The Rubottom oxidation was used in the synthesis of periplanone B, a sex pheromone excreted by the female American cockroach. 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. Mukaiyama aldol addition and Michael reactions. 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. [22] The groups of Y. Shi[23] and W. Adam[24] 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. [1] Poor atom economy is also a major issue with the reaction because it requires stoichiometric oxidant, which generates large amounts of waste. For more examples see refs[1][3][4]. [1][26] This methodology gives acyclic and cyclic α-hydroxy ketones in high yield with a cheap, commercially available oxidant. Davis[21] in 1987 and showcased the Davis chiral oxaziridine methodology to give good yields but modest enantiomeric excesses. The Rubottom oxidation is a useful, high-yielding chemical reaction between silyl enol ethers and peroxyacids to give the corresponding α-hydroxy carbonyl product. Unless otherwise noted, LibreTexts content is licensed by CC BY-NC-SA 3.0. With the exception of sodium hydride and sodium amide, most of these bases are soluble in THF. 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. [33] Basic hydrolysis to remove the hydroxyl ester moiety of pleuromutilin yielded mutilin. They hypothesized that the increased lifetime of the intermediate species would allow for over oxidation to occur. In the preparation of lithium diisopropylamide (LDA), for example, the only other product is the gaseous alkane butane. [1][9][10], In 1974, three independent groups reported on the reaction now known as the Rubottom oxidation:[1] A.G Brook,[6] A. Hassner,[11] and G.M. Ether solvents like tetrahydrofuran (THF) are commonly used for enolate anion formation. Once synthesized, the Samadi ketone could be elaborated to (−)-ovalicin through known steps. Halogenation of silyl enol ethers gives haloketones. Velutinol A[41] was first synthesized by Isaka and coworkers. The mechanism of the reaction was proposed in its original disclosure by A.G. Brook with further evidence later supplied by George M. Rubottom. Subsequent buffered Rubottom oxidation conditions with sodium bicarbonate in ethyl acetate afforded the α-hydroxy ketone as a single diastereomer. Ketene silyl acetals are related compounds formally derived from ketenes and acetals with general structure R-C=C(OSiR3)(OR'). Ovalicin, fumagillin, and their derivatives exhibit strong anti-angiogenesis properties and have seen numerous total syntheses since their isolation. [6][11][12] 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. Tautomers are rapidly interconverted constitutional isomers, usually distinguished by a different bonding location for a labile hydrogen atom and a differently located double bond. [29][30] The synthesis employed an anionic oxy-Cope rearrangement coupled to a Rubottom oxidation. With the exception of sodium hydride and sodium amide, most of these bases are soluble in THF. Tautomeric equilibria are catalyzed by traces of acids or bases that are generally present in most chemical samples. It is necessary, therefore, to achieve complete conversion of aldehyde or ketone reactants to their enolate conjugate bases by treatment with a very strong base (pKa > 25) in a non-hydroxylic solvent before any alkyl halides are added to the reaction system. [18] 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. 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. First, the authors originally generated the silyl enol ether using triethylamine, which gave a mixture of the desired kinetic product, (shown below) the undesired thermodynamic product, and hydrolysis back to mutilin. Even in such one-sided equilibria, evidence for the presence of the minor tautomer comes from the chemical behavior of the compound. [17], 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. After a Prilezhaev-type oxidation of the silyl enol ether with the peroxyacid to form the … [25] This methodology also gave high yields and enentioselectivities for silyl enol ethers as well as silyl ketene acetals derived from esters. 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. [5], Acyloins form upon organic oxidation with an electrophilic source of oxygen such as an oxaziridine or mCPBA.[6]. The mechanism whereby enols are formed in acidic solution is a simple, two step process, as indicated below: q Step 1 is simply the protonation of the carbonyl oxygen to form the conjugate acid of the carbonyl compound. A.; Herzon, S. B., Creative Commons Attribution-ShareAlike License, This page was last edited on 21 October 2020, at 11:34. In 1992, K.B. Because of the acidity of α hydrogens, carbonyls undergo keto-enol tautomerism. 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. Without BuLi the authors report a maximum yield of only 72%. [1][20] The introduction of chiral oxidants has also allowed for the synthesis of enantiopure α-hydroxy carbonyl derivatives from their corresponding silyl enol ethers. This highly optimized sequence features two important aspects. Certain other strong bases, such as alkyl lithium and Grignard reagents, cannot be used to make enolate anions because they rapidly and irreversibly add to carbonyl groups. [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. [1][28], 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. Both acyclic and cyclic silyl enol ether derivatives can be prepared in this way and subsequently be used as substrates in the Rubottom oxidation. [31] Chiral chromium catalyst B was developed the Jacobsen group and confers high levels of enantio- and diastereoselectivity. We also acknowledge previous National Science Foundation support under grant numbers 1246120, 1525057, and 1413739. Missed the LibreFest? 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. [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. Watch the recordings here on Youtube! [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). Because of its solubility in THF, LDA is a widely used base for enolate anion formation. Remember that proton transfers from oxygen to … [13][14], Considerable work by A.G Brook, during the 1950s on the mechanisms of organosilicon migrations, which are now known as Brook Rearrangements. The general structure is R2C=CR-OR where R = H, alkyl or aryl. Silyl enol ethers in organic chemistry are a class of organic compounds that share a common functional group composed of an enolate bonded through its oxygen end to an organosilicon group.

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