Diastereoselectivity in Lewis-acid-catalyzed Mukaiyama aldol reactions: a DFT study

Abstract

The basis for diastereoselectivity in Lewis-acid-catalyzed Mukaiyama aldol reactions was studied using density functional theory. By exploring the conformations of the transition structures for the diastereodifferentiating step of seven different reactions, simple models were generated. The effects of varying the substituents on the enol carbon and the α-carbon of the silyl enol ether from methyl to tert-butyl groups and the substituent on the aldehyde from methyl to phenyl groups were investigated by comparison of the transition structures for different reactions. Expanding on the previous qualitative models by Heathcock and Denmark, we found that while the pro-anti pathways take place via antiperiplanar transition structures, the pro-syn pathways prefer synclinal transition structures. The relative steric effects of the Lewis acid and trimethyl silyl groups and the influence of E/Z isomerism on the aldol transition state were investigated. By calculating 36 transition structures at the M06/6-311G*//B3LYP/6-31G* level of theory and employing the IEFPCM polarizable continuum model for solvation effects, this study expands the mechanistic knowledge and provides a model for understanding the diastereoselectivity in Lewis-acid-catalyzed Mukaiyama aldol reactions.

Figure 1

Example of a Mukaiyama aldol reaction.^,

Figure 2

Transition state models proposed by Heathcock.

Figure 3

(A) The general form of the Mukaiyama aldol reaction studied in this work. Substituents R¹, R², and R³ are varied throughout this study to explore their effects on the selectivity. (B) The three silyl enol ethers described in this study. (C) Depiction of our definition for the dihedral angle (ϕ) around the forming C—C bond. The antiperiplanar example shown corresponds to ϕ =180°.

Figure 4

The reaction pathway for the C—C bond formation in the reaction of (E)-3 with benzaldehyde.

Figure 5

Transition structure conformations studied for the Mukaiyama aldol reaction. The conformations are similar for both silyl enol ether isomers.

Figure 6

(A) Structure of entry 32, the transition state for the major anti-product in the reaction of (Z)-3 with benzaldehyde. (B) Side view of the structure of entry 32. (C) Structure of entry 34, the transition state for the minor syn-product in the reaction of (Z)-3 with benzaldehyde. (D) Side view of the structure of entry 34.

Figure 7

(A) Structure of entry 18 showing the lowest-energy pro-syn pathway for the reaction of (Z)-2 with acetaldehyde. (B) Side view of the structure of entry 18. (C) Structure of entry 20 showing the lowest-energy pro-anti pathway for this reaction. (D) Side view of the structure of entry 20. (E) Structure of entry 21, a minor pro-anti pathway, showing unfavorable interactions caused by proximity of aldehyde substituents to the tert-butyl group. (F) Side view of the structure of entry 21. The shortest distance between the aldehyde methyl group and the enol ether tert-butyl group is highlighted as 2.17 Å compared to 2.37 Å for the forming carbon-carbon bond. (G) Structure of entry 14 showing unfavorable interactions between the methyl group of acetaldehyde and the α-carbon hydrogen of the silyl enol ether and between the tert-butyl group and the Lewis acid. (H) Side view of the structure of entry 14.

Figure 8

Newman projections for the transition states of the reaction of (Z)-1 with acetaldehyde.

Figure 9

Silyl enol ethers (E)-1 and (E)-3 from the transition structure Entries 1 and 24. The carbon-carbon-silicon angles are highlighted for comparison.