Equatorial attack

The relation of rates of reduction with NaBH4 to variations in structure in a wide variety of monocyclic and bridged bicyclic compounds has also been discussed for example, a methyl a to a ketone slows the rate of reduction. Brown ° stated that reactions should not be discussed in terms of axial and equatorial attack, since the rates simply reflect differences in the energies of the possible transition states and not enough is known about the transition state to analyze it. He accepted th concepts of SAC and PDC, but preferred to call them steric strain contrpl and product stability control. ... 

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. 

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]. 

Since equatorial attack is roughly antiperiplanar to two C-C bonds of the cyclic ketone, an extended hypothesis of antiperiplanar attack was proposed39. Since the incipient bond is intrinsically electron deficient, the attack of a nucleophile occurs anti to the best electron-donor bond, with the electron-donor order C—S > C —H > C —C > C—N > C—O. The transition state-stabilizing donor- acceptor interactions are assumed to be more important for the stereochemical outcome of nucleophilic addition reactions than the torsional and steric effects suggested by Felkin. 

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. 

Exclusive exo (equatorial) attack is also observed with bicyclo[3.2.1]octan-3-one (5), whereas addition of methylmagnesium iodide to bicyclo[3.2.1]octan-2-one (7) affords the diastereomeric products in almost equal amounts5i. The cyclohexanone moiety of both bicyclic ketones 5 and 7 adopts a chair conformation and therefore the 3,5-diaxialethano bridge in... 

The chromium reagent, prepared from 3-bromopropene, exhibits a good ability to discriminate between axial and equatorial attack in 4-fcrf-butylcyclohexanone1. 

As a result, one might expect that there is only a slight difference between the iminium salts and the parent ketone (4-rm-butylcyclohcxanone) concerning the stereochemical course of the addition reaction and. actually, this assumption proves to be true. In each case the diastereomer resulting from the less hindered equatorial attack of the nucleophile clearly predominates10. 

Imine 214 (R = H) gave a 3 1 mixture of ot/(3 chloro epimers of 215 (R = H) when a mixture of Lewis acids, TiCl4, and Ti(OiPr)4 was used. The stereoselectivity of the formation of 215 is rationalized by a chair-like transition state 217 with equatorial attack of chloride ion <1998TL7239, 2000JOC655>. 

Another relevant example is found with the addition of 3-aminopropan-l-ol to 5-bromo-5-deoxy-D-xylose. The formation of the least stable stereomer 58 is 20 times as fast as that of 59 (at equilibrium [59]/[58] = 7.3).49 This kinetic selectivity was interpreted in terms of transition structures 60 and 61 which imply IV-alkylation of a tetrahydrooxazine intermediate as the discriminating step. The faster formation of the least stable product 58 arises from transition state 60 in which IV-alkylation corresponds to an axial attack of the oxazine intermediate. This is easier than equatorial attack in transition state 61 (Fig. 20). 

The formation of the products could be explained by hemiacetal formation followed by Prins cyclization and subsequent Ritter amidation. A tentative reaction mechanism to realize the cis selectivity is given in Fig. 20 and could be explained by assuming the formation of an (L )-oxocarbenium ion via a chair-like transition state, which has an increased stability relative to the open oxocarbenium ion owing to electron delocalization. The optimal geometry for this delocalization places the hydrogen atom at C4 in a pseudoaxial position, which favors equatorial attack of the nucleophiles. 

On the other hand, puckering the ring will destroy it equatorial attack cannot approach antiperiplanarity to the C2—C3 and C5—C6 bonds. We are thus led to the rule the more flattened the ring, the more axial attack. This flattening rule may help to rationalize experimental results quite difficult to understand otherwise. 

Axial attack is also favored on dioxanone rings, but equatorial attack is favored on dithianone rings. 

The simplest case of substrate-controlled diastereoselection is the incorporation of the controlling stereocenter and the prostereogenic center into a cyclohexane or cyclopentane ring. In the classical example of nucleophilic attack on a conformationally anchored cyclohexanone, axial and equatorial attack are possible, leading to diastereomers 1 and 2, respectively. 

A controversial topic to date is the establishment of which factors favor the formation of each of these diastereomers29. It appears that bulky nucleophiles prefer equatorial attack, whereas small nucleophiles, presumably due to stereoelectronic effects, add axially. 

In the heteroatom O-substituted cyclohexane 22 equatorial attack, to give 23a, is stereoelec-tronically even more favored than in the analogous carbocyclic case [d.r. (eq/ax) 85 15]81. 

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