Reducing agents bulky

L-Menthol [2216-51-5] (75) and D-menthol [15356-70-4] have been used as chiral auxiharies in the synthesis of optically active mandehc acids. Reduction of (-)-menthol ben2oylfomiate (76) with a stericaHy bulky reducing agent, ie, sodium bis(2-methylethoxy)aluminum hydride (RED-Al), followed by saponification, yields (R)-mandelic acid (32) of 90% ee. 

The stereoselective reactions in Scheme 2.10 include one example that is completely stereoselective (entry 3), one that is highly stereoselective (entry 6), and others in which the stereoselectivity is modest to low (entries 1,2,4, 5, and 7). The addition of formic acid to norbomene (entry 3) produces only the exo ester. Reduction of 4-r-butylcyclohexanone (entry 6) is typical of the reduction of unhindered cyclohexanones in that the major diastereomer produced has an equatorial hydroxyl group. Certain other reducing agents, particularly sterically bulky ones, exhibit the opposite stereoselectivity and favor the formation of the diastereomer having an axial hydroxyl groi. The alkylation of 4-t-butylpiperidine with benzyl chloride (entry 7) provides only a slight excess of one diastereomer over the other. 

In further modifications of these norprogestins, reaction of norethindrone with acetic anhydride in the presence of p-toluene-sulfonic acid, followed by hydrolysis of the first-formed enol acetate, affords norethindrone acetate (41). This in turn affords, on reaction with excess cyclopentanol in the presence of phosphorus pentoxide, the 3-cyclopentyl enol ether (42) the progestational component of Riglovic . Reduction of norethindrone affords the 3,17-diol. The 33-hydroxy compound is the desired product since reactions at 3 do not show nearly the stereoselectivity of those at 17 by virtue of the relative lack of stereo-directing proximate substituents, the formation of the desired isomer is engendered by use of a bulky reducing agent, lithium aluminum-tri-t-butoxide. Acetylation of the 33,173-diol iffords ethynodiol diacetate, one of the most potent oral proves tins (44). ... 

Cathodic reduction of bicyclic gem-dibromocyclopropane in the presence of chlorotrimethylsilane provides the exo-silylated isomer selectively. With a sacrificial Mg anode the current efficiency can be increased by sonication as the anode acts additionally as a chemical reducing agent [358]. The 2e reduction of (5 )-(+)-l-bromo-l-carboxy-2,2-diphenylcyclopropane showed that the stereoselectivity at a Hg cathode was strongly determined by the supporting electrolyte cation. With NH4+, a preferential retention of configuration was observed, which increased with a more negative reduction potential. By contrast, a R4N+ cation gives rise to a major inversion, which increases with the bulkiness... 

A good diastereocontrol is obtained for the debromination of Reaction (4.14) and it is attributed to the bulky reducing agent, which approaches the radical intermediate from the less hindered face anti to the two vicinal substituents [35]. 

In ketones having a chiral cluster next to the carbonyl carbon reduction with lithium aluminum hydride gave one of the two possible diastereomers, erythro or threo, in larger proportions. The outcome of the reduction is determined by the approach of the reducing agent from the least hindered side (steric control of asymmetric induction) [828]. With lithium aluminum hydride as much as 80% of one diasteromer was obtained. This ratio is higher with more bulky reducing hydrides [837]. 

In the presence of excess monoalkylamine, carbonyl compounds in aqueous solution are in equilibrium with the corresponding imine. In most cases these imines cannot be isolated but they are reduced at a less negative potential than the carbonyl compound. Selective reduction of such equilibrium mixtures is a useful route to alkylamines from ketones in yields of 70-90%. The process fails with hindered ketones such as camphor and with bulky amines such as fert.-butyl amine. Overall the reaction has advantages of lower costs and simpler work-up compared to the use of cyanoborohydride reducing agents. In the electrochemical reaction, protonation of carbanion intermediates occurs from the more hindered side and where two isomeric products are fomied, the least hindered amine predominates [193]. 

Oral progestational activity is retained when the ketone at the 3 position is reduced to an alcohol. Treatment of ethindrone (13-6) with the bulky reducing agent lithium aluminum-tri-ferf-butoxy hydride leads to attack from the more open a face and the formation of the 3 3 hydroxy derivative (14-1). Acylation under forcing conditions affords the 3,17-diacetate derivative, ethynodiol diacetate (14-2) [17]. 

Sterically bulky reducing agents, e.g. lithium tri-t-butoxyaluminium hydride, can selectively reduce acid chlorides to aldehydes at low temperatures (—78 °C). Lithium tri-t-butoxyaluminium hydride, LiAlH(0-t-Bu)3, has three electronegative oxygen atoms bonded to aluminium, which makes this reagent less nucleophilic than LiAlH4. 

Sterically bulky reducing agents, e.g. diisohutylaluminium hydride (DIBAH), can selectively reduce esters to aldehydes. The reaction is carried out at low temperatures (—78 °C) in toluene. Diisohutylaluminium hydride has two bulky isobutyl groups, which make this reagent less reactive than LiAlH4. 

In the attack by sterically undemanding reducing agents, this stereoelectronic effect is fully effective (for a completely different but perfectly diastereoselective reduction of 4-fert-butylcyclohexanone to the equatorial alcohol, see Figure 14.46). However, in the attack of such a bulky hydride donor as L-Selectride the stereoelectronic effect is overcompensated by the opposing steric effect discussed above. 

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