Stereoelectronic preferences

Soft electrophiles will prefer carbon, and it is found experimentally that most alkyl halides react to give C-alkylation. Because of the n character of the HOMO of the anion, there is a stereoelectronic preference for attack of the electrophile approximately perpendicular to the plane of the enolate. The frontier orbital is ip2, with electron density mainly at O and C-2. The tpi orbital is transformed into the C=0 bond. The transition state for an 8 2 alkylation of an enolate can be represented as below. 

Alkylations of 6-methoxycarbonyl six-membered cyclic (V-acyliminium ions show a strong preference for the formation of m-products. This is explained by the A0-3 strain between the substituent and the (V-mcthoxycarbonyl group of the iminium ion, forcing the substituent into an axial position. Stereoelectronically preferred axial attack by the nucleophile then leads to the 2,6-d.v-disubstituted piperidine derivatives. 

The high enantioselectivity again can be rationalized by enantioface-selective alkene coordination in 63 (Fig. 35). The olefin moiety is expected to bind trans to the upper imidazoline moiety [70,73] thereby releasing the catalyst strain. Coordination at this position may, in principal, afford four different isomers assuming the stereoelectronically preferred perpendicular orientation of the alkene and the Pt(II) square plane. In the coordination mode shown, steric repulsion between both olefin substituents and the ferrocene moiety is minimized. Outer-sphere attack of the indole core results in the formation of the product s stereocenter. 

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... 

The stereochemistry is controlled by a stereoelectronic preference for protonation perpendicular to the enolate system and, given that this requirement is met, the stereochemistry normally corresponds to protonation of the most stable conformation of the dianion intermediate from its least hindered side. 

The stereochemistry of the silyl ketene acetal can be controlled by the conditions of preparation. The base that is usually used for enolate formation is lithium diisopropyl-amide (LDA). If the enolate is prepared in pure THF, the F-enolate is generated and this stereochemistry is maintained in the silyl derivative. The preferential formation of the F-enolate can be explained in terms of a cyclic TS in which the proton is abstracted from the stereoelectronically preferred orientation perpendicular to the carbonyl plane. The carboxy substituent is oriented away from the alkyl groups on the amide base. 

From a synthetic point of view, the regioselectivity and stereoselectivity of the cyclization are of paramount importance. As discussed in Section 11.2.3.3 of Part A, the order of preference for cyclization of alkyl radicals is 5-exo > 6-endo 6-exo > 7-endo S-endo > 1-exo because of stereoelectronic preferences. For relatively rigid cyclic structures, proximity and alignment factors determined by the specific geometry of the ring system are of major importance. Theoretical analysis of radical addition indicates that the major interaction of the attacking radical is with the alkene LUMO.321 The preferred direction of attack is not perpendicular to the it system, but rather at an angle of about 110°. 

The stereoinductive effect of the a-substituent is often more powerful when this substituent is a polar group such as an alkoxy or amino gronp. In this instance as well, minimization of syn-pentane interactions with 3-monosnbstituted reagents is important, and the selectivity can be amplified if it acts in concert with other effects. Known models inclnde the stereoelectronic preference... 

Now two factors cooperate one being the preference for attack at the convex ring face and the second being the stereoelectronic preference for the formation of a civ-fused bicyclic skeleton 34. 

Suggest an explanation based on orbital interactions for the observed stereochemistry for E2 elimination reactions, that is, the strong stereoelectronic preference that the C—H and C—X bonds be anti-coplanar. 

In elimination from the threo compound 285, the situation is different because the stereoelectronic and conformational factors are not cooperative. Since expulsion of the leaving group from the stereoelectronically preferred carbanion 2tH is rendered difficult by severe Ar-ArS02 steric interactions, the anti elimination is slowed down and syn elimination via carbanions 292 and 293 become competitive."... 

Park, T. K. Danishefsky, S. J. A synthetic route to vallenamine an interesting observation concerning stereoelectronic preferences in the Sn2 reaction. Tetrahedron Lett. 1994, 35, 2667-2670. 

The stereoselectivity of conjugate addition reaction of 34 can be rationalized as follows. The conformation of 34 is restricted to A by the oxazolizinone ring, and the vinyl anion attacks from stereoelectronically preferred (3-axial direction to give rise to the adduct 35 exclusively. 

The stereoelectronic preference of sp2 centers in cyclohexane systems for axial attack128 is most probably also found in the peracid epoxidation of methylenecyclohexanes44, where selectivity for axial attack is 0.3 -0.6 keal/mol higher than predicted by the MM2 simulation throughout78. The effect is also detected in derivatives that are substituted in the methylene position, such as isopropylidene derivative 644, and even in annulated derivatives such as 7130 and 5-cholestene81 (see also Tables 3 and 4, Section 4.5.1.1.1.) or the corresponding bicyclic analogs132. 

The example studied in most detail is the bromination of 5a 3 ketones (i). The product from monobromination in acetic acid, with hydrogen bromide catalysis, is the sa-bromoketone (2). This appeared to contravene the principle [113] that stereoelectronic control favours the formation of the axial bromoketone, especially when kinetically-controlled bromination of the enol acetate (3 was found to give the same product [136]. Detailed experimental and theoretical investigations have established that the stereoelectronic preference for axial attack is fulfilled, by the molecule adopting a boat or flexible conformation (5) of ring A during attack by bromine, and changing later into the chair conformation (6)... 

Ring D ketones are subject to the same general principles in halogenation reactions. The observed preference for 16 a attack on enols of ly-ketones [i4g] is probably the result of stereoelectronic preference for attack (see p. 160) rather than purely an indication of steric compression, for equilibration of a i6-bromo-i7 ketone favours the i6/9-epimer /j, 97 ... 

There is no direct evidence as to the stereochemistry of the Se ester intermediate, but the stereoelectronically preferred... 

When the a-position is allylic, metalation is easier, and the resulting organolithium is not prone to oxidation y-substitution then predominates over a-substitution, as shown by the example in Scheme 11 The stereoelectronic preference of dipole-stabilized organolithiums for the nodal plane of the amide or amidine ir-system makes possible the directed metalation of bridgehead positions. Two examples are il-... 

Under optimized experimental conditions (CH2C12, MeOH (10 equivalents), HFTP (5 equivalents)) the reaction was complete at room temperature in less than 5h. Moreover, the reaction was still chemoselective (less than 5% of the elimination product 18), and completely stereoselective (the a stereoisomer was not detected) (see Scheme 6.9) [47], The nucleophile is delivered on the same P-face as the leaving group. Similar results from DHA glycosyl donor have been rationalized by the formation of the half-chair oxonium ion, and a stereoelectronically preferred axial addition with reactive nucleophiles [18c], Compared to the reaction of 17 with the stronger Ag+ electrophilic assistance (see Schemes 6.7 and 6.8), the low ratio of elimination product 16 and the high p-diastereoselectivity suggest a mechanism different from an addition on the oxonium ion 14. It is also clear... 

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