Aldol regiospecific

S-Ketoalkyltrimethylsilanes (6) can be employed to produce two types of aldols regiospecifically depending on whether enolate formation is arranged to precede or to occur simultaneously with desilylation (Scheme 19). ... 

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90).226,227 A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91).228 The combination of BiCl3-Al,229 CdCl2-Sm,230 and Zn-Et3B-Eb0231 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective (Eq. 8.92).232... 

Regiospecific and enantioselective aldol reactions 168) were also performed with SAMP (137). Lithiated hydrazones obtained from ketones (154) as described above were alkylated with carbonyl compounds and the adducts then treated with chloro-trimethylsilane. The resulting trimethylsilylethers (155) were finally oxidatively hydrolyzed to yield the chiral (3-hydroxyketones (156) (e.e. = 31-62%)168),... 

Lithium salts of ketone derivatives such as imines, oximes and hydrazones have also been used for directed aldol reactions (Scheme 103).374 375 A recent example involves triple coordination of lithium in a very rigid transition state, to lead to regiospecificity in the product (Scheme 104).376... 

Trimethylsilyl enolates of aldehydes and ketones are now established as highly useful synthetic intermediates.2 In particular, their Lewis acid-catalyzed reactions - e.g., alkylation 1 and mild, regiospecific aldol... 

Oshima and Nozaki generated the aluminum enolate regiospecifically by treatment of a-halo carbonyl compounds with Bu3SnAlEt2 subsequent reaction with aldehydes or ketones under mild conditions gave /3-hydroxy carbonyl compounds [117]. This subsequent aldol reaction is accelerated by the addition of catalytic Pd(PPh3)4 (Sch. 81). 

Trimethylsilyl enol ethers continue to be useful synthons for various aldol typeis,lb and Michael1 18 reactions. Their utility in part is due to their ease of regiospecific preparation, ease of cleavage and high reactivity. Danishefsky and coworkers have shown that silyl enol ethers react with dimethyl(methylene)ammonium iodide yielding Mannich bases.19 Otherwise inaccessible Mannich bases are accessible via the series below. 

Kobayashi et al. discovered that Yb(OTf)3 and other lanthanide triflates (l,ri(() lf)(, Ln=La, Pr, Nd, Sm, Eu, Gd, Dy, Ho, and Er) are excellent catalysts of hydroxymefhylation of propiophenone TMS enolate with aqueous formaldehyde solution at room temperature (Scheme 10.22) [70, 71]. The Yb(OTf) j-catalyzed hydroxymefhylation of a variety of SEE, including sterically hindered compounds, proceeds regiospecifically in high yield. In addition, almost 100% of Yb(OHf). is quite easily recovered from fhe aqueous layer and can be reused. Yb(OTf)3 also has high catalytic activity in fhe aqueous aldol reaction of other aldehydes. Interestingly, the catalytic activity is rather low in the absence of water. In aqueous media water would coordinate to ytterbium to form active ytterbium cations. 

There are many regiospecific reactions with aldehydes and ketones, such as the four-membered ring example 110 which gives an addition to the aldehyde 111 very like the aldol reaction with a silyl enol ether (and even uses the same catalyst, TiCI4) to give the unsaturated alcohol32 112 - presumably the key step is 113. 

Aldol reactions involving aluminum species are considered to be of less synthetic value because of the ambiguous isomerization of the aldol products, under the influence of the Lewis-acidic aluminum species. Efforts have been made to generate an aluminum enolate in a regiospecific manner. Addition of dialkylchloroalane and zinc to a mixture of an a-halo ketone (126) and an aldehyde leads to the formation of enolate (127), which subsequently reacts with the aldehyde, as shown in Scheme 53.71 This method is applicable to the construction of medium to large rings by intramolecular aldol cyclization of various a-bromocarboxylates of u)-hydroxy aldehydes (e.g. BiCHRC02(CH2) CH0 where — 9, 11 or 12 and R = H or Me). The macrolactonization proceeds in reasonable yield, as shown in Scheme 53. 

The so-called silyl enol ethers (enoxyorganylsilanes) are important synthones, e.g, for regiospecific preparation of enolates, aldol condensation, synthesis of a-substituted carbonyl derivatives and for thermal or photochemical cycloaddition. For the preparation of silyl enol ethers the corresponding aldehydes and ketones first have to be enolized and then treated with silylating agents in the presence of a base. Thus, from butanal (608) and Me3SiCl, cis/trans- 1-trimethylsiloxybut-l-ene (609) is obtained (equation 311)347, while 1-trimethylsiloxy-l-phenylethene (610) is the product from acetophenone (90a) (equation 312)347. 

For their second approach [84], Gurjar et al. have explored an Evans asymmetric aldol reaction, and a regiospecific ring opening of epoxides. They started their synthesis from (2S,3i )-epoxy-alcohol 121, which was prepared from propargyl alcohol 120 in six high yielding steps... 

Regiospecific aldol condensations. Methyl ketones can be converted into the kinetic lithium enolates by lithium diisopropylamide in THF at -78. These can be trapped by aldehydes to give aldols ... 

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