Spirocyclic core

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%. 

W.H. Moser and co-workers developed a new and efficient method for the stereocontrolled construction of spirocyclic compounds, including the spirocyclic core of the antitumor agent fredericamycin The strategy involved a one-pot aldol additioniBrook rearrangement cyclization sequence beginning from arene chromium tricarbonyl complexes and can formally be described as a [3+2] annulation. 

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). 

Scheme 32 Three component condensation of the spirocyclic core structure of the spirotry-prostatins by Williams and co-workers [138]...

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... 

Kim and and co-workers used ring-closing metathesis to construct the spirocyclic core of (-)-lepadiformine. (-)-Lepadiformine is a tricyclic perhydropyrrolo[2,l-y]quinolone that has recently gained attention due to its moderate in vitro tumor cell cytotoxicity and positive cardiovascular effects. Treatment of diene 183 with a catalytic amount of 4 in the presence of refluxing dichloromethane furnished the corresponding azaspiro cyclohexene 184 in near quantitative yield. 

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. 

Given that perhydrohistionicotoxin has a l,3-2 7,0 relationship, propose a Mannich reaction that might be used to contruct the spirocyclic core of 5. What stereochemical issues would have to be addressed in your proposed Mannich reaction. (Histrionicotoxin-4)... 

Brimble and coworkers used a three-step HWE/oxa-Michael/acid-catalyzed cyclization sequence to access the simplified spirocyclic core 243. Unfortunately, application of this method to a more complex substrate in order to obtain the substituted tetrahydrofuran was tmsuccessful [130]. However, Furstner and coworkers were able to effect a similar cascade from enone 244 in one step, affording tetracyclic spiroacetal 245 in excellent yield as a single isomer. 

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 same research group also explored a transannular nitrone-olefin [3 + 2] dipolar cycloaddition approach to the spirocyclic core of pinnaic acid, an inhibitor of phospholipase A2 (CPLA2) that was isolated from the Okinawan bivalve Pinna muricata The nitrone 34 was prepared by acidic hydrolysis of the ethylene ketal and the oxaziridine of 32 to generate transiently the keto... 

Wright DL, Schulte JP, Page MA. An imine addition/ring-closing metathesis approach to the spirocyclic core of haU-chlorine andpinnaic acid. Org. Lett. 2000 2 1847-1850. 

---