Propionate aldol addition anti-selective

The same bisoxazoline Cu(II) and Sn(II) complexes have been utilized successfully in the corresponding propionate aldol addition reactions (Scheme 8-7). A remarkable feature of these catalytic processes is that either syn or anti simple dia-stereoselectivity may be accessed by appropriate selection of either Sn(II) or Cu(II) complexes. The addition of either - or Z-thiopropionate-derived silyl ke-tene acetals catalyzed by the Cu(II) complexes afford adducts 78, 80, and 82 displaying 86 14-97 3 syn anti) simple diastereoselectivity. The optical purity of the major syn diastereomer isolated from the additions of both Z- and i -enol silanes were excellent (85-99% ee). The stereochemical outcome of the aldol addition reactions mediated by Sn(Il) are complementary to the Cu(U)-catalyzed process and furnish the corresponding anp -stereoisomers 79, 81, and 83 as mixtures of 10 90-1 99 syn/anti diastereomers in 92-99% ee. 

The auxiliaries R) and (S)-triphenylglycol 172 were also applied to achieve anti-selective propionate aldol additions, as shown by Braun and coworkers. It turned out that, for this purpose, the tertiary hydroxyl group of the propionate (R)-204 had to be protected by silylation. This was easily accomplished by a one-pot procedure that delivered the ester (R)-205. After deprotonation with LICA, the lithium enolate was transmetallated with dichloro(dicyclopentadienyl)zirconium and reacted with aliphatic aldehydes to give predominantly anti-diastereomers 206, the diastereomeric ratio surpassing 95 5. Reduction with lithium aluminum hydride finally led to diols 207 under the release of the chiral auxiliary R)-172. After its removal by chromatography, diastereomerically pure diols 207 were isolated with >95% ee (Scheme 4.45) [107]. For the benzaldehyde adduct 206 (R = Ph), alkaline hydrolysis was also performed and found to lead to epimerization to only a small degree. 

Catalysis with Bisoxazoline Complexes of Sn(II) and Cu(II). The bisoxazoline Cu(IT) and Sn(II) complexes 81-85 that have proven successful in the acetate additions with aldehydes 86,87, 88 also function as catalysts for the corresponding asymmetric propionate Mukaiyama aldol addition reactions (Scheme 8B2.8) [27]. It is worth noting that eithersyn or anti simple diastereoselectivity may be obtained by appropriate selection of either Sn(II) or Cu(II) complexes (Table 8B2.12). 

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 addition of propionate-derived enol silanes 140 deUvered 1,2-disubstitut-ed aldol adducts 141 and 142 in useful yields and selectivities (Eq. 17) [90]. As in the acetate-derived additions, the selectivity of the process was dependent on the thioalkyl substituent of the silyl ketene acetal 140. The 1,2-syn adduct was obtained from the addition of E-enolsilane and -butyl glyoxylate (Eq. 17, entry 3). Correspondingly, the formation of 1,2-anti adduct was observed in the addition of a-benzyloxy acetaldehyde and the Z-enol silane derived from the ferf-butyl thio ester. 

Compared to the aldol addition, the stereochemical scheme is complicated by the fact that the Michael acceptor may not always and not exclusively adopt the -configuration as shown in 421 but also as Z-diastereomer. The effect of this isomerism has been addressed in a fundamental contribution of Corey and Peterson, which is also one of the first applications of an auxiliary-based stereoselective Michael addition. The chiral lithium enolate 425 that was generated from the propionic ester 424 of phenylmenthol by deprotonation was assumed to adopt the enolate in fcr /is-configuration, in accordance with Ireland s model (cf Section 2.1). The reaction of the enolate with ( )- and (Z)-methyl crotonate led to the Michael products sy/i-426 and a f/-427, respectively. The Michael addition to ( )-crotonate was faster at low temperatures than that of the (Z)-diastereomer and provided higher chemical yields as well as syw-anti-selectivity and induced stereoselectivity. A closed, eight-membered transition state model 428 has been proposed that plausibly explains the opposite stereochemical outcome depending on the double-bond configuration of the Michael acceptor. As the rear side is shielded by the bulky 2-phenyl-2-propyl substituent, the attack of both croto-nates occurs at the Si-face of the enolate 425. Whereas Si-face of ( )-crotonate is selected for the addition of the enolate, the attack to (Z)-crotonate occurs predominantly from the e-face (Scheme 4.92) [206]. 

In addition to the advances in auxiliary-controlled acetate aldol addition reactions, a number of innovative solutions for the preparation of propionate-derived 1,2-anti products have also appeared using auxiliaries other than Evans oxazolidinone. The various successful approaches to anti aldol adducts stem from the design of novel auxiliaries coupled with the study of metal and base effects on the reaction stereochemistry. Masamune documented that the addition of optically active ester enolate 112 to aldehydes afforded anti aldol adduct 113 in superb yield and diastereoselectivity (Equation 10) [70]. After careful selection of the reaction conditions for the enolization of the ester [71], the aldol addition was successfully carried out with a broad range of substrates including aliphatic, aromatic, unsaturated, and functionalized aldehydes. An attractive feature of this process is the subsequent facile removal of the auxiliary (LiOH, THF/H2O) to afford the corresponding acid without concomitant deterioration of the configurational integrity of the products [70]. 

Aldol Reactions of Ester Derivatives. The Titanium(IV) C/tlor/dc-catalyzed addition of aldehydes to 0-silyl ketene acetals derived from acetate and propionate esters proceeds with high stereoselectivity. Formation of the silyl ketene acetal was found to be essential for high diastereoselectivity. Treatment of the silyl ketene acetal, derived from deprotonation of the acetate ester with LICA in THF and silyl trapping, with a corresponding aldehyde in the presence of TiCU (1.1 equiv) afforded the addition products in 93 7 diastereoselectivity and moderate yield (51-67%). Similarly, the propionate ester provides the anti-aldol product in high antilsyn selectivity (14 1) and facial selectivity (eq 4). 

Asymmetric Aldol Reactions. Reaction of (1) with Boron Tribromide in CH2CI2 affords, after removal of solvent and HBr, a complex (5) useful for the preparation of chiral enolates (eq 5). Complex (5) is moisture sensitive and is generally prepared immediately before use. For propionate derivatives, either syn or, less selectively, anti aldol adducts may be obtained by selection of the appropriate ester derivative and conditions. Thus reaction of f-butyl propionate with (5) and triethylamine produces the corresponding E 0) enolate, leading to formation of anti aldol adducts upon addition to an aldehyde (eq 6). Selectivities may be enhanced by substitution of the t-butyl ester with the (+)-menthyl ester. Conversely, reaction of 5-phenyl thiopropionate with (5) and Diisopropylethylamine affords the corresponding Z(0) enolates and syn aldol products (eq 7). ... 

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