A-Ketol acetates

As first demonstrated by Stork,the metal enolate formed by metal-ammoni reduction of a conjugated enone or a ketol acetate can be alkylated in liquic ammonia. The reductive alkylation reaction is synthetically useful since ii permits alkylation of a ketone at the a-position other than the one at whicf thermodynamically controlled enolate salt formation occurs. Direct methyl-ation of 5a-androstan-17-ol-3-one occurs at C-2 whereas reductive methyl-... 

Active metals readily cleave a-ketols and a-ketol acetates. Reductions can be carried out with the aid of lithium, barium or calcium in ammonia, or with zinc or tin, which are usually used in acidic media. Zinc is a relatively mild reducing agent and is therefore somewhat selective. Axial steroidal ketol acetates are reduced more readily than equatorial (equations 16 and 17). On the other hand, metal-ammonia systems are powerful reductants thus, calcium and barium reduce axial and equatorial isomeric ketol acetates with equal ease. Lithium is a more powerful reductant and frequently overreduces a-ketols... 

Reductive cleavage of a-ketol acetates can also be effected in moderate yield by Fe(CO)s. Ketones, esters and alkenes are unreactive toward this reagent. 

Oxazoles are also obtained by heating acetylenic alcohols, in which the acetylenic bond is in the a, /3-position to the hydroxy group, with acid amides in the presence of a mercury salt catalyst,137 or alternatively, by heating a-ketol acetates with nitriles in sulfuric acid.138 In those cases... 

Metal-ammonia solutions reduce conjugated enones to saturated ketones and reductively cleave a-acetoxy ketones i.e. ketol acetates) to the unsubstituted ketones. In both cases the actual reduction product is the enolate salt of a saturated ketone this salt resists further reduction. If an alcohol is present in the reaction mixture, the enolate salt protonates and the resulting ketone is reduced further to a saturated alcohol. Linearly or cross-conjugated dienones are reduced to enones in the absence of a proton donor other than ammonia. The Birch reduction of unsaturated ketones to saturated alcohols was first reported by Wilds and Nelson using lithium as the reducing agent. This metal has been used almost exclusively by subsequent workers for the reduction of both unsaturated and saturated ketones. Calcium has been preferred for the reductive cleavage of ketol acetates. 

The reductive cleavage of ketol acetates involves addition of two electrons to the system with fragmentation into an acetate ion and a ketone carbanion... 

Protonation of the a-carbanion (50), which is formed both in the reduction of enones and ketol acetates, probably first affords the neutral enol and is followed by its ketonization. Zimmerman has discussed the stereochemistry of the ketonization of enols and has shown that in eertain cases steric factors may lead to kinetically controlled formation of the thermodynamically less stable ketone isomer. Steroidal unsaturated ketones and ketol acetates that could form epimeric products at the a-carbon atom appear to yield the thermodynamically stable isomers. In most of the cases reported, however, equilibration might have occurred during isolation of the products so that definitive conclusions are not possible. 

Alcoholic potassium hydroxide or sodium hydroxide are normally used to convert the halohydrins to oxiranes. Other bases have also been employed to effect ring closure in the presence of labile functional groups such as a-ketols, e.g., potassium acetate in ethanol, potassium acetate in acetone or potassium carbonate in methanol.However, weaker bases can lead to solvolytic side reactions. Ring closure under neutral conditions employing potassiunT fluoride in dimethyl sulfoxide, dimethylformamide or A-methyl-pyrrolidone has been reported in the patent literature. 

It is to be noted that cupric acetate has been used to oxidize other systems, for example, a-ketols, phenols, thiols, and nitro-alkanes. 

Alkenes reacted with RuCyaq. CH3CO3H/CH3CN-CH2CI2 giving a-ketols thus cix-5-(methoxycarbonyl)-2-cyclohexenyl acetate (1) gave (2R, 35, 5R )-3-acetoxy-2-hydroxy-5-(methoxycarbonyl)-l-cyclohexanone (2) (Fig. 3.9, Table 3.2). Cortisone acetate was isolated in this way from epiandrosterone after a number of steps [179]. 

A. Mechanism of Reduction 1. Conjugated Enones and Ketol Acetates... 

The remarkable stability of the thiazole ring allowed synthetic manipulations of the thiazolyl ketol acetates, which extended considerably the scope of the above C-formylation method of furanoses and pyranoses. Instead of the reductive removal of the acetoxy group, the /V-glycosidation of either a- or p-anomer 73 with TMSN3 afforded stereoselectively the azido galactopyranoside 75 in 88% isolated yield (Scheme 22) [77]. The cleavage of the... 

The same type of reaction sequence was employed for the conversion of the thiazolyl ketol acetate 79 into the azido aldehyde 80 (Scheme 23) [77], a key precursor of the natural product hydantocidin 81 [78]. 

In a standard hydrolysis procedure the ketol acetate 1 was heated under reflux with 5% methanolic potassium hydroxide solution. The product (60-75% yield) was not the a-hydroxy ketone, however, but was shown to be the tetrahydronaphthol 2. 

While examples of intermolecular electrophilic additions to 7t-deficient heterocycles are reported less frequently than with -excessive heterocycles, intramolecular electrophilic cyclization strategies can be used to access some heterocycles of interest. In some cases, different reaction conditions can afford isomeric heterocycles as exemplified in the cyclization of 1,2-diaryl ketols with 2-amino-pyrazoles. With hydrogen chloride in the reaction media, pyrrolo[2,3-c]pyrazoles (170) are obtained, whereas imidazo[l,2-6]pyrazoles (171) were obtained in the absence of hydrogen chloride (Scheme 29) <84JHC945>. Cycloacylation of the a-(thiazolylthio)acetic acid (172) was accomplished with phosphorus oxychloride to give thiazole (173) (Equation (50)) <56AC(R)275>. 

In a second synthetic attempt, the diazo ketone 108 was converted to the a-ketol l-(3,4-dimethoxyphenyl)-4-hydroxy-3-pentanone via its acetate. The a-ketol was oxidized in situ with bismuth trioxide in the presence of ammonium acetate and 5-hydroxyvaleric anhydride (overall yield 0.2%). 

Acyloins have also been employed extensively as starting materials for the synthesis of imidazoles, usually in the presence of added aldehyde (or acid) and using ammoniacal cupric acetate to oxidize the acyloin to the corresponding a-dicarbonyl compound.24 Alicyclic and aromatic ketols and ketol acetates in an alcoholic solution of cupric acetate and ammonia undergo ring closure to the corresponding 2-imidazoyl ketones. Hence, benzoyl carbinol refluxed for 1 hour in... 

Ironically, until 1953, Nazarov incorrectly described the mechanism of the general transformation which now bears his name. In 1952, Braude and Coles were the first to suggest the intermediacy of car-bocations and demonstrated that the formation of 2-cyclopentenones actually proceeds via the a,a -divi-nyl ketones (equation 1). This fact together with further mechanistic clarification, has led to the specific definition of the Nazarov cyclization as the acid-catalyzed closure of divinyl ketones to 2-cyclopentenones. This process was already documented in 1903 by Vorliinder who isolated a ketol of unknown structure by treatment of dibenzylideneacetone with concentrated sulfuric acid and acetic acid followed by mild alkaline hydrolysis (equation 2). The correct structure of Vorliinder s ketol, finally proposed in 1955, ° arises from Nazarov cyclization followed by oxidation and isomerization. Other examples of acid-catalyzed cyclizations of divinyl ketones exist in the early literature. ... 

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