Stereoselectivity of hydride reducing agents

Table 2.4. Stereoselectivity of Hydride Reducing Agents toward Cyclic...

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. 

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. 

Diisobutylaluminium hydride (DIBAL-H) is a bulky hydride reducing agent that is very useful for the stereoselective reduction of prochiral ketones and reductions at... 

Lithium tri-fert-Butoxyaluminohydride is a bulky chemo- and stereoselective hydride reducing agent. Aldehydes are reduced chemoselectively in the presence of ketones and esters at low temperature. Ethers acetals, epoxides, chlorides, bromides, and nitro compounds are unaffected by this reagent. Reviews (a) Seyden-Penne, J. Reductions by the Alumino- and Borohydrides in Organic Synthesis Wiley-VCH NewYork, 1997, 2" edition, (b) Malek, J. Org. React. 1985, 34, 1-317. 

The reduction step was stereoselective with either Li A1H4 or LiBH4. In both cases, the hydride reducing agent first cleaved the acetate ester and then an intermediate ate complex transferred hydride ion intramolecularly in a cis fashion 235 to the unsaturated nitrile to give the correct stereochemistry 236. Finally cyclisation of the alcohol onto the nitrile to give the trans fused lactone 227 occurred in much the same way that nitriles are converted directly to ethyl esters with ethanol in acid solution. The overall yield of 227 was a respectable 40%. 

Previously, tin-ketyl radicals have been added to alkenes only in an intramolecular fashion. [9] In recent publications, however, pinacols and amino alcohols have been prepared by cyclisation of dicarbonyl compounds [10] or keto-oximes [11] with tributyltin hydride. Cyclisation of 1,5-ketoaldehydes 1 and 1,5-dialdehydes with tributyltin hydride yields cw-diols 2 with excellent stereoselectivities, whereas the keto-oxime 4 with four benzyloxy-substituents affords a 58 42 cis trans) mixture. The tran -product was transformed in two more steps to the potent glycosidase inhibitor 1-deoxynojirimycin (6). [lib] The reversibility of both the addition of the tributyltin-radical to the carbonyl group and the intramolecular radical C-C bond formation is believed to be responsible for the high selectivity in the formation of 2. In the cyclisation of 1,5-pentanedial the unhydrolyzed coupling product 3 could be isolated, therefore providing evidence for a new mechanistic variant of the pinacol reaction, in which only 1.2 equivalent of the reducing agent are necessary. 

Stereoselectivity in addition reactions of borane with bicyclic alkenes is similar to that observed for reduction of bicyclic ketones with hydride reducing agents. Boranes add to norbornene derivatives from the exo face (27 gave 85% exo attack upon reaction with diborane). In 27-30, all values are percentage yields of the organoborane products obtained by reaction from that face. Interestingly, only 80% exo attack was observed when 27 reacted with disiamylborane, and the size of the borane appears to have little effect on selectivity. 

Reduction.—The differences in stereoselectivity on reduction of several substituted cyclic and acyclic alkanones by hydride reducing agents (interalia LiBBu sH, L1BH4, or LiAlH4) have been documented. The lithium trialkylaluminium hydride (17) has been shown to reduce 4-t-butylcyclohexanone stereoselectively. ... 

Consult with your instructor before performing this experiment, in which you will determine the stereoselectivity of the reduction of 4-ferf-butylcyclohexanone with sodium borohydride. You might also be asked to use other hydride reducing agents and compare their stereoselectivities with that of sodium borohydride. Follow either... 

In the 4-ferf-butylcyclohexanone example, the steric environment is different on either face of the carbonyl group. In this case, the hydride reducing agent attacks more rapidly from the axial direction, and thus the equatorial alcohol (axial H) is the major product. This reaction pathway is preferred with the relatively small sodium borohydride and Uthium aluminum hydride reagents. When one stereoisomeric product is preferentially formed, the reaction is called a stereoselective reaction. 

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. 

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