FULL PAPER DOI: 10.1002/ejoc.201500926 Silyloxy Amino Alcohol Organocatalyst for Enantioselective 1,3-Dipolar Cycloaddition of Nitrones to α,β-Unsaturated Aldehydes Teppei Otsuki, [a] Jun Kumagai, [a] Yoshihito Kohari, [a] Yuko Okuyama, [b] Eunsang Kwon,* [c] Chigusa Seki, [a] Koji Uwai, [a] Yasuteru Mawatari, [a] Nagao Kobayashi, [d] Tatsuo Iwasa, [e] Michio Tokiwa, [f] Mitsuhiro Takeshita, [f] Atushi Maeda, [g] Akihiko Hashimoto, [h] Kana Turuga, [h] and Hiroto Nakano* [a] Keywords: Organocatalysis / Cycloaddition / Enantioselectivity / Diastereoselectivity / Nitrogen heterocycles / Amino alcohols The catalytic activity of a simple amino alcohol that contains a bulky super silyl group [i.e., tris(trimethylsilyl)silyl (TTMSS)] bonded to the oxygen atom at the γ-position along with a primary amine moiety was examined in the enantiose- lective 1,3-dipolar cycloaddition of nitrones to α,β-unsatu- rated aldehydes. The organocatalyst successfully provided Introduction The development of new optically active organocatalysts for use in asymmetric synthesis has attracted considerable interest in the scientific community over the past 10 years. [1] Excellent covalent and noncovalent organocatalysts have been developed for use in a wide range of reactions. Re- cently, we reported that an amino alcohol that contains a primary amino group can act as an efficient organocatalyst in the enantioselective Diels–Alder reaction of 1,2-dihy- dropyridines with dienophiles. [2] Amino alcohol A is stable when exposed to air and has the advantages of being easy [a] Department of Bioengineering, Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto, Muroran 050-8585, Japan E-mail: catanaka@mmm.muroran-it.ac.jp http://www3.muroran-it.ac.jp/hnakano/ [b] Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan [c] Research and Analytical Center for Giant Molecules, Graduate School of Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan http://www.kiki.chem.tohoku.ac.jp/index.html [d] Department of Chemistry, Graduate School of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan [e] Division of Engineering for Composite Functions, Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto, Muroran 050-8585, Japan [f] Tokiwakai Group, 62 Numajiri Tsuduri-chou Uchigo Iwaki 973-8053, Japan [g] Shin-Nihon Kogyo Co., Ltd., 6-5-8 Higashi 8-jyo, Asahikawa 070-0028, Japan [h] Technos Hokkaido Co., Ltd., 7-4-10 Chuwa 4-jo, Asahikawa 070-8044, Japan Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201500926. © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2015, 7292–7300 7292 optically active isoxazolidines in good chemical yields (up to 86 %) with excellent diastereoselectivities (endo/exo, up to 96:4) and enantioselectivities (up to 97 % ee). Furthermore, the obtained isoxazolidines were easily converted into γ- amino diols that contain three contiguous stereogenic cen- ters. to prepare and having the desirable structural characteris- tics. It is easily derived from the corresponding amino acid ester and contains both an amino covalent site and a hy- droxy noncovalent binding site in a single molecule (Scheme 1). The enantioselective 1,3-dipolar cycloaddition (1,3-DC) of nitrones to α,β-unsaturated aldehydes is an efficient reac- tion for the construction of optically active isoxazolid- ines. [3,4] Isoxazolidines are valuable chiral building blocks that are readily converted into γ-amino alcohols, β-amino acids, and β-lactams, which can be used in the synthesis of various biological compounds. [5] Although several groups have reported enantioselective organocatalytic versions of this cycloaddition, few examples have employed a primary amine [4f] in a 1,3-DC, and the catalytic effectiveness of an amino alcohol as an organocatalyst in a 1,3-DC has not yet been revealed. To further expand the usefulness of an amino alcohol with a primary amino group as an organocatalyst in asym- metric reactions, we focused on investigating simple amino alcohol A, which contains a primary amine moiety and a bulky substituent (Scheme 1). In the pathway for the 1,3- DC reaction, an iminium ion intermediate is first formed from the condensation of amino alcohol A with an α,β- unsaturated aldehyde in the presence of a proton from an acid additive. The steric influence between the α-, β-, or γ- substituents in this intermediate and the counter anion of the acid might control the approach of the nitrone sub- strate. Thus, we report herein that TTMSS-amino alcohol 1 [TTMSS = tris(trimethylsilyl)silyl], which contains a pri-