Baeyer–Villiger oxidation

Another reaction that can be associated with the strategy of the   Retrosynthesis is the oxidation of ketones by peroxyacids, better known as the Baeyer-Villiger reaction. In cyclic ketones, oxidation with peracids generates lactones. The groups attached to the asymmetric ketones have a migratory ability, which allows, in literal terms, to "insert an oxygen atom" between the carbonyl group and the migrating group, thus producing an ester or a lactone.

It should be taken into account that enones (α, β unsaturated ketones) are not good substrates for the Baeyer-Villiger oxidation, because the alkene is much more reactive than the ketone. However   There are special structures where the alkene can be protected by a nearby substituent due to the steric effect and thus direct the attack of the peracid towards the carbonyl group.



Remember that the migratory aptitude of the different groups, in the Baeyer-Villiger reaction, is as follows:

H> Ph> 3º alkyl> cycloalkyl> 2º alkyl> 1º alkyl> Me

Propose a synthesis plan for the following molecules:

MOb 56




MOb 57



MOb 58


MOb 59


MOb 60


mob 61


MOb 56. Retrosynthetic analysis.   The alpha amino acid the mob , it can be prepared by the reaction   Strecker's   and also one of the OH groups of benzene or both can result from the hydrolysis of an ester, formed by the Baeyer-Villiger oxidation, on a ketonic substrate. The rest of the IGFs are easy to execute based on basic reactions.


Synthesis. For   For the formation of the required Grignard, the ortho OH of the benzene is protected. The Strecker synthesis allows the formation of the alpha amino acid, which is oxidized according to Baeyer-Villiger with a peracid and the product undergoes acid hydrolysis of the ester group, which leads to the formation of the mob 56.


MOb 57 . Synthetic retro analysis . _ This MOb is a tertiary alcohol, so it can be prepared from an ester and an excess of Grignard. The precursor molecule formed is a 1,6-diCO compound, so it is resorted to reconnecting it in a lactone, which can be form from a ketone. This bicyclic ketone is functionalized with a point of unsaturation to achieve a Diels-Alder adduct structure. The carbonyl group can be formed from a compound containing a nitro group, by the Nef reaction  


synthesis .   It starts from the Diels-Alder reaction of a cyclohexadiene and a nitroethylene. The adduct formed is saturated, to proceed to the Baeyer-Villiger oxidation. The opening of the lactone and esterification of the acid group, forms an intermediate that is then treated with an excess of methyl magnesium bromide, to obtain the   MOb 57


MOb 58. Retrosynthetic analysis. The double bond conjugated to a C=O group, present in the mob , can be attacked   by a peracid to form an epoxide. However, when there is protection of the double bond with a group nearby bulky, this reaction can be avoided and only the Baeyer Villiger oxidation occurs, modifying the position adjacent to the C=O ketonic group.

mob58sol.png synthesis . The double bond, in the Diels-Alder adduct, can be protected   by the use of the benzyl (Bn) group. The nitro group of the dienophile is oxidized to a C=O group, by the Nef reaction, to then be oxidized by BV and thus arrive at the mob .


MOb 59 . Retrosynthetic analysis. It proceeds to disconnect the mob as 1,3-diCO, resulting in a 1,6-diCO precursor. It is not possible to reconnect it, so a –COOEt group is added to activate the Cα, and thus displace a halide from a γ-haloester.

Once again, an intermediate or precursor 1,3-diCO is generated, which, when disconnected, generates a new 1,6-diCO structure, which can now be reconnected to reach cyclohexene as starting material.


synthesis . The oxidative opening of a cyclohexene allows obtaining the precursor molecule that, after reacting with the γ-bromoester, gives rise to a molecule that, after a Dieckmann reaction, is easily transformed into the mob 59.


MOb 60 . Retrosynthetic analysis. It is assumed that the formation of the mob 60, is given by the Baeyer-Villiger reaction. The precursor formed is unlinked by cyclopropane, generating a synthetic α equivalent , β-insat.CO, which unlinks or forms the precursor molecule relative to 1,4-diCO. The disconnection of the latter, glimpses the starting materials.


synthesis . The acetaldehyde enolate combines with α-bromoketone to form a 1,4-diCO molecule, which in a basic medium and EtOH condenses with dehydration to form an α,β-unsaturated cyclopentanone. The Simonns-Schmidt reaction is continued to   form cyclopropane and a subsequent oxidation of it according to Baeyer-Villiger produces the mob 60.


MOb 61 . Retrosynthetic analysis . It is assumed that the mob 61, was formed by a Baeyer-Villiger oxidation reaction of a cyclopentanone. An adequate functionalization of this molecule allows disconnecting it as a   α,β-insatCO, which can be obtained from a suitable nitrile, which points to simple and affordable starting materials.


Synthesis. Propene and benzene are taken as starting materials, the strategy is to reduce the nitrile to CHO with DIBAL in hexane, to form the intermediate that by Robinson annulation (or annulation) and subsequent saturation, provides the adequate cyclopentanone to be oxidized by the Baeyer-Villiger procedure, to form the   MOb 61.