Reduction of Cyclic Ketones

All reducing agents used for reductions of aliphatic and aromatic ketones can be used for reduction of cyclic ketones to secondary alcohob (pp. 107 and 109). In fact, reduction of cyclic ketones is sometimes easier than that of both the above mentioned categories [262]. What is of additional importance in the reductions of cyclic ketones is stereoselectivity of the reduction and stereochemistry of the products. 

According to the older literature catalytic hydrogenation tends to favor cis isomers (where applicable) while reduction with metals gives trans isomers [846]. But even catalytic hydrogenation may give either cis isomers, when carried out over platinum oxide [847], or trans isomers, if Raney nickel is used 

Similarly reductions with metal hydrides, metals and other compounds may give predominantly one isomer. The stereochemical outcome depends strongly on the structure of the ketone and on the reagent, and may be alfected by the solvents. 

For example, reduction of 2-alkylcycloalkanones with lithium aluminum hydride in tetrahydrofuran gave the following percentage proportions of the less stable cu-2-alkylalkanol (with axial hydroxyl) 2-methylcyclobutanol 25%, 2-methylcyclopentanol 21%, 2-methylcyclohexanol 25%, 2-methylcy-cloheptanol 73%, and 2-methylcyclooctanol 73% (the balance to 100% being the other, trans, isomer) [837.  

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Scheme 9.22 Ru-catalysed DKR-reductions of cyclic ketones with TsDPEN ligand.

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... 

Reduction of cyclic ketones.l These complexes selectively reduce cyclic ketones to the less stable alcohol. The most stereoselective reagent is that in which the R group is /-butyl this complex is comparable to lithium trisiamylborohydride in stereoselectivity. 

Two factors control the course of reduction of cyclic ketones... 

The structure of the cyclic ketone is of utmost importance. Reduction of cyclic ketone by complex hydrides is started by a nucleophilic attack at the carbonyl function by a complex hydride anion. The approach of the nucleophile takes place from the less crowded side of the molecule (steric approach or steric strain control) leading usually to the less stable alcohol. In ketones with no steric hindrance (no substituents flanking the carbonyl group or bound in position 3 of the ring) usually the more stable (equatorial) hydroxyl is generated (product development or product stability control) [850, 851, 852, 555]. The contribution of the latter effect to the stereochemical outcome of... 

Stereoselective reductions of cyclic ketones have immense importance in the chemistry of steroids where either a or 5 epimers can be obtained. A few... 

Reductions of cyclic ketones to cycloalkanes, to pinacols and to alkenes are... 

Guy Lemiere was born in Antwerp, Belgium, and studied chemistry at the Universities of Antwerp and Ghent. In 1975 he obtained a PhD in organic chemistry from the University of Antwerp on the subject Study on enzymatic in vivo and in vitro reductions of cyclic ketones . He built up all his academic career at the University of Antwerp. His scientific interests evolved from the stereochemistry of enzymatic reactions to natural products and further to heterocyclic chemistry, especially the chemistry of pyridazines. In 2004 he organized together with Bert Maes the 9th International Symposium on the Chemistry and Pharmacology of Pyridazines in Antwerp. He is an author of around 80 scientific papers. 

Sodium borohydride reduction of cyclic ketone 109 produced alcohol 110 <1997BMC1327> (Equation 19). Biheterocyclic 2-hydroxyphosphonates 111 were synthesized by reactions of phospha-bicyclodecanones 112 with dimethylphosphonates in the presence of NaOH/MeOH <1996RJC567> (Equation 20). 1-Cyclohexylphosphin-4-one 113 was reduced to the corresponding alcohol 114 by sodium borohydride <2004TL407> (Equation 21). 

Asymmetric reduction of cyclic ketones. Prochiral cyclic ketones arc reduced to (R)-alcohols in 75-96% ee by a chiral hydride obtained by refluxing a mixture of lithium aluminum hydride, (— )-N-methylephedrine (I equiv.), and 2-ethylaminopyridine (2 cquiv.) in ether for 3 hours. Reduction of prochiral acychc ketones with this hydride also results in (R)-alcohols, but only in moderate yield. 

Stereoselective reduction of ketones. This borohydride (1) is comparable to lithium tri-.ver-butylborohydride (4. 312-313) for stereoselective reduction of cyclic ketones to the less stable alcohols, but less stereoselective than lithium trisiamylborohydride (7, 216-217). The by-product formed in reductions with I can be removed as an insoluble ate complex formed by addition of water, simplifying isolation of the reduction product. 

Prediction for the reduction of cyclic ketones on the basis of the Cram, Karabatsos and Felkin-Ahn models is usually unreliable and a simple model has yet to emerge. 

The stereochemical product ratio for the reduction of cyclic ketones by hydrides is affected by the structure of the cyclic ketone and the nature of the hydride used. The reduction of substituted cyclohexanones avoids product interconversion by conformational ring flip because of conformationally locked cyclohexanones. In such cases, axial attack is preferred over equatorial attack. 4-fert-Butylcyclohexanone (6.50) is reduced by NaBH4 and by LiAlH4 to give 86% and 92% of trans-4-fert-butylcyclohexanol (6.51), respectively. Hindered hydrides such as f-BusBHLi show more selectivity. 

The mechanism of reduction of cyclic ketones by LiAlH4 and NaBH4 is quite different. The LiAlH4 reduction involves reactant-like transition states (Scheme 6.18) and NaBH4 reductions involve product-like transition states (Scheme 6.19). The LiAlH4 reductions favour equatorial attack if bulky axial groups are present at C-3 and C-5 because of steric factors. Some non-steric factors which also favour equatorial attack can be explained by Felkin-Ahn rationalization on the basis of either torsional strain or the need for antiperiplanarity. 

Reduction of cyclic ketones. Competitive reductions of cyclic ketones of various types with lithium tri-/-butoxyaluminum hydride indicate that nonconjugated cnones are less reactive than cyclic staturaled ketones, but more reactive than conjugated cnones. Steric effects do not appear to be important, since 3-ketocyclohe ene (1) is less... 

The stereochemistry and mechanism of reduction of cyclic ketones by metal hydride reagents provided a unique Of rtunity for comparison of experimental results with theoretical expectation. The models proposed by Cram, Comforth and Karabatsos described above were inadequate to explain the stereochemical outcome, and so a wide range of models was developed to explain the dichotomy between cyclic and acyclic results. The theoretical basis, applications and limitations of these models have been critically reviewed. The effect of steric influences, torsional and electronic factors, and the nature of the cation on the rate of reduction, stereochemical outcome and position of the transition state have also been surveyed. ... 

The stereochemical characteristics of lithium trimethoxyaluminohydride and lithium aluminum hydride in the reduction of cyclic ketones were analyzed by a linear combination of steric strain and product stability control. Qualitative and quantitative explanation of the experimental observations was possible using this approach. ... 

It was originally believed that the dissolving metal reduction of cyclic ketones would invariably afford the more stable of a pair of epimeric ketones as the major product. Although it has since been established beyond reasonable doubt that these reactions are kinetically controlled and that the less stable epimeric alcohol frequently predominates, the belief persists that these reductions are under thermodynamic control. ... 

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 reductions of 1- and 12-keto steroids and their 1-decalone derivatives graphically illustrate the fact that dissolving metal reductions of ketones do not necessarily afford the more stable of a pair of epimeric alcohols. As a corollary, while the reduction of cyclic ketones is a synthetically useful procedure for the stereoselective preparation of secondary alcohols, it cannot be assumed that the thermodynamically stable alcohol will be the product which is obtained stereoselectively. 

The sterically encumbered L- and K-Selectrides also reduce aldehydes and ketones rapidly and quantitatively to the corresponding alcohols. One of the remarkable features of these reagents is their unusual ability to introduce major steric control in the reduction of cyclic ketones. Their applications as highly selective reducing agents will be discussed later in this chapter. 

Minor Differences. Another point of difference between British and American custom is the use of di in diphenyl (Britain) and of bi in biphenyl (U.S.A.). The British do not use double-molecule names such as bibenzoic acid (dicarboxy-diphenyl), because it is only the radical which is doubled. There is also the question of the state of reduction of cyclic ketones. The British define the state of reduction in the name of the compound, whereas American practice allows it to be taken for granted whenever possible. 

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