DOI: 10.1002/ejoc.201700399 Full Paper Diamino Alcohol Organocatalysts A Diamino Alcohol Catalyzed Enantioselective Crossed Aldol Reaction of Acetaldehyde with Isatins – A Concise Total Synthesis of Antitumor Agents Ummareddy Venkata Subba Reddy,* [a] Madhu Chennapuram, [a] Kento Seki, [a] Chigusa Seki, [a] Bheemreddy Anusha, [b] Eunsang Kwon,* [c] Yuko Okuyama, [d] Koji Uwai, [a] Michio Tokiwa, [e] Mitsuhiro Takeshita, [e] and Hiroto Nakano* [a] Abstract: Enantioselective crossed aldol reactions of isatin de- rivatives and acetaldehyde have been developed with a series of simple diamino alcohol catalysts to afford 3-substituted 3- hydroxyindolin-2-ones in high chemical yields (up to 95 %) and optical purities (up to 92 % ee). The synthetic potential of the present protocol has been demonstrated by concise, enantio- selective, protecting-group-free, and transition metal-free total Introduction In modern organic chemistry, the asymmetric aldol reaction cat- alyzed by small organic molecules is one of the important methods for carbon–carbon bond formation. [1] In the last dec- ade, there has been significant progress in the development of enantioselective, organocatalyzed aldol reactions of various aldehydes. [2] However, the direct crossed aldol reaction of acet- aldehyde, which is the simplest enolizable carbonyl compound, has been a challenging task. [3,4] There are several complications in using acetaldehyde in crossed aldol reactions: (1) acetalde- hyde can react as an electrophile in self-aldol reactions, (2) the reactivity of the α,α-unsubstituted aldehyde as both a nucleo- phile and an electrophile leads to side reactions, and (3) the dehydration of the resulting product is possible. The crossed aldol reaction between acetaldehyde as a nucleophile and a [a] Division of Sustainable and Environmental Engineering, Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto, Muroran 050-8585, Japan E-mail: catanaka@mmm.muroran-it.ac.jp uvsreddy@mmm.muroran-it.ac.jp http://www3.muroran-it.ac.jp/hnakano/ [b] Department of Chemistry, KVR Degree College (Women), Kurnool-518001, Andhra Pradesh, India [c] Research and Analytical Center for Giant Molecules, Graduate School of Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan E-mail: ekwon@m.tohoku.ac.jp [d] Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan [e] Tokiwakai Group, 62 Numajiri Tsuduri-chou, Uchigo Iwaki 973-8053, Japan Supporting information for this article is available on the WWW under https://doi.org/10.1002/ejoc.201700399. Eur. J. Org. Chem. 2017, 3874–3885 © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3874 syntheses of antitumor and antiviral agents with the trypt- anthrin architecture, that is, phaitanthrin B and cephalanthrin A, along with the biologically active indolidine alkaloids chimonamidine and donaxaridine as well as the formal synthe- sis of CPC-1. The highly enantioselective outcome of this cata- lytic crossed aldol reaction was evaluated by calculating the Gibbs free energies of the possible transition states. ketone as an electrophile has great significance as it results in a chiral quaternary carbon center, which is immensely valuable in synthetic chemistry. [5] Specifically, the enantioselective crossed aldol reaction of acetaldehyde (2) with isatin (1a) is a straightforward method to acquire chiral 3-substituted 3- hydroxyindolin-2-one (3a), which is a valuable building block for the synthesis of a broad range of biologically important mol- ecules (Scheme 1). Owing to its significance as a pharmaco- phore, in recent years, several research groups have developed Scheme 1. Retrosynthetic analysis of crossed aldol reactions of isatins with acetaldehyde and the synthetic importance of 3-substituted 3-hydroxy- indolin-2-ones.