Addition to Cyclohexanones

Symmetrical labile ethers such as cycloalkenyl ethers (15) or mixed acetals (16) can also be prepared from the 3-hydroxyl group by acid-catalyzed exchange etherification or by acid-catalyzed addition to cyclohexanone methyl enol ether. 

Axial addition to cyclohexanones.1 Addition of carbanions to cyclic ketones generally favors equatorial products. This preference may result from nonbonded interactions, since Trost et al. now find that the addition of LiCH2CN to cyclohexanones is axial selective (equation I). The preference for axial addition is even higher in the case of cyclohexenones ( 20 1). The axial selectivity of LiCH2CN is... 

The addition of trimethyltinlithium to triphenylvinylphosphonium bromide (Scheme 3) produced a new type of metallo-ylide (7), which on addition to cyclohexanone gave (8), containing a very nucleophilic double bond, which in the... 

Complete details are available concerning stereoselective addition of these reagents to chiral aldehydes or ketones and of crotyltitanium compounds to carbonyl groups (12, 354).2 The most diastereoselective additions to cyclohexanones known to date are effected with organotitanium reagents. 

It has however been suggested by Cieplak (9) that the stereochemistry of nucleophilic addition to cyclohexanone is determined by a combination of steric and stereoelectronic effects. According to this interesting model, steric hindrance favors the equatorial approach while electron donation favors the axial approach. The stereoelectronic effect favors the axial approach because the axial C —H bonds next to the carbonyl group (C — Ha and Cn-Ha) are better electron donors than the Cn-C-j and Cc-Cfi a bonds (cf 7A 7 and 7A-8). J... 

Cieplak, A. S. Stereochemistry of nucleophilic addition to cyclohexanone. The importance of two-electron stabilizing interactions. J. Am. Chem. Soc. 1981, 103, 4540-4552. 

Besides by these epoxidations, oxaspiropentanes have been prepared through the nucleophilic addition of 1-lithio- 1-bromocyclopropanes to ketones at low temperature. Thus for example, the dibromocyclopropane 96 prepared by addition of dibromo-carbene to cyclohexene 52) underwent metalation with butyllithium to give the lithio-bromocyclopropane 97 which was converted into the oxaspiropentane 98 upon simple addition to cyclohexanone, Eq. (28) 53,54). 

Wu, Y.-D. Tucker, J. A. Houk, K. N. Stereoselectivities of nucleophilic additions to cyclohexanones substituted by polar groups. Experimental investigation of reductions of trans-decalones and theoretical studies of cyclohexanone reductions. The influence of remote electrostatic effects, J. Am. Chem. Soc. 1991,113, 5018-5027. 

This seemingly simple result may have far reaching consequences. For example, it may help to explain the effect of added lithium salts in nucleophilic additions to cyclohexanones as discussed earlier in this chapter. Thus, model (63) shown in Figure 472.135-137 explain the enhancement of rate and may also be relevant to the origins of stereoselectivity in this reaction. Of course, the exact location of the lithium atom and the aggregation state of the adding nucleophile are subject to speculation, since for lithium these parameters seem to be highly variable. 

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. 

For axial and equatorial nucleophilic addition to cyclohexanone, the principle of microscopic reversibility dictates that frontier orbital analysis can be considered for addition of the nucleophile to the carbonyl or loss of nucleophile from the product. Since the reaction is considered to be exothermic the frontier orbital interaction that should best represent the transition energy is the orbital interaction of the nucleophile HOMO with the ketone n (LUMO) (Fig. 6-11). 

Figure 6-15. Transition states (3-21G ) for axial and equatorial AIH3 addition to cyclohexanone.

In 1968, Felkin noted that neither the Cram nor the Karabatsos models predict the outcome of nucleophilic addition to cyclohexanones [15], and fail to account for the effect of the size of R on the selectivity [16]. The point about cyclohexanones is particularly well-taken, since it is unlikely that the mechanisms of Grignard and hydride additions to cyclic and acyclic ketones differ significantly. The data in Table 4.1 indicate that as the size of the substituent on the other side increases, so does the selectivity, except for the single example where the large substituent is cyclohexyl and the carbonyl is flanked by a ter/-butyl. 

Figure 9.12 Comparison of the dominant transition state stabilizing hyperconjugative interactions for axial and equatorial nucleophilic addition to cyclohexanone according to the Cieplak s model compared to the...

The isolation and characterization of cyclohexanone monooxygenase (CHMO) from Acinetohacter sp. NCIB 9871 was reported in 1976 [68]. In addition to cyclohexanone and cydopentanone, CHMO was shown to be able to catalyze the oxidation of a variety of cyclic ketones to the corresponding lactones [69]. This attracted the attention of several other groups, which led to investigations of its mechanism [70, 71] as well as sequencing and doning [72]. It is by far the most extensively studied BVMO, and it has been used as a model system for up-scaling BVMO-mediated biocatalysis. 

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