Cyclohexanones stereoselective alkylation

In one of the first reported stereoselective alkylation reactions [18], Yamada described the use of a methyl prolinate as chiral auxiliary in the methylation of a cyclohexanone-derived enamine (Fig. 3 reaction D).The low stereoselectivity of the reaction clearly depends on the possibility for the alkylation to occur on a different conformation of the enamine, namely the one in which the C-C double bond is transoid to the stereocenter, that thus cannot exert any useful stereocontrol. 

Ireland and co-workers used a Wichterle sequence in their stereoselective syntheses of diterpenoid resin acids when annulations with methyl vinyl ketone resulted in polymeric tars. Stereoselective alkylation of cyclohexanone 34 with Wichterle s reagent afforded 35 as a single stereoisomer. Studies performed on this system determined that alkylation was favored cis to the C2 methyl group. After hydrolysis of the vinylic chloride 35 to the diketone 36, cyclization proved difficult due to the large amount of steric hindrance present in the molecule. Base-catalyzed cyclization resulted in only partial conversion to the desired octalone 37. It was found that a significant portion of the material was cleaved to the starting material for this sequence, monoketone 34, via facile reverse Michael addition when the side chain adopted an equatorial confirmation. 

The stereoselective reactions in Scheme 2.10 include one example that is completely stereoselective (entry 3), one that is highly stereoselective (entry 6), and others in which the stereoselectivity is modest to low (entries 1,2,4, 5, and 7). The addition of formic acid to norbomene (entry 3) produces only the exo ester. Reduction of 4-r-butylcyclohexanone (entry 6) is typical of the reduction of unhindered cyclohexanones in that the major diastereomer produced has an equatorial hydroxyl group. Certain other reducing agents, particularly sterically bulky ones, exhibit the opposite stereoselectivity and favor the formation of the diastereomer having an axial hydroxyl groi. The alkylation of 4-t-butylpiperidine with benzyl chloride (entry 7) provides only a slight excess of one diastereomer over the other. 

Stereoselective oxygen transfer to the sulphur atom of alkyl aryl sulphides catalyzed by 2-flavoenzyme monooxygenases afforded optically active sulphoxides in high optical yields . For instance, with ethyl p-tolyl sulphide as substrate cyclohexanone monooxygenase from Actinetobacter produces predominantly (— )-(S)-sulphoxide with 64% e.e. In contrast, FAD-containing dimethylaniline monooxygenase purified from hog liver microsomes affords (+ )-(i )-enantiomer of this sulphoxide with 90% optical purity . ... 

The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the reaction which is crucial in many cases is the stereoselectivity. The alkylation step has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, since the electrons which are involved in bond formation are the n electrons. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile will approach from the less hindered of the two faces, and the degree of stereoselectivity depends upon the steric differentiation. For simple, conformationally based cyclohexanone enolates such as that from 4 - /- b u ty I eye I o h cx an o ne, there is little steric differentiation. The alkylation product is a nearly 1 1 mixture of the cis and trans isomers. 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

This topological rule readily explained the reaction product 211 (>90% stereoselectivity) of open-chain nitroolefins 209 with open-chain enamines 210. Seebach and Golinski have further pointed out that several condensation reactions can also be rationalized by using this approach (a) cyclopropane formation from olefin and carbene, (b) Wittig reaction with aldehydes yielding cis olefins, (c) trans-dialkyl oxirane from alkylidene triphenylarsane and aldehydes, (d) ketenes and cyclopentadiene 2+2-addition, le) (E)-silyl-nitronate and aldehydes, (f) syn and anti-Li and B-enolates of ketones, esters, amides and aldehydes, (g) Z-allylboranes and aldehydes, (h) E-alkyl-borane or E-allylchromium derivatives and aldehydes, (i) enamine from cyclohexanone and cinnamic aldehyde, (j) E-enamines and E-nitroolefins and finally, (k) enamines from cycloalkanones and styryl sulfone. 

On the other hand, lithium enolates derived from substituted endocyclic ketones have largely been exploited in the synthesis of steroids since the regioselectivity of their deprotonation can be controlled and high levels of 1,2- and 1,3-stereoselection occur9,418. The control is steric rather than electronic, with the attack directed to the less substituted ji-face of the enolate for conformationally rigid cyclopentanones, whereas stereoelectronic control becomes significant for the more flexible cyclohexanones. Finally, an asymmetric variant of the formation of a-branched ketones by hydration of camphor-derived alkynes followed by sequential alkylation with reactive alkyl halides of the resulting ketones was recently reported (Scheme 87)419. 

The nitration of enol acetates with acetyl nitrate is a regiospecific electrophilic addition to the 3-carbon of the enol acetate, followed by a hydrolytic conversion of the intermediate to the a-nitro ketone. With enol acetates of substituted cyclohexanones the stereochemistry is kinetically established. So, 1-acetoxy-4-methylcyclohexene (22) yields the thermodynamically less stable rrans-4-methyl-2-nitrocylo-hexanone (24) in greater proportion cis. trans = 40 60) (equation 8). This mixture can be equilibrated in favor of the thermodynamically more stable cis diastereomer (23) (cis. trans = 85 15). Nitration of 1-ace-toxy-3-methylcyclohexene (25) leads to frans-3-methyl-2-nitrocyclohexanone (26), which is also the thermodynamically more stable isomer (equation 9). No stereoselection occurs in the kinetically controlled nitration with acetyl nitrate of l-acetoxy-5-methylcyclohexene (27 equation 10), but the 1 1 mixture of the 5-methyl-2-nitrocyclohexanones can be equilibrated in favor of the trcms diastereomer (28) (cis trans = 10 90). 2-Alkyl-2-nitrocyclohexanones cannot be prepared in acceptable yields by nitration of the corresponding enol acetates with acetyl nitrate. 

Recently Avery et al [94] have developed a stereoselective total synthesis of (+)-artemisinine starting from (R)-(+)-pulegone (92). Elaboration of 92 gives the known sulphoxide 93, which was allowed to undergo dianion alkylation and desul-phurisation to yield disubstituted-cyclohexanone (95). Homologation of the latter afforded the aldehyde % in two steps. This product was then converted into the silyl acetate (97), which underwent Tandem Claisen ester-enolate rearrangement to give the vinylsilane 98. Ozonolysis and cyclisation of 98 provided 7 (Scheme 10). 

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