23]. Because construction of tetrahydro-jS-carbolines is mostly dependent on the Pictet-Spengler [8-17] and related reactions [18-23], development of alternative synthetic methodologies is extremely important to ensure diversity-oriented synthesis. For other representative synthetic routes, see [24—31]. 

The central six-membered ring unit in the illudalane or pterosin class of sesquiterpenes makes them a suitable target for a proof of the synthetic power of the transition-metal-catalyzed [2 + 2 + 2] alkyne cycloaddition in natural product synthesis. A first example in this field was provided by the intramolecular version of the [2 + 2 + 2] alkyne cyclotrimerization in the synthesis of calomelanolactone (15) [8] and pterosin Z (16), both of which have been isolated Ifom the silver fern Pityrogramma calome-lanos (Scheme 7.4) [9]. Wilkinson s complex served here as the catalyst, and the cyclotrimerization of triyne 13 proceeded at room temperature to give the tricycle 14. The latter was used as a common synthetic intermediate for completion of the synthesis of calomelanolactone (15) and pterosin Z (16) within four and three synthetic steps, respectively. 

Treatment of ketone (69) with excess amounts of t-BuMe2SiOTf and bis[(k)-l-phenylethyl]amine ((i )-BPEA) gives tricyclic silyl aldolate (70) with moderate enantioselectivity [104]. The formation of (70) can be explained by the enol silylation to (71) followed by a tandem Michael-aldol reaction. The asymmetric induction by the chiral amine occurs in the enol silylation (Scheme 9.40). The combined use of silyl triflates and amines has been applied to an intramolecular aldol reaction for natural product synthesis [105]. 

The importance of the 1,3-dipolar cycloaddition reaction for the synthesis of five-membered heterocycles arises from the many possible dipole/dipolarophile combinations. Five-membered heterocycles are often found as structural subunits of natural products. Furthermore an intramolecular variant makes possible the formation of more complex structures from relatively simple starting materials. For example the tricyclic compound 10 is formed from 9 by an intramolecular cycloaddition in 80% yield ... 

An enantiospecific synthesis of longifolene was done starting with camphor, a natural product available in enantiomerically pure form (Scheme 13.31) The tricyclic ring was formed in Step C by an intramolecular Mukaiyama reaction. The dimethyl Multistep Syntheses substituents were formed in Step E-l by hydrogenolysis of the cyclopropane ring. 

Stockman and coworkers [329] developed a straightforward synthesis of a tricyclic compound 2-636 which has some resemblance to the spirocyclic portion of the natural product halichlorine (2-637) [330]. On treatment of the symmetrical ketone 2-633, accessible in five steps from alcohol 2-632, with hydroxylamine hydrochloride the spiro piperidine 2-636 could be obtained in 62% yield (Scheme... 

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