Axial attack

An interesting aspect of this reaction is the contrasting stereoselective behaviour of the dimethyisulfonium and dimethyloxosuifonium methylides in reactions with cyclic ketones (E.J. Corey, 1963 B, 1965 A C.E. Cook, 1968). The small, reactive dimethyisulfonium ylide prefers axial attack, but with the larger, less reactive oxosulfonium ylide only the thermodynamically favored equatorial addition is observed. 

Although the nature of the general polar effect suggested by Kamernitzsky and Akhrem " to account for axial attack in unhindered ketones is not clear, several groups have reported electrostatic interactions affect the course of borohydride reductions. Thus the keto acid (5a) is not reduced by boro-hydride but its ester (5b) is reduced rapidly further, the reduction of the ester (6b) takes place much more rapidly than that of the acid (6a). Spectroscopic data eliminate the possibility that in (5a) there is an interaction between the acid and ketone groups (e.g. formation of a lactol). The results have been attributed to a direct repulsion by the carboxylate ion as the borohydride ion approaches. " By contrast, House and co-workers observed no electrostatic effect on the stereochemistry of reduction of the keto acid (7). However, in this compound the acid group may occupy conformations in which it does not shield the ketone. Henbest reported that substituting chlorine... 

Site-specificity of the reaction is established in the first step since enolate formation involves the carbonyl carbon and the former halide bearing carbon, while the stereospecificity of the incoming deuterium is determined during the second step. It appears that the ketonization in deuterioacetic acid yields mainly the kinetic product (axial attack) although deuteration is... 

The optical rotatory dispersion curves of steroidal ketones permit a distinction to be made between the conformations, and assignment of configuration is possible without resorting to chemical methods (see, e.g. ref. 36) which are often tedious. The axial halo ketone rule and, in the more general form, the octant rule summarize this principle and have revealed examples inconsistent with the theory of invariable axial attack in ketone bromination. 2-Methyl-3-ketones have been subjected to a particularly detailed analysis. There are a considerable number of examples where the products isolated from kinetically controlled brominations have the equatorial orientation. These results have been interpreted in terms of direct equatorial attack rather than initial formation of the axial boat form. 

It is apparent that Corey s rule requires modification when strong steric opposition to axial attack exists. In an attempt to unify the conflicting views, Valls has suggested that Corey s principle of preferred axial attack, which ensures maximum overlap, be extended. 

The reactions of pyrrolidinocyelohexenes with acid have also been Considered from a stereochemical point of view. Deuteration of the 2-methylcyclohexanone enamine gave di-2-deuterio-6-methylcyclohexanone under conditions where ds-4-/-butyI-6-methyIpyrrolidinocycIohexene was not deuterated (2J4). This experiment supported the postulate of Williamson (2JS), which called for the axial attack of an electrophile and axial orientation of the 6 substituent on an aminocyclohexene in the transition state of such enamine reactions. These geometric requirements explain the more difficult alkylation of a cyclohexanone enamine on carbon 2, when it is substituted at the 6 position, as compared with the unsubstituted case. 

Syntlietic cliemists can now work witli tlitee-dlmensional pictures of tlie conjugate addition available on a website [80]. In tlie absence of steric hindrance i5-nietliylcydobexenone, for example), an "axial attack" tlitougb a balf-diait conformation is favored, while in tlie corLisone syntliesis an "equatorial attack" tliroLigli a half-boat conformation is favored because of tlie constraint imposed by tlie bicydic tings [83]. 

Dehydration of prednisolone acetate (175b) yields the corresponding 9,11 olefin. As a variation on the chemistry we have seen previously, this olefin is allowed to react with chlorine in the presence of lithium chloride. If this addition is assumed to proceed by the customary mechanism, the first intermediate should be the 9a,11a-chioronium ion. Axial attack by chloride anion from the 110 position will lead to the observed stereochemistry of the product dichlorisone (240). ... 

In the case of substituted cyclic ketones, particularly cyclohexanones, the stereochemical outcome of an addition reaction is determined by the predominance of either equatorial or axial attack of the nucleophile, leading to axial or equatorial alcohols, respectively 25 -27 (Figure 8). 

An empirically derived rule states that axial attack is favored with unhindered cyclic ketones where steric hindrance is negligible28. This leads to the concept of product development... 

Model calculations generally support Felkin s hypothesis35-38. However, an additional controlling factor is the stabilization of the transition state by the approach of the nucleophile antiperiplanar to a vicinal bond35. In the transition state for axial attack (Figure 8), the incipient bond is approximately antiperiplanar to two axial C — H bonds. Flattening of the ring improves this antiperiplanarity and, therefore, the more flattened the cyclic ketone, the more axial attack is preferred. 

The stereochemical outcome of nucleophilic addition reactions to cyclic ketones is the subject of numerous experimental and theoretical studies, with substituted cyclohexanones and cy-clopcntanones having been intensively studied. In addition reactions to substituted cyclohexanones 1 the problem of simple diastereoselectivity is manifested in the predominance of cither axial attack of a nucleophile, leading to the equatorial alcohol 2 A. or equatorial attack of the nucleophile which leads to the axial alcohol 2B. 

Although the true nature of the interaction leading to predominant axial attack remains a point of discussion and awaits final clarification, there is nevertheless a vast body of experimental results indicating the possibilities and limitations of diastereoselective addition to cyclic ketones. 

The methodology of precomplexing a cyclic ketone with MAD, followed by addition of a nucleophile, has also been successfully used for the mcthylation of 5a-cholestan-3-one (7). Thus, addition of methyllithium4 or methylmagnesium iodide57 to the steroidal ketone affords predominantly 3/ -methyl-5a-cholestan-3a-ol, whereas alkylation with melhyllithium/MAD almost exclusively affords 3a-methyl-5a-cholestan-3/J-ol via predominant axial attack of the nucleophile4. 

Although it might be expected that a larger substituent at the 2-position of cyclohexanone would hinder axial attack to a greater extent, addition reactions to 2-methyl-, 2-ethyl- and... 

Similar to cyclohexanones, substituted cyclopentanones also adopt a conformation with the substituents in a sterically favorable position. In the case of 2-substituted cyclopentanones 1 the substituent occupies a pseudoequatorial position and the diastereoselectivity of nucleophilic addition reactions to 1 is determined by the relative importance of the interactions leading to predominant fra s(equatorial) or cw(axial) attack of the nucleophile. When the nucleophile approaches from the cis side, steric interaction with the substituent at C-2 is encountered. On the other hand, according to Felkin, significant torsional strain between the pseudoaxial C-2—H bond and the incipient bond occurs if the nucleophile approaches the carbonyl group from the trans side. 

Alkylations of 6-methoxycarbonyl six-membered cyclic (V-acyliminium ions show a strong preference for the formation of m-products. This is explained by the A0-3 strain between the substituent and the (V-mcthoxycarbonyl group of the iminium ion, forcing the substituent into an axial position. Stereoelectronically preferred axial attack by the nucleophile then leads to the 2,6-d.v-disubstituted piperidine derivatives. 

Allylations of certain bicyclic A-acyliminium ions occur with complete stereoselectivity, as a result of stereoelectronically favored axial attack at the sterically less hindered convex face, independent of the stereochemistry of the acetoxy substituent in the first example. Thus, on... 

The LUMO of cyclohexanone 3 is an out-of-phase combination of the carbonyl It orbital with the orbital (5 in Fig. 4). The out-of-phase enviromnent disfavors attack from the face of the bonds (motif ii in Fig. 1). This leads to the axial attack of nucleophiles. The observed selectivities are in agreement with the orbital... 

Klein showed that axial reaction of the parent methylenecyclohexane 37 is preferred in hydroboration [106], The experimental data on the parent methylenecyclohexanone 37a accumulated by Senda et al. [107] and the more recent systematic studies by Cieplak et al. [108, 109] on jr-facial selectivities of 3-substituted methylene-cyclohexanes 37 have characterized the intrinsic features of the facial selection of methylenecyclohexanes. That is, axial preference of unsubstituted and 3-substituted methylenecyclohexanes was observed in oxymercuration [107] and epoxidation reactions [110], There is also an increase in the proportion of axial attack with increase in the electronegativity of the remote 3-equatorial... 

Ad(ii) On catalysts with pores and cavities of molecular dimensions, exemplified by mordenite and ZSM-5, shape selectivity provides constraints of the transition state on the S 2 path in either preventing axial attack as that of methyl oxonium by isobutanol in mordenite that has to "turn the comer" when switching the direction of fli t through the main channel to the perpendicular attack of methyl oxonium in the side-pocket, or singling out a selective approach from several possible ones as in the chiral inversion in ethanol/2-pentanol coupling in HZSM-5 (14). Both of these types of spatial constraints result in superior selectivities to similar reactions in solutions. 

The stereoselectivity is enhanced if there is an alkyl substituent at C(l). The factors operating in this case are similar to those described for 4-r-butylcyclohexanone. The tnms-decalone framework is conformationally rigid. Axial attack from the lower face leads directly to the chair conformation of the product. The 1-alkyl group enhances this stereoselectivity because a steric interaction with the solvated enolate oxygen distorts the enolate to favor the axial attack.57 The placement of an axial methyl group at C(10) in a 2(l)-decalone enolate introduces a 1,3-diaxial interaction with the approaching electrophile. The preferred alkylation product results from approach on the opposite side of the enolate. 

---