Heterofunctionalisation of Aldehydes and Ketones

The a-heterofunctionaUsation of aldehydes and ketones can be achieved via the reaction of chiral noirracemic metal-enolates with suitable electrophiles or by activation of the electrophilic heteroatom source with an enantiomerically pure Lewis add catalyst. Alternatively, metal-free a-functionalisation can be achieved via the reversible formation of enamines and this approach has proved a successful method for the synthesis of a range of enantioenriched a-heteroaldehydes and ketones. 

Chiral nonracemic a-hydoxylated ketones are commonly accessed by asymmetric epoxidation or dihydroxylation of enol ethers and this methodology is discussed in the relevant sections of this book. Another general method for the enantioselective a-oxygenation of ketones and aldehydes is by reaction of an electrophilic source of oxygen with chiral nonracemic enamines or enolates or in the presence of Lewis acids. 

Yamamoto and coworkers have developed an asymmetric a-aminoxylation of cyclic tributyltin enolates using nitrosobenzene (5.85) as oxygen source in the presence of Lewis acidic 1 1 silver-BINAP complexes. For example, the enolate (5.86) is converted into the a-aminoxyketone with high ee using this procedure. Cleavage of the N-0 bond is then effected with no racemization, using catalytic copper sulfate in methanol. 

Chiral nonracemic enamines formed in situ by reaction of aldehydes and ketones with proline-based organocatalysts also undergo stereoselective a-oxygenation. MacMillan and coworkers have achieved enantioselective a-oxidation of a range of aliphatic aldehydes such as (5.87) with 97-99% ee using proline in combination with nitrosobenzene (5.85). This method can be applied to the aminoxylation of six-membered cyclic ketones such as 1,4-cyclohexanedione monoethylene ketal (5.88). 59 

The direct a-amination of aldehydes and ketones provides a useful method for the synthesis of amino acids and, consequently, the asymmetric variant of this process using either metal-based complexes or organocatalysts has received much attention. 

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