Stereoselectivity cyclic ketones

An interesting aspect of this reaction is the contrasting stereoselective behaviour of the dimethyisulfonium and dimethyloxosuifonium methylides in reactions with cyclic ketones (E.J. Corey, 1963 B, 1965 A C.E. Cook, 1968). The small, reactive dimethyisulfonium ylide prefers axial attack, but with the larger, less reactive oxosulfonium ylide only the thermodynamically favored equatorial addition is observed. 

The enolates derived from cyclic ketones are necessarily /(-isomers. The enolate of cyclohexanone reacts with benzaldehyde to give both possible stereoisomeric products. The stereoselectivity is about 5 1 in favor of the anti isomer under optimum... 

A large amount of data has been accumulated on the stereoselectivity of reduction of cyclic ketones.120 Table 5.4 compares the stereoselectivity of reduction of several ketones by hydride donors of increasing steric bulk. The trends in the table illustrate... 

The overall transformation of this sequence corresponds to the aldol addition of an aldehyde with a cyclic ketone. The actual aldol addition frequently proceeds with low stereocontrol, so this sequence constitutes a method for stereoselective synthesis of the aldol adducts. The reaction has been done with several Lewis acids, including SnCl4, BF3, and Ti(0-/-Pr)3Cl. 

Reduction of cyclic ketones.l These complexes selectively reduce cyclic ketones to the less stable alcohol. The most stereoselective reagent is that in which the R group is /-butyl this complex is comparable to lithium trisiamylborohydride in stereoselectivity. 

All reducing agents used for reductions of aliphatic and aromatic ketones can be used for reduction of cyclic ketones to secondary alcohob (pp. 107 and 109). In fact, reduction of cyclic ketones is sometimes easier than that of both the above mentioned categories [262]. What is of additional importance in the reductions of cyclic ketones is stereoselectivity of the reduction and stereochemistry of the products. 

Stereoselective reductions of cyclic ketones have immense importance in the chemistry of steroids where either a or 5 epimers can be obtained. A few... 

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

Bordeau and coworkers have described an efficient and stereoselective synthesis of kinetic silylenol ethers. Less highly substituted silylenolates are regiospecifically prepared in high yield, around room temperature under kinetic conditions, from unsymmetric cyclic ketones and [(DA)2Mg] in THF/heptane (equation 68). 

Some examples of the synthetic usefulness of zincate reagents in organic synthesis are stereoselective alkylation reactions of cyclic ketones, conjugate-addition reactions... 

General and stereoselective synthesis of spiroethers and less thermodynamically stable spiroketals have recently been developed by Hadded and coworkers129,130. The key step is the intramolecular photocycloaddition of chiral dioxinones of type 305 to dihydropyrones. Subsequent fragmentation of the produced four-membered ring provides, after oxidative enlargement of the cyclic ketone, the thermodynamically less stable spiroketal 310 (R = H) as was demonstrated on photoproduct 308 (Scheme 66). 

Cyclic ketones may be reduced by thexylchloroborane-dimethyl sulfide (ThxBHCl.SMe2) and the related bromo and iodo compounds, in a stereoselective manner (equation 62)248. The selectivity increases with increasing halogen size. These reagents give much better selectivity than many of the more traditional ones, such as ThxBI D. 

Finally, ring expansions of cyclic ketones are an important method for the preparation of carbocyclic systems. Diazoalkanes allow this reaction to occur and involve C—C bond formation. When combined with carefully chosen organoaluminum compounds, this process can be performed in a highly stereoselective fashion (equation 148)541. 

Selective reductions This complex borohydride is particularly useful for selective 1,2-reduction of acyclic a,/ -cnones and of conjugated cyclohexenones to allylic alcohols. However, the 1,2-selectivity is less marked with conjugated cyclopentenones. The reagent reduces unhindered cyclic ketones to the more stable (equatorial) alcohols with stereoselectivity greater than that of sodium borohydride. 

Hirano et al. reported on the stereoselective cyclization to give tetralin derivatives using the phenanthrene-p-dicyanobenzene sensitizer system. Pandey independently reported the intramolecular photocyclization of methoxybenzene derivatives bearing silyl enol ether chromophore via their heterodimer radical cations in the presence of 1,4-dicyanonaphthalene gave benzo-annulated cyclic ketones in 70% yields [490] (Scheme 133). 

PdCl2(PhCN)2-catalysed Claisen rearrangement of the allyl vinyl ether 474 derived from cyclic ketone at room temperature affords the syn product 475 with high diastereoselectivity [203]. In contrast to thermal Claisen rearrangement, the Pd(II)-catalysed Claisen rearrangement is always stereoselective, irrespective of the geometry of allylic alkenes. The anti product is obtained by the thermal rearrangement in the presence of 2,6-dimethylphenol at 100 °C for lOh. 

Stereoselectivity in the reaction of acyclic ketone 270 is different from that of the cyclic ketone 256. The acetate in 271, prepared by reduction of the ketone 270 to alcohol with LiAlH and acetylation, was displaced with Me A1 from the exo side to give 272 with retention of the stereochemistry. No racemization of benzyl cation was observed. However, reaction of 270 with MeLi gave 274. The OH group of 274 was removed with hydride from the less hindered side as shown by 275 to give 276 with... 

A new catalytic cycle for the enantioselective protonation of cyclic ketone enolates with sulfinyl alcohols has been developed (Scheme 2)25 In this method, the achiral alcohol plays two roles it is involved in the turnover of the chiral proton source and also in the generation of a transient enolate through the reaction of its corresponding alkoxide with the enol trifluoroacetate precursor. Stereoselectivity was found highly dependent on the structure of the achiral alcohol. 

Remarkably, thermolysis of the Baylis-Hillman adducts 311 (R1 = alkyl or aryl Rz = Ac, CN, CC Me) in toluene at 210 °C in a sealed tube gave stereoselectively the cyclized product (+)-312, which included incorporation of the elements of the solvent and, when Rz = Ac, a single isomer was obtained (Equation 33). The yields were moderate (37-56%) and when RZ = CN and C02Me some racemization occurred. Similar results were obtained when either p-xylene or mesitylene was used but no reaction occurred when chlorobenzene or anisole was used. Unsaturated rings are obtained in similar yields and stereoselectivity if the N-substituent is an alkyne. In addition, benzene thiol reacted in boiling benzene in the presence of AIBN to give 313, which on ozonolysis yielded the cyclic ketones 314 ( = 1-3) in 52-70% yield <2001JOC1612>. 

Y. Senda, Role of the Fleteroatom on Stereoselectivity in the Complex Metal Flydride Reduction of Six-membered Cyclic Ketones, Chirality 2002, 14, 110-120. 

The key to the difference is in the conformations. The cyclic ketone has one conformation and the two approaches to the faces of the ketone are very different. The open-chain compound has an indefinite number of conformations as rotation about all the C-C bonds is possible. In any one conformation, attack on one face of the ketone or the other may happen to be preferred, but on average there will be very little difference. There is all the difference in the world between cyclic and open-chain compounds when it comes to stereoselective reactions. This is why we have made this topic into two chapters this one (33) dealing with rings, the next (34) with what happens without rings. 

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