Addition reactions stereochemical

Zincke-type salts derived from other aromatic nitrogen heterocycles also undergo Zincke reactions. The isoquinolinium salt 6 (Scheme 8.4.16) permitted incorporation of a phenyl ethylamine chiral auxiliary, providing salt 48. In this context and others (vide infra), Marazano and co-workers found that refluxing -butanol was a superior solvent system for the Zincke process. Additionally, the stereochemical integrity of the or-chiral amino fragment was reliably maintained. 

The stereochemical outcome of the Michael addition reaction with substituted starting materials depends on the geometry of the a ,/3-unsaturated carbonyl compound as well as the enolate geometry a stereoselective synthesis is possible. " Diastereoselectivity can be achieved if both reactants contain a stereogenic center. The relations are similar to the aldol reaction, and for... 

A sequence of straightforward functional group interconversions leads from 17 back to compound 20 via 18 and 19. In the synthetic direction, a base-induced intramolecular Michael addition reaction could create a new six-membered ring and two stereogenic centers. The transformation of intermediate 20 to 19 would likely be stereoselective substrate structural features inherent in 20 should control the stereochemical course of the intramolecular Michael addition reaction. Retrosynthetic disassembly of 20 by cleavage of the indicated bond provides precursors 21 and 22. In the forward sense, acylation of the nitrogen atom in 22 with the acid chloride 21 could afford amide 20. 

In the case of substituted cyclic ketones, particularly cyclohexanones, the stereochemical outcome of an addition reaction is determined by the predominance of either equatorial or axial attack of the nucleophile, leading to axial or equatorial alcohols, respectively 25 -27 (Figure 8). 

Since equatorial attack is roughly antiperiplanar to two C-C bonds of the cyclic ketone, an extended hypothesis of antiperiplanar attack was proposed39. Since the incipient bond is intrinsically electron deficient, the attack of a nucleophile occurs anti to the best electron-donor bond, with the electron-donor order C—S > C —H > C —C > C—N > C—O. The transition state-stabilizing donor- acceptor interactions are assumed to be more important for the stereochemical outcome of nucleophilic addition reactions than the torsional and steric effects suggested by Felkin. 

The stereochemical outcome of nucleophilic addition reactions to cyclic ketones is the subject of numerous experimental and theoretical studies, with substituted cyclohexanones and cy-clopcntanones having been intensively studied. In addition reactions to substituted cyclohexanones 1 the problem of simple diastereoselectivity is manifested in the predominance of cither axial attack of a nucleophile, leading to the equatorial alcohol 2 A. or equatorial attack of the nucleophile which leads to the axial alcohol 2B. 

In fact, the highest anti-Cram selectivity reported to date (96% de) was observed with the MAT-mediated addition of methylmagnesium bromide to 2-(l-cyclohexenyl)propanal3 i 36. The stereochemical outcome of this addition reaction can be explained as follows on treatment of the carbonyl compound with the large aluminum reagent, the sterically least hindered complex 9 is formed. Subsequent addition of the nucleophile from the side opposite to the bulky aluminum reagent produces the anti-Cram diastereomer preferentially. 

In addition reactions to chiral carbonyl compounds, the stereochemical course taken by resonance-stabilized alkali metals or magnesium benzyl anions resembles that taken by localized carbanions of similar bulk. Thus, conditions can be delineated which lead to either the steric approach or chelation control the following serve as examples. 

As a result, one might expect that there is only a slight difference between the iminium salts and the parent ketone (4-rm-butylcyclohcxanone) concerning the stereochemical course of the addition reaction and. actually, this assumption proves to be true. In each case the diastereomer resulting from the less hindered equatorial attack of the nucleophile clearly predominates10. 

A c/.v-fused chair-chair -like and a Tram-fused boat-boat -like transition state have been suggested to explain the stereochemical outcome from the addition reactions of the (E)- and (Z)-l-(/f>rf-butylsulfinyl)-2-methyl-2-butenes, respectively. 

The addition of the anions of racemic cyclic allylic sulfoxides to various substituted 2-cyclopentenones gives y-l,4-adducts as single diastereomeric products22. The modest yields were due to competing proton-transfer reactions between the anion and enone. The stereochemical sense of these reactions is identical to that for the 1,4-addition reaction of (Z)-l-(/erf-butylsulfinyl)-2-methyl-2-butene to 2-cyclopentenone described earlier. 

The configuration at sulfur is mainly responsible for the sense of asymmetric induction. It is of interest to note that butylcopper and lithium dibutylcuprate undergo addition reactions in the opposite stereochemical sense. The adducts can be converted to chiral /i-disubstituted carboxylic acids1. 

The addition reaction of enolates and enols with carbonyl compounds is of broad scope and of great synthetic importance. Essentially all of the stabilized carbanions mentioned in Section 1.1 are capable of adding to carbonyl groups, in what is known as the generalized aldol reaction. Enolates of aldehydes, ketones, esters, and amides, the carbanions of nitriles and nitro compounds, as well as phosphoms- and sulfur-stabilized carbanions and ylides undergo this reaction. In the next section we emphasize the fundamental regiochemical and stereochemical aspects of the reactions of ketones and aldehydes. 

Note also the stereochemistry. In some cases, two new stereogenic centers are formed. The hydroxyl group and any C(2) substituent on the enolate can be in a syn or anti relationship. For many aldol addition reactions, the stereochemical outcome of the reaction can be predicted and analyzed on the basis of the detailed mechanism of the reaction. Entry 1 is a mixed ketone-aldehyde aldol addition carried out by kinetic formation of the less-substituted ketone enolate. Entries 2 to 4 are similar reactions but with more highly substituted reactants. Entries 5 and 6 involve boron enolates, which are discussed in Section 2.1.2.2. Entry 7 shows the formation of a boron enolate of an amide reactions of this type are considered in Section 2.1.3. Entries 8 to 10 show titanium, tin, and zirconium enolates and are discussed in Section 2.1.2.3. 

Stereochemical Control by the Enolate or Enolate Equivalent. The facial selectivity of aldol addition reactions can also be controlled by stereogenic centers in the nucleophile. A stereocenter can be located at any of the adjacent positions on an enolate or enolate equivalent. The configuration of the substituent can influence the direction of approach of the aldehyde. 

These examples and those in Scheme 2.6 illustrate the key variables that determine the stereochemical outcome of aldol addition reactions using chiral auxiliaries. The first element that has to be taken into account is the configuration of the ring system that is used to establish steric differentiation. Then the nature of the TS, whether it is acyclic, cyclic, or chelated must be considered. Generally for boron enolates, reaction proceeds through a cyclic but nonchelated TS. With boron enolates, excess Lewis acid can favor an acyclic TS by coordination with the carbonyl electrophile. Titanium enolates appear to be somewhat variable but can be shifted to chelated TSs by use of excess reagent and by auxiliaries such as oxazolidine-2-thiones that enhance the tendency to chelation. Ultimately, all of the factors play a role in determining which TS is favored. 

Predict the stereochemical outcome of the following aldol addition reactions involving chiral auxiliaries. 

Ralph, J. Young, R. A. Stereochemical aspects of addition reactions involving lignin model quinone methides. J. Wood Chem. Technol. 1983, 3, 161-181. 

A number of photochemically induced 4 + 2 cycloadditions have been observed/131-150 This reaction can be either a concerted ( 4, + 20) or a ( 40 4- 2S) addition. The stereochemical consequences of the allowed reactions are as follows ... 

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