Month 2019 A Concise Stereoselective Synthesis of (R)-2-Benzylmorpholine and ML398 from (R)-(À)-2-Phenylglycinol Saúl Torres, a Manuel Velasco, a José Ángel Gallegos-Rojas, b Sylvain Bernès, c María L. Orea, a Joel L. Terán, a Gabriela Huelgas, d Víctor Gómez-Calvario, a and Jorge R. Juárez a * a Centro de Química, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Edif. IC8, Complejo de Ciencias, C.U., 72570, Puebla, Pue., Mexico b Instituto Tecnológico de Parral, 33850, Hidalgo del Parral, Chih., Mexico c Instituto de Física, Benemérita Universidad Autónoma de Puebla, 1IF2 (aka 110-B), Lab. 102, C.U., 72570, Puebla, Pue., Mexico d Departamento de Ciencias Químico-Biológicas, Universidad de las Américas-Puebla, Sta. Catarina Mártir, 72820, Cholula, Pue., Mexico *E-mail: jorge.juarez@correo.buap.mx Received June 6, 2019 DOI 10.1002/jhet.3657 Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com). We describe here an efficient stereoselective method for the preparation of (R)-2-benzylmorpholine and ML398. The present method features a high diastereocontrol using an endocyclic oxidation of phenylglycinol-derived morpholine and a stereoselective alkylation of chiral non-racemic morpholin-3-one as key steps. J. Heterocyclic Chem., 00, 00 (2019). INTRODUCTION C2-substituted morpholines are important structural cores present in many natural or synthetic compounds that exhibit interesting biological activities [1–6]. For example, the (R)-2-benzylmorpholine, a potent appetite suppressant drug [7], has also proven to be useful in the treatment of diabetes and cognitive disorders [8,9]; ML398, a potent and selective dopamine receptor antagonist (D4R), shows activity (in vivo) to reverse hyperlocomotion induced by cocaine (Figure 1) [10]. Interestingly, studies in the biological activities of (R)-2- benzyl morpholine and ML398 have shown that the (R)- enantiomers are the active isomers. To date, several methods for the preparation of (R)-2-benzylmorpholine have been reported, including chemoenzymatic methodologies [11], resolution with dibenzoyl-L-tartaric acid [7], as well as asymmetric synthesis based on α- aminooxylation [12] or Sharpless epoxidation [13], while ML398 has been obtained by asymmetric synthesis based on an organocatalytic α-chlorination of aldehydes [10]. The morpholin-3-one core has proven to be a versatile intermediate for the construction of morpholine derivatives [14–16]. Several methodologies for its obtainment through oxidation have been reported. Nevertheless, poor yields, by-products, and dependence on the catalyst have been the main drawbacks [17–21]. Therefore, the development of new efficient oxidation methods for the preparation of morpholin-3-one is highly desirable. In this context, we have reported an efficient endocyclic oxidation of phenylglycinol-derived piperidine to generate the corresponding piperidin-2-one [22]. Thus, the piperidin-2-one was a key intermediate in the enantioselective synthesis of (2′S,3R)-(+)-stenusine (a, Scheme 1). Now, in connection with our interest to synthesize chiral non-racemic heterocyclic compounds based on the use of (R)-(À)-2-phenylglycinol and that to the best of our knowledge no stereoselective syntheses of (R)-2-benzylmorpholine and ML398 have been reported, we present here a concise stereoselective synthesis of (R)- 2-benzylmorpholine and ML398 (b, Scheme 1). RESULTS AND DISCUSSION According to the retrosynthetic plan depicted in Scheme 2, the construction of (R)-2-benzylmorpholine and ML398 can be generated from amide derivatives 4a © 2019 Wiley Periodicals, Inc.