Enones, 367. borohydrides

Conjugate addition of methyl magnesium iodide in the presence of cuprous chloride to the enone (91) leads to the la-methyl product mesterolone (92) Although this is the thermodynamically unfavored axially disposed product, no possibility for isomerization exists in this case, since the ketone is once removed from this center. In an interesting synthesis of an oxa steroid, the enone (91) is first oxidized with lead tetraacetate the carbon at the 2 position is lost, affording the acid aldehyde. Reduction of this intermediate, also shown in the lactol form, with sodium borohydride affords the steroid lactone oxandrolone... 

All that remains before the final destination is reached is the introduction of the C-l3 oxygen and attachment of the side chain. A simple oxidation of compound 4 with pyridinium chlorochro-mate (PCC) provides the desired A-ring enone in 75 % yield via a regioselective allylic oxidation. Sodium borohydride reduction of the latter compound then leads to the desired 13a-hydroxy compound 2 (83% yield). Sequential treatment of 2 with sodium bis(trimethylsilyl)amide and /(-lactam 3 according to the Ojima-Holton method36 provides taxol bis(triethylsilyl ether) (86 % yield, based on 89% conversion) from which taxol (1) can be liberated, in 80 % yield, by exposure to HF pyridine in THF at room temperature. Thus the total synthesis of (-)-taxol (1) was accomplished. 

Chemo- and stereoselective reduction of (56) to (55) is achieved In highest yield by sodium borohydride in ethanol. The isolated ketone is reduced more rapidly than the enone and (55) is the equatorial alcohol. Protection moves the double bond out of conjugation and even the distant OH group in (54) successfully controls the stereochemistry of the Simmons-Smith reaction. No cyclopropanation occurred unless the OH group was there. Synthesis ... 

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). 

Reactions of highly electron-rich organometalate salts (organocuprates, orga-noborates, Grignard reagents, etc.) and metal hydrides (trialkyltin hydride, triethylsilane, borohydrides, etc.) with cyano-substituted olefins, enones, ketones, carbocations, pyridinium cations, etc. are conventionally formulated as nucleophilic addition reactions. We illustrate the utility of donor/acceptor association and electron-transfer below. 

Microemulsions are potentially useful reaction media because of their solubilizing ability (Mackay, 1981). Reductions of ketones and enones by borohydride go readily in microemulsions of CTABr, hexane and 1-butanol, and there is more 1,4-reduction than in 2-propanol (Jaeger et ah, 1984). 

Reduction of the azepinone ring in 63 can be accomplished selectively. Thus, hydrogenation results in selective 1,4-reduction of the enone moiety and furnishes the corresponding saturated ketone 65. Selective enone 1,2-reduction can be performed with n-BuLi-BHs to produce allylic alcohol 64. Reduction with borohydride is non-selective and gives saturated hydroxyl compound 66 (Scheme 13, Section 2.1.1.5 (2000T9351)). 

This procedure describes the preparation of 3-nitropropanai, 1, employing the rarely encountered 1,4-addition of ambident nitrite ion with its "softer N-atom,2 and further transformations of 1, as reported earlier.3 A similar preparation of 3-nitrobutanal from crotonaldehyde (3-butenal) is known,4 as well as analogous additions to a, 3-enones.2 The reduction of 1 to the alcohol 2, originally carried out with borane-dimethyl sulfide (BMS),3 is now more conveniently and economically done with sodium borohydride. The acetalization of 1 to yield the dimethyl acetal 3 is based on our earlier report.3... 

The synthesis of ( )-D-homotestosterone and ( )-progesterone has been accomplished via a now classical procedure involving the use of an isoxazole as an annelating agent (67JA5464). The enolate (424), prepared from 10-methyl-A1,9-octalin-2,5-dione, was alkylated by the 4-chloromethylisoxazole (425). The octalindione (426) was treated sequentially with one equivalent of sodium borohydride, hydrogenated, hydrogenolyzed and refluxed with sodium methoxide and then with sodium hydroxide to afford the crystalline enone (427). 

Compound 403 is readily reduced with sodium borohydride at -78°C and yields the monoalcohol 405 (115). It also reacts with potassium t -butyl hydroperoxide at -20°C and gives the cis-enone-perester carbonate 406 in high yield (116). This last transformation can be explained by retro-Claisen fragmentation of intermediate 407 followed by the elimination of methoxide ion from 408. It is also possible that 407 undergoes a direct stereoelectronically controlled Grob type fragmentation to compound 406. 

In order to transform the spirocyclic enone 445 to ( )-elwesine (439) and ( )-epielwesine (449), it was treated with boron trifluoride and dimethylsulfide to cleave the Al-carbobenzyloxy protecting group, and cyclization of the resulting amino enone spontaneously ensued to produce ( )-dihydrooxocrinine (447). Reduction of carbonyl function of 447 with sodium borohydride afforded ( )-3-epielwesine (449), which was converted to ( )-elwesine (439) by inversion of the hydroxyl function at C-3 via a Mitsunobu protocol using diethyl azodicarboxylate, triphenylphosphine, and formic acid. Attempted reduction of 447 directly to 439 by a Meerwein-Ponndorf-Verley reduction or with bulky hydride reagents gave only mixtures of 449 and 439 that were difficult to separate. 

The selective 1,2-reduction of enones with sodium borohydride is achieved in combination with CeCl3. 

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. 

Selective reductions.2 Zinc borohydride in DME can reduce saturated ketones and a,p-enals at —15° without effect on a,P-enones or saturated aldehydes. 

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 Michael addition of malonates to cyclic enones, catalyzed by chiral Ru( 6-arcnc)(p-lolucncsulfonyl-1,2-diaminc), has been performed to afford the adduct with excellent enantiomeric excess [91,92]. A related catalyst was designed to perform sequentially the Michael addition to cyclic enone and the enantioselective hydrogenation of the ketone. Thus, the chiral ruthenium catalyst B containing trans hydride and borohydride ligands was able to enan-tioselectively (96% ee) promote the Michael addition of malonate to cyclo-hexenone. Further in situ catalytic hydrogenation (400 psi H2) was performed and led to excellent diastereoselectivity trans/cis 30/1 [93] (Scheme 43). 

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