Metal enolates reduction

Catalytic hydrogenation of the 14—15 double bond from the face opposite to the C18 substituent yields (196). Compound (196) contains the natural steroid stereochemistry around the D-ring. A metal-ammonia reduction of (196) forms the most stable product (197) thermodynamically. When R is equal to methyl, this process comprises an efficient total synthesis of estradiol methyl ester. Birch reduction of the A-ring of (197) followed by acid hydrolysis of the resultant enol ether allows access into the 19-norsteroids (198) (204). 

An isolated acetoxyl function would be expected to be converted into the alkoxide of the corresponding steroidal alcohol in the course of a metal-ammonia reduction. Curiously, this conversion is not complete, even in the presence of excess metal. When a completely deacetylated product is desired, the crude reduction product is commonly hydrolyzed with alkali. This incomplete reduction of an acetoxyl function does not appear to interfere with a desired reduction elsewhere in a molecule, but the amount of metal to be consumed by the ester must be known in order to calculate the quantity of reducing agent to be used. In several cases, an isolated acetoxyl group appears to consume approximately 2 g-atoms of lithium, even though a portion of the acetate remains unreduced. Presumably, the unchanged acetate escapes reduction because of precipitation of the steroid from solution or because of conversion of the acetate function to its lithium enolate by lithium amide. 

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-... 

Conjugate reduction by the transition metal-hydride (TM - H) accompanied by transition metal enolate formation... 

In the general context of donor/acceptor formulation, the carbonyl derivatives (especially ketones) are utilized as electron acceptors in a wide variety of reactions such as additions with Grignard reagents, alkyl metals, enolates (aldol condensation), hydroxide (Cannizzaro reaction), alkoxides (Meerwein-Pondorff-Verley reduction), thiolates, phenolates, etc. reduction to alcohols with lithium aluminum hydride, sodium borohydride, trialkyltin hydrides, etc. and cyloadditions with electron-rich olefins (Paterno-Buchi reaction), acetylenes, and dienes.46... 

Further evidence for the intermediacy of a chiral metal enolate in the aldol process was provided in a subsequent publication (255). The authors found that this reaction could be equally well catalyzed by a Cu(I) complex (generated from the phosphine) and TB AT. Further, Tol-BINAPCuOf-Bu is also a competent catalyst for this reaction, underscoring the ability of the copper alkoxide to mediate desily-lation of the dienolsilane. The authors suggest that the dienolsilane effects the reduction of Cu(II) to Cu(I), although in light of the work of Lectka and co-workers (249) in this area, it seems equally likely that the phosphine mediates this reduction prior to introduction of the dienolsilane. Nevertheless, the intermediacy of a metal bound enolate seems assured. 

Reviews on stoichiometric asymmetric syntheses M. M. Midland, Reductions with Chiral Boron Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 2, Academic Press, New York, 1983 E. R. Grandbois, S. I. Howard, and J. D. Morrison, Reductions with Chiral Modifications of Lithium Aluminum Hydride, in J. D. Morrison, ed.. Asymmetric Synthesis, Vol. 2, Chap. 3, Academic Press, New York, 1983 Y. Inouye, J. Oda, and N. Baba, Reductions with Chiral Dihydropyridine Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 4, Academic Press, New York, 1983 T. Oishi and T. Nakata, Acc. Chem. Res., 17, 338 (1984) G. Solladie, Addition of Chiral Nucleophiles to Aldehydes and Ketones, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 6, Academic Press, New York, 1983 D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 1, Academic Press, New York, 1984. C. H. Heathcock, The Aldol Addition Reaction, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 2, Academic Press, New York, 1984 K. A. Lutomski and A. I. Meyers, Asymmetric Synthesis via Chiral Oxazolines, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 

As the synthetic value38 of regiospecifically generated enolates became apparent in the 1960s, new methods were discovered and developed to prepare them. Dissolving metal conjugate reduction of a,3-... 

Sodium borohydride (160) was found to serve as a hydrogen donor in the asymmetric reduction of the presence of an a,pi-unsaturated ester or amide 162 catalyzed by a cobalt-Semicorrin 161 complex, which gave the corresponding saturated carbonyl compound 163 with 94-97% ee [93]. The [i-hydrogen in the products was confirmed to come from sodium borohydride, indicating the formation of a metal enolate intermediate via conjugate addition of cobalt-hydride species (Scheme 2.17). 

Metal-ammonia reduction of ketones. Swiss chemists have reported a detailed study of the mechanism of this reaction, using for the most part (-l-)- 3,3-D2] camphor as substrate. The conclusions drawn have some useful practical applications. The choice of metal (Li, Na, or K) has little effect on the course of reduction to the thermodynamically more stable diastereoisomeric alcohol. The most important conclusion is that pinacol reduction can be suppressed completely in Na-NH3 reductions by use of ammonium chloride as the proton source, a finding first reported by Murphy and Sullivan.2 This salt also partially suppresses pinacol formation in Li-NHj reductions. It also suppresses reduction of enolates, and thus should decrease racemization in reduction of chiral ketones. 

Three main types of redox reactions of keto compounds leading to the formation of metal enolates have been reported (i) two-electron reduction of diketones or a,(f-unsaturated ketones or esters (equation 1), (ii) oxidative addition reactions (equation 2) and (iii) threefold deprotonation of diketoamines followed by a two-electron oxidation of the trianion by the metal (equation 3). 

Generally, the conditions employed in the work-up of metal-ammonia reductions leads to products having the more stable configuration at the a-carbon atom, but products having the less stable configuration at this center have been obtained by kinetic protonation of enolate intermediates.A more detailed discussion of stereochemistry in metal-ammonia reduction of a, -unsaturated carbonyl compounds is given in ref 10. 

Alcohols, such as methanol and ethanol, lead to the sole formation of saturated alcohols from unsaturated ketones when the former are present in excess during the reduction. Mixtures of ketones and alcohols are generally formed when 1 equiv. of these proton donors is employed. These alcohols have an acidity comparable to that of saturated ketones, and when they are present, an equilibrium can be established between the initially formed metal enolate and the saturated ketone. The latter is then reduced to the saturated alcohol. Such reductions generally do not occur to a very significant extent when 1 equiv. of r-butyl alcohoP or some less acidic proton donor, such as triphenylcarbinol, is employed. The acidity of the ketone involved, as well as the solubility of the metal enolate in the reaction medium, are important in determining whether alcohols are formed. 

Even though the reaction conditions may lead to formation of the metal enolate in high yield, further reduction may occur during the quenching step of the reaction. Alcohols such as methanol and ethanol convert metal enolates to saturated ketones much faster than they react with metals in ammonia, and quenching of reduction mixtures with these alcohols will usually lead to partial or complete conversion to alcoholic product rather than to the saturated ketone. Rapid addition of excess solid ammonium chloride is the commonly employed quench procedure if ketonic products are desired,but other reagents that destroy solvated electrons before neutralization may be employed, such as sodium ben-zoate, iron(III) nitrate, - sodium nitrite, bromobenzene, sodium bromate, 1,2-dibromoethane and acetone. 

Metal enolates as protecting groups for ketones. Barton et al.1 effected selective reduction of the 11-keto function of prednisone BMD (1) by conversion of the 3-keto group into the metal enolate (2) by trityllithium. Reduction of the 11-keto group in situ... 

---