Cram chelate

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. 

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... 

Grignard reagents because of Cram chelation to provide mainly adducts 2, precursors to optically active tertiary alcohols. However, if a THF solution of the Grignard reagent is added to a suspension of YbCl3 in THF and stored at 0° for 2 hours, the resultant species, RMgBr YbCU, reacts with 1 at -78° to provide 3 in 95.4% de in quantitative yield. 

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

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... 

Cram product Felkin-Anh product Cram chelate product... 

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. 

Felkin-Anh or Cram Chelate Selectivity in the Addition of Hydride Donors to Carbonyl Compounds with an O or N Atom in the a-Position ... 

In order for the Cram chelate product to predominate after the addition of a hydride donor to a chiral carbonyl compound, which contains a heteroatom in the a-position, this heteroatom and part of the reagent must he able to form a five-membered ring chelate. If this is not possible, one observes Felkin-Anh selectivity (provided one observes selectivity at all). This has the following interesting consequences for synthesis. 

The a-chiral ketone from Figure 10.18—the a-substituent is a benzyloxy group—is reduced to the Cram chelate product by Zn(BH4)2, a Lewis acidic reducing agent. The Zn2 ion first bonds the benzyl and the carbonyl oxygen to a chelate. Only this species is subsequently reduced by the BH 4 ion because a Zn2 -complexed C=0 group is a better elec-... 

Fig. 10.18. Ensuring Felkin-Anh versus Cram chelate selec-...

Fig. 10.19. Ensuring Felkin-Anh or Cram chelate selectivity in the addition of hydride donors to a-chiral carbonyl compounds by varying the protecting group on the stereodirecting heteroatom.

Grignard reagents also add diastereoselectively to oc-chiral, oc-oxygenated aldehydes and ketones. The chelation-controlled product constitutes the major product (Figure 10.41). It is the diastereomer that is produced via the Cram chelate transition state of Figure 10.16... 

In contrast, the diastereoselectivities of Figure 8.10 can be observed for many additions of hydride donors to carbonyl compounds which contain a stereocenter in the a position with an O or N atom bound to it. One of the product diastereomers and the relative configuration of its stereocenters is called the Felkin-Anh product. The other diastereomer and its stereochemistry are referred to as the so-called Cram chelate product. If the latter is produced preferentially, one also talks about the occurrence of chelation control or—only in laboratory jargon—of the predominance of the chelation-controlled product. ... 

The addition of a hydride donor to an a-chiral aldehyde with an OR or NR2 substituent at C-a or to an analogous ketone takes place via the so-called Cram chelate... 

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