2,3-anti products

E- and Z-silyl thioketene acetals give the 2,3-anti product. The 3,4-syn ratio is 50 1, and is consistent with the Felkin model. When this nucleophile reacts with 2-benzyloxypropanal (Entry 8), a chelation product results. The facial selectivity with respect to the methyl group is now reversed. Both isomers of the silyl thioketene acetal give mainly the 2,3-syn-3A-syn product. The ratio is higher than 30 1 for the Z-enolate but only 3 1 for the F-enolate. 

When an aldehyde is reacted with a ketone-derived enolate under equilibrating conditions, the thermodynamically more stable 2,3-anti product predominates regardless of the geometry of the enolate. If, however, the reaction is kinetically controlled, the (Z)- and ( )-enolates furnish 2,3-syn and anti aldol products, respectively. This behavior has been interpreted in terms of a chair-type transition state known as the Zimmerman-Traxler model. ... 

It is clear that the presence of the benzeneselenoethyl moiety in 21 or 22 is not required as a latent double bond in subsequent transformations. It would thus be synthetically more attractive to be able to prepare the unsaturated ketones directly. Reaction of AS-hexahy-dromandelic acid (3) with either (E)- or (Z)-propenyllithium followed by hydroxy silylation opens the way to both 34 and 35. Boron enolates of either 34 or 35, prepared in situ, undergo reaction with aldehydes to afford aldol products, albeit with low selectivity when R=TBS. Interestingly, the -isomer 34 provides mainly the 2,3-anti products 36 (1 3.5 syn. anti), while the Z-isomer 35 affords mainly the syn products 37 (3 1 to 10 1 syn anti). However, the corresponding O-triethylsilyl-protected boron enolates of 34 or 35 undergo smooth aldol reaction with aldehydes to yield the 1,3-syn products 37 with high diastereoselectivity (>100 1) (Scheme 6) [7]. 

The stereochemistry of both chlorination and bromination of several cyclic and acyclic dienes has been determined. The results show that bromination is often stereo-specifically anti for the 1,2-addition process, whereas syn addition is preferred for 1,4-addition. Comparable results for chlorination show much less stereospeciftcity. It appears that chlorination proceeds primarily through ion-pair intermediates, whereas in bromina-hon a stereospecific anfi-l,2-addition may compete with a process involving a carbocation mtermediate. The latter can presumably give syn or anti product. 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

A syn-selective asymmetiic nih o-aldol reaction has been reported for structurally simple aldehydes using a new catalyst generated from 6,6-bis[(tiiethylsilyl)ethynyl]BINOL (g in Scheme 3.18). The syn selectivity in the nitro-aldol reaction can be explained by steric hindrance in the bicyclic transition state as can be seen in Newman projection. In the favored h ansition state, the catalyst acts as a Lewis acid and as a Lewis base at different sites. In conbast, the nonchelation-controlled transition state affords anti product with lower ee. This stereoselective nitro-aldol reaction has been applied to simple synthesis of t/ireo-dihydrosphingosine by the reduction of the nitro-aldol product with H2 and Pd-C (Eq. 3.79). 

Optically active (Z)-l-substituted-2-alkenylsilanes are also available by asymmetric cross coupling, and similarly react with aldehydes in the presence of titanium(IV) chloride by an SE process in which the electrophile attacks the allylsilane double bond unit with respect to the leaving silyl group to form ( )-s)vr-products. However the enantiomeric excesses of these (Z)-allylsilanes tend to be lower than those of their ( )-isomers, and their reactions with aldehydes tend to be less stereoselective with more of the (E)-anti products being obtained74. 

The same reaction utilizing chlorotriisopropoxytitanium gives a lower yield and optical purity of the (Z)-anti product ( + )-4 (yield 33% 64% ee). Utilization of tetraisopropoxytita-nium causes complete racemization16. The reaction of (Z)-l-methylbutenyltitanium with both enantiomers of 2-( er/-butyldimethylsilyloxy)propanal proceeds only very sluggishly with approximately 20% yield99. The results are best explained by the assumption of a (twist)boat transition state. 

When an (/. )-cnolate is the starting material, the corresponding argument indicates that the transition state with R1 in an equatorial position 6a is favored compared to the diastereomeric alternative 6b, Thus, the anti-product is assumed to form predominantly. 

Silanes And Base. In the presence of bases, certain silanes can selectively reduce carbonyls. Epoxy-ketones are reduced to epoxy-alcohols, for example with (MeO)3SiH and LiOMe. ° Controlling temperature and solvent leads to different ratios of syn- and anti- products.Silanes reduce ketones in the presence of BF3-OEt2 ° and transition metal compounds catalyze this reduction. ... 

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

Scheme 2.2 illustrates several examples of the Mukaiyama aldol reaction. Entries 1 to 3 are cases of addition reactions with silyl enol ethers as the nucleophile and TiCl4 as the Lewis acid. Entry 2 demonstrates steric approach control with respect to the silyl enol ether, but in this case the relative configuration of the hydroxyl group was not assigned. Entry 4 shows a fully substituted silyl enol ether. The favored product places the larger C(2) substituent syn to the hydroxy group. Entry 5 uses a silyl ketene thioacetal. This reaction proceeds through an open TS and favors the anti product. 

Entries 10 to 14 show reactions involving acetals. Interestingly, Entry 10 shows much-reduced stereoselectivity compared to the corresponding reaction of the aldehyde (The BF3-catalyzed reaction of the aldehyde is reported to be 24 1 in favor of the anti product ref. 80, p. 91). There are no stereochemical issues in Entries 11 or 12. Entry 13, involving two cyclic reactants, gave a 2 1 mixture of stereoisomers. Entry Mis a step in a synthesis directed toward the taxane group of diterpenes. Four stereoisomeric products were produced, including the Z E isomers at the new enone double bond. 

Stereochemical Control by the Aldehyde. A chiral center in an aldehyde can influence the direction of approach by an enolate or other nucleophile. This facial selectivity is in addition to the simple syn, anti diastereoselectivity so that if either the aldehyde or enolate contains a stereocenter, four stereoisomers are possible. There are four possible chairlike TSs, of which two lead to syn product from the Z-enolate and two to anti product from the A-enolate. The two members of each pair differ in the facial approach to the aldehyde and give products of opposite configuration at both of the newly formed stereocenters. If the substituted aldehyde is racemic, the enantiomeric products will be formed, making a total of eight stereoisomers possible. 

Several a-methyl-(3-alkoxyaldehydes show a preference for 23-syn-3A-anti products on reaction with Z-enolates. A chelated TS can account for the observed stereochemistry.85 The chelated aldehyde is most easily approached from the face opposite the methyl and R substituents. 

In the reaction of a-methylthiobutanal, where the methylthio group has the potential for chelation, BF3 gave 100% of anti product, whereas TiCl4 gave a 5 1 sytr.anti ratio.93... 

The /(-titanium enolate was prepared by deprotonation with TMP-MgBr, followed by reaction with (/-PrO)3TiCl in the presence of HMPA. The TS for addition is also dominated by a polar effect and gives and 2,2 -anti product. 

The /V-acy10xaz01 idi n0nes give anti products when addition is effected by a catalytic amount of MgCl2 in the presence of a tertiary amine and trimethylsilyl chloride. Under these conditions the adduct is formed as the trimethylsilyl ether.129... 

Under similar conditions, the corresponding thiazolidinethione derivatives give anti product of the opposite absolute configuration, at least for cinnamaldehyde. 

Another promising boron enolate is derived from (-)-menthone.133 It yields -boron enolates that give good enantioselectivity in the formation of anti products.134... 

Derivatives with various substituted sulfonamides have been developed and used to form enolates from esters and thioesters.137 An additional feature of this chiral auxiliary is the ability to select for syn or anti products, depending upon choice of reagents and reaction conditions. The reactions proceed through an acyclic TS, and diastereoselectivity is determined by whether the E- or Z-enolate is formed.138 /-Butyl esters give A-enolates and anti adducts, whereas phenylthiol esters give syn adducts.136... 

Camphor-derived sulfonamide can also permit control of enantioselectivity by use of additional Lewis acid. These chiral auxiliaries can be used under conditions in which either cyclic or noncyclic TSs are involved. This frequently allows control of the syn or anti stereoselectivity.143 The boron enolates give syn products, but inclusion of SnCl4 or TiCl4 gave excellent selectivity for anti products and high enantioselectivity for a range of aldehydes.145... 

In Entry 5, the chirality at an alkylated succinate ester is maintained and a 9 1 dr favoring the anti product is achieved, based on a preferred orientation relative to the branched substituent. 

The anti stereochemistry is consistent with a cyclic TS, but the reaction is stereocon-vergent for the E- and Z-2-butenylstannanes, indicating that isomerization must occur at the transmetallation stage. The adducts are equilibrated at 82 °C and under these conditions the anti product is isolated on workup. 

BINAP-AgF gives good enantioselectivity, especially for the major anti product in the addition of 2-butenylstannanes to benzaldehyde.188 This system appears to be stereoconvergent, suggesting that isomerization of the 2-butenyl system occurs, perhaps by transmetallation. 

The stereoselectivity of the P-carboethoxyallylic boronate derived from the endo-phenyl auxiliary A (p. 803) toward R- and. S -glyccraldchydc acetonide has been investigated. One enantiomer gives the anti product in 98 2 ratio, whereas the other favors the syn product by a 65 35 ratio. Based on the proposed transition structure for this boronate, determine which combination leads to the higher stereoselectivity and which to the lower. Propose the favored transition structure in each case. 

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