Calculation of Stereoselectivity in the Boron-Mediated Aldol Reaction of Methyl Ketones

Jonathan M. Goodman, and Mark D Mackey
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, England

Abstract: The methyl aldol procedure presented in ECTOC worked well on achiral ketones, but further investigations showed that it was less successful with chiral ketones. A recent paper by Corey (Tetrahedron Letters, 1997, 38, 33-36) encouraged us to reinterpret our earlier calculations on these structures (Tetrahedron Letters, 1992, 33, 7219-7222), and to introduce an additional bonding interaction. An new procedure for calculating the stereoselectivity of boron-mediated aldol reactions will be presented, and the results of this new approach will be evaluated.

Boat transition state for boron-mediated aldol reaction of a methyl ketone

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Organometallic reagents have many applications in stereoselective carbon-carbon bond-forming reactions in organic synthesis. Only a few of these reactions, however, may be readily modelled to analyse and predict the stereoselectivity. One such reaction is the boron-mediated aldol reaction, which has an important place in asymmetric organic synthesis [1]. A computational model has been developed for this reaction, which successfully predicts the stereoselectivity of the aldol reactions of E and Z enol borinates derived from ethyl ketones [2], by calculating the structures and relative energies of the competing diastereomeric transition states. A similar model has also been developed for the addition of allyl- and crotylboranes to aldehydes [3]. Boron is particularly suited to this approach, because is cannot be more than four-valent, and ab initio calculations on boron-containing species are relatively straightforward, as it is in the first row of the periodic table. A similar approach could not easily be applied to the related reactions of allyl-tin compounds [4], nor other allyl-metal species, because of the difficulty of performing precise molecular orbital calculations, and because of the limitations of the molecular mechanics methods which were employed.

Reversal of methyl ketone selectivity

Figure 1 Reversal in stereoselectivity for methyl ketones

We have been puzzled, however, by the behaviour of enol borinates derived from methyl ketones, which show a reversal in stereoselectivity [5] when reacted with -pinene derived chiral ligands on the boron (Figure 1). This is not predicted by the computational model. Earlier work [6] shows that an empirical correction (neglecting some of the transition states) greatly improves the force field when applied to methyl ketones, but this does not account for the behaviour of enol borinates derived from chiral ketones. In addition, the empirical correction has no physical basis, and so is hard to interpret. In this work, we propose a new procedure for analysing the behaviour of enol borinates derived from methyl ketones, and analyse its results.
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