Acids as Proline Co-catalysts in the Aldol Reaction of 1,3-Dioxan-5-ones

Abstract

Proline-catalyzed aldol addition of 2,2-dialkyl-1,3-dioxan-5-ones to aldehydes requires the presence of water, pyridinium p-toluenesulfonate or lithium chloride to proceed with high yield and high enantioselectivity. Acyclic amino acids such as alanine, phenylalanine, lysine and valine also catalyze the reaction but overall show yields and selectivities inferior to those of proline. An ester of a proline analogue shows catalytic activity in the presence of PPTS, suggesting that, in the presence of a Brønsted acid, a free ­carboxyl group on the catalyst might not be critical.

organocatalysis - aldol reactions - catalysis - proline - ­additives

References and Notes

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<A NAME="RS11306ST-18">18</A>

Following up on a suggestion made by a referee, we have attempted to determine if the ester 8 hydrolyzed under the reaction conditions. However, there was no evidence of hydrolysis (no presence of benzyl alcohol by NMR) after stirring either compound 8, or its hydrochloride, in DMSO with H₂O and PPTS for 48 h at r.t.

<A NAME="RS11306ST-19">19</A>

Typical Procedure: Dioxanone (0.50 mmol) and aldehyde (0.50 mmol) were added to a flame-dried vial charged with proline (0.15 mmol) and an additive (0.15-0.50 mmol). Dry DMSO (0.30 mL) was added; the vial was flushed with nitrogen and stored in a refrigerator at 5 °C for 1-7 d. The reaction was then quenched with sat. NH₄Cl solution (5 mL) and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried with MgSO₄, concentrated and purified by flash column chromatography using silica gel (hexane-EtOAc). The diastereoisomer ratio and enantiomer ratio were measured by ¹H NMR [the latter NMR experiment was done in CDCl₃ or in C₆D₆ in the presence of Eu(tfc)₃ or (S)-(+)-TFAE]. It was established that passing the crude mixture through a short column charged with silica did not alter the enantio­mer ratio (even after repeated chromatography).