The Journal of Organic Chemistry
Article
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(minor) = 41.2 min; [α]D = −13.6 (c = 1.0, CHCl3); H NMR
(CDCl3) δ 4.25−4.4 (broad, 1H); 13C NMR (CDCl3) δ 149.6, 145.1,
144.2, 142.8, 142.5, 141.6, 133.6, 131.8, 129.4, 128.3, 125.4, 124.9,
124.5, 124.1, 122.4, 121.9, 115.5, 114.2, 112.2, 96.1, 77.2, 68.6, 64.6,
56.3, 55.6, 50.2, 46.1, 43.8, 30.1, 25.6, 25.2, 18.3, −4.77. HRMS (FD,
TOF) m/z: [M]+ calcd. for C31H40N2O7SSi, 612.2326; found,
612.2288.
General Procedure E: Deprotection with HCl; Removal of
the Nps Substituent. Protected tetrahydroisoquinoline (0.10−0.19
mmol) was dissolved in a mixture of dichloromethane (1.5 mL) and
ethanol (1.5 mL) at 0 °C. Concentrated HCl (0.15 mL) was added,
and after stirring at 0 °C for 1 h, the reaction mixture was diluted with
water (ca. 5 mL), and the water layer was extracted three times with
dichloromethane. Each dichloromethane extract was extracted back
with dilute HCl solution. The aqueous phase was evaporated, leaving
the tetrahydroisoquinoline as its hydrochloride, which was sufficiently
pure for analysis.
Isolation of the Free Base by Chromatography. The acidic
reaction mixture was diluted with dichloromethane, directly absorbed
on silica (ca. 3 g), evaporated, and applied to a silica column packed
with ethyl acetate. Elution with ethyl acetate removed Nps residues;
elution with EtOAc/methanol/conc NH4OH 93/5/2 and stepwise
increasing to 82/15/3 gave the free amine.
General procedure F: Deprotection with HCl; Simultaneous
Removal of the Nps, TBS, and MOM Substituents. Procedure E
was used, but the reaction was stirred at rt for 24 h. Note that the use
of more conc HCl gave a two-layer system and resulted in partial
hydrolysis of methoxy to hydroxy.
General Procedure G: N-Methylation. Unprotected 1,2,3,4-
tetrahydroisoquinoline (free base or hydrochloride, 0.1−0.15 mmol)
was stirred with paraformaldehyde (38 mg), zinc chloride (35 mg),
NaOAc (32 mg, only when hydrochlorides were used), and sodium
cyanoborohydride (33 mg) in methanol (5 mL) for 24 h at rt. The
reaction mixture was absorbed on silica and purified by chromatog-
raphy as described in general procedure E.
18c: Prepared from Amine 7 and Aldehyde 14c. Yellow glass
(77.5 mg, 0.143 mmol, 72%), 92% ee; tR (major) = 27.0 min, tR
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(minor) = 40.9 min; [α]D = −3.5 (c = 1.0, CHCl3); 1H NMR
1
(CDCl3) δ 4.25−4.5 (br, 1H); H NMR (500 MHz, toluene-d8, 90
°C) δ 7.95 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.05 (m, 1H),
6.70 (m, 2H), 6.56 (s, 1H), 6.27 (m, 2H), 5.87 (bs, 1H), 4.75 (m,
2H), 4.35 (m, 1H), 3.80 (s, 3H), 3.46 (m, 6H), 3.36 (m, 1H), 3.17 (m,
3H), 3.05 (m, 1H), 2.98 (m, 2H), 2.82 (bs, 1H), 2.42 (dt, J = 14.6, 4.3
Hz, 1H); 13C NMR (126 MHz, toluene-d8, 90 °C) δ 153.7, 146.0,
143.1, 138.6, 133.0, 125.4, 125.3, 124.4, 123.9, 115.5, 115.1, 108.3,
96.4, 60.0, 55.8, 55.4. HRMS (FD, TOF) m/z: [M]+ calcd. for
C27H30N2O8S, 542.1723; found, 542.1743.
19a: Prepared from Amine 6 and Aldehyde 14a. Yellow glass
(89.1 mg, 0.161 mmol, 81%), 86% ee; tR (major) = 25.7 min, tR
(minor) = 23.6 min (determined after O-methylation); [α]D20 = −15.8
(c = 1.0, CHCl3); H NMR (CDCl3) δ 4.25−4.40 (broad, 1H); 13C
1
NMR (CDCl3) δ 154.2, 144.7, 144.4, 144.2, 142.5, 141.7, 133.6, 131.8,
131.1, 130.4, 129.0, 126.8, 126.3, 126.2, 125.5, 124.8, 124.5, 124.1,
119.8, 119.7, 114.6, 114.1, 109.8, 109.5, 68.8, 65.4, 55.8, 50.0, 46.5,
43.9, 41.9, 30.0, 25.6, 25.5, 25.4, 18.1, −4.46. HRMS (FD, TOF) m/z:
[M]+ calcd. for C29H36N2O5SSi, 552.2114; found, 552.2156.
(R)-(+)-Norcoclaurine·HCl and (R)-(+)-Higenamine·HCl (20).
Obtained from 18a (40.0 mg, 0.069 mmol) as hydrochloride following
general procedure F (17.9 mg, 0.0583 mmol, 84%) after
recrystallization from methanol/ether; 89% ee. HPLC: obtained
19b: Prepared from Amine 6 and Aldehyde 14b. Yellow glass
(92.0 mg, 0.157 mmol, 79%), 86% ee; tR (major) = 33.2 min, tR
(minor) = 37.2; [α]D20 = −18.6 (c = 1.0, CHCl3); 1H NMR (toluene-
d8, 90 °C) δ 7.94 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.08−
6.90 (toluene +1H), 6.72−6.62 (m, 4H), 6.54 (s, 2H), 6.12 (s, 1H),
5.29 (s, 2H), 4.26 (dd, J = 6.6, 6.6 Hz, 1H), 3.47 (s, 3H), 3.32 (s, 3H),
3.06−2.89 (m, 2H), 2.83−2.66 (m, 1H), 2.36 (dt, J = 16.1, 4.8 Hz,
1H), 0.98 (s, 9H), 0.10 (s, 6H); 13C NMR (toluene-d8, 90 °C) δ
149.8, 145.3, 145.0, 144.8, 144.3, 142.7, 132.6, 131.7, 125.2, 124.9,
124.5, 123.59, 122.6, 122.3, 119.7, 114.7, 112.8, 109.9, 67.1, 55.2, 55.2,
48.6, 43.0, 29.5, 25.3, 17.98, −5.05. HRMS (FD, TOF) m/z: [M]+
calcd. for C30H38N2O6SSi, 582.2220; found, 582.2273.
19c: Prepared from Amine 6 and Aldehyde 14c. Yellow glass
(82.0 mg, 0.0161 mmol, 80%), 89% ee; Chiralcel AD, n-heptane/i-
propanol (v/v = 80/20) as eluent, flow 0.5 mL/min, tR (major) = 27.9
min, tR (minor) = 32.0 min; [α]D20 = −4.0 (c = 0.6, CHCl3); 1H NMR
(500 MHz, toluene-d8, 90 °C) δ 7.97 (dd, J = 8.7, J = 1.3 Hz, 1H),
7.58 (m, 1H), 7.1 (m, 1H), 6.70 (m, 1H), 6.69 (s, 1H), 6.29 (s, 2H),
6.13 (s, 1H), 5.42 (bs, 1H), 4.35 (dd, J = 6.9, 6.8 Hz, 1H), 3.80 (s,
3H), 3.46 (s, 6H), 3.33 (s, 3H), 2.7−3.5 (m, sH), 2.41 (dt, J = 16.2,
4.8 Hz, 1H); 13C NMR (toluene-d8, 90 °C) δ 154.5, 146.0, 133.6,
126.1, 125.6, 124.7, 115.5, 110.8, 109.3, 60.7, 56.6, 56.0. HRMS (FD,
TOF) m/z: [M]+ calcd. for C26H28N2O7S, 512.1617; found, 512.1607.
19d: Prepared from Amine 6 and Aldehyde 14d. Yellow glass
(80.0 mg, 0.166 mmol, 83%), 88% ee; HPLC, Chiralcel AD, n-
heptane/i-propanol (v/v = 70/30) as eluent, flow 0.4 mL/min, tR
(major) = 49.9 min, tR (minor) = 34.8 min (determined after O-
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from 21 (after O-methylation); [α]D = +23.4 (c = 1.0, MeOH),
lit.29 +25.0 (c = 1.0, MeOH); mp 272−277 °C (methanol/ether); H
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NMR (D2O) δ 7.06 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 8.2 Hz, 2H), 6.63
(s, 1H), 6.57 (s, 1H), 4.45−4.55 (m, 1H), 3.35−3.40 (m, 1H), 3.25−
3.33 (m, 1H), 3.13−3.23 (m, 1H), 2.76−2.92 (m, 3H); 13C NMR
(D2O) δ 154.8, 143.9, 142.7, 130.8, 126.6, 123.6, 123.1, 115.8, 115.6,
113.6, 56.1, 39.1, 38.2, 23.9.
(R)-(+)-Coclaurine·HCl (21). Obtained as hydrochloride by O-
methylation (general procedure D) from 18a (0.125 mmol), followed
by deprotection (method F) (28.7 mg, 0.092 mmol, 71%). HPLC:
89% ee, Chiralcel AD, n-heptane/i-propanol/diethylamine (v/v = 70/
30/0.1) as eluent, flow 0.5 mL/min, tR (major) = 30.2 min, tR (minor)
= 24.4 min; [α]D = +13.7 (c = 1.0, MeOH), (lit.30 +15 (c = 1.2,
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MeOH); mp 262−266 °C (methanol/ether), (lit.30 261−263 °C); 1H
NMR (CD3OD) δ 7.17 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H),
6.79 (s, 1H), 6.67 (s, 1H), 4.61−4.64 (m, 1H), 3.86 (s, 3H), 3.50−
3.55 (m, 1H), 3.25−3.45 (m, 2H), 3.13−3.23 (m, 1H), 2.90−3.2 (m,
3H); 13C NMR (CD3OD) δ 156.7, 147.7, 145.2, 130.2, 125.50, 123.53,
122.22, 115.44, 112.64, 111.11, 56.3, 54.9, 39.4, 38.9, 24.4.
(R)-(+)-Norreticuline (22). Obtained as free base by O-methylation
(general procedure D) from 18b (0.123 mmol), followed by
deprotection (method F) (32.5 mg, 0.925 mmol, 75%); mp 115−
120 °C; 89% ee, HPLC (determined for 23 after N-methylation);
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[α]D = +23.0 (c = 1.0, MeOH); H NMR (CD3OD) δ 6.89 (d, J =
8.2 Hz, 1H), 6.68−6.76 (m, 3H), 4.13 (dd, J = 9.4, 4.4 Hz, 1H), 3.84
(s, 3H), 3.83 (s, 3H), 3.2−3.25 (m, 1H), 3.13 (dd, J = 14.0, 4.5 Hz,
1H), 2.7−2.85 (m, H); 13C NMR (CD3OD) δ 146.6, 146.6, 146.4,
144.4, 130.4, 128.4, 124.7, 120.1, 115.76, 112.6, 111.5, 111.3, 56.3,
54.9, 54.8, 40.5, 39.8, 27.3.
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methylation); [α]D = −13.8 (c = 1.0, CHCl3); H NMR (CDCl3) δ
4.25−4.50 (broad, 1H); 13C NMR (CDCl3) δ 147.6, 144.4, 133.7,
133.4, 131.7, 128.8, 126.3, 126.1, 125.4, 124.7, 124.5, 124.2, 122.3,
121.5, 114.7, 114.1, 113.3, 112.4, 111.2, 110.9, 109.9, 109.4, 68.7, 65.2,
60.3, 55.9, 55.7, 50.0, 46.4, 44.1, 42.1, 29.9, 25.3, 14.1. HRMS (FD,
+
TOF) m/z [M + H] calcd for C25H26N2O6S, 482.1512; found,
(R)-(−)-Reticuline (23). Obtained from 22 (0.103 mmol) via
procedure G: glass (32.5 mg, 0.099 mmol, 96%), ee 87%. HPLC:
Chiralcel AD, n-heptane/i-propanol/diethylamine (v/v = 70/30/0.1)
as eluent, flow 0.5 mL/min, tR (major) = 23.1, min, tR (minor) = 28.7
min; [α]D20 = −60 (c = 1.0, CHCl3); 1H NMR (CDCl3) δ 6.76 (d, J =
1.9 Hz, 1H), 6.73 (d, J = 8.15 Hz, 1H), 6.58 (dd, J = 8.15, 1.9 Hz, 1H),
6.55 (s, 1H), 6.37 (s, 1H), 5.2−6.0 (bs, 2H), 3.855 (s, 3H), 3.85 (s,
3H), 3.70 (dd, J = 6.1, 6.1 Hz, 1H), 3.16−3.23 (m, 1H), 3.05 (dd, J =
14.1, 6.1 Hz, 1H), 2.75−2.88 (m, 3H), 2.58−2.63 (m, 1H), 2.47 (s,
482.1452.
General Procedure D: O-Methylation of the Pictet−Spengler
Products 18a, 18b, 19a, 19c and 19d. The 6-OH Pictet−Spengler
product (0.1−0.19 mmol) was stirred in a stoppered flask with K2CO3
(0.15g) and methyl iodide (40 μL) in anhydrous acetonitrile (3 mL)
for 18 h at 80 °C. Aqueous workup (ethyl acetate) gave the methylated
products in nearly quantitative yield, and they were directly
deprotected according to procedure E or F.
F
J. Org. Chem. XXXX, XXX, XXX−XXX