3-hydroxy-, aldol reaction with benzaldehyde

Heathcock and Dugger examined the enolate derived from methyl 3-methylcrotonate (equation 29). When the aldol reaction with benzaldehyde is carried out at -70 C and quenched at this temperature, diastereomeric aldols (12) and (13) are formed in a ratio of 3 2. However, if the aldolate is warmed to 15 C prior to work-up, lactone (14 80%) and hydroxy ester (15 12%) are produced. These results con-... 

The aldol condensation of benzaldehyde with the thioacetamide carbanion (RCHCSNRV), derived from the desilylation of the silyl-thioether with tetra-/i-buty-lammonium fluoride, is stereoselective at—80°C producing the erythro isomer of the p-hydroxy thioamide preferentially (Scheme 6.18, R = Me, erythro threo 95 5) via a conformationally mobile intermediate. However, when R is bulky, a greater amount of the threo isomer is formed. Predictably, as the reaction temperature is raised, so the stereoselectively decreases. This procedure contrasts with the corresponding condensation catalysed by titanium salts, where the complexed intermediate produces the threo isomer [47, 48],... 

In the aldol-Tishchenko reaction, a lithium enolate reacts with 2 mol of aldehyde, ultimately giving, via an intramolecular hydride transfer, a hydroxy ester (51) with up to three chiral centres (R, derived from rYhIO). The kinetics of the reaction of the lithium enolate of p-(phenylsulfonyl)isobutyrophenone with benzaldehyde have been measured in THF. ° A kinetic isotope effect of fee/ o = 2.0 was found, using benzaldehyde-fil. The results and proposed mechanism, with hydride transfer rate limiting, are supported by ab initio MO calculations. 

Asymmetric aldolreactions.1 The acetal (2) obtained by reaction of benzaldehyde with D-( — )-l (available from Aldrich) reacts with the ketone 3 to give the two possible crossed aldols in the ratio 16 1. The products can be converted into optically active /i-hydroxy ketones in three steps. 

Aliphatic esters have been condensed with benzaldehyde by means of sodium triphenylmethide. The reaction has been stopped at the aldol stage to give low yields (26-30%) of /3-hydroxy esters. ... 

The Mukaiyama reaction is an aldol-type reaction between a silyl enol ether and an aldehyde in the presence of a stoichiometric amount of titanium chloride. The reaction, which displays a negative volume of activation, could be performed without acidic promoter under high pressure [58]. In this case, the major product is the syn hydroxy ketone, not as for the TiCl4-promoted reactions which lead mostly to the anti addition product. Since the syn or anti selectivity is the result of two transition states with different activation volumes (AV n < AVfnti), it was of great interest to investigate the aldol reaction in water. Indeed, the reaction of the silyl enol ether of cyclohexanone with benzaldehyde in aqueous medium was shown to proceed without any catalyst and under atmospheric pressure, with the same syn... 

Although alkylation of 3-hydFoxy ester dianions occurs with high diastereofacial selectivity, the aldol reaction of the dianion obtained from methyl 3-hydroxybutanoate with benzaldehyde gives all four dia-stereomeric aldols in a ratio of 43 34 14 9 (equation 117). On the other hand, dianions of 8-hydroxy esters show rather good diastereofacial preferences under the proper conditions. Deprotonation of t-butyl-5-hydroxyhexanoate with lithium diethylamide in the presence of lithium triflate gives an enolate that reacts with benzaldehyde to give aldols (196) and (197) in a ratio of 91 9 (equation 118). Use of the r-butyldimethylsilyl ether instead of the alcohol resulted in no facial preference. 

In contrast, reaction of diethyl propionylphosphonate with lithium bis-(trimethylsilyl)amide (LiHMDS) at -78 °C gave the expected enolate as evidenced by its highly diastereoselective condensation with benzaldehyde, leading to the formation of 3-hydroxy-2-methyl-3-phenylpropionic acid (equation 91) " . An attempt was made to develop this concept to enantioselective aldol condensation. However, condensation of a cyclic chiral propionylphosphonamidate (31), synthesized from ( S)-A-isopropyl-4-aminobutan-2-ol, with benzaldehyde yielded 3-hydroxy-2-methyl-3-phenylpropionic acid in disappointingly low 47% e.e. (equation 92)... 

A slightly more complex case was investigated at about the same time by Woolsey and Khalil (1972), namely the reaction of l-diazo-3-phenylpropan-2-one with benzaldehyde (9-9). It is more complex because one might expect a reaction of the aldehyde with the CH2 group of the diazo ketone, and secondly, the reaction was run in ethanol with NaOH as base and not in the system used originally by Schollkopf and his coworkers. The product was, however, 2-diazo-l-hydroxy-l,4-di-phenylbutan-3-one, as expected for an aldol-type substitution. 

This aldol reaction is carried out using a base (triethylamine) and dibutylboron triflate plus benzaldehyde. The aldol product is formed with outstandingly good selectivity and in high yield, and all that remains is to remove the auxiliary with base and isolate the hydroxy-acid as a single diastereoisomer and a single enantiomer. 

When the aldolisation of cyclohexanone with aldehydes was performed in the presence of 4-hydroxy-prolinamide alcohols as the organocatalysts, the aldol adduct was obtained in comparable high yields and excellent enantioselectivities of up to 99% ee. Interestingly, the extension of this methodology to acetone provided by reaction with various benzaldehydes the corresponding aldol adducts in still excellent enantioselectivities in a range of 97-99% ee, as shown in Scheme 2.13. 

Asymmetric direct aldol reaction is a practical process to synthesize p-hydroxy-carbonyl compounds [28]. The phebox-Rh acetate complex 5- Pr serves also as an excellent catalyst for asymmetric direct aldol reaction of cyclic ketones with benzaldehyde derivatives (Scheme 24) [29]. For example, Scheme 24 shows that the reaction of cyclohexanone with 4-nitrobenzaldehyde using 5 mol% of 5- Pr and AgOTf gave the corresponding anri-p-hydroxyketone 36 preferentially in 79% yield with 87 % ee for the anti-isomer. The coupling reaction of cyclopentanone and acetone afforded p-hydroxyketones 37 and 38, respectively, with up to 91% ee. 

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