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Synlett 2006(15): 2387-2390  
DOI: 10.1055/s-2006-950421
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Marek Majewski*, Izabella Niewczas, Nagarjuna Palyam
Department of Chemistry, University of Saskatchewan, 110 Science Pl., Saskatoon, SK, S7N 5C9, Canada
Fax: +1(306)9664730; e-Mail: majewski@usask.ca;
Further Information

Publication History

Received 18 May 2006
Publication Date:
08 September 2006 (online)

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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.

Key words

organocatalysis - aldol reactions - catalysis - proline - ­additives

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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.

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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).