Asymmetric Synthesis DOI: 10.1002/ange.200703606 Highly Efficient Asymmetric Direct Stoichiometric Aldol Reactions on/in Water** Junmin Huang, Xiaotong Zhang, and Daniel W. Armstrong* Many enzymes catalyze reactions in water under mild conditions with high efficiency and excellent stereoselectivity. This highly effective and environmentally benign synthetic methodology is often regarded as a goal in modern organic chemistry. [1] Although enzymes have synthetic utility, they are usually limited by their lack of large-scale compatibility. [2] It is highly desirable to develop a chemical system that can mimic the action of enzymes and effect organic reactions in water with excellent efficiency and stereoselectivity. Water can be a safe, inexpensive, and environmentally friendly solvent, which makes its use favorable both in academic laboratories and in industry. The pioneering studies of Diels–Alder reactions in water by Breslow [3] in the early 1980s triggered a more widespread interest in the use of water as a medium for organic synthesis, not only because these reactions eliminate the necessity of vigorously drying solvents and substrates, but also because of the unique reactivity and selectivity often observed in aqueous reactions. In the past two decades considerable effort has been made in developing water-based synthetic organic reactions. [4] Thus far, only a relatively limited number of enantioselective organic reactions can be carried out effectively in this solvent and the associated mechanisms can be unclear. [5] Indeed, it appears that asym- metric synthesis in water is still not a routine or preferred procedure. Enantioselective metal catalysis has revolutionized asym- metric synthesis over the past 20 years and was recognized by the 2001 Nobel Prize in Chemistry. [6] Subsequently, the seminal work by List, Lerner, and Barbas on the intermo- lecular adaptation of the proline-catalyzed direct asymmetric aldol reaction [7] has focused attention on the catalytic asymmetric reaction by metal-free small organic molecules (organocatalysts). This synthetic approach has received much attention in light of its green chemistry advantages. [8] Proline is regarded as an effective and versatile small-molecule “enzyme” [9] that catalyzes a wide range of organic trans- formations. However, unlike enzymatic reactions in nature that occur in water, enantioselective organocatalytic process- es have typically been carried out in organic solvents. For example, proline-catalyzed aldol reactions [10] can only afford high enantioselectivity in solvents such as dimethylsulfoxide (DMSO) and N,N-dimethylformamide (DMF). The presence of a large amount of water has typically resulted in the formation of products with low or no enantioselectivity. [11] DMSO or DMF as solvents make the proline-catalyzed reaction workup and catalyst recycling difficult. In nature, aldolase enzymes catalyze the direct aldol reaction in water with excellent stereocontrol the reaction proceeds in a hydrophobic pocket to diminish contacts between bulk water and the reaction transition state. [8f] We therefore wanted to expand the concept of a hydrophobic pocket in water for the asymmetric assembly of direct aldol reactions under environmentally benign conditions. The field of enantioselective organocatalysis in water afforded further unsatisfactory results [11–14] until recently when breakthrough contributions were made by the groups of Barbas [15b,c] Takabe, [15b,c] and Hayashi. [15d,e] They used proline-derived catalysts in the presence of water to demon- strate the direct asymmetric aldol reaction and the Michael reaction with high yields and with excellent diastereoselec- tivities and enantioselectivities. Thereafter, many organo- catalysts have been designed for the direct aldol reaction and other reactions in aqueous conditions on the basis of the so- called “enamine catalysis”, a process that mimics type I aldolases. [15,16] It should be noted that with all of the organo- catalysts and reaction conditions, a large excess of ketone is employed. When an expensive ketone is used in large excess, it is not reassuring for the direct aldol reaction with atom- economical “green” credentials. In particular, the use of less- volatile ketones in large excess, for example, cyclohexanone (b.p. 155 8C), complicates the reaction workup and product purification. [13f] A highly efficient, stereoselective, and atom- economical reaction in water is currently a sought-after goal in chemistry. [17] Herein, we describe a tert-butylphenoxypro- line (4)/cyclodextrin system (Figure 1) for highly efficient asymmetric synthesis in water. We envision that cyclodextrins mimic enzymes to form a hydrophobic pocket in water, [17f] which can concentrate the organocatalyst and reactants, assemble substrates, diminish contacts between bulk water Figure 1. The asymmetric catalytic system in water mediated by water- soluble b-cyclodextrins. [*] Dr. J. Huang, X. Zhang, Prof.Dr. D. W. Armstrong Department of Chemistry and Biochemistry The University of Texas at Arlington Arlington, Texas 76013 (USA) Fax: (+ 1)817-272-0619 E-mail: sec4dwa@uta.edu [**] We gratefully acknowledge the RobertA. Welch Foundation Y-0026 for the support of this work. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Angewandte Chemie 9231 Angew. Chem. 2007, 119, 9231–9235 # 2007 Wiley-VCH Verlag GmbH & Co. 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