Stereoelectronic demands

Crotyl silanes offer the possibility of diastereoselectivity in reactions with aldehydes in the same way as the corresponding boranes. The mechanism is completely different because crotyl trialkylsilanes react via an open transition state as the silicon is not Lewis acidic enough to bind the carbonyl oxygen of the electrophile. Instead, the aldehyde has to be activated by an additional Lewis acid or by conversion into a reactive oxonium ion by one of the methods described above. The stereoelectronic demands of the allylic silane system contribute to the success of this transformation. Addition takes place in an Se2 sense so that the electrophile is attached to the remote carbon on the opposite side of the n system to that originally occupied by silicon and the newly formed double bond is trans to minimize allylic strain. 

The stereochemistry of the reactions of chiral carbonyl compounds with nucleophiles has been a topic of considerable theoretical and synthetic interest since the pioneering study by Cram appeared in 1952. The available predictive models focus entirely on the conformational and stereoelectronic demands of the chiral carbonyl substrate, the implicit assumption being that the relative stabilities of the competing transition states are determined only by stereoelectronics and the minimization of nonbonded interactions between the substituents on the chiral center and the nucleophile. These models totally ignore the possibility, however, that the geometric requirements of the nucleophile may also have an effect on reaction diastereoselectivity. Considerable evidence is now available, particularly in the reactions of Type I (Z)-crotylboronates and Z(0)-metal enolates, that the stereochemistry of the nucleophile is indeed an important issue that must be considered when assessing reaction diastereoselectivity. 

The nondassical 2-norbomyl ion 5 can be attacked on C and only from the backside of an orbital included into the multicentre orbital. In accordance with these stereoelectronic demands the group migrating from to is to have an exo configuration. 

Stereoelectronic effects and nonbonded interactions are non-cooperative in the reactions of (E)-allylboronates and x-heteroatom-substituted aldehydes. Thus, while transition state 8 experiences the fewest nonbonded interactions (gauche pentane type, to the extent that X has a lower steric requirement than R3), transition state 9 is expected to benefit from favorable stereoelectronic activation (Felkin-type)58f. This perhaps explains why the reaction of 2,3-[iso-propylidenebis(oxy)]propanal and ( >2-butenylboronate proceeds with a modest preference (55%) by way ol transition state 9. This result is probably a special case, how ever, since C-3 of 2.3-[isopropylidenebis(oxy)]propanal is not very stcrically demanding in 9 owing to the acetonide unit that ties back the oxygen substituent, thereby minimizing interactions with the... 

The preferred reaction mode has been found to be sensitive to the structure of the alkene and the difference in the reactivity has been explained in terms of steric and stereoelectronic factors. Therefore, in the case of the sterically less hindered disubstituted cis alkenes, the pathway along the open 1,6-dipole D is favored (stereoelectronic control), while the more space-demanding disubstituted trans alkenes react by the epoxidation mode (steric control) a similar situation applies to trisubstituted versus tetrasubstituted alkenes. This remarkable but complex product dichotomy in the oxidation of alkenes... 

Various diastereomeric di-, tri-, and tetrapeptides that carry the sterically demanding trifluoromethyl group instead of the natural a-proton at different positions within these short peptide sequences have been designed, and their stability towards enzymatic hydrolysis has been investigated. The structures of the a-trifluoromethyl (aTfm)-substituted amino acids are shown in Scheme 1. From these studies we gained valuable information on how a-trifluoromethyl-substi-tuted peptides may interact with proteins. The aTfm amino acids used in this study combine the conformational restrictions [49-52] of C -dialkylation with the unique stereoelectronic properties of the fluorine atom and have shown interesting effects on peptide-enzyme interactions [53,54]. 

The anomeric effect, a stereoelectronic effect, is explained in terms of lone pair-lone pair repulsion, dipole-dipole interactions and by M.O. theory. The equatorial positions of a carbohydrate are favored by sterically demanding substituents. However, electronegative groups at the anomeric center prefer the axial position because of the stereoelectronic effects. This fact is known as the anomeric effect.13 If there is a positive charge at the anomer substituent of a carbohydrate, the equatorial conformation is preferred. To explain this result a reverse anomeric effect was proposed and first detected at A-(tt-glycopyranosyl)pyridinium ions 31 and 32.14... 

The diastereoselectivity of the first two reactions shown in Scheme 2.19 [68] can also be interpreted as a result of a stereoelectronic effect. Although the diastereoselectivity of additions to enones is usually governed by steric effects, which lead to an addition of the nucleophile from the sterically less demanding side of the double bond (as in the third reaction in Scheme2.19 for additional examples, see Refs [69, 70]), the first two reactions shown in Scheme 2.19 are, surprisingly, syn-selective. Cyclopentenones [68, 71] and cycloheptenones [72] can also react with the same syn-diastereoselectivity. 

The slightly lower r value for the solvolysis of system [15] than for the a-methyl analogue [14], is presumably due to incomplete coplanarity of the aryl group with the cationic p-orbital in the transition state of [15] (Tsuji et al., 1990). In the solvolysis of 2,2-dimethylindan-l-yl chlorides (cf. Table 3), the vacant p-orbital developed at the benzylic position is in a proper stereoelectronic conformation to overlap the benzene ir-system and the r value is practically identical with that observed for the solvolysis of [14]-C1 (Fujio et al., 1992c). Consequently, the resonance demand for the SnI solvolysis of secondary a-alkylbenzyl systems must be appreciably and intrinsically higher than that for the solvolysis of tertiary a,a-dialkylbenzyl systems. 

Radical addition reactions are commonly used in organic synthesis. These additions range from the simple addition of halocarbons to tt bonds to cyclization reactions with demanding stereoelectronic requirements. 

Another stereoelectronic effect induced by electronegative substituents is the "Anh-Eisenstein effect [44] (Scheme 4.17) which can be of particular importance to the stereochemical outcome of enzymatic reactions involving fluorinated substrates [45]. In a-fluorocarbonyl compounds nucleophilic attack of the carbonyl group occurs preferentially anti to the fluorine substituent [46]. The resulting, unusually high stereospecificity, e.g. in some enzymatic reactions of fluorinated substrates [45], cannot be explained by the slightly different steric demands of hydrogen and fluorine alone. 

These results, while establishing the regiochemistry of triphenylphosphine attack, demand the involvement of the azetinium species 388, at least whenever retention is observed. Solvent effects and stereoelectronic factors in the structure of triphenylphosphonium enethiolates 379 determine the occurrence of two competing pathways, i.e. direct Sjy2 collapse (inversion) and elimination-addition via the dipolar species 388 (retention and/or inversion). 

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