Cyclohexanone equatorial attack

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 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. 

These alkoxytitanium homoenolates show high propensity for equatorial attack in their ir reactions with substituted cyclohexanones (Table 6). The basic trend of their chemical behavior is similar to that of simple titanium alkyls [35]. Chemo-selectivity of the reagent 19 is also noteworthy. The alkoxytitanium homoenolate reacts preferentially with an aldehyde even in the presence of a ketone Eq. (32). A notable difference of rate between the reaction with cyclohexanone and that with 2-methylcyclohexanone was also observed, the latter being far less reactive toward the homoenolate. 

The preferred direction of nucleophilic attack on cyclohexanones has also been explained in terms of the torsional strain between the forming carbon-nucleophile bond and the adjacent bonds on C(2) and C(6)66,68,81 (Scheme 17). If the ring is flat, attack from the axial side is staggered whereas equatorial attack is eclipsed. However, if the ring is puckered, attack from the axial side is eclipsed and the equatorial side is staggered. Shi and Boyd have confirmed with calculations at the 6-21G or 6-32G level that the flatter the ring the more axial attack80. 

If your memory of Chapter 18 s discussion of axial and equatorial attack on cyclohexanones is dim, you should refresh it now. We shall use several examples that build on what we said there p. 470). 

We discussed the reduction of cyclohexanones in Chapter 18 and established that reducing agents prefer the equatorial approach while small reagents may prefer to put the OH group in the more stable equatorial position. If the nucleophile is not H but something larger than OH then we can expect equatorial attack to dominate both because of ease of approach and because of product stability. 

Diethyl azodicarboxylate (DAD) behaves like a reactive electrophilic alkene and attack on a substituted cyclohexanone enamine can occur from an axial or equatorial direction depending on the steric effects in the transition state. For example, DAD reacts with 159 to give 160 by equatorial attack, together with 161 (ratio 1 9), whereas the... 

The stereochemistry of addition of an allylic organozinc reagent to a carbonyl group has received considerable attention. Both diallyl- and dicrotylzinc in their reactions with alkyl-substituted cyclohexanones display a strong preference for equatorial attack (formation of the rfl -alcohol) on the carbonyl group (5, 6), e.g.,... 

In the reaction of crotylzinc reagents with substituted cyclohexanone, the stereoselectivity decreases with increasing distance of the substituent from the carbonyl group, e.g., the percentage of equatorial attack decreases from 88.5% in 2-methyl- to 75% in 3-methyl-, and to 65% in 4-methylcyclohexanone (6). In a comparative study of this type of reaction, the highest stereoselectivity was observed for diallylzinc and the following sequence has been observed Mg < Cd < Zn (6, 7). 

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. 

In hydrogenolyses with HAICU, the dimethyl acetals of cyclobutanone and cyclohexanone are cleaved more slowly than that of 3-pentanone, while those of cyclopentanone and cycloheptanone are cleaved more rapidly (Table 1), as would be expected for a carbonium ion process. The differences in rate are small, suggesting that carbonium ion character is not strongly developed in the transition state. With the dimethyl acetal of 4-t-butylcyclohexanone, the hydride addition step occurs with strongly predominating axial addition when HAlCh is used Zn(BH4)2 with TMS-Cl, and TMS-H with TMSO-Tf are less selective (Table 2). Equatorial attack predominates, however, in the reduction of the ketone itself with TBDMS-H and TBDMS-OTf. ... 

Axial versus equatorial attack of magnesium tertiary-enolates on substituted cyclohexanones is affected by solvent (i.e., HMPA increases axial substitution) [18]. Increased basicity favors axial attack. The enolates were generated by reaction of j-PrMgCl with r-butylacetate [Eq. (14)]. 

Addition to cyclohexanones is considered to be influenced by two factors (i) the steric interaction of the incoming groups with 3,5-axial substituents and (ii) the torsional strain of the incoming groups with 2,6-axial substituents. Steric strain hinders axial attack, whereas torsional strain hinders equatorial attack. The actual stereochemistry of the addition depends upon which factor is greater in a particular case. The production of the desired isomer in high stereoselectivity is required from the synthetic point of view. 

There are two possible modes of delivery of the hydride to the carbonyl carbon of cyclohexanone (1) axial attack with formation of the equatorial alcohol and (2) equatorial attack with formation of the axial alcohol. Two factors are competing with each other (1) steric interaction of the incoming hydride with the 3,5-diaxial hydrogens in the axial attack and (2) torsional strain of the incoming hydride with the 2,6-diaxial hydrogens in the equatorial attack. 

Exo cycloalkylations have been used to synthesize ct5-1-decalones. For example, treatment of 2-methyl-3(4-tosyloxybutyl)cyclohexanone with sodium t-pentylate in benzene gave c/j-9-methyl-l-deca-lone (50) in 60% yield. Also, as shown in Scheme 28, conjugate addition-cycloalkylation was employed to synthesize a cw-fused decalone related to the sesquiterpene, ( )-valerane. Apparently, in these cases, the enolate intermediate adopts a conformation having the 4-bromobutyl side chain quasi-axial, and C—C bond formation occurs via equatorial attack to give initially a twist-boat conformation of the product. 

Because of the number of conformations that need to be considered for acyclic systems, cyclohexanones are somewhat simpler for analysis. However, even for these systems the situation is not easily amenable to isolating specific components of selectivity. Several explanations have been proposed over the years to account for the preference of axial attack of cyclohexanones by sterically unhindered nucleophiles (L1A1H4, NaBH4, AIH3) [9]. Equatorial attack is favoured for sterically hindered cyclohexanones or reducing agents (Fig. 6-7). 

The first explanation for the preference for axial attack by hydride in conforma-tionally rigid sterically unhindered cyclohexanones became known as product development control and was suggested to reflect a late transition state [22]. For hindered ketones steric interference with the nucleophile was considered to favour equatorial attack and this became known as steric approach control caused by an early transition state. Hudec [23] proposed that the preferred direction of approach to a carbonyl group is controlled by deviations in the angle by which the axis of the 7i -orbital of the carbonyl carbon atom is twisted thereby making the faces of the carbonyl diastereotopic. 

Figure 6-12. The effect of frontier orbital interactions of proximate C-H and RC-C bonds on A lumo-homo for nucleophilic axial and equatorial attack at cyclohexanones.

Numerous data have been recorded concerning the stereochemistry of the reduction of the substituted cyclohexanone derivatives, and in general, preferential axial attack occurs with LiAIH, derivatives, whereas equatorial attack takes place for trialkylborohydrides. This tendency is valid for this case and it is noteworthy that (IS, 3R)-3-(/ -tert-butylphenylthio)cyclohexanol is obtained almost exclusively by employing LiAlH(OBu )3 (entry 9). Thus, the 3-arylthio asymmetric center is effectively transferred to C-1, producing both configurational isomers (R and S) by suitable choice of reducing reagent. 

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