4-Substituted cyclohexanones, conformational

Synthetically useful stereoselective reductions have been possible with cyclic carbonyl compounds of rigid conformation. Reduction of substituted cyclohexanone and cyclopentan-one rings by hydrides of moderate activity, e.g. NaBH (J.-L. Luche, 1978), leads to alcohols via hydride addition to the less hindered side of the carbonyl group. Hydrides with bulky substituents 3IQ especially useful for such regio- and stereoselective reductions, e.g. lithium hydrotri-t-butoxyaluminate (C.H. Kuo, 1968) and lithium or potassium tri-sec-butylhydro-borates or hydrotri-sec-isoamylborates (=L-, K-, LS- and KS-Selectrides ) (H.C. Brown, 1972 B C.A. Brown, 1973 S. Krishnamurthy, 1976). 

The principles involved in the conformational analysis of six-membered rings containing one or two trigonal atoms, for example, cyclohexanone and cyclohexene are similar. The barrier to interconversion in cyclohexane has been calculated to be 8.4-12.1 kcal mol . Cyclohexanone derivatives also assume a chair conformation. Substituents at C2 can assume an axial or equatorial position depending on steric and electronic influences. The proportion of the conformation with an axial X group is shown in Table 4.4 for a variety of substituents (X) in 2-substituted cyclohexanones. 

TABLE 4.4 Proportion of Axial Conformation in 2-Substituted Cyclohexanones, in CDCI3... 

For cyclic ketones conformational factors also come into play in determining enolate composition. 2-Substituted cyclohexanones are kinetically deprotonated at the C(6) methylene group, whereas the more-substituted C(2) enolate is slightly favored... 

Deprotonation of carbonyl compounds by chiral amide bases followed by trapping with silylating agents or aldehydes has become a common method for de-symmetrizing prochiral and conformationally locked 4-substituted cyclohexanones and bicyclic ketones. The literature through 1997 has been reviewed [45]. 

The oxidation of imines derived from substituted cyclohexanones occurs predominantly from the equatorial direction. However, the product oxaziridines can undergo subsequent equilibration to favor a more stable conformation which places the bulkier nitrogen substituent in an equatorial conformation (equation 44)219. 

Consideration of the two half-chair conformations of 76 shows that a transition state resulting from axial attack on 76a would be destabilized relative to one resulting from attack on 76b. Both half-chair conformations of 75 (not shown) can undergo axial alkylation, thus leading to a mixture of R- and -substituted cyclohexanones, and the... 

Frovatnptan (6, SB-209509/VML-251), initially discovered by SmithKline Beecham, was licensed to Vanguard Medica/Vemalis for development. The marketing rights for frovatriptan have subsequently been licensed to Elan in the United States. Frovatriptan is a conformationally-restrained analog of the selective 5-HTi agonist 5-carbamoyltryptamine (5-CT). The key step in the syntheses involve Fischer reaction of 4-cyanophenylhydrazine (70) or 4-carboxamidophenylhydrazine (79) with an appropriately substituted cyclohexanone (Schemes 24-26).32,33... 

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. 

More recently, Usuki etal. studied, using NMR techniques, the conformation of spirocyclic oxaziridines 3 derived from substituted cyclohexanones <1995JOC8028>. Depending on substitution and on the stereochemistry, these compounds exhibit a substantial upfield shift of the cyclohexyl methylene or methane protons with a 1,3-diaxial relationship to the oxaziridine N-substituent. This effect is ascribed to a conformation that places an aromatic group over the plane of the cyclohexane ring. This conformation has also been observed in the solid state by X-ray crystallography and is further supported by molecular mechanics calculations. 

An alternate radical-induced addition-fragmentation sequence relies on the 1,4-elimination of a leaving group to drive the reaction. In this sequence, because the fragmentation is accompanied by the expulsion of a tiibutylstannyl radical, the requirement for the initial tributyltin hydride is only catalytic (Scheme 79). The stereospecificity of the reaction course has been rationalize in terms of a conformational preference for the elimination step, as depicted in Scheme 79 where the rran.r-substituted cyclohexanone forms only one double bond geometry in the product. As shown in equations (40) and (41), the ci.r-substituted cyclohexanones undergo the four- and three-carbon expansions stereospecifically to give the (Z)-alkenes. 

In the absence of one 1,3-diaxial R-H interaction in 3-substituted cyclohexanones, one might anticipate that Ep should be reduced by half. However, conformational studies have revealed varied results. Corey and Feiner propose to use the values of two-thirds Ar. 

An analysis of the solvent dependence of the A>c and /hh couplings combined with an analysis of the changes in the IR first overtone carbonyl bond intensities and theoretical calculations allowed Abraham and co-workers to determine directly the conformational equilibria in 2-bromocyclo-hexanone, a model compound, by the use of which the authors illustrated an improved method of conformational analysis of substituted cyclohexanones. 

Whitesell and Felman therefore concluded that an amine with a C2 axis of symmetry was required in order to ensure that the same side of the cyclohexene ring was shielded from attack whichever conformation of the enamine underwent alkylation. The en-antioselectivity was thereby considerably increased, but in the opposite chiral sense, by using the cyclohexanone enamine derived from ( + )-/mnj-2,5-dimethylpyrrolidine. This was assumed to have the S, S-configuration based on the results of the alkylation (Scheme 70). Optical yields of 82-93% ee were obtained. Also noteworthy was the low level of dialkylation observed (4-7%) and the fact that formation of enamine 77 was at least ten times faster using type 3A molecular sieves compared to 4A molecular sieves. Similar methodology has been applied to the alkylation of 4-substituted cyclohexanone enamines to give mainly the less stable trans disubstituted cyclohexanone s . 

An attempt has been made to calculate directly the optical rotatory strengths of methyl-substituted cyclohexanones. The results show a significant dependence of rotatory strength upon the conformation adopted about the C-methyl bond. 

Conformational considerations are of special importance in the reduction of flexible monocyclic ketones. For substituted cyclohexanones, the preference of the equatorial position over the axial orientation is reported in table form148. The effect is approximately additive and conformational equilibria can be calculated from the individual free energy values of conformation... 

Tormena and co-workers have continued their studies on conformational isomerism in 2-substituted cyclohexanones by the use of Vh2H3 couplings and the solvation model. The conformer energies in the solvents studied and the couplings for the distinct conformers have been obtained for 2-A,iV-dimethylamino, 2-methoxy, 2-methylthio and 2-methylseleno derivatives. 

Table 1.2 Conformational equilibria of 4-substituted cyclohexanones as determined by NMR spectroscopy at 30 3 [2]...

In 1953, Corey reported that conformational equiUbrium in a-chloro and bromo-substituted cyclohexanones strongly favors (>97%, 2.3kcal/mol) the axial conformer. IR-analysis of the carbonyl stretching frequencies indicated that this conformational effect is accompanied by a red-shift in the carbonyl absorption, indicative of the C = O bond weakening due to the Jt interaction. 

The consideration of the development of torsional strain in the transition state for nucleophilic addition afforded an explanation for product distributions observed in the addition of nucleophiles to substituted cyclohexanones. Dauben and co-workers reported that reduction of 4-methylcy-clohexanone with LiAlH4 produced 81% of the trans alcohol and 19% of the cis isomer. With 4-f-butylcyclohexanone, a conformationally more rigid struc-... 

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