(−)-Caseamine from Ceratocapnos heterocarpa: Structure and total synthesis

Total Synthesis of the Ortho-Hydroxylated Protoberberines (S)-Govaniadine, (S)-Caseamine, and (S)-Clarkeanidine via a Solvent-Directed Pictet–Spengler Reaction

“…When a free phenolic OH is the activator, the para product ( 28 ) is always formed in excess, but is accompanied by some ortho product. − Application of the solvent-directed Pictet–Spengler process (see Scheme ) to the tetrahydroprotoberberine synthesis with norcrassifoline and formaldehyde selectively produced both isomers under mild conditions (Scheme ). The para isomer ( S )-caseamine 24 was obtained by reaction of 23 with formaline in trifluoroethanol [64%, o/p = 14:86, >99% ee after recrystallization, [α] D 20 −314 (lit . [α] D 20 −328)].…”

“…Norcrassifoline ( 23 ) was also used as the synthetic precursor for the related protoberberines caseamine ( 24 18 ), displaying activity against urease, 11 and clarkeanidine ( 25 19 ). Biosynthetically, the ring closure of 1-benzyltetrahydroisoquinolines to tetrahydroprotoberberines does not proceed with formaldehyde but via the berberine bridging enzyme (BBE) catalyzed oxidation of N -methylated benzyltetrahydroisoquinolines, immediately followed by ring closure of the intermediate methylene iminium salt (Scheme 5).…”

“…The para isomer ( S )-caseamine 24 was obtained by reaction of 23 with formaline in trifluoroethanol [64%, o/p = 14:86, >99% ee after recrystallization, [α] D 20 −314 (lit. 18 [α] D 20 −328)]. Starting from 23 under aprotic conditions using paraformaldehyde in toluene, the ortho isomer ( S )-clarkeanide 25 was formed [55%, o/p = 86:14, 95% ee after crystallization, [α] D 20 −442 (lit.…”

“…Caseamine 24 (18) ee 99% (Chiralcel AD column, eluent n -heptane/2-propanol 70:30, flow 1.000 mL/min): [α] D 20 −314 (CHCl 3 + MeOH, c = 0.15) [lit. 18 [α] D –328 ( c = 0.04, CHCl 3 )]; mp 246–250 °C (lit. 18 mp 246–247 °C); 1 H NMR (300 MHz, d 6 -DMSO, partial overlap by solvent peaks) δ 8.64 (s, 1H), 8.54 (s, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.62 (s, 1H), 6.55 (d, J = 8.2 Hz, 1H), 6.46 (s, 1H), 3.80 (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.46–3.36 (m, 1H), 2.96 (dt, J = 10.4, 4.8 Hz, 1H), 2.83 (dt, J = 13.2, 5.6 Hz, 1H), 2.67 (dt, J = 15.8, 4.7 Hz, 1H), 2.40 (dd, J = 16.1, 11.3 Hz, 1H); 13 C{ 1 H} NMR (75 MHz, d 6 -DMSO) δ 145.8, 145.2, 144.6, 142.8, 127.8, 127.0, 125.6, 124.7, 118.7, 115.2, 110.0, 109.8, 57.0, 56.0, 55.7, 55.6, 47.9, 31.4, 29.3; HRMS (FD + ) m / z calcd for C 19 H 21 NO 4 (M + ) 327.1471, found 327.1499.…”

“…Chromatography (ethyl acetate and ethyl acetate/MeOH 97/3 gave additional caseamine (4.5 mg, total yield 0.080 mmol, 64%) and clarkeanidine 25 (4.4 mg, 0.013 mmol, 10%, spectra see next experiment). Caseamine 24 ee 99% (Chiralcel AD column, eluent n -heptane/2-propanol 70:30, flow 1.000 mL/min): [α] D 20 −314 (CHCl 3 + MeOH, c = 0.15) [lit . [α] D –328 ( c = 0.04, CHCl 3 )]; mp 246–250 °C (lit .…”