Cram’s chelation model

Scheme 4.4. Eliel s asymmetric addition to carbonyls using Cram s chelate model. Table 4.4. Asymmetric addition of nucleophiles to oxathianes and oxazines.

Hydride reductions of (7) can be controlled to give either the (R) or (5) secondary hydroxy compound with good selectivity by choice of the reducing agent. Lithium Tri-s-butylborohydride (L-Selectride ) provided the (5)-alcohol (according to Cram s chelate rule) and Diisobutylaluminum Hydride (DIBAL) gave the (R)-carbinol in excess (eq 7). The DIBAL results were rationalized in terms of the open-chain Comforth dipole model. ... 

The computational support for Felkin s torsional strain model and its success in interpretation of experimental diastereoselectivities has led to its widespread adoption. It appears to be the preeminent open transition state involved in reductions when chelation is not important. Complementary selectivity observed in reductions that do involve chelation may be understood in terms of Cram s cyclic model. 

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). 

If the organometallic reagent is capable of chelation, the second model becomes operative. This model, sometimes called Cram s cyclic model [147] involves the assistance of a che-... 

A short synthesis of L-( — )-rhodinose (635), the trideoxyhexose subunit of the antibiotic streptolydigin, takes advantage of the propensity of Grignard reagents to add to lactaldehydes under chelation control (Cram s cyclic model) to produce 5y -diols. 

Stereoselective Reductions. The reduction of 4-f-butylcyclo-hexanone and (1) by LiAlHa occurs from the axial direction to the extent of 92% and 85%, respectively. When a polymethylene chain is affixed diaxially as in (2), the equatorial trajectory becomes kineticaUy dominant (93%). Thus, although electronic factors may be an important determinant of r-facial selectivity, steric demands within the ketone carmot he ignored. The stereochemical characteristics of many ketone reductions have heen examined. For acychc systems, the FeUdn-Ahn model has heen widely touted as an important predictive tool. Cram s chelation transition state proposal is a useful interpretative guide for ketones substituted at C with a polar group. Cieplak s explanation for the stereochemical course of nucleophilic additions to cychc ketones has received considerable scmtiny. ... 

The additions of nucleophiles to aldehydes and ketones are promoted by coordination of a Lewis acid to the oxygen atom of the carbonyl group. The coordination with the metal enhances the electrophilicity of the C=0 group facilitating the attack of the nucleophile. From a stereochemical point of view, the presence of a Lewis acid is particularly important when a substituent with a heteroatom able to coordinate with the metal is placed next to the carbonyl group. In such cases, the prediction of the stereoselectivity of the reaction requires a chelated reactive conformation as that represented in Figure 4.2. This model is known as Cram s cyclic model and again the attack of flie nucleophile takes place preferentially from the less-hindered side. 

The stereochemical outcome of these reactions can be rationalized by means of a chelated Cram s cyclic model M ( /( ) (Scheme 11), where the N-Cbz group is the chelating ligand and the ju-tolylthio residue acts as the stereocontrolling large group. 

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. 

Despite the great deal of attention devoted to nucleophilic additions to a-chiral carbonyls, the source of stereoselectivity in these reactions (predicted by Cram s rules of asymmetric induction ) remains largely unresolved. Neither direct structural studies nor correlation of reactant and product stereochemistries have yielded any conclusive support for a single comprehensive model. Similarly, the effect of Lewis acids on these systems is only understood at the level of chelation-controlled additions (vide infra). 

Cram s rule (cyclic model) A model for predicting the major stereoisomer resulting from nucleophilic addition to an aldehyde or a ketone having an adjacent stereocenter that is capable of chelation (especially 5-membered ring chelation). After chelate formation, the nucleophile adds from the side opposite the larger of the remaining substituents on the a-stereocenter [48]. See Section 4.2. 

This chapter begins with a detailed examination of the evolution of the theory of nucleophilic attack on a chiral aldehyde or ketone, from Cram s original rule of steric control of asymmetric induction to the Felkin-Anh-Heathcock formulation. Then follows a discussion of Cram s simpler rigid model (chelate rule), then carbonyl additions using chiral catalysts and chiral (nonenolate) nucleophiles. The chapter concludes with asymmetric 1,4-additions to conjugated carbonyls and azomethines. 

Cram s rule rigid, chelate, or cyclic model... 

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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