Anri-aldol products

Reformatsky reactions. As activating agent for a-bromo esters CrClj-Lil shows excellent selectivity for aldehydes over ketones (>50 1 vs. methyl ketones and >200 1 for more bulky ketones). anri-Aldol products can be obtained. 

Aldol reaction. Aldol reaction catalyzed by proline and derivatives has been reviewed. A ball-mill operation on cycloalkanones, ArCHO with (5)-proline leads to predominantly anri-aldol products. The aldol reaction between 4-tetrahydrothiapyrone with the racemic 3-aldehyde based on the same heterocycle shows excellent enantiotopic group-selectivity and thence manifesting dynamic kinetic resolution. ... 

The nucleophilic component reacts in the aldol reaction in its enoUc form, usually chelated to a metallic cation as E- or Z-enolate. The stereochemistry of metal chelates plays a primary role in the stereoselectivity of the aldol reaction by controlled formation of syn- or anh -diastereomers. As a mle -isomers of enolates lead to anri-aldol products and Z-isomers to syn products. This outcome is explained by the Zimmerman-Traxler mechanism, which invokes a six-membered transition state (Scheme 4.10) [8, 9]. 

Asymmetric Aldol Reaction of Bromofluoroketene Silyl Acetal 2 Catalyzed by Lewis Acids 6. We next examined the aldol reaction of the bromofluoroketene silyl acetal 2 mediated by the catalyst 6 (30). The reaction was carried out by the addition of an aldehyde in nitroethane to a solution of 1.2 equivalents of the acetal 2 and 20 mol% of the catalyst 6 in the same solvent over 3 h at -7S°C and stirring at that temperature for an additional hour prior to quenching. As shown in Table II, the reaction of benzaldehyde afforded a 69 31 mixture of (2S,31 )- and (2R,3/ )-2-bromo 2-fluoro-3-hydroxy-3-phenylpropanoates. The enantiomeric excess of fte syn-isomer is 98% ee and diat of die an/i-isomer is 90% ee (entry 1). Although die reactions are not diastereoselective in all cases (synlanti = 69/31 to 46/54), aU syn- and anri-aldol products were obtained with excellent-to good chemical and optical yields. 

For the propionate aldol reaction the Li enolate (7), generated by deprotonation of 2,6-dimethylphenyl propionate with Lithium Diisopropylamide in EtiO, was chosen. Transmetalation with 1.25 equiv of an ethereal solution of (1) takes 24 h at —78 °C. The completion of this step is evident by the disappearance of racemic anti-a do (9) in favor of optically active yw-isomer (10) (91-98% ee) upon reaction with an aldehyde (RCHO) and aqueous workup. At this point, 3-11% of anri-aldol (9) remaining in the reaction mixture is optically active as well (eq 2). This awri-isomer (9) (94-98% ee) becomes the major product if the reaction mixture, containing the putative ( )-titanium enolate derived from (7), is warmed for 4-5 h to —30°C before reaction with an aldehyde (RCHO) again at —78 °C. Isomerization to the (Z)-titanium enolate is a possible explanation of this behavior. Some substrates, aromatic and unsaturated aldehydes, behave exceptionally, as a high proportion of yn-isomer (10) (19-77%) of lower optical purity (47-66% ee) is formed in addition to (9) (94-98% ee). After hydrolysis of the acetonide (6) the products (9/10) are isolated and separated by chromatography in 50-87% yield. The reactions of pivalaldehyde (R = r-Bu) are sluggish at —78°C and have therefore been carried out at —50 to —30°C. 

Stereoselective anti-aldol reactions. As part of a synthesis of polypropionate natural products, Evans et al. have studied the stereoselectivity of the reaction of isobutyraldehyde with the chiral /3-kctoimide la, which has been shown to undergo syn-sclectivc aldol reactions.4 Surprisingly, the (E)-boron cnolatc, generated in ether from dicyclohexylchloroborane and ethyldimcthylaminc, reacts with isobutyraldehyde to give the anti, am/-aldol 2 and the syn, anri-aldol 2 in the ratio 84 16. Similar diastereoselectivity obtains with the reaction of the isomeric /3-kctoimide lb. 

Ono and Kamimura have found a very simple method for the stereo-control of the Michael addition of thiols, selenols, or alcohols. The Michael addition of thiolate anions to nitroalkenes followed by protonation at -78 °C gives anti-(J-nitro sulfides (Eq. 4.8).11 This procedure can be extended to the preparation of a/jti-(3-nitro selenides (Eq. 4.9)12 and a/jti-(3-nitro ethers (Eq. 4.10).13 The addition products of benzyl alcohol are converted into P-amino alcohols with the retention of the configuration, which is a useful method for anri-P-amino alcohols. This is an alternative method of stereoselective nitro-aldol reactions (Section 3.3). The anti selectivity of these reactions is explained on the basis of stereoselective protonation to nitronate anion intermediates. The high stereoselectivity requires heteroatom substituents on the P-position of the nitro group. The computational calculation exhibits that the heteroatom covers one site of the plane of the nitronate anion.14... 

At low temperatures, the Zn enolate derived from dimethyl 3-methylpent-2-endioate 39 reacts with aldehydes in a one-pot aldolisation and cyclisation to yield the syn-dihydropyran-2-one 40. At the higher temperatures necessary to achieve reaction with a-aminoaldehydes, the anri-products predominate indicating thermodynamic control (Scheme 22) <99T7847>. An aldol condensation features in the asymmetric synthesis of phomalactone. The key step is the reaction of the enolate of the vinylogous urethane 41 with crotonaldehyde which occurs with 99% syn-diastereoselectivity and in 99% ee (Scheme 23) <99TL1257>. 

In addition to enol silyl ethers, an optically active boryl enolate underwent the highly anri-stereoselective aldol reaction with a wide variety of aldehydes in the presence of TiCU (Eq. 34) [120]. The vinyl sulfides shown in Eq. (35) reacted with a,fi-unsaturated ketones via the 1,4-addition pathway in the presence of a titanium salt, but the reaction was followed by the cleavage of a carbon-carbon bond in the cycloalkane to give open chain products in a stereoselective manner [121]. The 1,2-type addition was observed, if the olefinie acetal was used instead of the corresponding carbonyl compound, as shown in Eq. (36) [121], The successive scission of the carbon-carbon bond took place analogously to give the same type of products as shown in Eq. (35). 

The aldol reaction between two aldehydes leads to syn-adducts when promoted by TiCl and base. These products undergo isomerization to afford the anri-isomers on exposure to (( -PrO),Ti-TMEDA at -25°C. ... 

In addition to the acetate aldol problem, stereoselective aldol additions of substituted enolates to yield 1,2-anti- or f/treo-selective adducts has remained as a persistent gap in asymmetric aldol methodology. A number of innovative solutions have been documented recently that provide ready access to such products. The different successful approaches to anri-selective propionate aldol adducts stem from the design of novel auxiliaries coupled to the study of metal and base effects on the reaction stereochemistry. The newest class of auxiliaries are derived from A-arylsulfonyl amides prepared from readily available optically active vicinal amino alcohols, such as cw-l-aminoindan-2-ol and norephedrine. 

The second total synthesis of swinholide A was completed by the Nicolaou group [51] and featured a titanium-mediated syn aldol reaction, followed by Tishchenko reduction, to control the C21-C24 stereocenters (Scheme 9-30). The small bias for anri-Felkin addition of the (Z)-titanium enolate derived from ketone 89 to aldehyde 90 presumably arises from the preference for (Z)-enolates to afford anti-Felkin products upon addition to a-chiral aldehydes [52], i.e. substrate control from the aldehyde component. 

Phosphoramide ligands represei lation and aldol reaction. Their pref Aldol reaction with L-proline as crating anri-diols. Transition state catalyzed by Et2Zn-PhjPS in the p dazolidinones serve as chiral aux zolidinones. In employing 4-/-but equiv of a base leads to syn product... 

It is interesting to note that anri-selectivity of aldolization (with L-proline promotion) involving hydroxyacetone as the donor is switched in the Mannich reaction. Thus syn-2-hydroxy-3-arnino ketones are obtained as major products. 

It has also been shown that dimethylsilyl enolates can be activated by diisopropylamine and water and exhibit a high reactivity toward A -tosyl imines to give Mannich-type reaction products in the absence of a Fewis acid or a Bronsted acid. For example, the reaction of [(1-cyclohexen-l-yl)oxy]dimethylsilane with 4-methyl-A/ -(phenylmethylene)benzene sulfonamide gave re/-4-methyl-N- (f )-[(15)-(2-oxocyclohexyl)phenyl-methyl] benzenesulfonamide (anri-isomer) in 91% yield stereoselectively (99 1 antvsyn) (Eq. 11.30). On the other hand, Fi and co-workers reported a mthenium-catalyzed tandem olefin migration/aldol and Mannich-type reactions by reacting allyl alcohol and imine in protic solvents. 

Furthermore, the reductive aldol reaction can be used for the construction of ot,p,y-stereotriads. When the racemic phebox-Rh acetate complex 32 was subjected to the coupling reactions of (5)-2-phenylpropanal with acrylate, the Felkin-Anh product 31a with (2R,3/ ,45)-configuration was predominantly formed (Scheme 22) [27]. The anri -Felkin-Anh product 31b (enantiomer) was a minor diastereomer. The use of the chiral (S,S)-phebox-Rh complex 5- Pr for the coupling reaction with (S)-2-phenylpropanal resulted in the formation of the Felkin-Anh product with high ee and de. On the other hand, the use of (R)-2-phenylpropanal afforded the anti-Felkin-Anh product 31b as a major diastereomer with moderate enantioselectivity. Thus, a combination of (S)-2-phenylpropanal with the (S,S)-phebox-Rh complex 5- Pr is a matched pair. 

A possible transition state based on the Felkin-Anh model was shown in Scheme 23. Judging from the (2/ ,3R,4S)-configuration of the product 31a, the major product is likely formed via the Felkin TS 33 showing the Si face attack of the Rh-( )-enolate. This step could be the catalyst-controlled reaction with the chiral catalyst. According to the prochiral face discrimination in the phebox-Rh-catalyzed reductive aldol reaction with the linear substrate, the Re face attack of the Rh (fij-enolate in TS 34 is unfavorable. In the case of the (R)-aldehyde, the anri-Felkin-Anh s TS 35, which gives the (2R,3R,4R)-product 31b, takes the unfavorable conformation with the bulky phenyl group at the apical position. 

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