Pictet-Spengler Cyclization of 3,3-Diphenylalanine (DIP) (III), Synthesis of Optically Pure 1,2,3,4-Tetrahydro-4-phenyl-3-isoquinolinecarboxylic Acids, Novel α-Amino Acids for Peptides of Biological Interest

Synthesis and Pharmacological Characterization of 2-(2,6-Dichlorophenyl)-1-((1S,3R)-5-(3-hydroxy-3-methylbutyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (LY3154207), a Potent, Subtype Selective, and Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor

“…Synthesis of this intermediate started with ( R )-2-bromophenylalanine ( 4 ), which is commercially available in bulk (Scheme ). Functional group manipulations of the free amino acid resulted in the fully protected 5 , and the THIQ ring was subsequently formed through a Pictet–Spengler reaction . After exhaustive deprotection and reduction, amino alcohol 6 was protected to afford imine 7 after N -chlorination and base-mediated dehydrohalogenation .…”

“…Functional group manipulations of the free amino acid resulted in the fully protected 5, and the THIQ ring was subsequently formed through a Pictet−Spengler reaction. 60 After exhaustive deprotection and reduction, amino alcohol 6 was protected to afford imine 7 after N-chlorination and base-mediated dehydrohalogenation. 61 Finally, addition of MeMgCl in Et 2 O to this imine delivered 8 in trans diastereoselectivity (>9:1 dr).…”

Development of a Scalable Synthesis of Mevidalen (LY3154207), an Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor

“…Synthesis of 17 began with ( R )-2-bromophenylalanine ( 1 ). Esterification followed by methyl carbamate formation afforded the fully protected 8 , and the THIQ ring was subsequently formed through a Pictet–Spengler reaction (Scheme ). Over several steps, 9 was converted to imine 16 after N -chlorination and base-mediated dehydrohalogenation .…”

“…1 H NMR (mixture of rotamers, 400 MHz, DMSO-d 6 ) δ 12.40 (br, 1H),10.21 (br, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 8.4 Hz, 1H), 7.16−7.01 (m, 3H), 6.82 (d, J = 8.8 Hz, 2H), 5.21 (q, J = 6.4 Hz, 0.3H), 5.03 (q, J = 6.4 Hz, 0.7H),4.96 (br, 0.7H), 4.65 (brt, J = 4.8 Hz, 0.3H), 4.62−4.36 (brm, 1H), 4.29−4.21 (m, 2.7H), 4.10 (d, J = 16.8 Hz, 0.3H), 3.40−3.25 (brm, 3.3H), 2.97 (dd, J = 4.4, 15.6 Hz, 0.7H), 2.89−2.83 (m, 1H), 2.75−2.60 (m, 1.7H), 2.45−2.38 (m, 0.3H), 1.66−1.54 (m, 2H), 1.49 (d, J = 6.8 Hz, 0.9H), 1.23 (d, J = 6.4 Hz, 2.1H), 1.18 (s, 0.7H), 1.17 (s, 0.7H), 1.16 (s, 0.3H), 1.16 (s, 0.3H); 13 C NMR (mixture of rotamers, 100 MHz, DMSO-d 6 ) δ 167.3, 167.2, 167.0, 161.6, 141.5, 141.1, 139.3, 139.1, 135.6, 135.5, 133.6, 133.2, 131.5, 131.2, 130.7, 129.2, 129.1, 128.0, 127.9, 127.5, 126.5, 126.4, 123.9, 123.8, 121.4, 115.1, 68.8, 62.3, 59.1, 54.0, 52.8, 52.5, 51.2, 45.04, 44.97, 36.8, 36.5, 29.4, 29.3, 29.14, 29.06, 27.5, 27.4, 25.3, 25.1, 23.4, 23.3; IR (ATR, cm −1 ) 3409, 3254, 2977, 1682, 1627, 1607, 1590; DSC onset = 162.5 °C, max = 165.6 °C; LCMS (ESI, M + H + ) 450.2, 452.2.…”

Asymmetric syntheses of pipecolic acid and derivatives

“…Many pipecolic acid derivatives (Kemp and Sun, 1982), especially those bear-I~COOH H 1 Fig. 1 ing the tetrahydroisoquinoline skeleton (Chen and Goel, 1995;Kazmiersky and Hruby, 1988) have been developed for this purpose and some of these compounds will be presented thereafter.…”