Chelation model

In his original paper,2 Cram disclosed an alternative model that rationalizes the preferred stereochemical course of nucleophilic additions to chiral carbonyl compounds containing an a heteroatom that is capable of forming a complex with the organometallic reagent. This model, known as the Cram cyclic or Cram chelate model, has been extensively studied by Cram9 and by others,410... 

Cram s open-chain model 229 Cram s rule 229, 233 Cram chelate model 229 Cram cyclic model 229 Cram-Felkin-Anh model 191,207, 236 f 246 cubane 12,318 cyanoacetic acid 636 f. cyanohydrin, protected 145, 150 f. cyclic carbonate protection 541 f., 657, 659 f., 666, 670 cyclization -,6-endo 734 -, 5-exo 733 f. 

The chelate model, already proposed for a-sulfmyl esters (vide supra), explains the results in this case as well. 

These results may be rationalized by assuming a chelation model. The nucleophile preferentially attacks the less hindered side of the C — N double bond as depicted. 

The diastereoselectivity of the reaction may be rationalized by assuming a chelation model, which has been developed in the addition of Grignard reagents to enantiomerically pure a-keto acetals7,8. Cerium metal is fixed by chelation between the N-atom, the methoxy O-atom and one of the acetal O-atoms leading to a rigid structure in the transition state of the reaction (see below). Hence, nucleophilic attack from the Si-face of the C-N double bond is favored4. 

Of the various Lewis acid catalysts tested, SnCl4 gave the highest diastereoselective product formation with predominance for the antz-diastereoisomer. This azztz-selectivity can be rationalized by invoking the Cram chelation model. 

The same coordination is used to account for the observed anti preference in the allylation of (t-hydroxybutanal with allyl bromide/indium in water (Scheme 8.16). The intermediate leads to the anti product. In support of the intramolecular chelation model, it is found that if the hydroxy group is converted to the corresponding benzyl or t-butyldimethylsilyl ether, the reaction is not stereoselective at all and gives nearly equal amounts of syn and anti products. 

Diastereoselective addition of a wide range of Grignard reagents to C -alkyl and C-aryl-A-[a.-phenyl- or u-methyl-j3-(benzyloxy)ethyl nitrones is determined by the presence of a stereogenic A -substituent (136, 137). High diastereoselectiv-ity in the addition of organometalic compounds to A-(( i-methoxyalkyl) nitrones can be explained by a simple chelation model (Scheme 2.132) (136). 

In 1993, Evans and co-workers examined phe-box 6, /-pr-box 45, and bu-box 3 ligands in the Diels-Alder reaction of cyclopentadiene 68 and 3-acryloyl-l,3-oxazolidin-2-one 69 using a weak Lewis acid such as copper(II) triflate." The results are summarized in Table 9.9. The reaction was carried out between —50 and —78 °C for 3-18 h and achieved selectivities of up to 98 2 (endo/exo) with an endo ee of >98% (using bu-box 3). Interestingly, the enantiomer produced in these reactions was the (25) configuration, compared to the (2K) isomer obtained with iron(III) and magnesium(II) as reported by Corey. This observed stereochemistry was explained by the chelation model of the copper(II) complex 74 (Fig. 9.23)... 

As intuitively deduced, coordinating Y and Z must be removed or displaced in order for alkenes to coordinate and form an alkene tr-complex (Scheme 2). Since these intermediates, Cp 2MR(alkene), have never been observed in any detectable amounts for early transition metal-mediated polymerization, several chelate model systems have been devised (Figure 3). 

Aldol reactions of magnesium enolates are frequently more diastereoselective than the corresponding reactions of lithium enolates. The aldol condensation proceeds via a cyclic transition state in agreement with the Zimmerman-Traxler chelated model . 

The butynoate 14 adds to the chiral enone 3 from the a-surface with asymmetric induction probably rationalized by the chelate model 15. The initial product 16 of the 1,4-conjugate addition is capable of another intramolecular Michael addition to the triple bond resulting in conversion of 16 to 4. 

A seven-membered chelate model 343 was suggested to rationalize the observed high level of -selectivity. 

Here is another example of a reversal in selectivity that can be explained using a nonchela ted Felkin-Anh model with Na+ and a chelated model with Mg2+. 

A chelated model was proposed for phenylglycinol derived lactams see Reference 350. 

Syn-, anti- and acetate aldol derivatives can be synthesized by choosing appropriate enolization protocols (Scheme 5) [20]. With lithium, boron and tin Lewis acids,. tyn-aldols can be obtained via (Z)-enolates [21]. If enolization is carried out with lithium or tin, there are enough open coordination sites available to position the aldehyde and the enolate in accordance with the chelate model for the sultam auxiliary and with the Zim-mermann-Traxler model. The combination of these models predicts the formation of 22, which is indeed experimentally obtained. If Lewis acids with only two open coordination sites are used... 

Wong, S. S. Paddon-Row, M. N. The importance of electrostatic effects in controlling 7i-facial stereoselectivity in nucleophilic additions to carbonyl compounds An ab initio MO study of a prototype chelation model, J. Chem. Soc. Chem. Commun. 1991, 327-330. 

As a Stereochemical Prohe in Nucleophilic Additions. Historically, the more synthetically available enantiomer, (4R)-2,2-dimethyl-l,3-dioxolane-4-carhoxaldehyde, has been the compound of choice to probe stereochemistry in nucleophilic additions. Nevertheless, several studies have employed the (45)-aldeh-yde as a substrate. In analogy to its enantiomer, the reagent exhibits a moderate si enantiofacial preference for the addition of nucleophiles at the carbonyl, affording anti products. This preference for addition is predicted by Felkin-Ahn transition-state analysis, and stands in contrast to that predicted by the Cram chelate model. Thus addition of the lithium (Z)-enolate shown (eq 1) to the reagent affords an 81 19 ratio of products with the 3,4-anti relationship predominating as a result of preferential si-face addition, while the 2,3-syn relationship in each of the diastere-omers is ascribed to a Zimmerman-Traxler-type chair transition state in the aldol reaction. ... 

The diphenylalaninol-derived oxazolidinone skeleton was thus effective as a chiral auxiliary, and was then applied to the /3-radical addition of the a,/3-unsaturated compound 39 (Sch. 16) [32]. The high diastereofacial selectivity of the /3-radical addition can be explained by a chelation model XVII similar to XVI for the preceding allylation reaction. 

Hetero-Diels-Alder reactions starting with unsaturated compounds with heteroatom-carbon or heteroatom-heteroatom multiple bond(s) are also enhanced by Lewis acids [374-381]. Aldehydes and imines work as dienophiles under the influence of TiCU- Electron-rich dienes are generally a preferable partner, as shown in Eq. (149), in which the product was obtained virtually as a single isomer [382,383]. The importance of the choice of the Lewis acid in determining the stereochemical outcome of the reaction is illustrated in Eq. (150) [384]. The notion of chelation and of Felkin-Anh models, respectively, is valid for these Diels-Alder reactions. Diastereoi-somers other than those shown in Eq. (150) were not detected. The stereochemistry of the product in Eq. (149) could be also explained by the chelation model. 

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