Anti attack

Some reactions require the bonds being broken or made in a reaction to be aligned with other parts ti- or free electrons) of a molecule. These requirements are called stereoelectronic effects. Figure 3-6f shows that the bromide ion has to open a bro-monium ion by an anti attack in order that the new bond is formed concomitantly with the breaking of one bond of the three-membered ring. 

The stereochemistry of the Pd-catalyzed allylation of nucleophiles has been studied extensively[5,l8-20]. In the first step, 7r-allylpalladium complex formation by the attack of Pd(0) on an allylic part proceeds by inversion (anti attack). Then subsequent reaction of soft carbon nucleophiles, N- and 0-nucleophiles proceeds by inversion to give 1. Thus overall retention is observed. On the other hand, the reaction of hard carbon nucleophiles of organometallic compounds proceeds via transmetallation, which affords 2 by retention, and reductive elimination affords the final product 3. Thus the overall inversion is observed in this case[21,22]. 

Fn some cases, r-allylpalladium complex formation by retention syn attack) has been observed. The reaction of the cyclic allyiic chloride 33 with Pd(0) affords the 7r-allylpalladium chlorides 34 and 35 by retention or inversion depending on the solvents and Pd species. For example, retention is observed in benzene, THF, or dichloromethane with Pd2(dba)3. However, the complex formation proceeds by inversion in these solvents with Pd(Ph3P)4, whereas in MeCN and DMSO it is always inversion[33]. The syn attack in this case may be due to coordination of Pd to chlorine in 33, because Pd is halophilic. The definite syn attack in complex formation has been observed using stereoche-mically biased substrates. The reaction of the cxoallylic diphenylphosphino-acetate 36 with phenylzinc proceeds smoothly to give 37. The reaction can be explained by complex formation by a syn mechanism[31]. However, these syn attacks are exceptional, and normally anti attack dominates. 

Methybenzobicylo[2.2.2]octadiene showed a slight preference for syn attack of singlet oxygen [50] in contrast to the anti attack on 7-isopropylidenebenzonor-bomene (Scheme 34) [49]. 

Fig. 1.4. Transition structures for syn and anti attack on the kinetic enolate of trans-2,3-dimethylcyclopentanone showing the staggered versus eclipsed nature of the newly forming bond. Reproduced from J. Am. Chem. Soc., 121, 5334 (1999), by permission of the American Chemical Society. 

The solvomercuration of alkenes has been exhaustively studied and is now well understood. The mechanism of this reaction proceeds through two steps coordination of the mercuric ion to the alkene to form a fluxional cationic intermediate and subsequent nucleophilic anti-attack. Charge stabilization of the cationic intermediate constitutes one of the factors dictating the regioselectivity of the reaction (Scheme 11). 

In another example, Hg(OTf)2 has been used for the stereoselective ring expansion of 116 to 117 with excellent stereospecificity for the (Z)-isomer (Equation (43)).156 Carbomercuration reactions have also been observed for derivatives such as 118, which possesses both an allylic silane as well as an alkynyl functionality. For 118, the reaction affords the 5-m -ring compound 119 as the (Z)-isomer. Formation of the (/. )-isomcr is disfavored because the bulk of the TMS group precludes an anti-attack (Equation (44)).157... 

The mechanism of this new reaction is shown in Scheme 14. Coordination of the diene to palladium(II) makes the diene double bond electrophilic enough to be attacked by the allylsilane. The attack by the allylsilane takes place on the face of the diene opposite to that of the palladium (anti). This is the first example of an anti attack by an allylsilane on a 7T-(olefin)metal complex. Benzoquinone (BQ)-induced anti attack by chloride ion produces the product 58. 

In addition to /3-H elimination, olefin insertion, and protonolysis, the cr-metal intermediate has also proved to be capable of undergoing a reductive elimination to bring about an alkylative alkoxylation. Under Pd catalysis, the reaction of 4-alkenols with aryl halides affords aryl-substituted THF rings instead of the aryl ethers that would be produced by a simple cross-coupling mechanism (Equation (126)).452 It has been suggested that G-O bond formation occurs in this case by yy/z-insertion of a coordinated alcohol rather than anti-attack onto a 7r-alkene complex.453... 

The quantity (AE2nA2 + AE2 S03 ) will be more negative (i.e., more stabilizing) for syn than anti attack since the dominant contributor to the stabilization energy is the n. —02 interaction. It is clear, therefore, that nucleophilic attack syn to the leaving group will be favored over anti attack. 

Steric control has been invoked to explain the kinetic substituent effects as well as the syn stereoselectivity observed in these additions, for example to fraws-cyclooctene and traws-cyclononene. In these cyclic compounds, one side of the TT-bond is more shielded by the rest of the molecule and hence anti attack by a nucleophile is difficult. 

Depending upon the choice of substrates, the hydrosilylation of alkenes with (TMS)3SiH can also be highly stereoselective. The reaction of (TMS)3SiH with methylmaleic anhydride, proceeded regiospecifically to the less substituted side, but also diastereoselectively to afford the thermodynamically less stable cis isomer (Reaction 5.6) [25]. Stereoselectivity increased by decreasing the reaction temperature, indicating the difference in enthalpy of activation for syn vs anti attack. 

These cyclizations are usually highly stereoselective, with the stereochemical outcome being predictable on the basis of reactant conformation.14 The stereochemistry of cychzation products in the decalin family can be predicted by assuming that cyclizations will occur through conformations which resemble chair cyclohexane rings. The stereochemistry at ring junctures is that expected for anti attack at the participating double bonds ... 

Application of this one/pot protocol to the preparation of enantiopure amidine (215) derived from phenylglycine led to the formation of the desired cycloadducts (71). The reaction proceeded with good stereocontrol with an endo/exo ratio in the order of 10 1. In the case of the methyl ester derived product 216 (R = Me), a single isomer was isolated. The minor exo products 217 proved to have an unexpected stereochemistry at C(7), which was consistent with the energetically disfavored anti attack of the dipolarophUe, and it was therefore assumed that the product had... 

Structure can be described as a four-membered ring (TS in Scheme 8). The inclusion of a second equivalent of CHsMgCl, corresponding to an intermolecular mechanism, decreases the barrier height, and the process can be considered as an assisted intermolecular mechanism the first equivalent forms the chelate structure and the second CHsMgCl carries out the nucleophilic addition to the carbonyl group. The most favorable pathway corresponds to an intermolecular mechanism via an anti attack. Analysis of the results reveals that... 

Preferred anti attack of ylide, Bond rotation follows to As a result, this reaction often... 

Xenon fluorides may add to alkenes in the presence of HF or CF3COOH as catalyst.207-209 The addition, though, takes place via predominant anti attack and is not stereoselective.210 The formation of trifluoro and trifluoromethyl derivatives via radical intermediates, and trifluoroacetate incorporation were also observed.211,212... 

However, several factors can result in this simple pattern of stereospecific anti attack not being followed. The difference in size between the substituents H and R may not be sufficient to prevent reaction through the alternative conformation 132 (equation 93). This is most common when the substituent A is a proton. 

The electrophiles isobutyraldehyde and its dimethyl acetal gave surprisingly high ratios of syn anti attack, around 10 90. Since the silicon centre is more removed from the reactive site, this could be taken to indicate that electronic effects predominate. However, the intramolecular cyclization of 141 (equation 98) was found to take place with an enantiomeric excess of only 20%. 

A cyclohexenyl system can exist in the two conformations 81 and 82. A syn attack on ffl to give 84 should take place via a transition state having the chair-like stereochemistry 83 where the electron pair is oriented anti-periplanar to the C - X bond. An anti attack on 81 should occur via the twist-boat transition state 85 where the electron pair is syn to the C-X bond, yielding the product in the twist-boat conformation 86. A syn attack on conformer 82 should give 88 via the twist-boat 87 where the electron pair is antiperiplanar to the C —X bond, whereas an anti attack should give 90 via the chair form transition state 89 where the electron pair is syn to the C -X bond. 

The syn attack on 81 and the anti attack on 82 both lead to the chair-like transition states 83 and 89 so should be favored over the other two processes. Moreover, the transition state 83 which has an electron pair antiperi-... 

Once the most reactive substrate conformations are known, it remains to look for the best approach of the nucleophile. An anti attack is promoted by a favorable secondary overlap between the nucleophile and o (C L), which is shown by the double arrow. Syn attack is disfavored, both by a negative secondary overlap (wavy line) and by the eclipsed relationship between C L and Nu---C (Figure 6.6). To summarize, the Felkin transition states are favored because they correspond to the best trajectories for attacking the most reactive conformations. 

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