DOI: 10.1002/adsc.201100952 Samarium-Promoted Asymmetric Aldol–Tishchenko Reaction: Synthesis of Amino Acid-Derived 4-Amino-1,3-diols Humberto Rodríguez-Solla, a, * Carmen Concellón, a Paula Tuya, a Santiago García-Granda, b and and M. Rosario Díaz b a Departamento de Química Orgµnica e Inorgµnica, Facultad de Química, Universidad de Oviedo, Juliµn Clavería 8, 33071 Oviedo, Spain E-mail: hrsolla@uniovi.es b Departamento de Química Física y Analítica, Facultad de Química, Universidad de Oviedo, Juliµn Clavería 8, 33071 Oviedo, Spain Received: December 6, 2011; Revised: March 5, 2012; Published online: June 5, 2012 Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201100952. Abstract: A samarium-mediated novel synthesis of enantiopure 4-amino-1,3-diols is carried out through a samarium-promoted aldol–Tishchenko reaction starting from chiral a’-amino-a-chloro ketones (de- rived from natural a-amino acids) and aldehydes. The process takes place with moderate levels of ste- reoselectivity and in high yields. A mechanism is proposed to explain these results while the absolute configuration and structure of the aldol–Tishchenko adducts were established by X-ray analysis. This method has also been utilized for the synthesis of enigmols, 1-deoxysphingoid base analogues. Keywords: aldol reaction; amino acids; enolates; sa- marium; Tishchenko reaction The 4-amino-1,3-diol moiety belongs to a family of compounds – enigmols – which are known as 1-deoxy- sphingoid base analogues; they have demonstrated promising activity against prostate [1] and colon [2] cancer. These compounds are generally identified as a potential new class of anticancer principles. [3] The aldol–Tishchenko reaction (aldol/Tishchenko tandem process) [4] allows the conversion of aldehydes and ketones into 1,3-dihydroxy compounds. This reac- tion has been previously reported employing different catalysts such as samarium, [5] yttrium, [6] lithium, [7] tita- nium, [8] ytterbium, [9] zirconium, [10] aluminium, [11] and lanthanum [12] species. One of the most frequently used strategies to pre- pare enantiopure compounds is based on the use of optically active natural products as starting materials. Thus, a-amino acids have been one of the most uti- lized sources of chiral compounds in synthetic organic chemistry. Enantiopure a-amino ketones are easily obtained from readily available natural a-amino acids and they have been extensively utilized as building blocks in organic synthesis. In this sense, our group has previously described the synthesis of chiral a’- amino a-chloro ketones 1 by treatment of easily avail- able a-amino esters with in situ generated chlorome- thyllithium. [13] We have also described some synthetic applications of these a-amino chloromethyl ke- tones, [14] such as the preparation of enantiopure threo- aminoalkylepoxides, [15] 3-azetidinols, [16] amino epihalo- hydrins, [17] a’-amino-a,b-epoxy ketones, [18] aminoaziri- dines (from their ketimine derivatives), [19] g-amino ester azetidinium salts and epoxy esters, [20] amino-g- butyrolactones and butenolides, [21] pseudo-C 2 -symmet- ric diepoxides, [22] and chiral trisubstituted piperi- dines. [23] In recent years samarium diiodide has rapidly become an important reagent in organic chemistry be- cause of its versatility in one- and two-electron trans- fer reactions. Thus, since the pioneering studies of Kagan, [24] many synthetic applications of this reagent were reported from our group and others. [25] Encouraged by the pharmacological interest in enigmols, [1,2] and motivated by our studies on the syn- thetic applications of a’-amino-a-chloro ketones and the development of new applications of samarium diiodide in organic synthesis, in this communication we report the employment of a-amino chloromethyl ketones and aldehydes as starting materials for the synthesis of enigmol targets through an aldol–Tish- chenko reaction, this process being promoted by sa- marium diiodide. Our first attempts were performed using the N,N- dibenzylamino chloromethyl ketone derived from l- alanine 1a and n-octanal 2a. After searching for the optimum conditions for this reaction, 1.0 equiv. of 1a Adv. Synth. Catal. 2012, 354, 1679 – 1684  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1679 COMMUNICATIONS