DOI: 10.1002/adsc.200800558 Highly Efficient Organocatalyzed Direct Asymmetric Aldol Reactions of Hydroxyacetone and Aldehydes Xiaoyu Wu, a, * Zhixiong Ma, b Zhengqing Ye, b Shan Qian, b and Gang Zhao b, * a Department of Chemistry, Shanghai University, 99 Shangda Rd, Shanghai 200444, Peoples Republic of China Fax: (+ 86)-21-6683-4856; e-mail: wuxy@shu.edu.cn b Laboratory of Modern Organic Synthetic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, Peoples Republic of China Fax: (+ 86)-21-6416-6128; e-mail: zhaog@mail.sioc.ac.cn Received: September 11, 2008; Revised: November 30, 2008; Published online: January 2, 2009 Supporting information for this article is available on the WWW under http ://dx.doi.org/10.1002/adsc.200800558. Abstract: Novel organocatalysts derived from l- threonine and l-leucine have been synthesized for catalyzing direct aldol reactions of hydroxycetone and unactivated aliphatic aldehydes with as low as 2 mol% loading of the catalyst, good to excellent yields and excellent enantioselectivities have been achieved for aliphatic aldehydes, whereas aromatic aldehydes yield only moderate enantioselectivities. Keywords: aldehydes; aldol reaction; 1,2-diols; hy- droxyacetone; organic catalysis The a,b-dihydroxy ketone moiety is the core structure unit in a number of natural macrolide amphidinolides (Scheme 1). [1] Many of these compounds have shown strong cytotoxicity in anti-cancer studies. [1b,c] Their biological activities make them extremely attractive targets for synthetic organic chemists. [2] As for the construction of the key a,b-dihydroxy ketone moiety, several approaches have been reported. [2] Typically two strategies are used to control the stereochemistry: one uses chiral auxiliary, [2a–e] and the other one uses the Sharpless AD process. [2g–i] Nonetheless, both methods require several additional steps to transform the initial amide or ester groups into the desired ketone functional group via the corresponding Wein- reb amide. As part of our efforts in the total synthesis of am- phidinolides H, G and B, [2h,i] we envisioned that a direct aldol reaction of hydroxyacetone with the cor- responding aldehydes should produce the C 3 unit with the simultaneous control of the two hydroxy-substitut- ed stereogenic centers. Since the pioneering work of List [3] and Barbas, [4] organocatalysts have been widely utilized in the direct aldol reactions between ketones and aldehydes, and notable advances have been achieved over the last a few years in this field. [5] The use of hydroxyacetone as a donor in the direct aldol reaction was firstly introduced by List and co- workers. [3b] This reaction provided a product with a valuable 1,2-diol moiety. Since then extensive efforts have been made to improve the stereocontrol in this reaction with either hydroxyacetone or protected hy- droxyacetone as the substrates. [6] So far high levels of enantioselectivity have been achieved with both the syn and the anti products by utilizing chiral catalysts derived from primary and secondary amines. However, the aldol acceptors of these reactions are usually limited to aromatic aldehydes and a-hydroxy or a-amino aliphatic aldehydes. While it has been re- ported that branched aliphatic aldehydes are also ef- fective aldol acceptors in some cases, [3,4] linear aliphat- ic aldehydes are bad substrates in terms of yield and stereoselectivities. [6] Furthermore, the catalyst loading in these reactions typically ranges from 15 to Scheme 1. The a,b-dihydroxy ketone unit in amphidinolides. 158  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2009, 351, 158 – 162 COMMUNICATIONS