Birch reduction acetals

Selective reduction of a benzene ring (W. Grimme, 1970) or a C C double bond (J.E. Cole, 1962) in the presence of protected carbonyl groups (acetals or enol ethers) has been achieved by Birch reduction. Selective reduction of the C—C double bond of an a,ft-unsaturated ketone in the presence of a benzene ring is also possible in aprotic solution, because the benzene ring is redueed only very slowly in the absence of a proton donor (D. Caine, 1976). 

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 crude ketal from the Birch reduction is dissolved in a mixture of 700 ml ethyl acetate, 1260 ml absolute ethanol and 31.5 ml water. To this solution is added 198 ml of 0.01 Mp-toluenesulfonic acid in absolute ethanol. (Methanol cannot be substituted for the ethanol nor can denatured ethanol containing methanol be used. In the presence of methanol, the diethyl ketal forms the mixed methyl ethyl ketal at C-17 and this mixed ketal hydrolyzes at a much slower rate than does the diethyl ketal.) The mixture is stirred at room temperature under nitrogen for 10 min and 56 ml of 10% potassium bicarbonate solution is added to neutralize the toluenesulfonic acid. The organic solvents are removed in a rotary vacuum evaporator and water is added as the organic solvents distill. When all of the organic solvents have been distilled, the granular precipitate of 1,4-dihydroestrone 3- methyl ether is collected on a filter and washed well with cold water. The solid is sucked dry and is dissolved in 800 ml of methyl ethyl ketone. To this solution is added 1600 ml of 1 1 methanol-water mixture and the resulting mixture is cooled in an ice bath for 1 hr. The solid is collected, rinsed with cold methanol-water (1 1), air-dried, and finally dried in a vacuum oven at 60° yield, 71.5 g (81 % based on estrone methyl ether actually carried into the Birch reduction as the ketal) mp 139-141°, reported mp 141-141.5°. The material has an enol ether assay of 99%, a residual aromatics content of 0.6% and a 19-norandrost-5(10)-ene-3,17-dione content of 0.5% (from hydrolysis of the 3-enol ether). It contains less than 0.1 % of 17-ol and only a trace of ketal formed by addition of ethanol to the 3-enol ether. 

When double bonds are reduced by lithium in ammonia or amines, the mechanism is similar to that of the Birch reduction (15-14). ° The reduction with trifluoro-acetic acid and EtsSiH has an ionic mechanism, with H coming in from the acid and H from the silane. In accord with this mechanism, the reaction can be applied only to those alkenes that when protonated can form a tertiary carbocation or one stabilized in some other way (e.g., by a OR substitution). It has been shown, by the detection of CIDNP, that reduction of a-methylstyrene by hydridopenta-carbonylmanganese(I) HMn(CO)5 involves free-radical addition. ... 

Birch reduction-alkylation of 5 with 2-bromoethyl acetate was carried out with complete facial selectivity to give 57. This tetrafunctional intermediate was converted to the bicyclic iodolactone 58 ( > 99% ee) from which the radical cyclization substrate 59 was prepared. The key radical cyclization occurred with complete regio- and facial-selectivity and subsequent stereoselective reduction of the resulting tertiary radical gave 60 with the required trans BC ring fusion.The allylic alcohol rmit of (+)-lycorine was obtained by a photochemical radical decarboxylation, 62 63. 

Birch reduction of the norgetrel intermediate 5 oil owed by hydrolysis of the enol ether gives the enone oxidation of the alcohol at 17 leads to dione 7. Fermentation of that intermediate in the presence of the mold PeniciIlium raistricky serves to introduce a hydroxyl group at the 15 position W. Acetal formation with neopentyl glycol affords the protected ketone which consists of a mixture of the A and A isomers (2 ) hindrance at position 17 ensures selective reaction of the 3 ketone. The... 

The superfluous bromine is then removed by reduction with zinc in acetic acid (26-1). The 20 ketone is next protected against the strongly reducing conditions in the subsequent step by conversion to the ethylene glycol acetal (26-2). Birch reduction with lithium in liquid ammonia in the presence of ethanol proceeds as usual to the dihydrobenzene (26-3). Treatment of this last product with mineral acid serves to hydrolyze both the enol ether at the 3 position and the acetal at the... 

DL-Dihydrostreptose and its ribo isomer were similarly obtained. Birch reduction of 2-methyl-3-furoic acid, followed by addition of methanol, bromination, and dehydrobromination, gave 402 as a mixture of the isomers. Hydroxylation of 402 with osmium tetraoxide-so-dium chlorate, and subsequent treatment with acetone-sulfuric acid afforded three isomeric acetals (403-405). The structures of these compounds were assigned on the basis of their H-n.m.r. spectra. In addition, the relationship between 403 and 404 was established by hydrolysis and reglycosidation. The methyl esters 403-405 were quantitatively reduced to the corresponding alcohols. The mixture of alcohols obtained from 403 and 404 was converted into crystalline 5-deoxy-3-C-(hydroxymethyl)-l,2-0-isopropylidene-a-DL-ribofuran-ose (406), which was compared directly with a sample prepared from D-xylose. Methyl 5-deox y-3-C-(hydroxy methyl)-2,3-O-isopropy lidene-/3-DL-lyxofuranoside (407), obtained by reduction of 405 with lithium aluminum hydride, was hydrolyzed with dilute hydrochloric acid, to give a,/3-DL-dihydrostreptose.2,ifi... 

Polyketides.1 Polyketides are useful as precursors to acetate-derived natural products, but they are unstable owing to a marked tendency to undergo internal condensation. A new synthesis involves ozonolysis of products of Birch reduction. An example is the synthesis of the polyketide 3 from the aromatic system 1. 

The two free hydroxy groups are First protected with acetic anhydride. In a second step the acetyl group is reductively cleaved by a Birch reduction with lithium in liquid ammonia.19 Lithium dissolves in the ammonia with the formation of solvated electrons. Stepwise electron transfer to the aromatic species (a SET process) leads first to a radical anion, which stabilizes itself as benzylic radical 38 with loss of the oxygen substituent. A second SET process generates a benzylic anion, which is neutralized with ammonium chloride acting as a proton source (see Chapter 12). 

The methods which are available for the protection of the aromatic carbonyl group are similar to those for the aliphatic and alicyclic analogues (Section 5.8.8, p. 623). It should be noted however, that when a cyclic acetal is used as the protecting group, a Birch reduction (Section 7.5) on the protected compound usually results in hydrogenolysis of the protecting acetal. 

An important advance was made when it was observed that photolysis of the (3-enamido ketone 165, which was readily available from the indoline 163 by Birch reduction followed by N-aryloylation, delivered the lactam 168 as the only photoproduct (Scheme 17) (125). Reduction of 168 with LiAlH4 gave ( )-a-anhydrodihydrocaranine (143), which was then converted to ( )--y-lycorane (93) on hydrogenation over Adams catalyst in acetic acid. In a similar fashion, irradiation of the bromo or iodo enaminones 166 (Z = Br, I), which were obtained by alkylation of the intermediate imino ether formed on Birch reduction of 163, afforded a mixture (approximately 3 2) of the lactam 168 together with the photoreduction product 167 (126). 

The synthesis of prostaglandin PGB1 as described by Morin et al. (Eli Lily Research Labs.), starts with 7-(2-methoxyphenyl)heptanoic acid 142 which is converted into 143 through Birch reduction, esterification and acetalization. Ozone cleavage of 143 and cyclization of the resulting dialdehyde affords cyclopentene carbaldehyde 144 which was subjected to ( )-selective Wittig olefination with... 

Catalytic hydrogenation offers the mildest and one of the most efficient means for cleaving benzylidene acetals to toluene and the corresponding dioL The reaction is especially useful for reactions on a small scale performed on frail substrates as exemplified by the final step in a short synthesis of Oteandolide by Evans and co-workers [Scheme 3.54J.88 Birch reduction involving sodium or lithium in liquid ammonia in the presence of a proton source such as ethanol accomplishes the clean scission of a benzylidene acetal but few functional groups are compatible with such powerfully reducing conditions and the reaction is seldom used.89... 

Kinoshita and coworkers have found that, in contrast to the result obtained using Pr OH (equation 14), in the presence of nucleophilic alcohols (MeOH, EtOH) the Birch reduction of 3-furoic acid leads to the corresponding acetal (equation 15). ... 

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