Nucleophile-controlled stereoselective

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... 

These considerations show that the orbital interactions cited by Cieplak cannot be the controlling orbital interactions in nucleophilic additions. Why, then, is the Cieplak hypothesis nevertheless successful in so many cases It is important first of all to acknowledge that there are a number of effects operating in nucleophilic additions, and no single one of them controls stereoselectivity in every case [69]. The question is to determine the relative magnitudes of these and to have some useful generalisations about which effects operate in different types of molecules. 

Chamberlin AR, Dezube M, Dussault P, McMills MC (1983) Iodocyclization of allylic alcohol derivatives containing internal nucleophiles. Control of stereoselectivity by substituents in the acyclic precursors. J Am Chem Soc 105 5819-5825... 

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. ... 

The alkynyl reagent 9 was recently introduced for the dia stereoselective synthesis of tertiary propargylic alcohols144. 9 can be prepared as a solid 1 1 complex with tetrahydrofuran by treatment of 9-methoxy-9-borabicyclo[3.3.1]nonane with (trimethylsilylethynyl)lithium, followed by addition of boron trifluoride-diethyl ether complex. The nucleophilic addition of reagent 9 to (R)-2-methoxy-2-methylhexanal (10) afforded a mixture of the diastereomers 11 with a considerable preference to the nonchelation-controlled (3S,4R)-isomer144. 

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. 

Typically, lyases are quite specific for the nucleophilic donor component owing to mechanistic requirements. Usually, approach of the aldol acceptor to the enzyme-bound nucleophile occurs stereospedfically following an overall retention mechanism, while the facial differentiation of the aldehyde carbonyl is responsible for the relative stereoselectivity. In this manner, the stereochemistry of the C—C bond formation is completely controlled by the enzymes, in general irrespective of the constitution or configuration of the substrate, which renders the enzymes highly predictable. On the other hand, most of the lyases allow a reasonably broad variation of the electrophilic acceptor component that is usually an aldehyde. This feature... 

Palladium-catalyzed cyclization of alkenes and alkynes were reported by Balme and co-workers.143 144 Intramolecular carbopalladation occurs to give polycyclic compounds. It has been shown that the nucleophile type has a large influence on the cyclization process. Both 5-exo- and 6-endo-cyclization are observed for substrates with nitrile (116 and 118) and ester (120, 122, and 124) substituents, respectively (Scheme 36). When a mixed nucleophile (CN and C02Me) is used, a mixture of 5-exo and 6-endo products is obtained. The chemoselectivity is controlled by the size of the nucleophile used. The stereochemistry of the initial double bond plays an important role on the stereoselectivity of the cyclization. (Z)-olefins (118 and 120) and (/. )-olefins (116 and 124) afford as- (119 and 121) and trans-cyclization products (117 and 123), respectively. 

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. 

Similar schemes can be developed easily for analogous reactions of acceptor-substituted polyenes. For example, a triene with an acceptor group in 1-position can form six regioi-someric products of Michael addition and electrophilic capture, and each of these exists as E/Z stereoisomers, diastereomers and/or enantiomers. Thus, reactions of this type are only useful if both the regio- and stereoselectivity can be controlled fortunately, only one isomeric Michael adduct is formed in many cases. This is true in particular for polyunsaturated Michael acceptors which bear at least one triple bond besides one or more double bonds. An additional feature of the latter substrate type is that nucleophilic additions can... 

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