Novel Stereoselective Syntheses of the Fused Benzazepine Dopamine D₁ Antagonist (6aS,13bR)-11-Chloro-6,6a,7,8,9,13b-hexahydro-7-methyl- 5H-benzo[d]naphth[2,1-b]azepin-12-ol (Sch 39166):  2. l-Homophenylalanine-Based Syntheses

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-homophenylalanine (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-dimethoxyethyl)-1,2,3,4-tetrahydro-N-methyl-2-naphthalenamine (2), a key intermediate in the previouslydescribed 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 1nter, 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-butanone (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-naphthalenyl]carbamate (16), which is reduced and alkylated as before to produce 2.

Proline Ester Enolate Claisen Rearrangement and Formal Total Synthesis of (−)-Cephalotaxine

“…The reaction was stirred at room temperature for 15 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH/AcOH, 90:10:2) to give compound 14 (904 mg, 3.6 mmol, 74% for two steps) as a white solid. mp 92 °C; [α] D 20 = +183.8 (c 1.0, MeOH); 1 H NMR (500 MHz, CD 3 OD) δ 7.44 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H), 4.41 (d, J = 12.9 Hz, 1H), 4.22 (d, J = 12.9 Hz, 1H), 4.00 (t, J = 8.1 Hz, 1H), 3.80 (s, 3H), 3.52 (m, 1H), 3.23 (m, 1H), 2.47 (m, 1H), 2.11 (m, 2H), 1.95 (m, 1H); 13 (R,E)-4-(6-(2-(Trityloxy)ethyl)benzo [d][1,3]dioxol-5-yl)but-3-en-2-yl (4-Methoxybenzyl)-L-prolinate (15). To a solution of N-PMB proline (14, 2 equiv, 393 mg, 1.7 mmol) in CH 2 Cl 2 (8 mL) were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2 equiv, 321 mg, 1.7 mmol) and 4-(dimethylamino)pyridine (0.3 equiv, 31 mg, 0.25 mmol) at room temperature.…”

“…Direct one-pot reduction of the resulting Friedel− Crafts adduct with borane tert-butylamine complex provided tricyclic compound 22. 15 The formation of the cyclopentene ring of I was achieved using an ester group and olefin moiety. To this end, methyl Treatment of amino alcohol 19 with methanesulfonyl chloride provided the aziridinium 24 very quickly even at low temperatures.…”

Optimization Strategy of Novel Peptide-Based Michael Acceptors for the Treatment of Human African Trypanosomiasis

“…1 H NMR and 13 C NMR chemical shifts (δ) are expressed in ppm, and coupling constants ( J ) are given in Hz. Compounds 5a – m , ,− 6a – d , 6f – j , ,,− and 10 were synthesized according to standard procedures and spectroscopic data are in agreement to those reported in literature.…”

“…Synthesis of terminal olefin 11 was carried out following the procedure described for compound 8a , using 10 as acid. Yield: 79%; R f = 0.41 (light petroleum/EtOAc, 9:1); consistency: white powder.…”

Novel Stereoselective Syntheses of the Fused Benzazepine Dopamine D1 Antagonist (6aS,13bR)-11-Chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H- benzo[d]naphth[2,1-b]azepin-12-ol (Sch 39166): 1. Aziridinium Salt Based Syntheses

“…In principle, the aziridinium cation 20 could also be produced from the regioisomeric tertiary amino alcohol 24 . A hybrid route was developed for its synthesis which starts from the known ketocarbamate 34 (Scheme ), which was prepared from (+)- l -homophenylalanine following the procedure of McClure et al. , Reduction of 34 with LiAlH 4 afforded primarily the trans amino alcohol 35 in 84% yield ( trans : cis ratio >39:1). Alkylation with bromoacetaldehyde dimethyl acetal then produced 24 in 84% yield.…”