Nucleophile-controlled stereoselective reactions

Stereoselective reactions of this type known at present only deal with four- or five-membered cyclic iV-acyliminium ions. The reactions with carbon nucleophiles usually lead to rra/u-substi-tuted compounds with very high stereoselectivity due to steric control by the substituent already present in the ring. 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

Mattay et al. examined the regioselective and stereoselective cyclization of unsaturated silyl enol ethers by photoinduced electron transfer using DCA and DCN as sensitizers. Thereby the regiochemistry (6-endo versus 5-exo) of the cyclization could be controlled because in the absence of a nucleophile, like an alcohol, the cyclization of the siloxy radical cation is dominant, whereas the presence of a nucleophile favors the reaction pathway via the corresponding a-keto radical. The resulting stereoselective cis ring juncture is due to a favored reactive chair like conformer with the substituents pseudoaxial arranged (Scheme 27) [36,37]. 

Electrophilic addition to double bonds gives three-membered ring intermediates with Br2, with Hg2+, and with peroxy-acids (in which case the three-membered rings are stable and are called epoxides). All three classes of three-membered rings react with nucleophiles to give 1,2-difunctionalized products with control over (1) regioselectivity and (2) stereoselectivity. Protonation of a double bond gives a cation, which also traps nucleophiles, and this reaction can be used to make alkyl halides. Some of the sorts of compounds you can make by the methods of this chapter are shown below. 

These conformational preferences can be used for the control of reaction stereoselectivity. For example, whereas the reduction of 4-Me-cyclohexanone mostly gives the trans product, reduction of the 4-Cl-cyclohex-anone leads to the preferential formation of the cis product. Assuming the common axial preference for the nucleophilic attack at the carbonyl, the differences in reaction selectivity should reflect the different axial/ equatorial populations of the two carbonyl reactants. Similar conformational preferences were suggested for the nucleophilic attack at oxonium ions (Figure 6.89). ... 

When racemic 2-ethylpiperidine was reacted with the provisional chiral conformation of 3a, similar results were obtained as the reaction with 2-methylpiperidine. However, when racemic 3-methylpiperidine was used as a nucleophile, the substitution reaction occurred quantitatively however, the ee value resulted in 17%. The methyl group at the 3-position of the paperidine ring was insufficient to control the stereoselectivity because of the distance between the reacting nitrogen atom and the substituent. On the contrary, the substituent at the 2-positions worked sufficiently as strong chiral flags to control the stereoselectivity. 

A very important relationship between stereochemistry and reactivity arises in the case of reaction at an 5 carbon adjacent to a chiral center. Using nucleophilic addition to the carbonyl group as an example, it can be seen that two diastereomeric products are possible. The stereoselectivity and predictability of such reactions are important in controlling stereochemistry in synthesis. 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

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