2-Cyclohexenone conformation

The addition of large enolate synthons to cyclohexenone derivatives via Michael addition leads to equatorial substitution. If the cyclohexenone conformation is fixed, e.g. as in decalones or steroids, the addition is highly stereoselective. This is also the case with the S-addition to conjugated dienones (Y. Abe, 1956). Large substituents at C-4 of cyclic a -synthons direct incoming carbanions to the /rans-position at C-3 (A.R. Battersby, 1960). The thermodynamically most stable products are formed in these cases, because the addition of 1,3-dioxo compounds to activated double bonds is essentially reversible. 

Among molecules 2-8 the oxo derivative 2 is the best studied by experimental and theoretical methods. It was established that cyclohexene ring in molecule 2 adopts a sofa conformation according to NMR [38, 39], microwave [40], Raman [41] and IR [42 5] spectroscopic studies. The same results were obtained from theoretical calculations by molecular mechanics [46,47] and quantum chemical HF/6-3 lG(d,p) and MP2/6-31G(d,p) methods [48]. More detailed analysis of cyclohexenone conformation by MP2/6-31 lG(d,p) method indicated that its conformation may be described as slightly distorted sofa [49]. Similar conclusion was made based on results of X-ray diffraction study of inclusion complex [50] containing molecule 2. 

These remarkable observations stimulated an investigation to understand the origin of the directing effect. To clarify the contribution of the axially- and equato-rially-oriented oxygen atoms in the ketal, a survey of the reaction of three confor-mationally biased t-butyl cyclohexenone ketals 78, 81 and 84 was undertaken (Scheme 3.26) [56]. In each case, careful conformational analysis provides critical clues to rationalizing selectivity. 

A comprehensive stereochemical study was carried out concerning the reactions of cyclic enones27. The additions to cyclohexenones and -heptenones containing either a 4-methyl or 5-methyl substituent were studied. Surprisingly, the same selectivity trends were found for the six-membered rings as well as for the conformationally much more complex seven-mcmbercd rings. 

The coordinated cyclohexenones react from half-chair conformations A and B in order to show a maximum of tr-overlap. The 4-methyl-2-cyclohexenone prefers, for stereoelectronic factors, the half-chair A, which leads to the ci.s-product on (2-propenyl)silane addition (path a), even if this is not the sterically least hindered approach. 

The addition of the lithium enolates of methyl acetate and methyl (trimelhylsilyl)acetate to ( + )-(S)-2-(4-methylphenylsulfinyl)-2-cycloalkenones gives, after desulfurization, (/ -substituted cycloalkenones. A higher level of selectivity is observed with the a-silyl ester enolate and in the cyclohexenone series13. The stereochemical outcome is rationalized by assuming attack on a ground-state conformation analogous to that in Section 1.5.3.2.1. 

Carbonyl insertion is preferentially observed in the photoindueed reaction of 22 to give the cyclohexenones 25 and 26 as shown in Scheme 9 [17]. The acyl complex 24 is involved as an intermediate. The eyclohexenone formation appears to be susceptible to conformational effect, as observed in the facile rearrangement of 27 to 28. 

If thermal motion on the Ti (or Si) surface leads to a quasi-equilibrium distribution of molecules between several minima, some of them are likely to provide a faster return to So than others and they will then drain the excited state population and determine which products will be formed. This is a straight-forward kinetic problem and it is clear that the process need not be dominated by the position of the lowest-energy accessible minimum in the excited hypersurface. Such minima may correspond to conformers, valence isomers, etc. Of course, it is well known that ground-state conformers may correspond to excited-state isomers, which are not in fast equilibrium. 65,72) Also, there is no reason why several separate minima in Si or Ti could not correspond to one minimum in So, and there is some evidence that this situation indeed occurs in certain polycyclic cyclohexenones. 73,74)... 

Conformationally constrained 2-cyclohexenones which cannot undergo the lumiketone rearrangement (cf. chapter 3.1.5) are efficiently reduced to cyclohexanones (4.18) 420). 

The foregoing stabilizing 1,3-diaxial interaction was shown to have potentially useful applications for stereochemical control of addition reactions56. The /l-trimethylstannyl cyclohexenone ketal 65 affords a nearly 1 1 mixture of isomeric c/s-diols 66 and 67 when hydroxylated with OsC>4 (equation 25). However, the chlorostannane 68 upon hydroxylation with OSO4, then Sn methylation, yields a 94 6 mixture favoring the a,a,-diol 66. Evidently, the conformational change induced by the 1,3-diaxial donor-acceptor... 

Conjugated j-f/varm -enones display n-rr (300-350 nm) and n-n (230 260 nm) transition Cotton effects, whose sign can be useful in predicting the absolute configuration of the molecule. For 2-cyclohexenones and their polycyclic analogs the signs of these Cotton effects are due to the helicity of the chromophore, (i.e., conformation of the molecule) and due to the interaction with substituents in the vicinity of the chromophore50-51. 

Reactions on SP2 Type Unsaturated Systems Considering a conformationally rigid cyclohexenone such as 76, an attack by a nucleophile with stereoelectronic control on the top face yields the boat-like enolate ion 77 whereas that on the bottom face gives the chairlike enolate ion 78. The second process should therefore be favored as suggested by Toromanoff (31). 

If a new chiral centre is formed on a saturated six-membered ring, conformational control is a possibility. We have already seen conformational effects in the reduction of ketone 48 and the same kind of arguments apply to attack on ketones by carbon nucleophiles. The alcohol 59, needed to make an analgesic 58, can obviously be made from the ketone 60 and that is the result of conjugate addition to cyclohexenone.12... 

Cyclohexenones are even flatter than cydohexenes, but it is convenient to draw them in a similar conformation. Conjugate addition to this substituted cyclohexenone gives the trans product. 

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