Bicyclic fragments, Grob fragmentation

Vamos M, Ozboya K, Kobayashi Y (2007) Synthesis of bicyclic pyroglutamic acid featuring the Ugi reaction and a unique stereoisomerization at the angular position by Grob fragmentation followed by a transannular ketene [2-1-2] cycloaddition reaction. Synlett 1595-1599. Kreye O, Westermann B, Wessjohann LA (2007) A stable, convertible isonitrile as a formic acid carbanion [-COOH] equivalent and its application in multicomponent reactions. S3mlett 20 3188-3192... 

Ozonolysis of diketone carbonate 417 in methanol afforded an almost quantitative yield of the bicyclic diene triketone hydroxy-ester 418 (119). This remarkable transformation can also be readily explained. Ozonolysis of 417 produces the tetraketone intermediate 419 followed by methanol addition to produce the hemi-ketal 420 which undergoes a retro-Claisen reaction to 421. Then, loss of carbon dioxide from 421 yields 418. Again, 420 could also undergo a Grob type fragmentation to yield 418 directly. 

The pioneering woik of Ohloff in this field is shown by his historic paper on the synthesis of both (118) and (119). Inter alia, the bicyclic tosylate (121) provides, by Grob fragmentation, the unsaturated ketone (122), which also has a strong musk odour. 

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. 

Unsymmetrical alkenes can be prepared by mixed intermolecular reactions if one of the components, commonly acetone, is used in excess (equation 83). As the isopropyl group is a common subunit of many terpenes this method provides a valuable route for its introduction. Pattenden and Robertson used such a reaction followed by a Grob-type fragmentation in their preparation of the daucenone (42) from the readily enolized ketone (43). The bicycle (42) was used as an intermediate for the synthesis of the diterpene ( )-isoamijiol (44 equation 84). Mixed couplings are not restricted to acetone, and almost any carbonyl may be used. For example, Paquette et al. employed the aldehyde (45) in a synthesis of ( )-a-vetispirene (46 equation 85). More complex mixed couplings are also possible. For example, the aldehydes (47) and (48) are coupled efficiently to the stilbene (49), which in turn is converted to phenan-threne alkaloids such as atherosperminine and thalictuberine (equation 86). ... 

Even more extended fragmentation cascades have been reported. For example, Grob reported formation of acyclic nitriles from the Beckmann fragmentation of bicyclic Ts-oximes (Figure 8.23). Electron flow that led to the scission of two C-C and one N-O bond started from the two strong donors (the appropriately oriented lone pairs of the two oxygen atoms in the tetrahedral intermediate). 

Thomas investigated the chemistry of 8-azabicyclo[1.2.1]octanes, the core structure of the tropane alkaloids, and unexpectedly observed a Grob fragmentation instead of the predicted elimination reaction. Upon treatment of mesylate 27 with potassium /-butoxide in dimethyl sulfoxide, silyl cleavage affords alkoxide 28 which fragments to yield formaldehyde, a mesylate anion, and bicycle 29. Exposure of 27 to DBU in acetonitrile leads to the desired E2 reaction with complete suppression of the Grob fragmentation. ... 

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. ... 

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