Enones hydrogen-bonding

A mechanistic rationale for the observed cw-selectivity has been proposed based on preorganisation of the Breslow-type intermediate and imine through hydrogen bonding 253, with an aza-benzoin oxy-Cope process proposed. Reaction via a boat transition state delivers the observed cw-stereochemistry of the product (Scheme 12.57). Related work by Nair and co-workers (using enones 42 in place of a,P-unsaturated sulfonylimines 251, see Section 12.2.2) generates P-lactones 43 with fran -ring substituents, while the P-lactam products 252 possess a cw-stereo-chemical relationship. 

Resolution of bicyclic enones. This optically active diol selectively forms a hydrogen-bonded insoluble complex with one enantiomer of the bicyclic enone 2, which when heated liberates ( — )-2 of 100% ee. This resolution is useful for a few... 

Product 34 predominates in the polar aprotic solvent (acetonitrile), while in the polar protic solvent (methanol) products 35 are formed preferentially. The different products are caused by the relative rate of deprotonation against desilylation of the aminium radical, that is in turn governed by the action of enone anion radical in acetonitrile as opposed to that of nucleophilic attack by methanol. In an aprotic, less silophilic solvent (acetonitrile), where the enone anion radical should be a strong base, the proton transfer is favoured and leads to the formation of product 34. In aprotic solvents or when a lithium cation is present, the enone anion radical basicity is reduced by hydrogen bonding or coordination by lithium cation, and the major product is the desilylated 35 (Scheme 4). 

The main features are a le reduction of the hydrogen-bonded enone leading to an enol radical that tautomerizes to a more easily reducible keto radical or dimerizes. 

The additional structure C, which cannot be drawn for an unconjugated carbonyl derivative, implies that the carbonyl band in an enone has more single bond character and is therefore weaker. The involvement of a carbonyl group in hydrogen bonding reduces the frequency of the carbonyl stretching vibration by about 10 cm-. This can be rationalised in a manner analogous to that proposed above for free and H-bonded 0-H vibrations. 

Moreover, the enone olefinic bond is reduced with total regioselectivity and A/B cis, 5[5-3-oxo derivatives are produced with stereoselectivity values up to 89%. The 3-oxo group is hydrogenated according to a subsequent, well separated step (mono dihydrogenation selectivity up to 95%), giving equatorial alcohols. 

Although the present procedure attaches the isoxazole via alkylation of a /9-keto ester, there are several different methods by which attachment could have been effected. Both alkylation of a cyclohexanone enamine6 and direct alkylation of an enone anion followed by hydrogenation of the enone double bond have been used successfully.2,3... 

Addition of the thiophenolate anion to the / -carbon atom of the enone is the chirality-determining step it is, at the same time, rate-determining. The transition state is a ternary complex comprising the catalytic base in the protonated form, the thiophenolate anion, and the enone. The last is activated to nucleophilic attack by hydrogen-bonding to the catalysts / -hydroxy group. The chiral cinchona bases thus act as bifunctional catalysts. 

An enantioselective intermolecular Michael addition of aldehydes (138) to enones (139), catalysed by imidazolidinones (140), has been reported. Chemoselectivity (Michael addition versus aldol) can be controlled through judicious choice of hydrogen bond-donating co-catalysts. The optimal imidazolidinone-hydrogen bond donor pair affords Michael addition products in <90% ee. Furthermore, the enamine intermediate was isolated and characterized and its efficacy as a nucleophile in the observed Michael addition reactions was demonstrated.172... 

Another mechanistically interesting example was reported by Ikariya et al. in 2003 (Scheme 10) [12], The authors focused on the basic character of the Ru-amido complex 21. The reaction of dimethyl malonate with 21 afforded a C-bound Ru-enolate, the structure of which was supported by X-ray analysis. It was considered that the N-H moiety plays a role in bringing the enones to the optimum position by hydrogen bonding, as shown in 22 C-C bond formation then occurs at relatively high reaction temperature, affording the desired adduct in 97 % ee. Before this report appeared, a related catalyst system had been examined by Suzuki et al. for the Type I reaction [4f]. 

Nagasawa and co-workers reported the use of a chiral bis-thiourea catalyst (108) for the asymmetric MBH reactions of cyclohexenone with aldehydes [95]. Since others had already shown that thioureas form hydrogen bonds with both aldehydes and enones, it was hypothesized that the inclusion of two thiourea moieties in close proximity on a chiral scaffold would organize the two partners of the MBH reaction and lead to enantiofacial selectivity. Initial studies showed that the achiral 3,5-bis-(trifluoromethyl)phenyl-substituted urea increased the rate of MBH reaction between benzaldehyde and cyclohexenone. These authors then showed that chiral 1,2-cyclohexyldiamine-linked bis-thiourea catalyst 108, used at 40 mol% loading in the presence of 40 mol% DMAP, promoted the MBH reactions of cyclohexenone with various aliphatic and aromatic aldehydes (40) to produce allylic alcohols in moderate to high yields (33-99%) and variable enantio-selectivities (19-90% ee Table 6.33). 

Recently, Maruoka described the novel dual function catalyst 26 bearing hydroxyl groups which were incorporated to allow hydrogen bonding to the enolate intermediate. Indeed, 26 was found to catalyze enone epoxidation with 89-99% tt [67]. Interestingly - and unlike some other systems - alkyl substitution is tolerated (Scheme 12.14). 

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