Novel Stereoselective Syntheses of the Fused Benzazepine Dopamine D 1 Antagonist (6a S ,13 bR)-11-Chloro-6,6a,7,8,9,13b-hexahydro-7-methyl- 5 H-benzo[d]naphth[2,1- b]azepin-12-ol (Sch 39166): 2. L -Homophenylalanine-Based Syntheses Richard W. Draper, Donald Hou,* Radha Iyer, Gary M. Lee, Jimmy T. Liang, Janet L. Mas, and Eugene J. Vater Chemical Process Research and DeVelopment Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-0539 Abstract: Two enantioselective syntheses of the fused benzazepine dopamine D 1 antagonist (6aS,13bR)-11-chloro-6,6a,7,8,9,13b- hexahydro-7-methyl-5H-benzo[d]naphth[2,1-b]azepin-12-ol (1) are described in which the starting material is (+)-L-homophe- nylalanine (6). In the first approach, methyl (2S)-(1,2,3,4- tetrahydro-1-oxo-2-naphthalenyl)carbamate (5) is prepared by intramolecular Friedel-Crafts cyclization of N-carbomethoxy (+)-L-homophenylalanine (9). Subsequent alkylation of 5 with (4-chloro-3-methoxyphenyl)magnesium bromide, deoxygenation with Et 3 SiH, reduction, alkylation, and epimerization yields (+)- trans-(1R,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxy- ethyl)-1,2,3,4-tetrahydro-N-methyl-2-naphthalenamine (2), a key intermediate in the previously described route to 1 (Draper, R. W.; Hou, D.; Iyer, R.; Lee, G. M.; Liang, J. T.; Mas, J. L.; Tormos, W.; Vater, E. J.; Gu 1 nter, F.; Mergelsberg, I.; Scherer, D. Org. Process Res. DeW. 1998, 2, XXXXX). A complementary route to 2 is also described in which arylation of an N-protected, carboxyl-activated (+)-L-homophenylalanine affords (2S)-1-(4- chloro-3-methoxyphenyl)-2-(methoxycarbamoyl)-4-phenyl-1-bu- tanone (26). Reduction of the latter compound followed by an acid-catalyzed, diastereoselective cyclization affords (+)-(1R,2S)- [1-(4-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydro-2-naphthale- nyl]carbamate (16), which is reduced and alkylated as before to produce 2. Introduction In the preceding paper we described several enantio- selective syntheses based on a chiral aziridinium salt ap- proach to the novel, selective, dopamine D 1 receptor antagonist Sch 39166 (1), whose pharmacological profile makes it an important commercial synthetic target. 1 In this paper, we describe a number of alternative stereoselective syntheses of 1 starting from the readily available synthon (+)-L-homophenylalanine (6). 2 Two parallel retrosynthetic analyses of the key tricyclic compound 2, a known precursor 1 of 1, are illustrated in Scheme 1. Disconnection of the seven-membered ring and removal of the 2-carbon appendage leads to a synthon such as 3, which might be assembled from an organometallic reagent derived from 5-bromo-2-chloroanisole and a suitably protected 2-amino-1-tetralone 5. 5 in turn might be generated by an internal Friedel-Crafts cyclization of an appropriate (+)-L-homophenylalanine derivative. An alternative retrosynthetic analysis juxtaposes the order of scission of the C ring and attachment of the A ring. Cleavage of the tetralin C 13a -C 13b bond and elimination of the two-carbon chain suggests the amino alcohol intermediate 7, which could be constructed by arylation of a suitable carboxyl group activated (+)-L-homophenylalanine deriva- tive. We report herein the realization of the synthesis of 1 along both of these pathways. Results and Discussion Of the various blocking groups such as the trifluoroacetyl group, 3a phenylsulfonyl group, 3b and ethoxycarbonyl group, 3b normally used for N-protection of amino acids during Friedel-Crafts reactions, McClure 4 reported that the car- bomethoxy group is superior, as they found that N-methyl- carbamate protected (+)-L-homophenylalanine undergoes a stereoselective Friedel-Crafts cyclization to give the N- protected aminotetralone ring system with high ee. This was fortuitous, since for our purposes the carbomethoxy group not only can serve to protect the nitrogen but also, upon reduction, can be transformed to the N-methyl group of 1. Following McClure’s procedure, 4 6 was converted in three steps to 5 in 86% overall yield with excellent ee (>98%) * To whom correspondence should be sent: Schering-Plough Research Institute, 2015 Galloping Hill Rd., Mailstop K-15-2, 2800, Kenilworth, NJ 07033. Tel: (908) 298-7121. FAX (908) 298-6610. E-mail: donald.hou@spcorp.com. (1) See preceding paper and references therein for an introduction to the pharmacology of 1 and a discussion on alternative synthetic approaches: Draper, R. W.; Hou, D.; Iyer, R.; Lee, G. M.; Liang, J. T.; Mas, J. L.; Tormos, W.; Vater, E. J.; Gu ¨nter, F.; Mergelsberg, I.; Scherer, D. Org. Process Res. DeV. 1998, 2, 175. (2) (+)-L-Homophenylalanine is available in bulk quantities from Tanabe U.S.A., Inc., and Aceto Corporation (U.S. Representative for Ajinomoto). (3) (a) Norlander, E. J.; Payne, M. J.; Njoroge, F. G.; Vishwanath, V. M.; Han, G. R.; Laikos, G. D.; Balk, M. A. J. Org. Chem. 1985, 50, 3619. (b) Buckley, T. F., III; Rapoport, H. J. Am. Chem. Soc. 1981, 103, 6157. (4) McClure, D. E.; Lumma, P. K.; Arison, B. H.; Jones, J. H.; Baldwin, J. J. J. Org. Chem. 1983, 48, 2675. Organic Process Research & Development 1998, 2, 186-193 186 • Vol. 2, No. 3, 1998 / Organic Process Research & Development S1083-6160(97)00122-9 CCC: $15.00 © 1998 American Chemical Society and Royal Society of Chemistry Published on Web 04/28/1998