Stereoelectronics, eliminations additions

Figure 6.67 Stereoelectronics of eliminations and additions, (a) Orbital overlap favouring anti elimination/addition. (b) Cartoon of least-motion arguments favouring anti elimination. The dotted line represents the reference plane, which is perpendicular to the plane of the paper, (c) Biirgi-Dunitz-like approach in Michael additions and examples.

These results, while establishing the regiochemistry of triphenylphosphine attack, demand the involvement of the azetinium species 388, at least whenever retention is observed. Solvent effects and stereoelectronic factors in the structure of triphenylphosphonium enethiolates 379 determine the occurrence of two competing pathways, i.e. direct Sjy2 collapse (inversion) and elimination-addition via the dipolar species 388 (retention and/or inversion). 

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. 

The crystal structures of thiamin-dependent enzymes (see next section) as well as modeling102 103 suggest that lactylthiamin pyrophosphate has the conformation shown in Eq. 14-21. If so, it would be formed by the addition of the ylid to the carbonyl of pyruvate in accord with stereoelectronic principles, and the carboxylate group would also be in the correct orientation for elimination to form the enamine in Eq. 14-21, step b.82 83a A transient 380- to 440-nm absorption band arising during the action of pyruvate decarboxylase has been attributed to the enamine. 

The term stereoselective is often confused with the term stereospecific, and the literature abounds with views as to the most satisfactory definition. To offer some clarification, it is perhaps timely to recall a frequently used term, introduced a decade or so ago, namely the stereoelectronic requirements of a reaction. All concerted reactions (i.e. those taking place in a synchronised process of bond breaking and bond forming) are considered to have precise spatial requirements with regard to the orientation of the reactant and reagent. Common examples are SN2 displacement reactions (e.g. Section 5.10.4, p. 659), E2 anti) elimination reactions of alkyl halides (e.g. Section 5.2.1, p.488), syn (pyrolytic) elimination reactions (Section 5.2.1, p.489), trans and cis additions to alkenes (e.g. Section 5.4.5, p. 547), and many rearrangement reactions. In the case of chiral or geometric reactants, the stereoisomeric nature of the product is entirely dependent on the unique stereoelectronic requirement of the reaction such reactions are stereospecific. 

Fumarate hydratase. The most studied enzyme of this group is probably the porcine mitochondrial fumarate hydratase (fumarase see also Chapter 9), a tetramer of 48.5-kDa subunits with a turnover number of 2 x 10 s T It accelerates the hydration reaction more than lO -fold. A similar enzyme, the 467-residue fumarase C whose three-dimensional structure is known, is foxmd in cells of E. coli when grown aerobically. The product of the fumarate hydratase reaction is L-malate (S-malate). The stereospecificity is extremely high. If the reaction is carried out in HjO an atom of H is incorporated into the pro-R position, i.e., the proton is added strictly from the re face of the trigonal carbon (Eq. 13-12). To obtain L-malate the hydroxyl must have been added from the opposite side of the double bond. Such anti (trans) addition is much more common in both nonenzymatic and enzymatic reactions than is addition of both H and OH (or -Y) from the same side (syn, cis, or adjacent addition). For concerted addition it is a natural result of stereoelectronic control. Almost all enzymatic addition and elimination reactions involving free carboxylic acids are anti with the proton entering from the re face. 

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... 

Thus, both the trans-addition and tram-elimination are strongly favored over the corresponding civ-variants due to stereoelectronic effects. In 1,2-migrations, the migrating group is always anti to the leaving group on the adjacent carbon. 

Fig. 4.30) with various substitution pattern at Cl and C2 were investigated. Experiments with alkyl substituents at C2, in place of the sulfur heteroatoms, eliminate the viability of a chelation-controlled selectivity and reveal the significance of geminal substitution [geminal substitution influenced the selectivity in other oxocarbenium ion systems [108]]. Perturbation of the Cl substituent of the oxocarbenium ion intermediate has little effect on reaction stereoselectivity, and analysis of this observation lends additional support for stereoelectronically preferred inside attack of the nucleophile. The results demonstrate that selective formation of the 1,4-c/s product 84 does not require a chelated transition stracture, reinforcing the utility of the inside attack model to analyze the reactivity of complex five-membered ring oxocarbenium ion intermediates. 

---