This review describes the importance and usefulness of pot-economy and one-pot reactions in current synthetic organic chemistry.

A subtle change in catalyst structure can sometimes improve catalytic activity dramatically, as we found in our recent study on a-aminoxylation, tandem O-nitroso aldol/Michael reactions, and Mannich reactions catalyzed by the siloxyproline 4, a highly active proline surrogate (Scheme 1).[1] The simple introduction of a siloxy group into the proline structure leads to an increase in the catalytic activity, thus allowing a decrease in catalyst loading and shorter reaction times, without compromising the enantioselectivity, and is accompanied by broadening of the substrate scope. This higher activity can be attributed to the increased solubility of 4 in organic solvents. The fact that the substitution of a hydroxy group for a siloxy group can dramatically affect catalytic activity prompted us to investigate other catalytic systems, and these investigations led us to the diphenylprolinol silyl ether 2. The parent diphenyl-2-pyrrolidinemethanol (1, diphenylprolinol), a commercially available amino alcohol developed by Corey and co-workers, has proved to be a very useful ligand for asymmetric synthesis: B-alkylated oxazaborodine is a useful catalyst for the CBS reduction, [2] while an effective, asymmetric Lewis acid catalyst prepared from B-aryl oxazaborodine and a Brønsted acid promotes the Diels-Alder reaction of a broad range of substrates with excellent enantioselectiv-

Going green: The synthetically very important aldol reaction can proceed in water without a metal catalyst with excellent enantioselectivity. The key to the reaction is a small, synthetic organic catalyst based on trans‐hydroxyproline with a siloxy group. Thus, this method is an environmentally friendly process for the synthesis of chiral molecules.

No abstract

The amine-catalyzed enantioselective Michael addition of aldehydes to nitro alkenes (Scheme 1) is known to be acid-catalyzed (Fig. 1). A mechanistic investigation of this reaction, catalyzed by diphenylprolinol trimethylsilyl ether is described. Of the 13 acids tested, 4-NO 2 ÀC 6 H 4 OH turned out to be the most effective additive, with which the amount of catalyst could be reduced to 1 mol-% (Tables 2 -5). Fast formation of an amino-nitro-cyclobutane 12 was discovered by in situ NMR analysis of a reaction mixture. Enamines, preformed from the prolinol ether and aldehydes (benzene/molecular sieves), and nitroolefins underwent a stoichiometric reaction to give single all-trans-isomers of cyclobutanes (Fig. 3) in a [2 þ 2] cycloaddition. This reaction was shown, in one case, to be acid-catalyzed (Fig. 4) and, in another case, to be thermally reversible (Fig. 5). Treatment of benzene solutions of the isolated aminonitro-cyclobutanes with H 2 O led to mixtures of 4-nitro aldehydes (the products 7 of overall Michael addition) and enamines 13 derived thereof (Figs. 6 -9). From the results obtained with specific examples, the following tentative, general conclusions are drawn for the mechanism of the reaction (Schemes 2 and 3): enamine and cyclobutane formation are fast, as compared to product formation; the zwitterionic primary product 5 of C,C-bond formation is in equilibrium with the product of its collapse (the cyclobutane) and with its precursors (enamine and nitro alkene); when protonated at its nitronate anion moiety the zwitterion gives rise to an iminium ion 6, which is hydrolyzed to the desired nitro aldehyde 7 or deprotonated to an enamine 13. While the enantioselectivity of the reaction is generally very high (> 97% ee), the diastereoselectivity depends upon the conditions, under which the reaction is carried out (Fig. 10 and Tables 1 -5). Various acid-catalyzed steps have been identified. The cyclobutanes 12 may be considered an off-cycle reservoir of catalyst, and the zwitterions 5 the key players of the process (bottom part of Scheme 2 and Scheme 3).

A subtle change in catalyst structure can sometimes improve catalytic activity dramatically, as we found in our recent study on a-aminoxylation, tandem O-nitroso aldol/Michael reactions, and Mannich reactions catalyzed by the siloxyproline 4, a highly active proline surrogate (Scheme 1).[1] The simple introduction of a siloxy group into the proline structure leads to an increase in the catalytic activity, thus allowing a decrease in catalyst loading and shorter reaction times, without compromising the enantioselectivity, and is accompanied by broadening of the substrate scope. This higher activity can be attributed to the increased solubility of 4 in organic solvents. The fact that the substitution of a hydroxy group for a siloxy group can dramatically affect catalytic activity prompted us to investigate other catalytic systems, and these investigations led us to the diphenylprolinol silyl ether 2. The parent diphenyl-2-pyrrolidinemethanol (1, diphenylprolinol), a commercially available amino alcohol developed by Corey and co-workers, has proved to be a very useful ligand for asymmetric synthesis: B-alkylated oxazaborodine is a useful catalyst for the CBS reduction, [2] while an effective, asymmetric Lewis acid catalyst prepared from B-aryl oxazaborodine and a Brønsted acid promotes the Diels-Alder reaction of a broad range of substrates with excellent enantioselectiv-

A catalytic enantioselective direct conjugate addition of nitroalkanes to alpha,beta-unsaturated aldehydes using diphenylprolinol silyl ether as an organocatalyst has been developed. Using this methodology as a key step, short syntheses of therapeutically useful compounds have also been accomplished.

What expression best conveys the recent examples of “aqueous” organocatalyzed aldol reactions? It is suggested that a reaction occurs “in water” if the participating reactants are dissolved homogeneously in water (or buffer), or “in the presence of water” if it proceeds in a concentrated organic phase with water present as a second phase that influences the reaction in the former.