Just add water to improve the performance of direct aldol reactions like that shown. Previously, aldehydes with high water‐affinity or ‐solubility were considered unsuitable for asymmetric synthesis.

The approach using pyrrolidine enamine as substrate has been studied for this synthesis, and an important catalyst structural feature has been developed. After survey of pyrrolidine-based Brønsted acid catalyst, tetrazole catalyst (3f) was found to be optimal in synthesis of aminooxy carbonyl compounds in high yields, with complete enantioselectivity not only for aldehydes but also for ketones. R egio-and stereoselective replacement of hydrogen by oxygen results in a rapid increase of molecular complexity (1-6). We recently described the catalytic enantioselective synthesis of ␣-hydroxy carbonyl compounds from ketone enolates (7). This method depends heavily on the new nitroso aldol synthesis (Eq. 1 and refs. 8 and 9), and by choosing the right catalyst, nitrosobenzene can function as an oxy electrophile for the enantioselective introduction of oxygen to ␣-position at carbonyl derivatives. The silver 2,2Ј-bis(diphenylphosphino)-1,1Ј-binaphthyl (BINAP) catalyst has been developed further into a highly reactive complex to generate ␣-aminooxy ketone with excellent regio-and enantioselectivity (Eq. 2).In 1972, Lewis et al. (10) reported the reaction of nitrosobenzene with 1-morpholin-1-ylcyclohexene followed by simple hydrolysis to give the hydroxyamino ketone as the major product. Surprisingly, however, we found that the similar reaction of nitrosobenzene with 1-pyrrolidin-1-ylcyclohexene followed by treatment with acetic acid gave rise to the aminooxy ketone almost exclusively (Eq. 3). The observed discrepancies may originate from the structural difference of enamines (11-18). We describe herein careful experiments on nitrosobenzene with pyrrolidine.More recently MacMillan and coworkers (19), Zhong (20), and Hayashi et al. (21) independently reported the enantioselective nitroso aldol synthesis of nitrosobenzene and simple aldehydes using proline catalyst (Eq. 4). In fact, a series of recent reports of organic catalysts have shown that natural amino acid proline has been used to activate ketones and aldehyde as nucleophilic enamine intermediates for various reactions (22)(23)(24)(25). We also reported a diamine-protonic acid catalyst (26, 27) and pyrrolidine-base tetrazole catalyst (28, 29) for asymmetric direct aldol reaction with high catalyst turnover. Herein we report that the tetrazole catalyst gave the aminooxy carbonyl compound in high yields with complete enantioselectivity not only for aldehydes but also for ketones (Eq. 5 and refs. 30 and 31). Experimental ProceduresPreparation of L-Pyrrolidine-2-yl-1H-tetrazole (3f) (Scheme 1 and refs. 32 and 33). The ammonium hydrogen carbonate (1.26 eq) was added to the stirred solution of carbobenzyloxy-L-proline (1 eq), pyridine, and Boc 2 O (1.30 eq) in MeCN and stirred for 20 h. The solvent was removed, and the residue was diluted with ethyl acetate, washed with water, extracted with ethyl acetate, dried This paper was submitted directly (Track II) to the PNAS office.Abbreviations: ee, enantiomeric excess; rt, room temperature.

Mit Wasser geht's besser! Das gilt für direkte Aldolreaktionen wie die gezeigte. Bisher erachtete man Aldehyde mit hoher Wasseraffinität oder Wasserlöslichkeit als für die asymmetrische Synthese nicht zugänglich.

Enantioselective syntheses Enantioselective syntheses O 0031Asymmetric Direct Aldol Reaction Assisted by Water and a Proline-Derived Tetrazole Catalyst. -The title compound (PTZ) is found to be an efficient catalyst for asymmetric aldol reactions using water-soluble aldehydes hitherto considered to be unsuitable for asymmetric syntheses. -(TORII, H.; NAKADAI, M.; ISHIHARA, K.; SAITO*, S.; YAMAMOTO, H.; Angew.