Four-substituted cyclohexanone

As the WT CHMO was known to react (S) selectively with simple four-substituted cyclohexanone derivatives [84—87], it was logical to test mutant 1-K2-F5 as a catalyst in the BV reaction of other ketones. For example, when 4-methoxycyclohexanone (38) was subjected to the BV reaction catalyzed by mutant 1-K2-F5, almost complete enantioselectivity was observed in favor of the (S)-lactone (39) (98.5% ee), in contrast to the WT, which is considerably less selective (78% ee) (see Scheme 2.11) [89]. 

P-Hydroxy sulfoximines are thermally labile and revert to their starting carbonyl compound and sulfoximine on mild thermolysis. This property has been exploited effectively as a method for the resolution of racemic chiral cyclic ketones.65 For example, the addition of the lithium salt of (+)-(S)-2b (99% ee) under kinetically controlled conditions (-78 °C) to racemic menthone gave three of the four possible diastereomeric adducts. The major two adducts resulted from attack on the menthone from the equatorial direction. These diastereomeric adducts could be readily separated by column chromatography. Thermolysis of the individual two major diastereomeric carbinols at 140 °C gave d- and /-menthone, respectively, in high enantiomeric purities (90-93% ee). This methodology has been successfully applied to the resolution of other 2-substituted cyclohexanones as well as other chiral ketones that have served as advanced synthetic intermediates for the synthesis of natural products.66-69... 

Minato et have reported the isolation of acorenone (149) from Acorus calamus L. The physical properties (m.p., [ajp) which they ascribe to this compound are markedly different from two previous sets of data. Hydrogenation ofacorenone is reported to give isoacorone (150 R = Me, = H)andacorone (150 R = H, R = Me). Recently, Conia et al. have demonstrated that thermal cyclization (220 °C) of the appropriately substituted cyclohexanone (151) [derived from (-+- )-3-methylcyclohexanone] yielded four isomeric spiro-diketones closely related to the acorane skeleton. The intermediacy of the isopropylidene isomer (152) was indicated and from a detailed study of n.m.r. solvent shifts and c.d. spectra it was concluded that these four spiro-diketones can be represented as (153)—(156). 

An alternate radical-induced addition-fragmentation sequence relies on the 1,4-elimination of a leaving group to drive the reaction. In this sequence, because the fragmentation is accompanied by the expulsion of a tiibutylstannyl radical, the requirement for the initial tributyltin hydride is only catalytic (Scheme 79). The stereospecificity of the reaction course has been rationalize in terms of a conformational preference for the elimination step, as depicted in Scheme 79 where the rran.r-substituted cyclohexanone forms only one double bond geometry in the product. As shown in equations (40) and (41), the ci.r-substituted cyclohexanones undergo the four- and three-carbon expansions stereospecifically to give the (Z)-alkenes. 

Chen et al. have further applied the TFA salt of 9-amino-9-deoxyepiquinine lo as chiral organocatalyst to the desymmetrization of prochiral a,a-dicyanoalkenes from 4-substituted cyclohexanones via domino Michael-Michael addition reactions with a, 3-unsaturated ketones. These reactions exhibited high synthetic efficacy and bicyclic products 16 with two new C—C bonds, and four stereogenic centers... 

Lewis acid catalyzed aldol coupling of silyl enol ethers with substituted cyclohexanone acetals showed an excellent preference for equatorial attack (95-l(X)%). In accord with this general rule, additions of a silyl enol ether to equatorially or axially substituted chiral spiroketals derived from -menthone gave 00% equatorial attack and formation of a single one of the four possible diastereoisomers (Scheme 9) 3, 4 -pjjjg methodology, followed by protection of the hydroxy group (X = OTHP, (XIPh.i) and alkaline removal of the chiral auxiliary was used for the synthesis of several natural products. ... 

Hence, the first clearcut evidence for the involvement of enol radical cations in ketone oxidation reactions was provided by Henry [109] and Littler [110,112]. From kinetic results and product studies it was concluded that in the oxidation of cyclohexanone using the outer-sphere one-electron oxidants, tris-substituted 2,2 -bipyridyl or 1,10-phenanthroline complexes of iron(III) and ruthenium(III) or sodium hexachloroiridate(IV) (IrCI), the cyclohexenol radical cation (65" ) is formed, which rapidly deprotonates to the a-carbonyl radical 66. An upper limit for the deuterium isotope effect in the oxidation step (k /kjy < 2) suggests that electron transfer from the enol to the metal complex occurs prior to the loss of the proton [109]. In the reaction with the ruthenium(III) salt, four main products were formed 2-hydroxycyclohexanone (67), cyclohexenone, cyclopen tanecarboxylic acid and 1,2-cyclohexanedione, whereas oxidation with IrCl afforded 2-chlorocyclohexanone in almost quantitative yield. Similarly, enol radical cations can be invoked in the oxidation reactions of aliphatic ketones with the substitution inert dodecatungstocobaltate(III), CoW,20 o complex [169]. Unfortunately, these results have never been linked to the general concept of inversion of stability order of enol/ketone systems (Sect. 2) and thus have never received wide attention. 

A number of typical alkylations of various phenols are shown in Table 6.1 (refs. 1-7). A novel feature of four of these procedures is the o-substitution which resulted. This feature, particularly where metallic systems are involved, reflects the tautomeric nature of phenols. While benzenoid intermediates represent the most obvious choice of starting material, the facile dehydrogenation of an alkylated cyclohexanone has also been used. Thus cyclohexanone and propanal (2 equivs.) heated at 150 C in the presence of bis-cyclopentadienyl zirconium dichloride afforded 2,6-di-n-propylphenol in 69% yield (ref.8). 

Muthusamy and co-workers have demonstrated [82] the reactions of the bicyclic ylide 57, generated from the diazocarbonyl compoimd 56, with symmetrical and unsymmetrical dipolarophiles. Thus, exposure of the cyclohexanone-substituted a-diazocarbonyl compound 56 to DMAD in the presence of Rh2(OAc)4 as the catalyst has furnished the cycloadduct 58 (Scheme 16). This cycloaddition was diastereoselective and, in the case of unsymmetrical dipolarophiles such as methyl methacrylate and propargyl bromide, they were regioselective and afforded oxygen heterocycles 59 and 60, respectively. The same research group has reported the 1,3-dipolar cycloaddition of the bicyclic carbonyl yUde 57 with other dipolarophiles, namely fulvenes [83]. In these tandem cycUzation-cycloaddition reactions involving fulvenes, four stereocenters and two new C-C bonds are formed in a single step. Symmetrical dipolarophiles such as macrocycHc olefins were also used for diastereoselective 1,3-dipolar cycloaddition reaction with 56 [84]. 

A four-component, one-pot reaction of aromatic aldehyde, cyclohexanone, malononitrile, and amines was reported in basic IL [BMImJOH, providing A-metltyl or A-aiyl-substituted 2-amino-4-aiyl-5,6,7,8-tetrahydroquinoline-3-caibonitriles in excellent yields [112] (Scheme 7.10). 

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