Anri-aldol reaction

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... 

The present procedure is a modification of that originally reported by the submitter and co-workers.2 This procedure is applicable to a large scale preparation of the title compound in high overall yield (-80%) without purification of the intermediates by chromatography. The title compound is reported to be a useful reagent for anri-selective aldol reactions with dicyclohexylboron triflate and triethylamine as enolization reagents.3... 

If another equivalent of titanium(IV) chloride is added to the boronenolates and only subsequently the aldehyde is introduced, the reaction proceeds via the open transition state 25 and leads to the anri-aldols 26 [22]. The aldehyde attacks the enolate from the sterically favored lower face, and the group R is oriented away from the auxiliary. 

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. 

As above (eq 1), a major drawback of this reagent is the lack of a readily available enantiomer. There are many alternative methods for the enantioselective propionate aldol reaction. The most versatile chirally modified propionate enolates or equivalents are N-propionyl-2-oxazolidinones, a-siloxy ketones, boron enolates with chiral ligands, as well as tin enolates. Especially rewarding are new chiral Lewis acids for the asymmetric Mukaiyama reaction of 0-silyl ketene acetals. Most of these reactions afford s yw-aldols good methods for the anri-isomers have only become available recently. ... 

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). 

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. 

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. ... 

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. 

Additive aldol reaction. An anri-selective synthesis of 5-phenylthio esters of 3-hydroxy-2-phenylthiomethylalkanethiolates from a mixture of acryloyl chloride, PhSLi and aldehydes is mediated by MgBr2 OEt2. 

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 anri-selective aldol reaction between cyclohexanone and ArCHO reaches >99% ee if it is conducted in the presence of trawi -4-(4-t-butylphenoxy)-L-piDline and sulfated P-cyclodextrin in water at room temperature. Another catalyst is cw-A-fl-adamantane-carboxamido)-(5)-proline (1) in conjunction with P-cyclodextrin. ... 

Acceleration of aldol reactions.2 In the absence of a catalyst, silyl enol ethers ordinarily do not react with aldehydes even at high temperatures. Thus the dimcthylphenyl-silyl ether 2a does not react with C<,H jCHO at 150°. In contrast, the silacyclobutane analog (2b), prepared from 1, reacts with C HsCHO at 27° to form syn- and anri-aldols in 12 1 ratio. This stereoselectivity is the opposite of that obtained by the TiCI4-catalyzed reaction. l-Chloro-l-mcthylsilacyclobutane, CHi(CI)Si(CH2)3, is even more effective than 1 for this aldol reaction. It is prepared from (3-chloropropyl)dichloromethylsilane. It is particularly useful for aldol reactions with acyclic silyl ketene acetals (equation II). 

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. 

Under the same conditions, similar anri-selective aldol reactions obtain with several other chiral ethyl ketones such as 3.4... 

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... 

Aldol reactions. Titanium -ate complexes effect anri-selective aldolization (5 examples, 72-81%). 

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]. 

Scheme 4.12 anri-Directed aldol reaction of boronic complexes of chiral oxazolidinones... 

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. 

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. 

Evans et al. utilized the chiral oxazolidones to prepare optically pure 3-hydroxy-a-amino acids,important constituents of peptides and 3-lactams. As shown in Scheme 31, an asymmetric aldol reaction using the boron enolate derived from the V-(a-haloacyl)oxazolidone (68) provides the jyn-3-hydroxy-a-halocarbonyl derivative (69), which is converted to the anri-3-hydroxy-a-azidocarbonyl derivative (70)... 

Alternative routes to labeled anri-/3-hydroxy-a-amino acids of the a//o-threonine type are described in Section 11.3.9. They involve aldol reactions of haloacetyl-Evans and -Oppolzer auxiliaries to give iyn-/3-hydroxy-a-halo derivatives, whose a-halo groups are then inverted by nucleophilic displacement with azide ion. ... 

The uncatalyzed aldol reaction of highly reactive enoxysilanes such as enoxysilacyclobutanes has previoudy been reported to proceed through six-membeied cyclic transition states (32,55), and the torsional structure of the difluoroketene acetal 5 is considered to be more suitable for the uncatalyzed aldol reaction tfian the planar geometry of 4 because the acetal 5 has a geometrical similarity to the ketene acetal in die cyclic transition states. As mentioned above (Scheme 1), a 60 40 mixture of the syn- and anri-aldols was obtained at 40°C from the bromofluoroketene silyl acetal 2 (E/Z =62/38), suggesting that the uncatalyzed aldol reaction of the fluorine-substituted ketene acetals 1 and 2 proceeds preferentially through boat-like cyclic transition states. Denmark et aL proposed diat the boat-like transition states are extremely predominant in the uncatalyzed aldol reaction of enoxysilacyclobutanes and trichlorosilyl enolates (55,54). 

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. 

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 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. 

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