Mukaiyama aldol reaction chelation effects

Several reactions of carbonyl groups in an LPDE system have been examined. Mukaiyama aldol reactions are effectively promoted in an LPDE solution, and remarkable chelating effects of oxygen functional groups at the a-positions of aldehydes are observed (Scheme 4).16,17 Regarding... 

The mechanism of the Mukaiyama aldol reaction largely depends on the reaction conditions, substrates, and Lewis acids. Linder the classical conditions, where TiCl4 is used in equimolar quantities, it was shown that the Lewis acid activates the aldehyde component by coordination followed by rapid carbon-carbon bond formation. Silyl transfer may occur in an intra- or intermolecular fashion. The stereochemical outcome of the reaction is generally explained by the open transition state model, and it is based on steric- and dipolar effects. " For Z-enol silanes, transition states A, D, and F are close in energy. When substituent R is small and R is large, transition state A is the most favored and it leads to the formation of the anf/-diastereomer. In contrast, when R is bulky and R is small, transition state D is favored giving the syn-diastereomer as the major product. When the aldehyde is capable of chelation, the reaction yields the syn product, presumably via transition state h. ... 

The Eu-catalyst Eu(dppm)3 provides a remarkable level of chemoselectivity but is only effective for the Mukaiyama-aldol reaction of aldehydes with several ketene silyl acetals (KSA) (Table 2-3) [55]. When ketones and aldehydes are treated, respectively, with KSA and ketone-derived silyl enol ethers, no reaction results. The rate enhancement by chelation control (entry 4, Table 2-3) is intriguing. This is a feature common to other Lewis acids such as TiC [56] or LiC104 [57],... 

Trimethylsilyloxyfuran 338 has shown promise as a masked butenolide fragment To fuUy exploit these qualities, the threo versus erythro (339 vs 340) diastereoselectivity in aldol-type additions has to be controlled. In fact it has been shown that this is easily achieved by appropriate reaction conditions. Applying Mukaiyama conditions (i.e., using the silyl enol ether as the donor in the presence of a Lewis acid such as TESOTf to generate oxonium species) leads to threo preference for 339, presumably via an open transition state, whereas desilylation with TBAF generates the erythro-diastereomer 340, this time via a closed Diels-Alder (or Zimmerman-Traxler)-like transition state. In both cases, chelating effects can be ruled out... 

In the discussion of the stereochemistry of aldol and Mukaiyama reactions, the most important factors in determining the syn or anti diastereoselectivity were identified as the nature of the TS (cyclic, open, or chelated) and the configuration (E or Z) of the enolate. If either the aldehyde or enolate is chiral, an additional factor enters the picture. The aldehyde or enolate then has two nonidentical faces and the stereochemical outcome will depend on facial selectivity. In principle, this applies to any stereocenter in the molecule, but the strongest and most studied effects are those of a- and (3-substituents. If the aldehyde is chiral, particularly when the stereogenic center is adjacent to the carbonyl group, the competition between the two diastereotopic faces of the carbonyl group determines the stereochemical outcome of the reaction. 

---