Hydroxyalkylation enolates

The reaction of tnfluoromethyl-substituted A -acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enarmnes [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomlnle [2,47], alkynes [42], electron-nch heterocycles [43], 1,3-dicarbonyl compounds [44], organolithium compounds [45, 46, 47, 48], and Gngnard compounds [49,50], readily undergo hydroxyalkylation with hexafluoroace-tone and amidoalkylation with acyl imines denved from hexafluoroacetone... 

Li s group prepared a series of substituted 2-(hydroxyalkyl)tetrahydroquinohne derivatives 2-619 and 2-620 starting from anilines 2-617 and cyclic enol ethers 2-618 in the presence of catalytic amounts of InCl3 (Scheme 2.141) [322], Good yields of 73-90 % were obtained with an electron-donating or no substituent R at the aniline moiety. 

In a similar way, Carreaux and coworkers [53] used 1-oxa-l,3-butadienes 4-155 carrying a boronic acid ester moiety as heterodienes [54], enol ethers and saturated as well as aromatic aldehydes. Thus, reaction of 4-155 and ethyl vinyl ether was carried out for 24 h in the presence of catalytic amounts of the Lewis acid Yb(fod)3 (Scheme 4.33). Without work-up, the mixture was treated with an excess of an aldehyde 4-156 to give the desired a-hydroxyalkyl dihydropyran 4-157. Although this is not a domino reaction, it is nonetheless a simple and useful one-pot procedure. 

The linear sequence starts from (-l-)-carvone (67) (Scheme 12). Establishing the quaternary center at Cl was achieved via a successive enolate alkyla-tion/hydroxyalkylation to furnish hydroxyketone 68. Reduction of the enone... 

Diisobutylaluminium phenyl tellurolate, a highly air- and moisture-sensitive reagent, prepared by reaction of diisobutylaluminium hydride with diphenyl ditelluride, undergoes an in situ addition to a,jS-unsaturated carbonyl compounds, leading to the corresponding jS-phenyltelluroaluminium enolate. This intermediate is hydrolysed by aqueous HCl into jS-phenyltelluro compounds or smoothly affords an aldol reaction with aldehydes to give a-hydroxyalkyl-jS-phenyltellurocarbonyl compounds. 

An unexpected reactivity in the functionalization of 2-acyl-l,3-dithianes has been reported by Mioskowski and co-workers. They found that 2-acyl-l,3-dithianes with no further heteroatom at the acyl side chain react with aldehydes to give 2-acyl-2-hydroxyalkyl-l,3-dithianes, whereas a silyl-protected hydroxy group in the side chain of the 2-acyl-l,3-dithiane led to formation of the aldol product at the opposite site of the carbonyl group. Acyl chlorides always react with 2-acyl-l,3-dithianes to give the enol esters (Scheme 81) <2003TL213>. 

However, as the C-6 position is a a-carbonyl position, the preparation of various penem-based antibiotics becomes easily accessible with the aid of enolate reactivity. The example depicted in Scheme 33 is a mild and efficient method for the preparation of l-hydroxyalkyl(aryl) penems 59 from 6 -brornopcncrns <2004JOC5850>. 

The lithium anion of chloromethyl phenyl sulfoxide reacts with tetrahydrofuran-2-ones 1011 to afford a diastereo-meric mixture of hemiacetal adducts 1012, the potassium enolate of which is treated with /-BuLi followed by addition of a proton source leading to to-hydroxyalkyl ketenes 1013, which themselves cyclize to 6-substituted tetrahydropyran-2-ones in excellent overall yield (Scheme 263) <1998TL9215>. 

Hydroxyalkylation of Enolates with Carbonyl Compounds ( Aldol Addition ) Synthesis of /3-Hydroxyketones and /3-Hydroxyesters... 

The synthesis of dihydrofuran derivatives such as 177 has been performed to explore scope and limitations of the Lewis acid promoted hydroxyalkylation of siloxycyclopropanes. Table 6 shows that aromatic as well as aliphatic ketones can efficiently be incorporated. Enolization of ketones does not occur and a 1-methyl group at the cyclopropane is no obstacle for the reaction, which now binds the carbonyl compound to a quartemary center with surprisingly high efficiency (entry 5). Albeit there are some restrictions with regard to the substitution pattern of the cyclopropanes, bicyclic siloxycyclopropanes also give good yields (e.g. entry 6 and Eq. 76). Further examples of the tetrahydrofuran synthesis from intermediate y-lactols with... 

As mentioned in the last paragraph, the methodology employing Lewis acids for activation of siloxycyclopropanes has certain restrictions with regard to the substitution pattern. Therefore an alternative path to prepare hydroxyalkylated adducts would be most valuable. It can actually be achieved via enolates of methyl 2-siloxy-cyclopropanecarboxylates, which add cleanly to many carbonyl compounds (Eq. 83)96). 

The stereoselectivity of this reaction rises when more bulky nucleophiles are employed (compare entries 7, 3,1, and 5). This is most impressively demonstrated by comparison of the y-lactol reduction with its allylation leading to 205 or 206, respectively (Scheme 10). Formation of tetrahydrofuran derivative 208, dihydrofuran 209, or unsaturated a-methylen-y-butyrolactone 207 illustrate that various modes of straightforward work-up procedures provide two different five membered heterocycles 93 b-96). A second example without the geminal dialkyl substitution at C-3 of the siloxy-cyclopropane depicted in Eq. 86 making available the annulated tetrahydrofuran-3-carboxylate 210 underlines the generality of the C-C-bond forming hydroxyalkylation reaction via ester enolates. 

As mentioned earlier, the primary adducts 198 are isolable with good yields in exceptional cases only. To determine the stereoselectivity of the hydroxyalkylation step, the enolate of the more stable /m-butyldimethylsiloxy derivative 211 has been combined with acetone. The two diastereomeric adducts 212 and 213 could be isolated and separated by chromatography 96 b). Interestingly the product 213 formed by the contrasterical approach of the electrophile predominates although the effect is much less pronounced than with alkyl halides (see above). 

Double aldol reaction proceeds stereoselectively at the cr-carbon of ketones to give a-( 1 -hydroxyalkyl)-/ -hydro-xyalkylketones (double aldols) in good to high yields. In situ generated tin(ll) enolates play a key role in this reaction (Equation (87)).244... 

Bu3SnLi adds to ,/3-unsaturated esters, and the resulting Li-enolate reacts with 3-methyl-2-butenal to afford 7-hydroxyalkyl tins which are treated with BF3-OEt2 to produce vinyl cyclopropane carboxylic esters (chrysanthemic acid) (Equation (111)).280... 

In the presence of a proton source, the O-M bond of the metal ketyl radical anion is protonated to form a carbinol radical 5. Further reduction then forms a hydroxyalkyl carbanion 6 and protonation gives an alcohol product (Scheme 4.5). Competing processes include dimerisation of the metal ketyl radical anion to give pinacol products or disproportionation to give an enolate and an alkoxide (Scheme 4.5).10... 

Mn-enolates can also be hydroxyalkylated by reacting with a vast array of aldehydes to give syn-aldol products in good yields. The stereoselectivities obtained from Mn- and Li-enolates... 

Aldol reactions of aldehydes with the -stannyl a-selanyl enolate generated from 2-phenylselanylcyclopent-2-enone directly produced 2-(l-hydroxyalkyl) cyclopenten-2-ones in high yields [55] (Scheme 43, reaction l).The n-Bu3SnSePh elimination was explained by lithium aldolate assistance. The nature of the nucleophile has a dramatic effect on the stereochemistry of the 1,4-addition products isolated after protonolysis. The use of lithium dibutylcuprate afforded cz5-compounds, whereas Me3SiLi or, better, a mixed silylcuprate, furnished the trans-isomers as the major products [56] (Scheme 43, reaction 2). 

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