Anti-Cram-Felkin product, aldol reactions

All types of nucleophiles protected at C3 show a predominant effect in driving the aldol reaction in the direction of favoring the anti-Cram/Felkin product. This characteristic seems to be independent of the nature of the aldehyde. The best selectivities were obtained with nucleophile 50 and even superior to that, nucleophile 15 protected as an acetonide. The final part of this chapter will focus on a special type of aldehyde where a long range effect improves the stereochemical outcome of the aldol reaction. 

The stereoselectivity of the antibody-catalyzed addition of acetone to aldehyde 67 revealed that the ketone was added to the re-face of 67 regardless of the stereochemistry at C2 of this substrate. The aldol process follows a classical Cram-Felkin mode of attack on (S)-67 to generate the (4S,5S)-68 diastereomer and the anti-Cram-Felkin mode of attack on the (R)-67 to yield the (4S,5R)-69 diastereomer. The products are formed at a similar rate and yield, therefore there is no concomitant kinetic resolution of the racemic aldehyde. The two antibodies differ in their diastereofacial selectivity, reflecting the ability of the antibodies to orient the 67 on opposite sides of the prochiral faces of the nucleophilic antibody-enamine complex of acetone. Heath cock and Flippin [79] have shown that the chemical reaction of the lithium enolate of acetone with (S)-67 yields the (4S,5S)-68 diastereomer a 5% de for this Cram-Felkin product. The generation of the (4S,5R)-69 and (4R,5R)-70 products in a ratio of 11 1 by the... 

The stereochemical outcome of the Mukaiyama reaction can be controlled by the type of Lewis acid used. With bidentate Lewis acids the aldol reaction led to the anti products through a Cram chelate control [366]. Alternatively, the use of a monoden-tate Lewis acid in this reaction led to the syn product through an open Felkin-Anh... 

Traditional models for diastereoface selectivity were first advanced by Cram and later by Felkin for predicting the stereochemical outcome of aldol reactions occurring between an enolate and a chiral aldehyde. [37] During our investigations directed toward a practical synthesis of dEpoB, we were pleased to discover an unanticipated bias in the relative diastereoface selectivity observed in the aldol condensation between the Z-lithium enolate B and aldehyde C, Scheme 2.6. The aldol reaction proceeds with the expected simple diastereoselectivity with the major product displaying the C6-C7 syn relationship shown in Scheme 2.7 (by ul addition) however, the C7-C8 relationship of the principal product was anti (by Ik addition). [38] Thus, the observed symanti relationship between C6-C7 C7-C8 in the aldol reaction between the Z-lithium enolate of 62 and aldehyde 63 was wholly unanticipated. These fortuitous results prompted us to investigate the cause for this unanticipated but fortunate occurrence. 

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. ... 

Lithium enolates, in contrast, either give predominantly the product predicted by the Cram-Felkin-Anh model or react more or less non-stereoselectively. Thus, the favored formation of the syn-aldol product in the reaction of 2-phenylpropanal with the lithium enolates of acetone, pina-colone, methyl acetate, or N,N-dimethylacetamide is in accordance with Cram s rule or the Felkin-Anh model (Eq. (35)). However, a rather moderate syyr.anti ratio of 3 1 is typical of this type of reaction [51, 67]. 

The stereoselectivity of the addition of pinacolone enolsilane 1 to P-alkoxy aldehydes bearing two stereocenters depends on the ability of the metal to form intermediate chelates. Those metals that monocoordinate the carbonyl group form Fel-kin products and the stereochemistry of these aldols is predicted by the Felkin-Anh s model. For metals chelating both the carbonyl and alkoxy groups, anti-Felkin products are obtained. In these cases the cyclic-Cram s model has to be used to predict the stereochemical outcome of the reaction. Therefore, non-chelated (Felkin-Ahn) and chelated models (cyclic-Cram) have been successively applied to understand the stereochemistry of the final reaction products. 

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