Cyclization Robinson ring annelation

The most abundant and widely used monoterpenes, pinenes and their analogues, are often upgraded to more sophisticated structures with a Robinson annelation as the key step. However, as a result of unusual stereochemical constrains imposed by the bicyclic ring, only certain conformational isomers of the pinane skeleton undergo the annelation. Whereas the diketone (41) derived from n. v-inethylnopinone cyclized satisfactorily to the tricyclic ketone under Robinson conditions (Scheme 5.18), the epimeric diketone would not.64... 

The second stage is the formation of a new enolate on the other side of the ketone from the first. Note that the original enolate, the intermediate in the conjugate addition, can cyclize to give only an unstable four-membered ring so this cyclization would be reversible, The next intermediate, the aldol product, is often isolated from Robinson annelations, the Robinson annelation mechanism—stage 2 the intramolecular aldol reaction... 

The first enol you saw at the start of Chapter 21 was the stable enol of dimedone , 5,5,-dimethyl-cydohexa-l,3-dione. This six-membered ring is made by a close analogue of the Robinson annelation. The only difference is in the cyclization step, which is a Claisen ester condensation rather than an aldol reaction. 

This principle is often applied to molecules. If a nucleophile is joined to the carbonyl group it is to attack by a short chain of covalent bonds, it may be able to reach only one side of the carbonyl group. An example from a familiar reaction concerns the Robinson annelation. The first step, Michael addition, creates a stereo genic centre but no relative stereochemistry. It is in the second step—the aldol cyclization—that the stereochemistry of the ring junction is decided. 

Similar behavior with the simpler 1,5-diketone (65) has been documented by Marshall and Schaeffer. As shown in equation (12()), diketone (65) cyclizes to octalone (66) under basic conditions and to the bicyclo[3.3.1]nonenone (67) under acidic conditions. The regiochemistry of ring closure in this system is sensitive to the exact reaction conditions. For example, diketone (65), an intermediate in the acid-mediated Robinson annelation process, cyclizes to octalone (66 equation 121). In this example, it is... 

The 4-(chloromethyl)isoxazole 13, which is readily accessible from 3,5-dimethyloxazole, serves as a C4-building-block in annulations to cycloalkanones (isoxazole annelation according to Stork). The primary step is alkylation leading to product 14, a masked triketone. On hydrogenation, the isoxazole ring is reductively opened and cyclization via the enaminone 15 leads to the enamine 16. On treatment with sodium hydroxide, this is converted into the bicycloenone 17 by hydrolysis, acid fission of the y dicarbonyl system and an intramolecular aldol condensation (analogous to a Robinson annu-lation) ... 

Intramolecular aldol condensations are often more successful than the inter-molecular type. A particularly important example of the synthetic use of intramolecular condensation is in the Robinson annelation, a procedure that constructs a new six-membered ring from a ketone that has an enolizable hydrogen. The stages in which this alkylation-cyclization occurs are outlined below. The cyclization... 

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