FULL PAPER DOI: 10.1002/ejoc.201201144 Simple Ionic Liquid Supported C 2 -Symmetric Bisprolinamides as Recoverable Organocatalysts for the Asymmetric Aldol Reaction in the Presence of Water Sergei V. Kochetkov, [a] Alexandr S. Kucherenko, [a] Galina V. Kryshtal, [a] Galina M. Zhdankina, [a] and Sergei G. Zlotin* [a] Keywords: Aldol reactions / Asymmetric catalysis / Enantioselectivity / Organocatalysis / Water chemistry C 2 -Symmetric (S)-prolinamides modified with ionic groups and bearing achiral diamine units were synthesized. Their potency as reusable organocatalysts for asymmetric aldol re- actions of cycloalkanones or methyl ketones with aromatic (heteroaromatic) aldehydes in the presence of water was Introduction Asymmetric organocatalysis is an intensively developing area of modern organic chemistry. [1] Mimicking natural en- zymes, small chiral organic molecules [2] used as catalysts al- low the synthesis of polyfunctional compounds with high enantiomeric purity from simple prochiral precursors. [3] The asymmetric aldol reaction is an important enzymatic (aldolases [4] ) and organocatalytic transformation that is widely used to build carbon–carbon bonds in organic com- pounds. [5] A number of organocatalysts have been devel- oped for this reaction [6] over the past decade, and prolin- amide derivatives are among the most popular and efficient ones. [7] However, the majority of these catalysts are lost during product isolation and their commercial application is challenging. We have recently developed novel C 2 -symmetric organ- ocatalyst 1 with the (1R,2R)-bis[(S)-prolinamido]cyclohex- ane unit tagged with two imidazolium + /PF 6 – ion pairs (Fig- ure 1) [8] (references on other reusable proline- and prolin- amide-type organocatalysts attached to polymers or ionic groups are given in ref. [8] ). In the presence of this hydro- phobic catalyst, aromatic or heteroaromatic aldehydes react with linear or cyclic ketones in an aqueous medium (a “green” solvent, [9] in which natural aldolases “work” [4] ) un- der heterogeneous conditions (they were characterized as reactions “on water” by Sharpless [10a] and more accurately as reactions “in the presence of water” by Hayashi [10b] ) to [a] N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia Fax: +7-0-499-135-53-28 E-mail: zlotin@ioc.ac.ru Homepage: http://www.ioc.ac.ru/english/modules/common/ showfile.php?file=labs/lab_11/index Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201201144. Eur. J. Org. Chem. 2012, 7129–7134 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 7129 demonstrated. The 1,4-diaminobenzene-derived catalyst ex- hibited good catalytic performance and excellent recover- ability over at least 15 reaction–regeneration cycles under the studied conditions. afford chiral β-hydroxyketones with high diastereo- (anti/syn up to 99:1) and enantioselectivity (up to 99 % ee). Unlike the few other known reusable prolinamide-based or- ganocatalysts that can be used in asymmetric aldol reac- tions in an aqueous environment, [11] compound 1 retained its catalytic properties over ten reaction cycles and no cata- lyst reactivation was needed. Figure 1. Supported C 2 -symmetrical bisprolinamide organocatalyst 1 synthesized previously. However, bisamide 1 is a rather complex and expensive compound that contains six stereocenters. We wondered whether this complexity was compulsory for securing the high stereodifferentiating ability of catalyst 1 or if available prolinamides bearing achiral diamine spacers instead of the (1R,2R)-diaminocyclohexane unit would have stereoinduc- tion and recoverability characteristics similar to those of catalyst 1. A recently synthesized C 2 -symmetrical 4-silyl- oxyproline derivative, in which two prolinamide units are linked together by a simple –(CH 2 ) 6 – linker, [7j] displayed somewhat lower enantioselectivities in asymmetric aldol re- actions (especially in reactions with a cyclopentanone do- nor) than C 2 -symmetrical bisprolinamides containing chiral binam [7k] or trans-1,2-diamino-1,2-diphenylcyclohexane scaffolds. [7b] As far as we know, supported C 2 -symmetrical prolinamides bearing achiral linkers have not been re- ported, and their influence on the stereochemical outcome of a reaction can hardly be predicted. Herein we report the synthesis of novel ionic liquid supported bisamides 2a–c, in