Stereoelectronic requirements

A systematic effort to correlate ease of ring closure with the stereoelectronic requirements of the transition state has been developed by Baldwin and co-workers. They classify ring closures with respect to three factors (a) ring size, (b) the hybridization of the carbon at the reaction site, and (c) the relationship (endocyclic or exocyclic) of the reacting bond to the forming ring. Certain types of ring closures are found to be favorable whereas others are unfavorable for stereoelectronic reasons. The relationships are summarized in Table 3.12. 

This stereoelectronic requirement would lead to a large distortion of the normal geometry of a five-membered ring and introduce strain. It is this distortion and strain that disfavor the 5-endo-trig cyclization. In contrast, 5-endo-dig cychzation is feasible because the acetylenic system provides an orbital that is available for a nearly planar mode of approach. 

The terms favored and disfavored imply just that. Other factors will determine the absolute rate of a given ring closure, but these relationships point out the need to recognize the specific stereoelectronic requirements which may be imposed on the transition state in ring-closure reactions. 

In general, the stereoselectivity of enolate alkylation can be predicted and interpreted on the basis of the stereoelectronic requirement for approximately perpendicular approach to the enolate in combination with selection between the two faces on the basis of steric factors. 

When this stereoelectronic requirement is combined with a calculation of the steric and angle strain imposed on the transition state, as determined by MM-type calculations, preferences for the exo versus endo modes of cyclization are predicted to be as summarized in Table 12.3. The observed results show the expected qualitative trend. The observed preferences for ring formation are 5 > 6, 6 > 7, and 8 > 7, in agreement with the calculated preferences. The relationship only holds for terminal double bonds. An additional alkyl substituent at either end of the double bond reduces the relative reactivity as a result of a steric effect. 

Intramolecular Friedel-Crafts acylation has been observed with bonellin dimethyl ester (20).53 The reaction proceeds in contrast to corresponding porphyrins, very smoothly with concentrated sulfuric acid because the propanoic acid side chain at the sp3 center is located above the macrocyclic ring system and therefore can better fulfill the stereoelectronic requirements for the ring-closure reaction. The ring closure is accompanied by racemization in the product 21. 

A stereoelectronic requirement in radical addition to carbon-carbon double bonds first became apparent from studies on radical cyelization and the reverse (Fragmentation) reactions.54 56 It provides a rationalization for the preferential formation of the less thermodynamically stable exo-product (i.e. head addition) from the cyelization of to-alkcny] radicals (16 - Scheme 1.5). s 57 G4... 

A method for the stereospecific synthesis of thiolane oxides involves the pyrolysis of derivatives of 5-t-butylsulfinylpentene (310), and is based on the thermal decomposition of dialkyl sulfoxides to alkenes and alkanesulfenic acids299 (equation 113). This reversible reaction proceeds by a concerted syn-intramolecular mechanism246,300 and thus facilitates the desired stereospecific synthesis301. The stereoelectronic requirements preclude the formation of the other possible isomer or the six-membered ring thiane oxide (equation 114). Bicyclic thiolane oxides can be prepared similarly from a cyclic alkene301. 

These examples illustrate the issues that must be considered in analyzing the stereoselectivity of enolate alkylation. The major factors are the conformation of the enolate, the stereoelectronic requirement for an approximately perpendicular trajectory, the steric preference for the least hindered path of approach, and minimization of torsional strain. In cyclic systems the ring geometry and positioning of substituents are often the dominant factors. For acyclic enolates, the conformation and the degree of steric discrimination govern the stereoselectivity. 

This means that if a reaction is carried out on a compound that has no stereoisomers, it cannot be stereospecific but at most stereoselective. The concerted reactions, including SN2 displacements, E2 elimination of alkyl halides, anti and Syn addition to alkenes are all stereoselective. In the case of chiral or geometric substrates the nature of the product depends on the unique stereoelectronic requirement of the reaction. These are examples of stereospecific reactions. 

Because the three-electron-bonded radicals are formed at the cost of the removal of the nitrogen p-electron, such cation-radicals should be considered as p-acids. Of course, the formation and behavior of these p-acids have to be dependent on steric factors. Works by Tomilin et al. (1996, 2000), Bietti et al. (1998), Dombrowski et al. (2005), and Yu et al. (2007) should be mentioned as describing stereoelectronic requirements to formations and configurational equilibria of A-alkyl-substituted cation-radicals. 

The initial step in the alternative hydrolysis mechanism is protonation of the ring 0i by Glu 35 (Scheme I). Cleavage of the endocyclic C1-O5 bond forms the acyclic oxocarbonium ion intermediate, which is stabilized by Asp 52. Attack by water, cleavage of the C1-O4 bond, and ring closure then lead to the observed products. Existing experimental data on lysozyme hydrolysis are consistent with Scheme I (see references in Post and Karplus ( )). Moreover, distortion of the ring in site D is not required and the antiperiplanar orientation of an exocyclic O4 lone pair orbital relative to the cleaved C1-O5 bond found in the simulation (see section on "Enhancement of a Substrate Conformation Optimum for Catalysis") is in accord with stereoelectronic requirements (1 ). ... 

The is-boron enolates of some ketones can be preferentially obtained with the use of dialkylboron chlorides.17 The data in Table 2.3 pertaining to 3-pentanone and 2-methyl-3-pentanone illustrate this method. Use of boron triflates with a more hindered amine favors the Z-enolate. The contrasting stereoselectivity of the boron triflates and chlorides has been discussed in terms of reactant conformation and the stereoelectronic requirement for perpendicular alignment of the hydrogen being removed with the carbonyl group.18 The... 

Dunathan suggested that this stereoelectronic requirement explains certain side reactions observed with PLP-requiring enzymes. The idea also received support from experiments with a bacterial a-dialkyl-glycinedecarboxylase.231 232 The enzyme ordinarily catalyzes, as one half-reaction, the combination decarboxylation-transamination reaction shown in Eq. 14-37. It also acts on both d- and L-alanine, decarboxylating the former but catalyzing only removal of the a-H... 

The allylic alcohol binds to the remaining axial coordination site, where stereochemical and stcrcoelectronic effects dictate the conformation shown in Figure 6A.9 [6]. The structural model of catalyst, oxidant, and substrate shown in Figure 6A.9 illustrates a detailed version of the formalized rule presented in Figure 6A. 1. Ideally, all observed stereochemistry of epoxy alcohol and kinetic resolution products can be rationalized according to the compatibility of their binding with the stereochemistry and stereoelectronic requirements imposed by this site [6]. A... 

The stereoelectronic requirements of groups undergoing base-promoted elimination is also easily seen by stereochemical studies. Treatment of trans-2-methylcyclohexyl tosylate gives 3-methylcyclohexene as the major product while treatment of czs-2-methylcyclohexyl tosylate gives the more stable 1-methylcyclohexene as tire only product. 

The examples presented above point out some important features about organic reactions. First, many have distinct stereoelectronic requirements that must be met... 

The stereoelectronic requirements for carbonyl addition are that electron donation occurs by interaction of die donor with the it orbital of the carbonyl group. To meet the stereoelectronic requirements and explain the diastereoselectivity, the Zimmerman-Traxler model is used. Interaction of the lithium cation with the oxygen of die enolate and of die carbonyl electrophile leads to a six-membered... 

As a consequence of this stereoelectronic requirement, the opening of a symmetrical epoxide (61 by a nucleophile gives a product of defined stereochemistry (cf. J). The same requirement necessarily holds for the reverse process, i, e. 7 6. Indeed, the formation of an epoxide from 7 can be regarded as an internal SN2 reaction (footnote 20 in ref. 4, see also 5). 

There are four possible transition states in the reduction of 27 wherein maximum orbital overlap can be maintained with respect to the attacking hydride reagent and the developing electron pair on nitrogen. Two of these (cf. dotted arrow in 29 and 30) require boat-like transition states in order to satisfy the stereoelectronic requirements and are unfavorable kinetic-ally. Of the two possible chair-like transition states (cf solid arrow in 29 and 30) the latter suffers from a strong steric interaction between the nucleophile and the C-8 pseudo-axial hydrogen. The process 30 + 32 is thus disfavored by comparison with the process 29 31. 

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