Cram-chelation control

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... 

Another example of this process is delineated in equation (19). In this case, chiral imine (53) was found to react under Lewis acid catalysis with diene (54) to provide adduct (55) stereoselectively via a Cram chelation controlled process. This cycloadduct was transformed in a few steps to amino sugar (56). 

Chelation Control Model- "Anti-Cram" selectivity... 

For Lewis acid induced reactions between a-alkoxyaldehydes and allylstannanes, either Cram or chelation control is observed depending on the choice of Lewis acid and the O-substituent88. 

Excellent chelation control was observed using tributyl(2-propenyl)stannane and a-benzyloxy-cyclohexaneacetaldehyde with magnesium bromide or titanium(IV) chloride, whereas useful Cram selectivity was observed for boron trifluoride-diethyl ether complex induced reactions of the corresponding ferr-butyldimethylsilyl ether89. 

The Lewis acid mediated addition of silyl enol ethers or silylketcne acetals to oc-alkoxyaldehydcs is the most versatile and reliable method of providing chelation control in aldol-type additions3. The stereochemical outcome is as predicted by Cram s cyclic model11 ... 

Normally, the addition of C-nucleophiles to chiral a-alkoxyaldehydes in organic solvents is opposite to Cram s rule (Scheme 8.15). The anti-Cram selectivity has been rationalized on the basis of chelation control.142 The same anti preference was observed in the reactions of a-alkoxyaldehydes with allyl bromide/indium in water.143 However, for the allylation of a-hydroxyaldehydes with allyl bromide/indium, the syn isomer is the major product. The syn selectivity can be as high as 10 1 syn anti) in the reaction of arabinose. It is argued that in this case, the allylindium intermediate coordinates with both the hydroxy and the carbonyl function leading to the syn adduct. 

Product stereochemistries can be greatly influenced by these chelation control effects. This was first observed by Cram.10 There are many controversies about this topic, and the issue remains a topic of investigative interest.11 Without kinetic data, it has been suggested that it is impossible to distinguish the following two mechanistic types 12... 

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... 

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. ... 

Two factors may lead to modification or reversal of Cram selectivity (a) chelation control by neighbouring groups [40], as in the addition of Grignard reagents to a protected L-threose in which the xylo product predominated [41], e.g. 

On the other hand, chelation-controlled aldol reactions usually provide the awh -Cram aldol. This has been early illustrated by Heathcock and coworkers76 who reported that the proportion of the exclusive syn condensation products B and C (>98%) of the bulky enolate A (Scheme 116) was completely reversed when a chelating group was present on the aldehyde backbone (although the chelating ability of the f-butyl dimethylsilyloxy group is questionable566). 

Addition of crotyltri-n-butyltin (5 11, 143) to chiral a-alkoxy aldehydes (6) presents a more complicated situation, since four products are possible. Products 7 and 8 result from chelation-controlled diastereofacial selectivity products 9 and 10 are products of Cram-Felkin control. In the reaction catalyzed by BF, etherate the major products are 7 and 9 in the ratio 67 33. Use of TiCl4 or MgBr, results in formation of only 7 and 8. With the former catalyst the 7/8 ratio is 63 37 with the latter, 92.5 7.5. The almost exclusive formation of 7 is consistent with the known ryn-stereoselectivity in the reaction of 5 with achiral aldehydes. 

---