DOI: 10.1002/chem.201000376 Brønsted Acid Assisted Regio- and Enantioselective Direct O-Nitroso Aldol Reaction Catalysed by a ,a-Diphenylprolinol Trimethylsilyl Ether Antonia Mielgo, Irene Velilla, Enrique Gómez-Bengoa, and Claudio Palomo* [a] Dedicated to Professor Saverio Florio on the occasion of his 70th birthday Introduction The asymmetric O-nitroso aldol reaction is an important tool for the preparation of enantioenriched a-hydroxy car- bonyl compounds. [1] In this reaction two important issues are the enantioselectivity and regioselectivity—attack through the nitrogen atom (oxyamination reaction) or oxygen atom (aminoxylation reaction). [2] First insights by Yamamoto et al. on the reaction of nitrosobenzene with silyl or metal enolates revealed that the regioselectivity of the process is dependent on the nature of the enolate and the presence or absence of a Lewis acid catalyst. [3] Later, the same author reported that in the presence of sub-stoichio- metric amounts of glycolic acid the reaction of nitrosoben- zene with pre-formed enamines preferentially afforded O- nitroso aldol products (aminoxylation). Conversely, in the presence of a,a,a’,a’-tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5- dimethanol (TADDOL), the a-amino derivatives were ex- clusively obtained (oxyamination). [4] Some examples of highly enantioselective nitroso aldol reactions have also been realised through in situ generation of the reactive en- amine by using proline (1) and secondary amines 2–6 (Scheme 1) in sub-stoichiometric quantities. [5] A common structural feature of all these catalysts is the presence of a Brønsted acid functionality as key element for controlling regioselectivity. [6] Thus, catalysts with strong acidic function- alities, such as carboxylic acids or sulfonamides (1–4 in Scheme 1A), predominantly give a-oxygenated products, whereas those that contain less acidic functionalities, namely, hydroxy groups (5, 6 in Scheme 1B), afford mainly a-oxyaminated compounds. Keywords: amino alcohols · enam- ine activation · aldehydes · nitroso aldol reaction · organocatalysis Abstract: In the presence of p-nitrobenzoic acid, the O-nitroso aldol reaction of nitrosobenzene with enolisable aldehydes may be promoted by commercially avail- able a,a-diphenylprolinol trimethylsilyl ether. The reaction proceeds with good yields and essentially complete enantioselectivity, with catalyst loadings in the 5– 10 mol % range. The resulting a-oxyaldehyde adducts may be transformed in situ into a-oxyimines, which provide 1,2-amino alcohols upon treatment with Grignard reagents, in good overall yield (45–59 %) and with typical diastereomeric ratios  95:5. [a] Dr. A. Mielgo, I. Velilla, Dr. E. Gómez-Bengoa, + Prof. Dr. C. Palomo Departamento de Química Orgµnica I, Universidad del País Vasco Manuel Lardizabal 3, 20018 San Sebastiµn (Spain) Fax: (+ 34) 943015270 E-mail: claudio.palomo@ehu.es [ + ] Computational study. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201000376. Scheme 1. Organocatalysts for the nitroso aldol reaction: A) Catalysts for aminoxylation, B) Catalysts for oxyamination. TMS = trimethylsilyl, TBS = tert-butyldimethylsilyl.  2010 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim Chem. Eur. J. 2010, 16, 7496 – 7502 7496