Recent disclosures from these laboratories have demonstrated the concept of Lewis base catalysis in asymmetric aldol additions 1 as illustrated in the reaction of trichlorosilyl enolates and aldehydes in the presence of a catalytic amount of chiral phosphoramides. 2 For example, trichlorosilyl enolate 1 reacts with benzaldehyde in very high enantio-and diastereoselectivity with 10 mol % of phosphoramide (S,S)-4, Scheme 1. On the basis of the geometry-dependent diastereoselectivity observed, these reactions are proposed to proceed via closed, chairlike transition structures organized about a hexacoordinate siliconate. 2b We now report evidence in support of a mechanistic hypothesis that a hexacoordinate, cationic silicon species with two chiral phosphoramide molecules is on the pathway from E-enolates to anti aldol products.Phosphoramide (S,S)-4 dramatically accelerated the reaction in Scheme 1. In the absence of the catalyst the reaction between 1 and 2 was very slow; after 8 min at -78 °C only 2.3% conversion to the aldol product was detected by NMR (2% isolated). On the other hand, with 10 mol % of (S,S)-4 the reaction proceeded to 100% conversion in 8 min at -78 °C (95% isolated).To evaluate the effects of catalyst structure on rate and selectivity, we surveyed the series of achiral phosphoramides 5a-d (Chart 1) with regard to their ability to promote the aldol process in Scheme 1. The results, Table 1, showed that increasing the bulk of the substituent had a dramatic effect on the diastereoselectivity of the reaction.

Both chiral and achiral phosphoramides of diverse structure were prepared from diamines by the coupling to phosphorus(V) or phosphorus(III) reagents. Several enantiopure 1,2-diphenyl-1,2-ethanediamine analogues have been prepared by the reductive coupling of the corresponding N-silylimine with NbCl(4)(THF)(2) and subsequent resolution by the formation of diastereomeric menthyl carbamates. (S,S)-N,N'-Di-(1-naphthyl)-1,2-diphenyl-1,2-ethanediamine 15 was prepared by the arylation of (S,S)-1,2-diphenyl-1,2-ethanediamine with naphthyl iodide.

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The mechanism of the catalytic, enantioselective addition of trichlorosilyl enolates to aldehydes has been investigated. Kinetic studies using ReactIR and rapid injection NMR (RINMR) spectroscopy have confirmed the simultaneous operation of dual mechanistic pathways involving either one or two phosphoramides bound to a siliconium ion organizational center. This mechanistic dichotomy was initially postulated on the basis of catalyst loading studies and nonlinear effects studies. This duality explains the difference in reactivity and stereoselectivity of various classes of phosphoramides. Determination of Arrhenius activation parameters revealed that aldol addition occurs through the reversible albeit unfavorable formation of an activated complex, and natural-abundance 13C NMR kinetic isotope effect (KIE) studies have determined that the turnover limiting step is the aldol addition. A thorough examination of a range of phosphoramides has established empirical structure-activity selectivity relationships. In addition, the effects of catalyst loading, rate of addition, solvents, and additives have been studied and together allow the formulation of a unified mechanistic picture for the aldol addition.

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