Stereoselectivity of Hydride Reduction

CHAPTERS REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS 

With less hindered hydride donors, particularly NaBH4 and LiAlH4, cyclohexanones give predominantly the equatorial alcohol. The equatorial alcohol is normally the more stable of the two isomers. However, hydride reductions are exothermic reactions with low activation energies. The transition state should resemble starting ketone, so product stability should not control the stereoselectivity. One explanation of the preference for formation of the equatorial isomer involves the torsional strain that develops in formation of the axial alcohol.  

Oxygen moves away from equatorial hydrogens no torsional strain 

An alternative suggestion is that the carbonyl group Ti-antibonding orbital which acts as the lowest unoccupied molecular orbital (LUMO) in the reaction has a greater density on the axial face. It is not entirely clear at the present time how important such orbital effects are. Most of the stereoselectivities which have been reported can be reconciled with torsional and steric effects being dominant. See Section 3.10 of Part A for further discussion of this issue. 

When a ketone is relatively hindered, as for example in the bicyclo[2.2.1]heptan-2-one system, steric factors govern stereoselectivity even for small hydride donors. 

Torsional strain as oxygen passes through an eclipsed conformation 

112j T. Ikeno, T. Kimura, Y. Ohtsuka, and T. Yamada, Synlett, 96 (1999). 

A large amount of data has been accumulated on the stereoselectivity of reduction of cyclic ketones.120 Table 5.4 compares the stereoselectivity of reduction of several ketones by hydride donors of increasing steric bulk. The trends in the table illustrate 

Cherest, H. Felkin, and N. Prudent, Tetrahedron Lett., 2205 (1968) M. Cherest and H. Felkin, Tetrahedron Lett., 383 (1971). 

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Reduction of 3-trimethyls1lyl-2-propyn-l-ol exemplifies the problem of stereoselectivity in hydride reduction of acetylenic alcohols to E-allyl alcohols.4 Early reports5 that lithium aluminum hydride stereoselectively reduced acetylenic alcohols gave way to closer scrutiny which revealed a striking solvent dependence of the stereochemistry. Specifically, the... 

Reductions of cyclic ketones by dissolving metals are frequently highly stereoselective and these reductions have been used to obtain secondary alcohols which are difficult or impossible to prepare by metal hydride reduction. In terms of yield, the best results are usually obtained either by reductions with alkali metals (commonly Li) in liquid NH3 in the presence of proton donors or with active metals in an alcohol. Although a number of explanations have been advanced for the stereoselectivity of these reductions, they are all rationalizations with dubious predictive value." There are, however, a number of empirical generalizations which are based on a considerable body of experimental data, specifically ... 

The stereoselectivity of the ionic hydrogenation reaction appears to be controlled by the steric size of the trialkylsilane in the reduction of A ° -octalin (109 equation 46), which shows a high degree of sensitivity to the steric size of the organosilane hydride donor. ° However, in the reduction of (112 equation 47) there is a considerably smaller change in the range of stereoselectivity of the reduction process. The lower sensitivity in the stereoselectivity of reduction of (112) relative to (109) has been interpreted... 

However, the stereoselective reductions of the 5-substituted adamantanones 3.50 [CT2, G5, KA4, LL5], and bicyclo-[2.2.2]-octan-2-one 3.51 [MK5] have been interpreted in terms of Cieplak s model [C6, CT3]. Unfortunately, the observed stereoselectivities are low (de <40%), so that it is difficult to dissect the various parameters involved in such reductions [CHS, N2], The electronic contribution to the stereoselectivity of the reduction of substituted 9-benzonorbomenones 3.52 is very important [G5, OTl, OT2] (Figure 3.20). Halogen substituents on the aromatic ring favor syn attack by all hydrides on those very rigid systems. Electrostatic effects have been invoked to interpret these results [PW2, WTl]. 

Stereoselective reduction of ketones. The Luche reagent is useful for selective reduction of ketones in the presence of aldehydes, and for selective reduction of enones and enals to alcohols. The reagent can also invert the selectivity of hydride reduction of cyclic ketones such as la. Reduction of la with a metal boron and aluminum hydrides. 

Cerium(III) chloride as well as some other lanthanide salts invert the stereoselectivity of the reduction of bicyclo[3.1.0]hexane-2,4-diones and bicyclo[3.1.0]hexane-2-ones compared to sodium borohydride in methanol alone. This reversal leads to the more favored attack of the hydride from the most hindered, concave face of these molecules to give exo-4-hydrobicyclo[3.1.0]hexan-2-ones and exo-bicyclo[3.1.0]hexan-1 -ols, respectively, in excellent yields37 If Luche conditions are used on 30 at low temperatures, complete stereoselectivity is induced in the production of 31. 

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... 

The chemical reduction of enamines by hydride again depends upon the prior generation of an imonium salt (111,225). Thus an equivalent of acid, such as perchloric acid, must be added to the enamine in reductions with lithium aluminum hydride. Studies of the steric course (537) of lithium aluminum hydride reductions of imonium salts indicate less stereoselectivity in comparison with the analogous carbonyl compounds, where an equatorial alcohol usually predominates in the reduction products of six-membered ring ketones. 

Perhaps of more significance is a detailed study132 into the reductive desulphonylation of 7-methyl-7-phenylsulphonylestratrienes. The goal was stereoselective removal of the sulphonyl group, and hydride reductions, alkali-metal-amalgam reductions and electrochemical reductions were explored. The latter proved to be the most effective and the best results are illustrated in Scheme 3. 

Halterman and McEvoy studied hydride reduction of a functionalized 2,2-diarylcyclopen-tanone 8 (Fig. 5) containing an unsubstimted phenyl group and a para-substituted phenyl group, both geminal substituents being assumed to be sterically equivalent [67]. The stereoselective reduction with sodium borohydride of a... 

Analogously, for preparation of racemic carba-a-glucopyranose 49 from 52, esterification of (—)-52 furnished the ester 95, which was transformed into compound 96 by debromination with zinc dust and acetic acid. Stereoselective hydroxylation of 96 with osmium tetraoxide and hydrogen peroxide, followed by acetylation, gave compound 97. Lithium aluminum hydride reduction of 97, and acetylation of the product, gave pentaacetate 98, which was converted into 99 by hydrolysis. ... 

Chelation Control. The stereoselectivity of reduction of carbonyl groups can be controlled by chelation when there is a nearby donor substituent. In the presence of such a group, specific complexation among the substituent, the carbonyl oxygen, and the Lewis acid can establish a preferred conformation for the reactant. Usually hydride is then delivered from the less sterically hindered face of the chelate so the hydroxy group is anti to the chelating substituent. 

After the initial two reports of Rh- and Co-catalyzed reductive aldol couplings, further studies did not appear in the literature until the late 1990s. Beyond 1998, several stereoselective and enantioselective reductive aldol reactions were developed, which are catalyzed by a remarkably diverse range of metal complexes, including those based upon Pd, Cu, Ir, and In. In this chapter, transition metal-catalyzed aldol, Michael, and Mannich reactions that proceed via transition metal hydride-promoted conjugate reduction are reviewed. 

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