Hydride agents stereoselectivity

The ability of coenzyme NAD(P)+ (57, R = sugar) and its mimics to accept and deliver hydride ion stereoselectively via 1,4-dihydropyridine intermediates has spurred much interest. Much work involving NADIP)" " and its simpler derivatives (56 R = PhCH2, BNAH R = C12H25, DNAH) as chiral reducing agents has been reported. ... 

A noteworthy development is the use of KH for complexing alkylboranes and alkoxyboranes to form various boron hydrides used as reducing agents in the pharmaceutical industry. Potassium tri-j -butylborohydride [54575-50-7] KB(CH(CH2)C2H )2H, and potassium trisiamylborohydride [67966-25-0] KB(CH(CH2)CH(CH2)2)3H, are usefiil for the stereoselective reduction of ketones (66) and for the conjugate reduction and alkylation of a,P-unsaturated ketones (67). 

Although estrone and estradiol (26) have both been isolated from human urine, it has recently been shown that it is the latter that is the active compound that binds to the so-called estrogen receptor protein. Reduction of estrone with any of a large number of reducing agents (for example, any of the complex metal hydrides) leads cleanly to estradiol. This high degree of stereoselectivity to afford the product of attack at the alpha side of the molecule is characteristic of many reactions of steroids. 

As all four of the hydrides can eventually be transferred, there are actually several distinct reducing agents functioning during the course of the reaction.60 Although this somewhat complicates interpretation of rates and stereoselectivity, it does not detract from the synthetic utility of these reagents. Reduction with NaBH4 is usually done in aqueous or alcoholic solution and the alkoxyboranes formed as intermediates are rapidly solvolyzed. 

Alkylborohydrides are also used as reducing agents. These compounds have greater steric demands than the borohydride ion and therefore are more stereoselective in situations in which steric factors come into play.72 These compounds are prepared by reaction of trialkylboranes with lithium, sodium, or potassium hydride.73 Several of the compounds are available commercially under the trade name Selectrides .74... 

Although sodium borohydride appears to be the most popular reducing agent, a significantly better endo selectivity was achieved in the reduction of bicyclo[3.2.0]hept-2-en-6-ones using lithium tri-fer -butoxyaluminum hydride instead, e.g. formation of 3.251 In another study,99 lithium tri-sec-butylborohydride was found to reduce (la,4a,5a)-4-benzy)oxycarbonyl-2-oxabi-cyclo[3.2.0]heptan-6-one to (la,4oc,5a,6/i)-4-benzyloxycarbonyl-2-oxabicyclo[3.2.0]heptan-6-ol (4) with complete stereoselectivity. 

Reduction of ketones. Reduction of ketones with metals in an alcohol is one of the earliest methods for effecting reduction of ketones, and is still useful since it can proceed with stereoselectivity opposite to that obtained with metal hydrides.1 An example is the reduction of the 3a-hydroxy-7-ketocholanic acid 1 to the diols 2 and 3. The former, ursodesoxycholic acid, a rare bile acid found in bear bile, is used in medicine for dissolution of gallstones. The stereochemistry is strongly dependent on the nature of the reducing agent (equation I).2 Sodium dithionite and sodium borohydride reductions result mainly in the 7a-alcohol, whereas reductions with sodium or potassium in an alcohol favor reduction to the 7p-alcohol. More recently3 reduction of 1 to 2 and 3 in the ratio 96 4 has been achieved with K, Rb, and Cs in f-amyl alcohol. Almost the same stereoselectivity can be obtained by addition of potassium, rubidium, or cesium salts to reductions of sodium in t-amyl alcohol. This cation effect has not been observed previously. 

Asymmetric reduction of a,/ -unsaturated carbonyl compounds using chiral complexes (Section 5.4.1, p. 521) could feasibly lead to optically active allylic alcohols. Other reducing agents which have some merit of regioselectivity, but not stereoselectivity, are sodium cyanoborohydride,244 and sodium boro-hydride in the presence of lanthanide salts.245... 

Sml2 reduces aldehydes and ketones to the corresponding alcohols. As there are numerous hydride reducing agents for the reduction of aldehydes and ketones, this functional group transformation has not been used widely. In some cases, however, Sml2 can display useful reactivity, stereoselectivity and chemoselec-tivity that more conventional reagents cannot achieve. 

This new reagent is an active reducing agent and reduces cyclic and bicyclic ketones with supcrstcreoselectivity. Thus reduction of 2-mcthylcyclohexanone (I) gives rw-2-methylcyclohexanol in 99.3 (, purity. Note that reduction with lithium trimethoxy-aluminum hydride alone yields (2) in 69% yield. Thus increasing the size of the alkyl substituents on boron enhances the stereoselectivity of the borohydride anion. Even... 

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