Rubottom oxidation

[8] After a Prilezhaev-type oxidation of the silyl enol ether with the peroxyacid to form the siloxy oxirane intermediate, acid-catalyzed ring-opening yields an oxocarbenium ion.

[1][4] Low temperatures allow the standard Rubottom oxidation conditions to be amenable with a variety of sensitive functionalities making it ideal for complex molecule synthesis (See synthetic examples below).

[1] The Rubottom oxidation has remained largely unchanged since its initial disclosure, but one of the major drawbacks of standard conditions is the acidic environment, which can lead to unwanted side reactions and degradation.

A simple sodium bicarbonate buffer system is commonly employed to alleviate this issue, which is especially problematic in bicyclic and other complex molecule syntheses (see synthetic examples).

Sharpless showed that the asymmetric dihydroxylation conditions developed in his group could be harnessed to give either (R)- or (S)- α-hydroxy ketones from the corresponding silyl enol ethers depending on which Chinchona alkaloid-derived chiral ligands were employed.

The Adam group also published another paper in 1998 utilizing manganese(III)-(Salen)complexes in the presence of NaOCl (bleach) as the oxidant and 4-phenylpyridine N-oxide as an additive in a phosphate buffered system.

[1][27] The Rubottom group found that lead(IV) acetate in DCM or benzene gave good yields of acyclic and cyclic α-hydroxy esters after treatment of the crude reaction mixture with triethylammonium fluoride.

The silyl enol ether intermediate could then be treated with mCPBA under Rubottom oxidation conditions to give the desired α-hydroxy carbonyl compound that could then be carried on to (±)-periplanone B and its diastereomers to prove its structure.

Brevisamide, a proposed biosynthetic precursor for a polyether marine toxin, was synthesized by Ghosh and Li, one step of which is a Rubottom oxidation of the cyclic silyl enol ether under buffered conditions.

[32] The stereocenters conveniently set in the Diels-Alder reaction direct the oxidation to the less hindered face, giving a single diastereomer, which could then be carried on in 14 more steps to Brevisamide.

Subsequent treatment with lithium hexamethyldisilazide (LiHMDS) and TMSCl gave the TMS-protected silyl enol ether, which was immediately subjected to an acetic acid- (HOAc) pyridine- (Py) buffered Rubottom oxidation before acidic hydrolysis to afford 2S-hydroxymutilin.

[34] Second, while oxidation occurred from the desired convex face of the silyl enol ether, the authors saw a significant number of overoxidation products that they attributed to the stability of the oxocarbenium ion intermediate under sodium bicarbonate buffered conditions.

After a significant amount of optimization, it was found that an HOAc/Py buffer trapped the oxocarbenium intermediate and prevented overoxidation to exclusively give 2S-hydroxymutilin after hydrolysis of the silyl protecting groups.

[40] A standard Rubottom oxidation gives a single stereoisomer due to substrate control and represents the key stereogenic step in the route to the Samadi ketone.

It is likely that the close proximity of the hydroxyl group in the syn isomer acidifies the ring-fusion proton through hydrogen-bonding interactions, thus facilitating regioselective deprotonation by triethylamine.

The silyl enol ether was then treated with excess mCPBA to facilitate a “double” Rubottom oxidation to give the exo product with both hydroxyl groups on the outside of the fused ring system.

[2][43] This interesting sequence features the addition of excess n-butyllithium (BuLi) in the presence of lithium diisopropylamide (LDA) for full conversion of the bicyclic ketone derivative to the corresponding silyl enol ether.