Stereoelectronic effect Steric approach control

Steric and stereoelectronic effects control the direction of approach of an electrophile to the enolate. Electrophiles approach from the least hindered side of the enolate. Numerous examples of such effects have been observed. In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a slight... 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

A new strategy for the synthesis of erythromycin A and closely related mac-rolide antibiotics was elaborated in our laboratory (88). This new approach to synthesis is based on the knowledge that stereoelectronic effects control the conformation of acetals. The strategy is based on the 1,7-dioxaspiro-[5.5]undecane system which was found to be conformationally rigid, existing in conformation J50 only (see Chapter 2). This is so because in this confor-mation, steric effects are at their minimum and the acetal function has... 

Over the past decade, the stereocontrolled reduction of enantiomerically pure P-ketosulfoxides by hydride reagents, particularly within the Solladid research group, has sparked considerable interest, as an approach to many synthetically important intermediates and biologically active molecules of defined chirality. The applications described below outline the effectiveness of the chiral sulfoxide moiety as a stereocontrol element, and highlight the ready removal of the sulfoxide group after its contribution to the synthetic scheme. In all cases, the sense of stereochemical induction can be rationalized and predicted on the basis of steric, stereoelectronic and/or chelation control factors. 

When the carbonyl group is exo to a ring as in cyclohexanone, both the equatorial and the axial approach can lead to a chair intermediate (cf. 7 and 8) with stereoelectronic control because, in each case, the oxygen atom has an electron pair antiperiplanar to the C-Y bond. So, in this case, one process is favored over the other solely on the basis of steric effects and torsional strain due to the presence of the ring (8). ... 

The bicyclic enone 84 in which ring A can adopt the two conformations 85 and 86 can now be examined. A stereoelectronically controlled attack of cyanide ion on the o face of conformation 85 gives the chair-like intermediate 87 while that on the B face of conformation 86 yields the chair-like intermediate 88. An approach from the top face of 85 or the bottom face of 86 is not considered because it leads to intermediates having a boatlike conformation. Intermediate 87 with its trans junction is more stable on the basis of steric effects than intermediate 88 which has a cis ring junction consequently, the formation of the a-cyano adduct 89 should prevail over the B-cyano adduct 90. 

The stereochemistry of nucleophilic 1,4-additions to enones (Michael-type additions) is controlled by stereoelectronic factors. In the absence of compelling steric effects, the nucleophile approaches the [3-carbon of the enone antipamllel to the neighboring (y) pseudoaxial substituent (circled H in the example below). 

---