Efficient Synthesis of Chiral Isoquinoline and Pyrido[1,2-b]- isoquinoline Derivatives via Intramolecular Heck Reactions Francisco Sa  nchez-Sancho, Enrique Mann, Bernardo Herrado  n* Instituto de Quõ Âmica Orga  nica General, C.S.I.C., Juan de la Cierva 3, 28006 Madrid, Spain Fax: (+34) 91±5644±853, e-mail: herradon@iqog.csic.es Received January 14, 2001; Accepted february 16, 2001 Introduction Partially reduced isoquinoline (e. g., A, Figure 1) [1] and pyrido[1,2-b]isoquinoline (e. g., B) [2,3] derivatives are frequently found in a variety of natural products and biologically active compounds. Although several syntheses of these heterocycles have been re- ported, [4±6] most of them have yielded racemic mate- rials or have furnished scantily functionalized com- pounds. In connection with an ongoing project on the synthesis of peptide conjugates bearing peptidic fragments on a heterocyclic scaffold, [7,8] we have re- quired efficient accesses to some chiral functiona- lized heterocycles with isoquinoline and pyrido[1,2- b]isoquinoline backbones (A and B). The retrosyn- thetic analysis for these compounds is indicated in Figure 1 and involves intramolecular Heck reac- tions [9] as the key steps for the formation of the bicy- clic and tricyclic systems. The substrates for these cy- clizations (compounds C and D) can be prepared, in enantiomerically pure form, from readily available chiral amino acids (E) and amino alcohols (F), re- spectively. In this paper we report straightforward and stereoselective syntheses of some enantiomeri- cally pure isoquinoline (5) and pyrido[1,2-b]isoquino- line (10) derivatives. Furthermore, we describe some interesting observations that show that the outcome of the Heck cyclization of N-(2-iodobenzoyl)-g-ami- no-a,b-unsaturated esters and related compounds de- pends on the experimental conditions and the struc- ture of the substrate. During the development of this project, [7,10] the synthesis of isoquinoline derivatives using intramolecular Heck reaction has been re- ported by the groups of Tietze, [11] Goff, [12] Gibson, [13] and De Mesmaeker. [14] Results and Discussion The synthesis of the isoquinolidinone derivatives 5a± c is indicated in Scheme 1. The hydrochlorides of (S)- alanine methyl ester (1a), (S)-valine methyl ester (1b), and (S)-phenylalanine methyl ester (1c) were converted in nearly quantitative yield to the corre- sponding N-(2-iodobenzoyl) derivatives 2a, 2b, and 2c, respectively, by acylation with 2-iodobenzoyl chloride. Compounds 2a±c were transformed in high yield to the corresponding N-acylated-1,2-amino al- 360 Ó WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2001 1615-4150/01/34301-360±368 $ 17.50-.50/0 Adv. Synth. Catal. 2001, 343, No. 4 FULL PAPERS Abstract: The palladium(0)-catalyzed reaction of derivatives of g-amino-a,b-unsaturated esters bear- ing an N-(2-iodobenzoyl) substituent results in an intramolecular Heck reaction, the outcome of which depends on the structure of the substrate as well as on the experimental conditions. The methodology developed has been ap- plied to the efficient synth- eses of chiral isoquinoline and pyrido[1,2-b]isoquino- line derivatives. Keywords: biaryls; intramolecular Heck reaction; isoquino- lines; pyrido[1,2-b]- isoquinolines; palla- dium. Figure 1. Structure of the target molecules and retrosyn- thetic analysis of the heterocycles A and B.