Lone pairs esters

Reversible interaction of the carbonyl group with an azine lone-pair (cf. 245) should facilitate substitution adjacent to the heteroatom by the anion of a )3-hydroxyethyl ketone. A similar cyclic intermediate (246) is presumably responsible for the cyclization of acetylene dicarboxylic esters with azines. Similar cyclic intermediates... 

Notice in the list of Lewis bases just given that some compounds, such as carboxylic acids, esters, and amides, have more than one atom ivith a lone pair of electrons and can therefore react at more than one site. Acetic acid, for example, can be protonated either on the doubly bonded oxygen atom or on the singly bonded oxygen atom. Reaction normally occurs only once in such instances, and the more stable of the two possible protonation products is formed. For acetic add, protonation by reaction with sulfuric acid occurs on... 

The conformational analysis of methyl pyruvate shows that it can have two conformers. In the second conformer the two carbonyls are in syn position. The anti-syn conformational change requires 3 kcal. The [CDqIq qJ - methyl pyruvate ] complex ((R) form) was also calculated and shown in Figure 8. In the above complex the "directionality" of the lone pair of electrons of the quinuclidine nitrogen is advantageous for interactions with both the keto and the ester carbonyl groups. 

The reaction of 151 with methanol to give dimethyl phosphate (154) or with N-methylaniline to form the phosphoramidate 155 and (presumably) the pyrophosphate 156 complies with expectations. The formation of dimethyl phosphate does not constitute, however, reliable evidence for the formation of intermediate 151 since methanol can also react with polymeric metaphosphates to give dimethyl phosphate. On the other hand, reaction of polyphosphates with N-methylaniline to give 156 can be ruled out (control experiments). The formation of 156 might encourage speculations whether the reaction with N,N-diethylaniline might involve initial preferential reaction of monomeric methyl metaphosphate via interaction with the nitrogen lone pair to form a phosphoric ester amide which is cleaved to phosphates or pyrophosphates on subsequent work-up (water, methanol). Such a reaction route would at least explain the low extent of electrophilic aromatic substitution by methyl metaphosphate. 

The tosyl protecting group of 4a is removed with sodium naphthalide at -60 °C, and an intramolecular nucleophilic attack of the nitrogen lone pair to the epoxide takes place spontaneously to afford the pyrrolidine hydroxy ester as a labile reaction product, which is immediately protected as the corresponding silyl ether 3a in 68%... 

Amides may be hydrolysed to carboxylic acids by either acids or bases, though hydrolysis is considerably slower than with esters. Although amines are bases and become protonated on nitrogen via the lone pair electrons, we know that amides are not basic (see Section 4.5.4). This is because the lone pair on the nitrogen in amides is able to overlap into the carbonyl... 

Whereas the pATa for the a-protons of aldehydes and ketones is in the region 17-19, for esters such as ethyl acetate it is about 25. This difference must relate to the presence of the second oxygen in the ester, since resonance stabilization in the enolate anion should be the same. To explain this difference, overlap of the non-carbonyl oxygen lone pair is invoked. Because this introduces charge separation, it is a form of resonance stabilization that can occur only in the neutral ester, not in the enolate anion. It thus stabilizes the neutral ester, reduces carbonyl character, and there is less tendency to lose a proton from the a-carbon to produce the enolate. Note that this is not a new concept we used the same reasoning to explain why amides were not basic like amines (see Section 4.5.4). 

Acetyl-CoA is a good biochemical reagent for two main reasons. First, the a-protons are more acidic than those in ethyl acetate, comparable in fact to a ketone, and this increases the likelihood of generating an enolate anion. As explained above, this derives from sulfur being larger than oxygen, so that electron donation from the lone pair that would stabilize the neutral ester is considerably reduced. This means it is easier for acetyl-CoA to lose a proton and become a nucleophile. Second, acetyl-CoA is actually a better electrophile than ethyl acetate. 

For this mechanism to be correct, it is also necessary for the dioxaborolane to exist in conformation B with the two -COaiPr units pseudoaxial. In any other conformation of the dioxaborolane, or if other C-COaiPr bond rotational isomers are considered, the ester and aldehydic oxygen atoms are too far removed to interact. It should be noted further that reasonable transition states for C-C bond formation are not accessible if the aldehyde is symmetrically disposed with respect to the dioxaborolane system. Clockwise rotation about the B-O bond as indicated in B moves the aldehyde nonbonding lone pair away from the proximate ester carbonyl and leads to the favored transition state A. 

One further point is worthy of brief mention. While we have focused on lone pair/lone pair repulsive interactions that destabilize transition state C, it is conceivable that A is actually stabilized relative to C by a favorable charge-charge interaction between the ester carbonyl (5 ) and the aldehydic carbonyl carbon (5+) owing to the proximity of these groups in A. While it is not yet possible to resolve the relative contributions of these distinct stereoelectronic effects, it is clear that our mechanistic proposal e)mlains the experimental results only if the dioxaborolane and the C-COaiPr bonds exist in the conformations indicated in B. Any conformational infidelity at either site would be expected to lead to diminished enantioselectivity. 

Originally, it was proposed that lone pair repulsions between one of the tartrate ester carbonyl oxygens and the aldehyde oxygen in transition structure 60 were responsible for the preference for transition structure 59 and the consequent enantiofacial selectivity (Scheme 5). Recent theoretical calculations. 

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