Grob fragmentation rings

The [i,y fragmentation is known as Grob fragmentation. Its synthetic application is usually in the construction of medium-sized rings by fragmentation of fused ring systems. 

One would expect that as this Grob fragmentation becomes a better understood process, it will see more use in highly specific complex ring rearrangements. 

Copper-mediated sulfide elimination can lead to ring opening reactions. The hydroxy thioacetal 83, when treated first with n-BuLi and then with CuOTf afforded 84 in 92 % yield via a Grob fragmentation (Sch. 21) [47]. Two equivalents of the Lewis acid were required for the reaction because one equivalent complexes the alk-oxide and a second is necessary to activate the sulfide for elimination. Ring enlargement occurred upon treatment of 85 with CuOTf in benzene through the intermediacy of the thio-substituted epoxide 86 [48]. a-Phenylthiocyclohexanone 87 was obtained in 83 % yield. 

The total synthesis of the phenolic sesquiterpene (+)-parviflorine was accomplished by L.A. Maldonado and co-workers. The key step in the synthetic sequence was the reaction of an enamine with acrolein to form a bicyclic intermediate, which was subjected to a Grob fragmentation to afford the eight-membered ring of the natural product. The bicyclic ketone substrate was refluxed in benzene using a Dean-Stark trap and the resulting enamine was taken to the next step as crude material. 

In Grieco s synthesis of compactin, the required stereochemical information in the A ring was embedded in the oxabicyclic subunit of compound 225 [192]. Ring opening was induced by base promoted Grob fragmentation which generated formaldehyde and decalin 226, Eq. 138. 

Several examples of the stereoselective formation of cyclopentane rings promoted by samarium diiodide have been reported. Thus a pinacol-like coupling of a 1,5-dialdehyde derivative produced 75 in which the newly formed hydroxyl groups R, R were in a y/z-arrangement. (See Vol. 29, p.238, ref. 95 for a related reaction). In contrast, reaction of a 5-hexenal, produced by zinc-assisted Grob fragmentation of a methyl 6-deoxy-6-iodopyranoside, produced 76 and 77 in which the exocyclic groups R, R (or R, R ) were anti to each other. ... 

Grob fragmentation reactions have proved useful in organic synthesis, as, for example, in the synthesis of compounds with larger rings (equation 10.11). ... 

The Grob fragmentation is a useful synthetic tool for the construction of rings with six to eight members beginning with a bicyclic structural moiety. One example enables the production of substituted benzenes from readily available bicycles. Khan demonstrated that polyhalogenated (chloro and bromo) phenols (e.g., 36) result from treatment of bicyclic ketones (e.g., 35) with PTSA in toluene. ... 

---