FULL PAPER DOI: 10.1002/ejoc.201000473 A General Methodology for the Enantioselective Synthesis of 1-Substituted Tetrahydroisoquinoline Alkaloids Mercedes Amat,* [a] Viviane Elias, [a] Núria Llor, [a] Fabiana Subrizi, [a] Elies Molins, [b] and Joan Bosch [a] Dedicated to Prof. Dr. Antonio García Martínez on the occasion of his retirement Keywords: Alkaloids / Heterocycles / Lactams / Asymmetric synthesis / Total synthesis Starting from tricyclic lactam 2, which is easily accessible by cyclocondensation of δ-oxoester 1 with (R)-phenylglycinol, a three-step synthetic route to enantiopure 1-substituted tetra- hydroisoquinolines, including 1-alkyl-, 1-aryl-, and 1-benzyl- Introduction The tetrahydroisoquinoline ring system is present in nu- merous structurally diverse natural products exhibiting a wide range of biological and pharmacological activities. [1] In particular, simple 1-substituted tetrahydroisoquinolines are of great interest not only as alkaloids themselves but Figure 1. Selected 1-substituted tetrahydroisoquinoline alkaloids. [a] Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain Fax: +34-934-024-539 E-mail: amat@ub.edu [b] Institut de Ciència de Materials de Barcelona (CSIC), Campus UAB, 08193 Cerdanyola, Spain Eur. J. Org. Chem. 2010, 4017–4026 © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4017 tetrahydroisoquinoline alkaloids, as well as the tricyclic alka- loid (–)-crispine A, has been developed. The key step is a stereoselective α-amidoalkylation reaction using the appro- priate Grignard reagent. also as useful key intermediates in the synthesis of more complex alkaloids. This has stimulated the development of a number of methodologies aimed at the enantioselective synthesis of 1-substituted tetrahydroisoquinoline deriva- tives [2] (Figure 1). In previous work, we demonstrated that phenylglycinol- derived oxazolopiperidone lactams are versatile scaffolds that allow the regio- and stereocontrolled introduction of substituents at different positions of the piperidine ring, Scheme 1. Natural and bioactive products prepared from phenyl- glycinol-derived lactams.