Disconnection of ketones

Disconnection of ketones gives the synthon (1), for which we have previously used an ester, and a Grignard reagent. However, this approach is doomed from the start (see Chapter 10) as the ketone is formed in the presence of the Grignard reagent and is more reactive than the ester. Alcohols arc formed. 

The C-C=0 and C-CN bond cleavage reactions are of fundamental interest to the organometaUic community. However, recent intensive studies in this area have also attracted practitioners of organic synthesis since these reactions enable new bond disconnections of ketones and nitriles, thus leading to innovative approaches to constructing complex molecules [82]. 

Grignard addition to COg must be the answer with this crowded acid and this leads us back to alcohol (20), Disconnection of any group now gives a simple ketone and an available alkyl halide. As we shall see in Chapter 11, it is best to divide the molecule into two nearly equal parts, so we shall use disconnection (a). 

In an early attempt to synthesise camphor, dlol (1) was an important intermediate. We shall want to disconnect the ring from the chain, so a preliminary disconnection of a methyl group gives an ct-hydroxy ketone (2) which can be made from ketone (3) and an acyl anion equivalent. 

Disconnection of the ether la now a good idea as it leaves an ct-hydroxy ketone to be made by acyl anion equivalent addition. We prefer (10) as the acetylene anion can then serve as synthon (4). 

Workers studying the eyelisation of acetylenic alcohols decided to make (30), Disconnection of the acetylene leaves a-hydroxy ketone (31), Since this ketone is blocked on one side by the aromatic ring it is reasonable to make (31) from (33) via bromoketone (32). Ana lysis... 

This is a l,4 diketone and disconnection of the central bond separates the two rings. We require a specific enol equivalent lor (4) - they used activated ketone (6) - and a reagent for unnatural synthon (5) -they used a-chloroketone (7). 

The tvans alcohol (47) might be made by reduction of ketone (48). Oxidation of (45) would give (48), but an alternative is to add an activating group and disconnect as a 1,3-dicarbonyl compound - standard strategy ior a symmetrical ketone. 

The common atoms are marked in (25a) and the best disconnections correspond to the intramolecular alkylation of ketone (26) or (27). 

Other bonds that merit attention are those connecting C(7) through C(ll). These could be formed by one of the many methods for the synthesis of ketones. Bond disconnections at carbonyl centers can involve the 0=C-C(a) (acylation, organometallic addition), the C(a)-C((3) bond (enolate alkylation, aldol addition), or C((3)-C(7) bond (conjugate addition to enone). 

Finally, disconnection of the two appendages leads to bicyclic ketone 9 which can be disconnected into 2-cyclohexenone 10 and isobutylene, according to a -(2+2) cycloreversion. 

It is clear from the examples in this book that the use of biocatalysis can produce some very cost-effective and environmentally acceptable processes, and the authors anticipate that the use of this technology will increase as synthetic organic chemists realize its value and begin to look for strategic disconnections in the synthetic sequence of new target molecules where a biocatalytic step can be applied to utmost benefit. Thus, biocatalysis should be seen as a routine part of the synthetic toolbox and, in some cases, the reagent of choice for transformations such as the reduction of ketones to chiral alcohols, and not as a technology of last resort when all else has failed. 

Now we go back to A and consider disconnection at a different bond. Suppose we recognize that alcohol A could easily come from reduction of ketone K. 

An alternative representation of the disconnection strategy shown on p. 606 for these methods of synthesis of ketones is formulated below. 

In the case of cyclopropyl methyl ketone, disconnection of either the 1,2- or 1,3-carbon-carbon bond of the cyclopropane ring results in the preferred charge distribution shown in (4), namely, the carbanion site is adjacent to the meso-merically stabilising carbonyl group, and the carbocation site may be viewed as a halide-carrying carbon. The reagent equivalent may therefore be 5-chloro-pentan-2-one. 

The disconnection of both carbon-carbon double bonds in tetraphenylcyclo-pentadienone (14) ( tetracyclone ), in the manner of the examples above, leads to recognition of benzil and dibenzyl ketone as the reagents for its synthesis. 

---