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Synlett 2011(4): 508-512  
DOI: 10.1055/s-0030-1259525
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© Georg Thieme Verlag Stuttgart ˙ New York

Enantioselective Direct Aldol Reactions of Achiral Ketones with Racemic Enolizable α-Substituted Aldehydes: Scope and Limitations

Dale E. Ward*, Vishal Jheengut, Garrison E. Beye, H. Martin Gillis, Athanasios Karagiannis, Fabiola Becerril-Jimenez
Department of Chemistry, University of Saskatchewan, Saskatoon, SK, S7N 5C9, Canada
Fax: +1(306)9664730; e-Mail: dale.ward@usask.ca;
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Publikationsverlauf

Received 7 December 2010
Publikationsdatum:
02. Februar 2011 (online)

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Abstract

Aldol reactions of racemic enolizable dioxolan-protected α-substituted-β-ketoaldehydes with representative achiral ketones catalyzed by proline or 5-(2-pyrrolidine-2-yl)-1H-tetrazole in wet DMSO proceed with dynamic kinetic resolution (or via DYKAT with an α-substituted-β-alkoxyaldehyde) to give adducts with high dr and ee.

Key words

aldol reaction - chiral aldehydes - kinetic resolution - organocatalysis - polypropionates

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11

Little or no aldol adducts were observed in CHCl3, MeCN, or THF.

12

A solution of 5c (2 M in DMF), H2O (1 equiv), and 6 (0.2 equiv) at r.t. for 2 d gave a 1:1.1 mixture (by ¹H NMR) of 2c and 5c (46% isolated; dr = 20, ee >95%).

13

A DMSO solution of (-)-5a, H2O (8 equiv), and 6 (0.2 equiv) at r.t. for 4 d gave a 1:1.8 mixture (by ¹H NMR) of (±)-2a and (-)-5a (43% isolated; dr >20, ee >95%).

14

After 2 d, a solution of (±)-2b in DMSO containing D2O
(20 equiv) and either 4 or 6 (0.5 equiv) showed >90% deuteration of the α-CH confirming racemization under these conditions.

15

We were unable to determine the ee for 13a.

16

Subjecting 11a or 11b to the reaction conditions confirmed their susceptibility to elimination, particularly in the presence of 6.

20

We were unable to determine the ee for 17. ¹H NMR of the crude product suggested the possible presence of minor amounts of other adducts arising from 14 but these could not be quantified or isolated. The maximum yield of enantiopure 18 from this reaction is 50%.

25

The mixture is initially homogeneous but becomes solid as 5a precipitates. Diastereoselectivity was improved with small amounts of water (2 equiv, dr >20; 0 equiv, dr = 13) but the reaction was suppressed with larger amounts (ref. 4).

26

Presumably by increasing the solubility of 6 and increasing the rate of racemization of 2a.