Syn-aldol product

In general, syn aldol products are achievable with high selectivity, anti aldols are more difficult... 

This methodology has provided an alternative, highly enantioselective route to sertraline 1 [94]. Insertion into the oxygen-activated CH2 position of allyl ethers yields syn-aldol products with high stereocontrol (Eq. 13) [97], and... 

In 1991, Kobayashi el al. prepared novel chiral S/N ligands for the tin-mediated aldol reaction of silyl enol ethers with aldehydes. As an example, the reaction of benzaldehyde afforded the expected syn aldol product as the major product with a good yield and an enantioselectivity of up to 92% ee (Scheme 10.26). Moreover, other aldehydes such as substituted benzaldehydes or aliphatic unsaturated aldehydes were converted into their corresponding aldol products with enantioselectivities of more than 90% ee. It was checked that the corresponding diamine ligands provided less active complexes for the same reactions. 

Accordingly, Liu et al.4 have designed two types of aldol reagents that can lead to opposite stereochemistry in aldol condensation reactions. In the following structures, compound 4 can be used for obtaining anti- Ao products, and compound 5 can be employed for synthesizing syn-aldol products (Scheme 3-3). 

Double asymmetric induction (See section 1.5.3) can also be employed in aldol reactions. When chiral aldehyde 15 is treated with achiral boron-mediated enolate 14, a mixture of diastereomers is obtained in a ratio of 1.75 1. However, when the same aldehyde 15 is allowed to react with enolates derived from Evans auxiliary 8, a syn-aldol product 16 is obtained with very high stereo-... 

Ketone donors bearing a-heteroatoms are particularly useful donors for the enamine-catalyzed aldol reactions (Scheme 18). Both anti and syn aldol products can be accessed in remarkably high enantioselectivities using either proline or proline-derived amide, sulfonamide, or peptide catalysts. The syn selective variant of this reaction was discovered by Barbas [179]. Very recently, Luo and Cheng have also described a syn selective variant with dihydroxyacetone donors [201], and the Barbas group has developed improved threonine-derived catalysts 71 (Scheme 18) for syn selective reactions with both protected and unprotected dihydroxyacetone [202]. 

Extending the reaction to acyclic trans-allyl silyl ethers 220 results in the highly diaster-eoselective formation of syn-aldol products 221 (Eq. 30) [143]. Even higher stereoselectivity can be achieved with the tetraalkoxysilanes 222, where both the diastereo- and en-antioselectivity for the formation of 223 are exceptional (Eq. 31) [144]. C-H insertion into tetraethoxysilane 222 generates the syn-aldol product 223 in 70% yield (>94% de) with 95% enantiomeric excess. 

In a follow-up paper (J. Am. Chem. Soc. 2004,126, 5352), Professor Nelson used the commercially-available base quinaldine 7a (R=H) or its TMS ether 7b (R=TMS). Catalysts 7a and 7b are both efficient and give > 95% , but lead to opposite absolute configurations of the products. As with catalyst 3, the syn aldol product predominates, but now branched aldehydes such as 6 also participate efficiently in the reaction. This is another example of enantioselective catalysis by a small organic molecule. 

The reaction proceeds via the re-side of the enolate and the re-side of the aldehyde 8. The afore mentioned transition state 27 leads to the Evans -syn-aldol product 9 in about 57 % yield and an excellent selectivity of >95 5.6... 

The stereochemical course of the aldol reaction can be controlled by the judicious selection of the enolization reagents. Treatment of propionate esters with <7-Hex2BOTf and triethylamine produced anti-aldol products, and that of with Bu2BOTf and diisopropylethylamine selectively gave syn-aldol products after reaction with aldehydes (Equation (180)).684 685 Complementary anti- and yy/z-selective asymmetric aldol reactions were also demonstrated in structurally related chiral norephedrine-derived propionate esters (Equation (181)).686... 

Tf we choose the group X , next to the carbonyl group, to be large, then we can be sure of getting just the ds-enolate. So, for example, the lithium enolate of this f-butyl ketone forms just as one geometrical isomer, and reacts with aldols to give only the syn aldol product. 

With smaller B substituents, the m-erilolate forms selectively. Here, the boron is part of a bicyclic structure known as 9-BBN (9-borabicyclononane—you will meet this in Chapter 47). The bicyclic part may look large but, as far as the rest of the molecule is concerned, it s Tied back behind the boron, and the methyl group can easily lie cis to oxygen. The ds-enolate then gives syn aldol products. Di-tt-butylboron triflate (B BOTf) also gives cis-enolates. 

An asymmetric synthesis of the aminocyclopentitol has been achieved from an acylated oxazolidinone (Scheme 38).110 Thus, the acylated oxazolidinone 295 was subjected to boron triflate-catalyzed condensation with 3-butenal to yield the syn aldol product 297 in 63% yield. Similarly, the A-acyloxazoI idineth ione 296 delivered the aldol adduct 298 in 75% yield when enolized with TiCl4-(—)-sparteine and then... 

Mn-enolates can also be hydroxyalkylated by reacting with a vast array of aldehydes to give syn-aldol products in good yields. The stereoselectivities obtained from Mn- and Li-enolates... 

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). ... 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

Enantioselective Aldol Reactions. The use of 1 for generating two contiguous stereocenters via an asymmetric aldol condensation has also been investigated,but only with marginal success. For example, reaction of the lithium enolate derived from tert-butyl propionate with the /Y-lithio derivative of 1, followed by condensation with benzaldehyde, provided a mixture of anti and syn aldol products in poor-to-modest % ee (eq 8). 

We have inevitably drawn the syn aldol product as one enantiomer but so far there is no control over absolute stereochemistry. The aldehyde is itself a single enantiomer and so the two faces of the carbonyl group are diastereotopic and which one the enolate will attack would normally be determined by the usual Felkin argument. 

Treatment of N-acyloxazolidinones with di-n-butylboron triflate in the presence of Et3N furnishes the (Z)-(O) boron enolates. These on treatment with aldehydes give the corresponding 2,3-syn aldol products (the ratio of syn- to anti- isomers is typically 99 1 ). On hydrolysis they produce chiral a-methyl-(3-hydroxy carboxylic acids, as exemplified below. The facial selectivity of the chiral boron enolate is attributed to the favored rotomeric orientation of the oxazolidinone carbonyl group, where its dipole is opposed to the enolate oxygen dipole. At the Zimmerman-Traxler transition state, the aldehyde approaches the oxazolidinone appendage from the face of the hydrogen rather than from the benzyl substituent. 

The observed stereoselectivity in the Evans aldol reaction can be explained by the ZImmerman-Traxler transition state model. There are eight possible transition states, four of which would lead to the anti aldol product. These, however, are disfavored due to the presence of unfavorable 1,3-diaxial interactions (not depicted below). The possible transition states leading to the syn aldol product are shown below. The preferred transition state leading to the product is transition state A, where the dipoles of the enolate oxygen and the carbonyl group are opposed, and there is the least number of unfavored steric interactions. 

Glucolipsin A, a glycolipid possessing glycokinase-activating properties, was discovered at Bristol-Myers Squibb, but the absolute stereochemistry of the natural product remained elusive. A. Furstner and co-workers elucidated the absolute stereochemistry via synthesis and spectroscopic analysis of the natural macrolide and its Cj-symmetric stereoisomers." In their approach, they utilized the Evans aldol reaction that provided the syn aldol product with good yield and excellent diastereoselectivity. 

D.L Boger et al. reported the total synthesis of bleomycin A2. They devised an efficient synthesis for the construction of the tripeptide S, tetrapeptide S, and pentapeptide S subunits of the natural product." " " In their strategy, they utilized an Evans aidoi reaction between the (Z)-enolate derived from (S)-4-isopropyl-3-propionyl-oxazolidin-2-one and A/-Boc-D-alaninal. In order to synthesize one of the diastereomers of the pentapeptide S subunit, they carried out an Evans aidoi reaction between the same aldehyde and the (Z)-enolate of (R)-4-isopropyl-3-propionyl-oxazolidin-2-one. The formation of the diastereomeric syn aldol product in this reaction clearly shows that the stereochemical outcome of the transformation is determined by the chiral auxiliary. 

The asymmetric total synthesis of cytotoxic natural product (-)-FRI 82877 was accomplished by D.A. Evans and co-workers." " To establish the absolute stereochemistry, a boron mediated aldol reaction was utilized applying (R)-4-benzyl-A/-propionyl-2-oxazolidinone" as a chiral auxiliary to yield the syn aldol product. 

Evans aldol reaction Reaction of boron enolates with aldehydes to afford syn aldol products. 162... 

Schneider, C. The silyloxy-Cope rearrangement of syn-aldol products evolution of a powerful synthetic strategy. Synlett 2001, 1079-1091. 

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