Lithium borohydride enones

A convenient method for the specific introduction of 2H or 3h (or both) into a molecule is by ketone reduction with labeled metal hydride. Beale and MacMillan (10) have utilized this method for the preparation of GAs labeled at the 1, 2 or 3 positions from GA3 or GA7 (Figure 12). One point of interest is the lithium borohydride reduction of the enone formed by manganese dioxide oxidation of GA3 or GA7. When the reaction is carried out in anhydrous tetrahydrofuran it proceeds in two steps. Initially the lithium enolate is formed which incorporates a proton at carbon-2 from the acid used in the work-up, forming the 3 ketone. This ketone is reduced to the 3 -alcohol by the borohydride which is decomposed more slowly than is the lithium enolate. Thus it is possible to introduce two different labels in a single reaction. 

Enantioselective reduction of an a, -enone. One of the final steps in a synthesis of palytoxin, a toxin of marine soft corals containing 115 carbon atoms and 60 chiral centers, involves, in addition to the usual deprotections, enantioselective reduction of an enone to an allylic alcohol. A mixture (1 1) is obtained with borohydrides, but lithium borohydride combined with EuC13 provides an 8 1 mixture, with the desired isomer being favored. 

The reaction of the aldehyde 174, prepared from D-glucose diethyl dithio-acetal by way of compounds 172 and 173, with lithium dimethyl methyl-phosphonate gave the adduct 175. Conversion of 175 into compound 176, followed by oxidation with dimethyl sulfoxide-oxalyl chloride, provided diketone 177. Cyclization of 177 with ethyldiisopropylamine gave the enone 178, which furnished compounds 179 and 180 on sodium borohydride reduction. 0-Desilylation, catalytic hydrogenation, 0-debenzyIation, and acetylation converted 179 into the pentaacetate 93 and 5a-carba-a-L-ido-pyranose pentaacetate (181). 

Reductions. This hydride is a strong reducing agent comparable to other lithium trialkylhydrides. It is superior to DIBAH for selective 1,2-reduction of enones. Reduction of ketones, esters, acid chlorides, and anhydrides proceeds at -78°. However, ketones can be reduced selectively in the presence of an ester. Esters are reduced to a mixture of an alcohol and an aldehyde. Complete reduction to an alcohol can be effected by reduction at -78° with 2 equiv. of 1 and then with excess sodium borohydride. Tertiary amides are reduced by 1 equiv. of the reagent to aldehydes in generally high yield. Selective reduction of primary halides in the presence of secondary halides is possible. 

Such a phenol keto-tautomer equivalent strategy was used for conjugate reduction of cyclic enones (equation 5). The quinone monoketals 9 and para-quinol ethers 10 were used as precursors to keto-tautomer equivalents of substituted phenols, namely enones 11, which were prepared by action of bis(2,6-di-fert-butyM-methylphenoxy)methylaluminium (MAD), followed by addition of lithium tri-iec-butyl borohydride (L-Selectride). The enones 11 obtained are reasonably stable at a freezer temperature without aromatization. ... 

Successful application of the Mitsonobu epimerization procedure to an eudesmanic alcohol 44 to bring about inversion of configuration at C(l) is the crucial step in the Harapanhalli synthesis of erivanin (50) from santonin (Scheme 7) [16]. Reduction of enone 43, prepared from santonin in 10 steps, with sodium borohydride furnished the )8-alcohol 44 as the sole product. This product results from the approach of the hydride anion from the less hindered Of-face of the molecule. The chemical modification of the C(3)-C(4) double bond to give a 3a-hydroxy-A4-i4 rnoiety was accomplished via the epoxide 46 and its rearrangement in a basic medium. Epoxidation of 44 with MCPA yielded only one product without any directing effect exerted by the homoallylic alcohol. Treatment of 46 with lithium diisopropylamide (EDA) afforded l-e/>/-erivanin (47). For the synthesis of erivanin (50), epimerization at C(l) prior to the A -modification sequence was required. Attempts to epimerize this carbon atom in 44 by acetolysis of the tosyl derivative 45 were unsuccessful as they led to eliminated product 13 (Scheme 3). 

Trialkyl borohydrides such as Lithium Tri-s-butylborohydride and Potassium Tri-s-butylborohydride are superior reagents for the chemoselective 1,4-reduction of enones. On the other hand, 1,2-reduction can be obtained by using NaBHj in the mixed solvent MeOH-THF (1 9), or with NaBHj in combination with CeCH or other lanthanide salts. ... 

The simplest products are formed when Nu=H, but this poses a problem of regioselectivity in the nucleophilic attack step a nucleophilic hydride equivalent that selectively undergoes conjugate addition to the enone is required. This is usually achieved with extremely bulky hydride reagents such as lithium or potassium tri(sec-butyl)borohydride (often known by the trade names of L- or K-Selectride, respectively). In this example, K-Selectride reduces the enone to an enolate that is alkylated by methyl iodide to give a single regioisomer. 

The synthesis of lupeol starts with the cyclization of 6-methoxy-p-methyl-a-tetralone 28 with 4-7V 7V -dimethylamino-2-butanone methiodide in the presence of potassium /-butanolate to l,9,10,10a-tetrahydro-7-methoxy-3(2//)-phenanthrone 27. Reduction with sodium borohydride and subsequent hydrogenation of the enone CC double bond in the presence of palladium and strontium carbonate as slightly deactivated catalyst gives the oetahydrophenanthrol 26. Partial reduction of the benzenoid ring to the enone is aceomplished by lithium in liquid ammonia. The enone is derivatized to the benzoate 25 in order to protect the hydroxy group prior to the subsequent synthetic steps. 

Other Anhydrides.—The enones (42) and (43) have been prepared by oxidation of the corresponding allylic alcohols with manganese dioxide. Whereas the oxiran derivative (44) afforded the allylic alcohol (45) on treatment with butyl-lithium, the /yxo-isomer (46) gave the 2-substituted glycal (47). Enols with equatorially oriented hydroxy-groups were obtained when the enones (42) and (43) were reduced with sodium borohydride. 

In 1999 Holmes and coworkers reported preliminary results on the enantioselective synthesis of the Overman indohzidinone (—)-2369 by a route involving a diastereoselective intramolecular [3 + 2] cycloaddition of nitrones such as 2374. Full experimental details as well as the conversion of 2369 into (+)-aUopumihotoxin 323B (1714) were subsequently published. In this apphcation (Scheme 303), base-induced aldol reaction between 2369 and aldehyde (—)-2375, prepared in eight steps from (S)-3-bromo-2-methylpropanol, produced a mixture of diastereomers (—)-2376. Base-promoted dehydration of the trifluoroacetates gave rise to a single enone (- -)-2377, which was reduced stereoselectively with tetramethyl-ammonium tris(acetoxy)borohydride iyide supra) followed by mild deprotection of the benzyloxymethyl ether with lithium di-tefi-butylbiphenyl (LiDBB) to give the target alkaloid 1714. 

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