Spirocyclic core synthesis

Notwithstanding this safety aspect, mCPBA continues to be used as an epoxidizing agent. In one such reaction, a diepoxidation (equation 1) was brought about as a key step in the synthesis of the spirocyclic core of aranorosin15, which is a novel antibiotic. A radical inhibitor was added in order to achieve an acceptable yield of 46%. 

The synthesis of the spirocyclic core [70-77] is obviously the most difficult task, the biomimetic approach being the most frequent way of preparing it. The strategy is based on the hipervalent iodine-mediated oxidative hydroxylation of a tyrosinal derivative followed by a cis-bisepoxidation. The shortest way [75] involved the introduction of the side chain as an amide of tyrosine ethyl ester. Aranorosin was obtained after DIBAL reduction to the aldehyde, oxidation to the dienone with phenyliodosyl bis(trifluoroacetate) (PIFA) and final epoxidation (Scheme 24). 

The oxidatively induced cyclization of N-protected tyrosine 242 has been used as an approach to the spirocyclic core intermediate product 243 (Scheme 3.99), which is an important step in the total synthesis of the antitumor antibiotic aranorosin [310],... 

Srikrishna and co-workers employed a similar strategy for the general synthesis of a spirocyclic core inherent to several acomeols. " Treatment of diene 76 with 3 mol % catalyst loading of 4 in refluxing benzene provided... 

An oxidative Prins-pinacol tandem process mediated by hypervalent iodine reagent was recently established by the Canesi group [93] and it was used for the formal synthesis of (-)-platensimycin (Scheme 14) [94]. The strategy allowed rapid access to the highly functionahzed spirocyclic core present in the target natural product. 

One of the pioneering applications of iV-heterocyclic car-bene (NHC) organocatalysts in the view of synthesizing natural products is the application by Orellana and Rovis of a Stetter reaction to construct the spirocyclic core of the antibiotic FD-838 (Scheme 11.46). Applying the triazole NHC precursor and activating the catalyst with 20 mol% of potassium 1,1,1,3,3,3-hexamethyldisilazide [potassium bis (trimethylsilyl)amide] (KHMDS), compound 197 underwent the Stetter reaction in a perfect 99% ee. This simplified skeleton of the bioactive molecule was one of the first examples applying the great power of NHC catalysis toward natural product synthesis. 

The synthesis of the bisbenzannelated spiroketal core of the y-rubromycins was achieved by the research team of C.B. de Koning." The key step was the Nef reaction of a nitroolefin, which was prepared by the Henry reaction between an aromatic aldehyde and a nitroalkane. The nitroolefin was a mixture of two stereoisomers, and it was subjected to catalytic hydrogenation in the presence of hydrochloric acid. The hydrogenation accomplished two different tasks it first converted the nitroalkene to the corresponding oxime and removed the benzyl protecting groups. The oxime intermediate was hydrolyzed to a ketone that underwent spontaneous spirocyclization to afford the desired spiroketal product. 

Interestingly, the same cychzation with a 4-hydroxyphenyl substituent as in 89 proceeds to an entirely different product 90. In this case, the authors employed Selectfluor 91 as oxidant for paUadium(IV) generation. Nucleophihc attack of the arene at the palladium(IV) center leads to reductive C-C bond formation, providing spirocyclic cyclohexadienones. The latter product was considered as a potential precursor to the synthesis of the platenmysin core. 

There are numerous examples of RCM in the literature and ring sizes from 5 upwards have been formed in this way. RCM was used for the formation of both a five-membered ring and a six-membered ring in a synthesis of the core stmcture of the dumsins (Scheme 8.62). Treatment of the substrate 8.221 for the first RCM with the first-generation Grubbs catalyst resulted in formation of the spirocyclic cyclopentene... 

For their 2010 synthesis of the immunosuppressive polyketides dalesconols A and B [143], Snyder and co-workers developed an outstanding one-pot cascade to forge the bicyclo[5.3.0]decanyl core of these targets from the judiciously functionalized and protected precursors 276. The ultimate addition of DIB in TFE at low temperature served to transform in situ the phenols 277 into the five-membered carbo-spirocyclic cyclohexa-2,5-dienone intermediates 278, which were then efficiently converted into dalesconols A and B (Fig. 67) [143]. 

Romo and coworkers have utilized an enantioselective Cu(II)-catalyzed Diels-Alder cycloaddition to set the key all-carbon quaternary stereocenter in the spiro-cyclic imine core of the marine toxin immunogen (—)-Gymnodimine (251) [76]. Cu(SbF6)2/t-Bu-BOX (13)-catalyzed cycloaddition of diene (248) to a-methylene lactam (247) provides spirolactam (249) in high yield with high stereoselectivity (Scheme 17.55). Subsequent synthetic efforts resulted in an efficient synthesis of the spirocyclic imine portion of (251). 

This method has also been utilized by Brimble and coworkers [71] in their formal synthesis of betkelic acid 96 (Scheme 25). Addition of trimethylsilyl enol ether 92 to oxonium ion 93 (generated by treatment of hemiacetal 91 with boron trifluoride diethyl etherate) and subsequent cyclization provided the hemiacetal 94. Finally, hydrogenolysis of the benzyl ethers in the presence of catalytic acid induced spirocyclization, affording the tetracyclic core of berfcelic acid, 95, in moderate yield over 3 steps. 

The spirocyclic oxindole core structure was constructed by an asymmetric 1,3-dipolar cycloaddition in the total synthesis of (—)-spirotryprostatin B. A reaction of oxazi-none 137 with aldehyde 138 and oxindole 139 resulted in spirooxindole 141 via the chiral azomethine yhde 140, simultaneously creating three bonds and four stereogenic centers in one step (Scheme 16.20). ... 

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