Journal Name Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx Dynamic Article Links ► ARTICLE TYPE This journal is © The Royal Society of Chemistry [year] [journal], [year], [vol], 00–00 | 1 Aqueous solutions of facial amphiphilic carbohydrates as sustainable media for organocatalyzed direct aldol reactions Ana Bellomo, a,b Richard Daniellou, a,b,£, * and Daniel Plusquellec a,b * Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x 5 The organocatalyzed direct aldol reaction was efficiently performed in aqueous solutions of facial amphiphilic carbohydrates with high diastereoselectivity and yield. Such sustainable media in addition with the use of 2% catalyst loading pave the way for the development of original 10 ecofriendly procedures through non-covalent induction. Introduction The aldol reaction is one of the most powerful methods of forming carbon-carbon bonds and has tremendous synthetic applications. 1 Biological systems have perfected this 15 stereospecific transformation by using enzymes: type I aldolases function via the formation of an enamine intermediate with a lysine residue whereas type II aldolases activate substrates by forming a zinc enolate. Despite their lack of large-scale compatibility and their narrow substrate specificity, aldolases 20 represent a great source of inspiration for the development of catalysts. For example, catalytic antibodies have already demonstrated to be useful tools in organic chemistry. 2 Seminal works of List, Lerner and Barbas have also proved that small molecules like L-proline are able to act as enamine-based aldol 25 catalysts whose simplicity contrast with the complex machinery of enzymes. 3 However, even if these asymmetric reactions are efficiently performed using both metal- and organocatalysts in organic solvents, similar transformations in water generally require the use of additives or co-solvents, or are just impossible 30 to perform. 4 As an alternative to the de novo design of water-compatible catalysts, 5 we wish to develop environmentally friendly, efficient and stereoselective protocols based on aqueous solutions of 35 sustainable natural products. Especially, inexpensive carbohydrates like sucrose 1 or alkyl β-D-fructopyranosides 2 6 exhibiting facial amphiphilic characters, i.e. their pyranoside ring displaying both a hydrophilic face and a hydrophobic region (Fig. 1), have already demonstrated their potency in selectively 40 promoting reductions, epoxidations and indium-promoted allylations. 7 Faster reactions as well as better solubility of the organic reactants were also observed. Thus, such original media may constitute alternative solvents for the development of sustainable chemistry. 45 Fig. 1 Structure and hydrophobic areas of facial amphiphilic carbohydrates 1-2. 50 Herein we wish to report our findings concerning the mild and stereoselective direct aldol reaction of cyclic ketones in aqueous carbohydrate solutions. Small organic catalysts were selected considering the formation of an enamine intermediate, resembling the mechanistic pathway followed by L-proline and its 55 analogues. 8 Noteworthingly, as previous experiments have shown the low potency of carbohydrates to orientate cyclic ketones in water, 7c we envisioned that sugars may still be involved in the transition state, diminishing contacts with bulk water 9 and allowing the orientation of the assumed enamine-incoming 60 aldehyde intermediate, thus influencing the stereochemical outcome of the reaction. Results and Discussion The direct aldol reaction of cyclohexanone (5 equiv.) and m- nitrobenzaldehyde (1 equiv.) in 1M aqueous solution of ethyl β- 65 D-fructopyranoside 2b was chosen as a model (Table 1). Initial screenings were focused on the catalytic efficiency of commercially available bases and their influence on the diastereoselectivity. Furthermore, fixed catalyst loadings of 2 mol % were used. As expected, L-proline was completely inefficient 70 for catalysing aldolisation in water (entry 1). 10 Ethanolamine, a mimic of the lysine side chain, afforded compound 3 in nearly 90% yield (entries 2-3) but with long reaction times and expected poor selectivities. The use of pyrrolidine as catalyst showed better results (entries 4-5), enabling the completion of the reaction in 75 about 1 hour. For the first time, 2b was able to influence significantly the syn/anti ratio increased to 1.9:1. L-Prolinol (entries 6-7) exhibited low reactivity and similar 3:1 diastereoselectivities whether the sugar additive was present or not. The existence of steric hindrance at position 2 of the 80