Rubottom Oxidation

The Rubottom oxidation is a useful, high-yielding chemical reaction between silyl enol ethers and peroxyacids to give the corresponding α-hydroxy carbonyl product.Kürti, pp. 388–389.Myers, A.G. Chemistry 215: Oxidation
. chem.harvard.eduLi, pp. 478–479.Chen, B. C.; Zhou, P.; Davis, F. A.; Ciganek, E. (2003) “α-Hydroxylation of Enolates and Silyl Enol Ethers." in ''Organic Reactions''; Ed. Overman, L.E. Wiley, Chapter 1, pp. 1–355, . The mechanism of the reaction was proposed in its original disclosure by A.G. Brook with further evidence later supplied by George M. Rubottom. 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. This intermediate then participates in a 1,4-silyl migration (Brook rearrangement) to give an α-siloxy carbonyl derivative that can be readily converted to the α-hydroxy carbonyl compound in the presence of acid, base, or a fluoride source.Myers, A.G. Chemistry 215
Protective Groups-Silicon-Based Protection of the Hydroxyl Group
chem.harvard.eduKocieński, P.J. (2005) ''Protecting Groups''. 3rd Edition, Thieme, pp. 188–230, .

Reaction mechanism

History

In 1974, three independent groups reported on the reaction now known as the Rubottom oxidation: A.G Brook, A. Hassner, and G.M. Rubottom. Considerable precedent for the reaction already existed. For instance, it was known as early as the 1930s that highly enolizable β-dicarbonyl compounds would react with peroxyacids, although it was not until the 1950s and 60s α-hydroxy β-dicarbonyl compounds were in fact the product.

Considerable work by A.G Brook, during the 1950s on the mechanisms of organosilicon migrations, which are now known as Brook Rearrangements.Kürti, pp. 64–65.Li, pp. 68–99. In 1974, C.H. Heathcock described the ozonolysis of silyl enol ethers to give a carboxylic acid product via oxidative cleavage where silyl migrations were observed as side reactions and exclusively in the case of a bicyclic system.

General features

The original implementations of the Rubottom oxidation featured the peroxyacid meta-chloroperoxybenzoic acid (mCPBA) as the oxidant in dichloromethane (DCM), in the case of Hassner and Brook, and hexanes for Rubottom. While the reaction has been tweaked and modified since 1974, mCPBA is still commonly used as the oxidant with slightly more variation in the solvent choice. DCM remains the most common solvent followed by various hydrocarbon solvents including pentane and toluene. Notably, the reaction proceeds at relatively low temperatures and heating beyond room temperature is not necessary. 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). Silyl enol ether substrates can be prepared regioselectively from ketones or aldehydes by employing thermodynamic or kinetic control to the enolization prior to trapping with the desired organosilicon source (usually a chloride or triflate e.g. TBSCl or TBSOTf). As illustrated by the synthetic examples below, silyl enol ethers can be isolated prior to exposure to the reaction conditions, or the crude material can be immediately subjected to oxidation without isolation. Both acyclic and cyclic silyl enol ether derivatives can be prepared in this way and subsequently be used as substrates in the Rubottom oxidation. Below are some representative Rubottom oxidation products synthesized in the seminal papers.

In 1978, Rubottom showed that siloxy 1,3 dienes, derived from acyclic or cyclic enones could also serve as substrates for the Rubottom oxidation to forge α-hydroxy enones after treatment with triethyl ammonium fluoride. These substrates give a single regioisomer under the reaction conditions due to the electron-rich nature of the silyl enol pi-bond (See synthesis of Periplanone B below).

Modifications and improvements

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). The introduction of chiral oxidants has also allowed for the synthesis of enantiopure α-hydroxy carbonyl derivatives from their corresponding silyl enol ethers. The first example of an enantioselective Rubottom oxidation was published by F.A. Davis in 1987 and showcased the Davis chiral oxaziridine methodology ( Davis oxidation) to give good yields but modest enantiomeric excesses. In 1992, K.B. 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 groups of Y. Shi and W. Adam published another enantioselective variant of the Rubottom oxidation in 1998 using the Shi chiral ketone in the presence of oxone in a buffered system to furnish α-hydroxy ketones in high yield and high enantiomeric excess. 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. This methodology also gave high yields and enentioselectivities for silyl enol ethers as well as silyl ketene acetals derived from esters.

Along with chiral oxidants, variants of mCPBA have been examined. Stankovic and Espenson published a variation of the Rubottom oxidation where methyltrioxorhenium is used as a catalytic oxidant in the presence of stoichiometric hydrogen peroxide. This methodology gives acyclic and cyclic α-hydroxy ketones in high yield with a cheap, commercially available oxidant. An inherent problem with mCPBA is its inability to oxidize silyl ketene acetals. In order to synthesize α-hydroxy esters, different oxidants are needed such as NaOCl (see above), lead(IV) acetate, or a hypofluorous acid-acetonitrile (HOF-ACN) complex. 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. Later, the highly electrophilic HOF-ACN complex was used by S. Rozen to oxidize a variety of electron rich silyl enol ethers, silyl ketene acetals, and bis(silyl acetals), derived from carboxylic acids, in good yields at or below room temperature.

Applications in synthesis

The following examples represent only a small portion of syntheses that highlight the use of the Rubottom oxidation to install an important α-hydroxy functionality. Some of the major features of the following syntheses include the use of buffered conditions to protect sensitive substrates and the diastereoselective installation of the α-hydroxy group due to substrate controlled facial bias. For more examples see refs

The Rubottom oxidation was used in the synthesis of periplanone B, a sex pheromone excreted by the female American cockroach.Nicolaou, K.C; Sorensen, E. J (1996) ''Classics in Total Synthesis: Targets, Strategies, Methods'', Wiley, pp. 211–220, . The synthesis employed an anionic oxy-Cope rearrangement coupled to a Rubottom oxidation. After heating in the presence of potassium hydride (KH) and 18-crown-6 (18-C-6) to effect the anionic oxy-Cope, the enolate intermediate was trapped with trimethylsilyl chloride (TMSCl). 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. Chiral chromium catalyst B was developed the Jacobsen group and confers high levels of enantio- and diastereoselectivity. 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.

Wang and coworkers developed a robust, kilogram-scale synthesis of the potent derivative 2S-hydroxymutilin from pleuromutilin, an antibiotic produced by various species of basidiomycetes. Basic hydrolysis to remove the hydroxyl ester moiety of pleuromutilin yielded mutilin. Subsequent treatment with lithium hexamethyldisilazide (LiHMDS) and TMSCl gave the TMS-protected silyl enol ether, which was immediately subjected to an acetic acid