Transition structures chelation control

The high diastereoselectivity which is found in the nucleophilic addition of Grignard reagents to chiral 2-0x0 acetals can be explained by a chelation-controlled mechanism. Thus, coordination of the magnesium metal with the carbonyl oxygen and the acetal moiety leads to a rigid structure 3A in the transition state with preferred attack of the nucleophile occurring from the S/-side. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Herein, the stereogenic center in 2-12 controls the stereochemistry in the way that the Michael addition occurs from the less-hindered a-face of the enolate to the si-side of the crotonate 2-13 according to transition structure 2-16. The second Michael addition occurs from the same face, again under chelation control, followed by an axial protonahon of the formed enolate to give the cis-compound 2-14a. It should be noted that after the usual aqueous work-up procedure an inseparable... 

In the early stages of the project, we reasoned that the sulfoxide unit might be expected to influence the transition state geometry of the 2-acyl side chain, perhaps by chelation to a metal counterion, and hence control the stereochemistry of a wide range of functional group transformations. Indeed, a chelation control model of the reactivity of the 2-acyl dithiane 1-oxide systems has allowed us to rationalize, and predict, the stereochemical outcome of most of the reactions studied so far. These predictions have, in many cases, been confirmed by X-ray structure determination of the relative stereochemistries within product structures.1-4... 

A high degree of stereoselectivity can be realized under chelation control, where an oxygen atom of an ether function (or more generally a Lewis base) in the a-, P- or possibly y-position of carbonyl compounds can serve as an anchor for the metal center of a Lewis acid. Since Cram s pioneering work on chelation control in Grignard-type addition to chiral alkoxy carbonyl substrates [30], a number of studies on related subjects have appeared [31], and related transition state structures have been calculated [32], Chelation control involves Cram s cyclic model and requires a Lewis acid bearing two coordination sites (usually transition metal-centered Lewis acids). 

The reaction of //-methyl-2-butenylsilanes 36 and stannanes with chiral a-al-koxyaldehydes has also been reported [33]. Surprisingly, the anti homoallylic alcohols were predominantly observed (94/6, ant i/syn) when a bivalent Lewis acid such as SnCl4 was used (Scheme 10-13). A synclinal transition structure is proposed to account for the observed selectivity. In the chelation-controlled reactions the synclinal transition structure is favored over the corresponding antiperiplanar transition structure because there exists an open space wherein the complexed Lewis acid can reside. The monovalent Lewis acid BF3-OEt2 provides the expected syn homoallylic alcohol, presumably through the antiperiplanar transition structure shown (66% of the product was the syn alcohol 37). 

Equation (12) illustrates the following general principle electrophiles able to form a chelated complex with the Lewis acid e.g. 28) control (usually invert) the simple stereoselection of the reaction . The major isomer (29) is, in fact, syn. Adducts (29) and (30) were then transformed, by simple functional group chemistry, into (+)-PS-5, a carbapenem antibiotic. Transition structure models for this process are discussed in detail in Section 2.4.4.1. 

As 19 and the (S) aldehyde fonn a matched pair (they cooperate to realize the same stereochemical result) while 19 and the (R) aldehyde form a mismatched pair, only the (S) enantiomer of the starting 95.5/4.5 S/R mixture of aldehyde 44 reacts with 19, and the condensation occurs with concomitant kinetic resolution. The relative configuration of the three contiguous chiral centers is a result of chelation control (C-3,C-4 anti) and syn simple stereoselection (C-2,C-3 syn) in agreement with the transition structure model A (Figure 3). An example of the mismatched pair is shown below here the (lR,2S)-N-methylephedrine derived silyl ketene acetal 16 reacts with (S) 44 (e.e. 91%) to give a mixture of the adducts 46 and 47 in poor yield. 

Stereochemical results were similar to previous studies, with a predominance of anti products observed for the allylation of aromatic and alkyl aldehydes using y-substituted allylic bromides. In the same paper, the system was also used for the allylation of unprotected carbohydrates, a use that is particularly advantageous for such water-soluble substrates. As with aldehydes that possess functional groups at the a-position that is Lewis basic, a five-membered chelation transition state was proposed to account for the proportion of syn products. The group extended this work to the synthesis of P-trifluoromethylated allylic alcohols [32], and the effects of chelation control was again demonstrated in dramatic stereochemical reversal from minor structural changes in the aldehyde (Figure 8.13). 

Use of y-alkoxy-substituted allylic stannane reagents with a-benzyloxy aldehydes provides convenient access to 1,2,3-triol subunits (Equation 8) [92]. Keck reported the chelation-controlled formation of 113 as a single dia-stereomer and suggested that this product is the result of the intermediacy of transition state structure 112, analogous to 100. 

In the absence of Lewis acid the stereochemical outcome was controlled by the conformation of the starting radicals XIII (Sch. 11). Divalent Lewis acids such as MgBr2 or Mgl2 could alter the structure of the transition state XIV to the bidentate chelate, thus changing the diastereofacial selectivity of the addition reaction. 

Although these deprotonations are kinetically controlled we were surprised to learn that simple semiempirical (PM3) calculations on the diastereomeric lithium intermediates are consistent with the observed selectivities [80]. Apparently, similar structural features determine the relative energies of the diastereomeric transition states and diastereomeric ground states in these internal chelate-directed lithiations. A further conclusion can be drawn (with more uncertainty) due to the favorable complexation of the lithium cation by four donor ligands, most intermediates (if not all) are monomeric and have a very low tendency for oligomerization. 

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