Journal of Natural Products
Article
solution. A white precipitate was observed during the addition. Once
the addition was complete, a solution of triethylamine (3.2 mL, 23.2
mmol) in THF (20 mL) was added dropwise at 0−10 °C. The
reaction was warmed to ambient temperature and stirred for 3 h. The
product did not precipitate from solution, as typically observed for
analogous substrates. The solvent was distilled to provide a golden
honey-like oil, which was taken up in methylene chloride and filtered
over a pad of silica (ca. 50 g). The pad was washed with 500 mL of
10% MeOH/CH2Cl2. The filtrate was concentrated to a yellow solid
(8.0 g, 99%, 98% UPLC purity): mp 172−175 °C; 1H NMR (CDCl3,
400 MHz) δ 10.16 (1H, d, J = 10.6 Hz), 7.67 (1H, d, J = 3.3 Hz),
7.41−7.25 (10H, m), 7.09 (1H, t, J = 7.9 Hz), 7.02 (1H, d, J = 8.1
Hz), 6.90 (1H, dd, J = 7.6, 0.9 Hz), 4.59 (2H, s), 4.38 (2H, s), 2.40
(3H, s); 13C NMR (CDCl3, 101 MHz) δ 185.19, 170.96, 168.70,
144.21, 139.07, 137.93, 136.11, 135.33, 128.88, 128.68, 128.34,
128.30, 127.99, 127.76, 124.75, 118.24, 115.96, 113.87, 110.83, 50.50,
min; then o-xPCl37 (1.47 g, 6.71 mmol) in dry THF (30 mL) was
added dropwise. The reaction was warmed to ambient temperature
and stirred for 30 min. TLC (2% MeOH/CHCl3) indicated complete
consumption of starting material with a large more polar product spot
and a smaller less polar spot (later revealed to be about 6%
diphosphorylated product). The reaction mixture was dumped into
ice water (100 mL) and extracted with 3 × 100 mL of CHCl3. The
extract was washed with saturated sodium bicarbonate, then dried
over sodium sulfate, filtered, and concentrated. The resulting tan solid
was purified by flash chromatography (2% MeOH/CHCl3/0.2%
NH4OH) to provide the target compound as a shiny off-white solid
1
(2.3 g, 82%): mp 135−139 °C; H NMR (400 MHz, CDCl3) δ 8.73
(1H, s), 7.39 (2H, dt, J = 7.2, 3.7 Hz), 7.29 (7H, dd, J = 5.8, 3.1 Hz),
7.11 (2H, t, J = 8.5 Hz), 7.02 (1H, t, J = 7.9 Hz), 6.85 (1H, d, J = 2.5
Hz), 5.41 (2H, t, J = 13.3 Hz), 5.25 (2H, dd, J = 19.5, 13.6 Hz), 3.58
(2H, s), 3.16 (2H, t, J = 7.8 Hz), 2.83−2.74 (2H, m), 2.27 (3H, s);
13C NMR (100 MHz, CDCl3) δ 144.22, 139.24, 138.85, 135.17,
+
46.17, 21.42.; HRMS (ESI) calcd for C26H23N2O4 427.1653 [M +
H]+, found 427.1677.
129.30, 129.08, 129.07, 128.19, 126.89, 122.59, 121.93, 118.76,
113.07, 108.85, 108.63, 68.96, 62.19, 59.07, 42.08, 24.78; HRMS
(ESI) calcd for C26H28N2O4P+ 463.1781 [M + H]+, found 463.1784.
3-((3-(2-(Dibenzylamino)ethyl)-1H-indol-4-yl)oxy)-1,5-
dihydrobenzo[e][1,3,2]dioxaphosphepine 3-Oxide (19). To a
solution of 17 (2.2 g, 6.2 mmol) in anhydrous THF (50 mL)
under Ar at −78 °C was added a BuLi solution (2.5 M in THF, 2.4
mL, 6.0 mmol) dropwise. The blue-gray solution stirred for 15 min at
−78 °C then warmed to −30 to −40 °C. A solution of o-xPCl37 (1.62
g, 7.41 mmol) in THF (25 mL) was added dropwise by syringe pump
over 1 h while maintaining a reaction temperature of about −35 °C.
The reaction was warmed to 0 °C and quenched by the addition of
aminopropyl silica gel (5 g). The suspension was filtered and washed
with EtOAc (∼100 mL). The resulting tan filtrate was concentrated to
an off-white solid, which was purified by flash chromatography (2%
MeOH/CHCl3/0.2% NH4OH) to provide the target compound as a
tan solid (2.7 g, 81%): mp 152−155 °C; 1H NMR (400 MHz,
CDCl3) δ 8.53 (1H, s), 7.44−7.31 (7H, m), 7.31−7.16 (8H, m), 7.06
(2H, t, J = 8.4 Hz), 7.02−6.95 (1H, m), 6.66 (1H, s), 5.31 (2H, t, J =
13.3 Hz), 5.18 (2H, dd, J = 19.7, 13.6 Hz), 3.67 (4H, s), 3.17 (2H, t, J
= 7.6 Hz), 2.84 (2H, t, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ
(ppm) 144.18, 140.07, 138.76, 135.14, 129.30, 129.05, 128.72,
128.16, 126.71, 122.43, 121.81, 118.81, 113.09, 108.82, 108.59, 77.42,
77.10, 76.78, 68.87, 58.17, 54.64, 24.64; HRMS (ESI) calcd for
C32H32N2O4P+ 539.2094 [M + H]+, found 539.2091.
3-(2-(Benzyl(methyl)amino)ethyl)-1H-indol-4-ol (16). To a sol-
ution of 14 (6.0 g, 17 mmol) in 2-MeTHF (160 mL) was added LAH
(13 mL, 4 M in Et2O) at 0 °C dropwise. The yellow mixture was
heated at reflux (∼78 °C) under nitrogen for 3 h. The reaction was
monitored by LCMS periodically: at 1 h, LCMS analysis revealed a
1:3 mix of a β-hydroxy intermediate (m/z 297.1604) and product (no
other significant peaks were present); at 2 h, no additional change was
observed, so an additional 1 equiv of LAH (4.3 mL) was added. The
reaction was left to stir overnight. The reaction was analyzed after
refluxing for a total of 17 h and was found to still contain about 9% of
the hydroxy intermediate. The reaction was cooled to 5 °C, and
Glauber’s salt (Na2SO4·10H2O) was added in portions; the
temperature was not allowed to rise above 15 °C. The suspension
was left to stir for 1 h, then filtered to give an initially clear filtrate that
quickly turned purple-brown. The filtrate was passed through a plug
of silica (ca. 40 g) and washed with 10% MeOH/dichloromethane
(DCM) (400 mL). The resulting tan filtrate was concentrated to a
brown oil that became a foam under high vacuum and ultimately
solidified (4.1 g, 85%): mp 51−53 °C; 1H NMR (400 MHz, CDCl3)
δ 8.07 (1H, d, J = 9.2 Hz), 7.33 (2H, dq, J = 5.4, 3.0 Hz), 7.29 (3H,
dd, J = 5.1, 2.2 Hz), 7.11 (1H, t, J = 7.9 Hz), 6.89 (1H, d, J = 8.1 Hz),
6.79 (1H, d, J = 2.3 Hz), 6.69 (1H, d, J = 7.6 Hz), 3.68 (2H, s), 3.01−
2.94 (2H, m), 2.83−2.76 (2H, m), 2.37 (3H, s); 13C NMR (100
MHz, CDCl3) δ (ppm) 151.70, 138.96, 135.41, 130.27, 128.35,
127.75, 123.42, 121.01, 117.87, 114.32, 106.50, 102.94, 62.82, 59.20,
42.19, 25.01; HRMS (ESI) calcd for C18H21N2O+ 281.1649 [M +
H]+, found 281.1651.
3-(2-(Dibenzylamino)ethyl)-1H-indol-4-ol (17). To a solution of
15 (3.65 g, 8.54 mmol) in 2-MeTHF (100 mL) was added LAH (8.54
mL, 34.15 mmol, 4 M in Et2O) at 0 °C dropwise. The yellow mixture
was heated at reflux (∼78 °C) under nitrogen for 6 h. The reaction
stalled containing about 9% of the hydroxy intermediate evidenced by
LCMS. The reaction was cooled to 5 °C, and Glauber’s salt (Na2SO4·
10H2O) was added in portions; the temperature was not allowed to
rise above 15 °C. The suspension was left to stir for 1 h, then filtered
to give an initially clear filtrate, which darkened quickly. The filtrate
was passed through a plug of silica (ca. 40 g) and washed with 20%
MeOH/DCM (200 mL). The resulting filtrate was concentrated to a
brown oil that became a foam under high vacuum and ultimately
solidified to an off-white solid (2.7 g, 88%): mp 52−55 °C; 1H NMR
(400 MHz, CDCl3) δ 7.82 (1H, s), 7.37 (5H, dd, J = 7.5, 1.9 Hz),
7.32−7.21 (6H, m), 7.10 (1H, t, J = 7.8 Hz), 6.88 (1H, d, J = 8.0 Hz),
6.75 (1H, d, J = 2.3 Hz), 6.69 (1H, d, J = 7.6 Hz), 3.77 (4H, s), 2.92−
2.81 (4H, m); 13C NMR (100 MHz, CDCl3) δ 151.41, 138.74,
135.82, 130.41, 128.29, 127.54, 123.41, 120.57, 117.88, 114.52,
106.46, 102.98, 59.35, 55.00, 25.20; HRMS (ESI) calcd for
C24H25N2O+ 357.1962 [M + H]+, found 357.1966.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
■
sı
1H and 13C NMR spectra for all final products and
intermediates; UPLC chromatograms and low/high
collision energy HRMS spectra for 4−7 (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Alexander M. Sherwood − Usona Institute, Madison, Wisconsin
Authors
Adam L. Halberstadt − Department of Psychiatry, University of
California San Diego, La Jolla, California 92093, United
States; Research Service, VA San Diego Healthcare System, San
Diego, California 92161, United States
Adam K. Klein − Department of Psychiatry, University of
California San Diego, La Jolla, California 92093, United States
John D. McCorvy − Department of Cell Biology, Neurobiology,
and Anatomy, Medical College of Wisconsin, Milwaukee,
Wisconsin 53226, United States
3-((3-(2-(Benzyl(methyl)amino)ethyl)-1H-indol-4-yl)oxy)-1,5-
dihydrobenzo[e][1,3,2]dioxaphosphepine 3-Oxide (18). To a
suspension of NaH (60%, 268 mg, 6.71 mmol) in dry THF (15
mL) at 0 °C under Ar was added 16 (1.71 g, 6.10 mmol) in dry THF
(20 mL). The robin’s egg blue suspension was stirred at 0 °C for 15
F
J. Nat. Prod. XXXX, XXX, XXX−XXX