Addition reactions remote substituent effects

The reaction of dienes with quinazarin quinone has received considerable attention as a key step in the synthesis of the anti-tumour drugs such as adriamycin (101). Unwanted addition to the internal double bond often occurred and it is clear that any regiospecific synthesis of these compounds based on this approach will require a careful appraisal of seemingly remote substituent effects upon the orientation of the addition step (Scheme 54). The Diels-Alder addition of 1-methoxybuta-diene to 2-hydroxymethyl-5-methoxybenzoquinone gave the adduct (102) exclu-... 

The effect of a remote substituent on the facial selectivities in a nucleophilic conjugate addition has been investigated for the reaction of EtSH with a series of dibenzobicyclo[2.2.2]octatrienes (84). Syn-addition proved to be favoured for nitro substituent and polar solvents increased the selectivity (Table 5).19... 

We have investigated the substituent effects of the olefin and enophile that lead to cyclobutane formation. Reaction occurs exclusively with the unsubstituted double bond of the NBD irrespective of the electronic nature of the substituent (Y) giving type I [2 + 2] adducts (Scheme 21). In addition, only two of the remaining isomers are observed in most cases. We find that cyclobutane formation is particularly facile when unreactive dienes are reacted with very reactive alkenes. We also observed a clear trend between the exo versus endo mode of reaction and the electron density on the remote, unreacting alkene of the NBD. The specific examples are outlined following. 

The study of structure-reactivity relationships by the organic chemist Hammett showed that there is often a quantitative relationship between the two-dimensional structure of organic molecules and their chemical reactivity. Specifically, he correlated the changes in chemical properties of a molecule that result from a small change in its chemical structure that is, the quantitative linear relationship between electron density at a certain part of a molecule and its tendency to undergo reactions of various types at that site. For example, there is a linear relationship between the effea of remote substituents on the equilibrium constant for the ionization of an acid with the effect of these substituents on the rate or equilibrium constant for many other types of chemical reaction. The relative value of Hammett substituent constants describes the similarity of molecules in terms of electronic properties. Taft expanded the method to include the steric hindrance of access of reagents to the reaction site by nearby substituents, a quantitation of three-dimensional similarity. In addition, Charton, Verloop, Austel, and others extended and refined these ideas. Finally, Hansch and Fujita showed that biological activity frequently is also quantitatively correlated with the hydrophobic character of the substituents. They coined the term QSAR, Quantitative Structure-Activity Relationships, for this type of analysis. 

In contrast, the need to evaluate the relative rates of competing radical reactions pervades synthetic planning of radical additions and cyclizations. Further, absolute rate constants are now accurately known for many prototypical radical reactions over wide temperature ranges.19,33 3S These absolute rate constants serve to calibrate a much larger body of known relative rates of radical reactions.33 Because rates of radical reactions show small solvent dependence, rate constants that are measured in one solvent can often be applied to reactions in another, especially if the two solvents are similar in polarity. Finally, because the effects of substituents near a radical center are often predictable, and because the effects of substituents at remote centers are often negligible, rate constants measured on simple compounds can often provide useful models for the reactions of complex substrates with similar substitution patterns. 

The stereoselectivity of the aldol additions shown in Schemes 5.25 and 5.26 are obviously the result of a complex series of factors, among which are the Felkin-Anh preference dictated by the a-substituent on the aldehyde, the proximal stereocenters on the enolate, etc. Additionally, the more remote stereocenters, such as at the p-position of the aldehyde, may influence the selectivity of these types of reactions. Evans has begun an investigation into some of the more subtle effects on crossed aldol selectivity, such as protecting groups at a remote site on the enolate [131], and of P-substituents on the aldehyde component [132], and also of matched and mismatched stereocenters at the a and P positions of an aldehyde (double asymmetric induction) [133]. Further, the effect of chiral enolates adding to a,P-disubstituted aldehydes has been evaluated [134]. The latter turns out to be a case of triple asymmetric induction, with three possible outcomes fully matched, partially matched, and one fully mismatched trio. 

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