Cram selectivity transition state models

The Reason for Cram and Anti-Cram Selectivity and for Felkin-Anh and Cram Chelate Selectivity Transition State Models... 

Panek and co-workers demonstrated that the reaction of (5)-2-benzyloxypropa-nal (17) with the allylic silane (5)-18 under the influence of Bp3-OEt2 gave the syn homoallylic alcohol 19 with excellent level of Felkin induction [35]. Interestingly, the high level of syn selectivity was also observed in the condensation of 17 and (/ )-18. On the other hand, the reaction of 17 with (5)-18 in the presence of TiCLj produced anti homoallylic alcohol 20 almost exclusively, whereas the reaction with (R)-18 promoted by TiCL afforded syn homoallylic alcohol 21. Presumably, the reactions proceeded through a Cram chelate transition state model... 

In additions of hydride donors to a-chiral carbonyl compounds, whether Cram or anti-Cram selectivity, or Felkin-Anh or Cram chelate selectivity occurs is the result of kinetic control. The rate-determining step in either of these additions is the formation of a tetrahedral intermediate. It takes place irreversibly. The tetrahedral intermediate that is accessible via the most stable transition state is produced most rapidly. However, in contrast to what is found in many other considerations in this book, this intermediate does not represent a good transition state model for its formation reaction. The reason for this deviation is that it is produced in an... 

After Cram had discovered the selectivities now named after him, he proposed the transition state model for the formation of Cram chelate products that is still valid today. However, his explanation for the preferred formation of Cram products was different from current views. Cram assumed that the transition state for the addition of nucleophiles to a-alkylated carbonyl compounds was so early that he could model it with the carbonyl compound alone. His reasoning was that the preferred conformation of the free a-chiral carbonyl compound defines two sterically differently encumbered half-spaces on both sides of the plane of the C=0 double bond. The nucleophile was believed to approach from the less hindered half-space. 

The Cram selectivity is consistent with Felkin-Ahn addition, as shown in Figure 8a, with the large phenyl substituent controlling the organometallic approach. In addition, Yamamoto et a/. have proposed more detailed chair-like transition state models shown in Figures 8b and 8c to account for the un-... 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

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. 

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... 

In most cases, Crams rule (sec. 4.7.B) predicts the major isomer when the reaction partner (or partners) contain a chiral center. To understand how this rule applies to orientational and facial selectivity, we must understand the transition state of the reaction (invoke the Zimmerman-Traxler model or one of the other models for predicting diastereoselectivity). The Zimmerman-Traxler model is used most often, and if it is applied to 423 and 424, the syn selectivity can be predicted. The facial selectivity shown in 427 and 428 arises from the methyl group. In 428, the enolate approaches from the face opposite the methyl, leading to diminished steric interactions and syn product (429). If the enolate approaches via 427, the steric impedance of the methyl group destabilizes that transition state relative to 428. In both 427 and 428, a Cram orientation is assumed (see above) although other rotamers are possible. The appropriate rotamer for reaction therefore is that where Rl is anti to the carbonyl oxygen. Since the phenyl group is Rl, 427 and 428 are assumed to be the appropriate orientation for the aldehyde. If an aldehyde or ketone follows anti-Cram selectivity, this aldehyde orientation must be adjusted. 

Cram selectivity (sec. 4.7.B) results from approach of the enolate over the less hindered face of the stereogenic center of the aldehyde (over the hydrogen, Rs) rather than over the larger methyl group (Rm)-The phenyl group is taken to be Rl and it is anti to the carbonyl oxygen. This model assumes a reasonable steric difference between Rm and Rs (as in the Cram model), and if the steric difference between the two groups is small, there is little facial selectivity in the transition state and poor enantioselectivity in the final product. 

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. ... 

Another often discussed set of electronic effects in the transition state involves interaction of a stretched or forming (incipient) bond with the adjacent donors and acceptors. This interaction has been discussed particularly frequently in relation to the selectivity of nucleophilic additions to carbonyl compounds. Cram first proposed arguments based on steric effects, which were expanded upon by Felkin and Anh. The Felkin-Anh model suggests that the best acceptor group is positioned antiperiplanar to the incoming nucleophile in order to maximize a... 

Dimethyl(phenyl)silane reduces aldehyde and ketone carbonyls with the aid of fluoride ion or acid. a-Acylpropionamides, 1-aminoethyl ketones, and 1-alkoxyethyl ketones are readily converted into the corresponding -hydroxy amides, o -amino alcohols, and a-alkoxy alcohols, respectively. The stereoselectivity is complementary and generally high erythro (or syn) isomers are obtained with trifluoroacetic acid (TFA), whereas threo (or anti) isomers are obtained with fluoride ion activator (eq 1). The erythro selectivity in the acid-promoted carbonyl reduction is ascribed to a proton-bridged Cram s cyclic transition state. On the other hand, the threo selectivity in the fluoride-mediated reduction is explained in terms of the Felkin-Anh t) e model, wherein a penta-or hexacoordinated fluorosilicate is involved. No epimerization at the chiral center is observed during the reaction. 

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