Cram 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. 

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. 

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. ... 

When the boron ligands and the aldehyde are both chiral, the inherent stereoselectivities of each partner may be either matched or mismatched (Chapter 1). In principle, a chiral aldehyde could derive facial selectivity from either the Felkin-Anh-Heathcock model (Figures 4.8 and 4.10) or the Cram-chelate model (Figure 4.11). However, because the boron of these reagents can accept only one additional ligand, chelation is not possible. Therefore only the Felkin-Anh-Heathcock effects... 

Oishi272 and co-workers studied the diastereoselectivity of several reducing agents that reacted both with a-alkoxy and a-hydroxy ketones (254-see Table 4.7).222 These results indicate a distinct preference for the anti (erythro) diastereomer 256 when Zn(BH4)2 was used for reduction of the keto-alcohol. More anti product was obtained with LiAlH4, but the reaction was less selective. The Cram chelation model for the anti transition state (257) to give 256 was favored over the model for syn selectivity (delivery over the methyl... 

The Cram chelation model (sec. 4.7.B) is an example where the chelation effects of the heteroatom influence the rotamer population and, thereby, the selectivity of the reduction. Zinc borohydride [Zn(BH4)2], effectively chelates the carbonyl oxygen and alcohol oxygen atoms in the reduction of 42 and leads to intermediate 43. Transfer of hydride to the carbonyl gave primarily the anti diastereomer, 45 (4 96, 44/45). When the chelating hydroxyl group was blocked as a tert-butyldiphenylsilyl ether (in 46 - sec. 7.3.A.i), reduction with Red-Al (sec. 4.3) led to a reversal in selectivity (96 4, 47/48).The ability to chelate a heteroatom varies with the reagent used. Lithium aluminum hydride shows less selectivity, due in part to poorer coordination with the heteroatom and reduction of 42 gave a 27 73 mixture of 44 and 45,... 

The observed syn diasteieoselectivity may be rationalized by assuming a Cram chelation model which leads to attack on the si diastereotopic face (Scheme 23). 

Scheme 2.11 Cram chelate model for the Grignard addition.

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