Access to 6a-Alkyl Aporphines: Synthesis of (±)-N-Methylguattescidine

Article abstract of DOI:10.1021/acs.joc.6b02024

(-)-N-Methylguattescidine (3) is an alkaloid recently isolated from Fissistigma latifolium and assigned as a rare example of a 6a-alkyl aporphine. Herein, we report the synthesis of (±)-3 and the des-hydroxyl derivative 4 using our previously reported ortho-phenol arylation methodology mediated by the XPhos precatalyst as a key synthetic step. In addition, substituents on the aryl halide portion of the ortho-phenol arylation substrates significantly influenced the formation of an oxidized side product.

Full text of DOI:10.1021/acs.joc.6b02024

Note
pubs.acs.org/joc
Access to 6a-Alkyl Aporphines: Synthesis of
( )‑N‑Methylguattescidine
Angela F. Ku† and Gregory D. Cuny*,‡
‡
†Department of Chemistry and Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Science and
Research Building 2, Houston, Texas 77204, United States
S
* Supporting Information
ABSTRACT: (−)-N-Methylguattescidine (3) is an alkaloid recently isolated from Fissistigma latifolium and assigned as a rare
example of a 6a-alkyl aporphine. Herein, we report the synthesis of ( )-3 and the des-hydroxyl derivative 4 using our previously
reported ortho-phenol arylation methodology mediated by the XPhos precatalyst as a key synthetic step. In addition, substituents
on the aryl halide portion of the ortho-phenol arylation substrates significantly influenced the formation of an oxidized side
product.
ether arylations only occurred with syn-isomers.7 Herein, we
porphine alkaloids are natural products possessing a
A1,2,3,4-tetrahydroisoquinoline tetracyclic ring system. report the expansion of this methodology to the syntheses of
( )-3 and des-hydroxyl derivative 4 via anti-isomer 6 using the
strategy outlined in Figure 2.
Various aporphine alkaloids have been identified from natural
sources,1 with many of these compounds displaying interesting
biological properties, such as antimicrobial,2a anticancer,2b,c and
central nervous system (CNS) related activities.2d−f However,
aporphines with a substituent at the 6a-position have rarely
been reported (Figure 1). In two cases, the 6a-alkyl aporphines,
i.e., guattescine (1a) and guattescidine (2a),3 were subse-
quently revised to non-6a-alkyl structures 1b and 2b,
respectively.4 Recently, the aporphine (−)-N-methylguattesci-
dine (3) was isolated from the bark of the shrub Fissistigma
latifolium (Annonaceae) and assigned with a methyl at the 6a-
position.5 In addition, this compound was predicted by
molecular docking simulation to be a human DEK oncoprotein
ligand,6 suggesting potential anticancer activity. Therefore, we
set out to establish a synthetic methodology to provide access
to 6a-alkyl aporphines in order to confirm the structure of 3
and to generate other 6a-alkyl aporphines for pharmacological
evaluation.
Our laboratory previously reported syntheses of several 7-
hydroxyaporphine alkaloids characterized with an anti-config-
uration between protons 6a and 7, such as (−)-oliveroline and
(−)-noroliveroline, from enantiopure mandelic acids.7 With a
designated stereocenter at C-7, a diastereoselective one-pot
cyclization favoring anti-isomers, followed by an ortho-phenol
arylation mediated with the XPhos precatalyst, resulted in
enantiopure intermediates that were readily converted to a
series of aporphines. We also found that ortho-phenol arylations
were feasible with both syn- and anti-isomers, whereas ortho-
The feasibility of the strategy was first examined by targeting
des-hydroxyl derivative 4. As illustrated in Scheme 1, the
synthesis commenced with Grignard addition of methyl
magnesium chloride to N-acylcarbamate 7, which was prepared
from 2-bromomandelic acid.7 In this reaction, the methyl group
was selectively introduced to the more electron deficient amide
at −30 °C.8 Furthermore, addition occurred to the less
sterically hindered face, furnishing diastereomer 8 in 80% yield
as the only product. The relative configuration was confirmed
based on strong correlations in the 2D-NOESY spectra
between the proton on the carbon atom in the cyclic carbamate
and the adjacent methyl group. Acid-mediated cyclization of 8
in the presence of the Lewis acid BF3·OEt2 generated only the
anti-isomer 9 in 99% isolated yield. The diastereoselectivity
observed with this substrate may be enhanced due to allylic
strain between the methyl and the N-phenethyl groups in the
iminium intermediate since lower diastereoselectivity (dr
87:13) was obtained for a similar substrate that had a proton
in place of the methyl.7 Treatment of 9 with 10 mol % XPhos
precatalyst in the presence of Cs2CO3 at 110 °C for 40 min
furnished intermediate 6 in 77% yield. The predicted anti-
configuration of the methyl group at C-6a and the proton at C-
7 in 6 (atoms C-9 and C-10, respectively, in Figure S1) was
Received: August 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b02024
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Note
Figure 1. (a) Structure revisions of guattescine and guattescidine.4 (b) Reported structure of (−)-N-methylguattescidine (3)5 with ring system atoms
numbered.
Figure 2. Retrosynthetic analysis of 4.
Scheme 1. Synthesis of Des-hydroxyl Derivative 4
confirmed by X-ray crystallography. Following demethylation
of 6 with BBr3 and treatment of 10 with CH2Br2,
oxazoloaporphine 11 was formed in 85% yield over two
steps. Reduction of 11 with DIBAL-H gave N-methyl 7-
hydroxyaporphine 5 in 65% yield. Finally, the desired product 4
was obtained in 88% yield by oxidation of 5 with Dess−Martin
periodinane (DMP).
Scheme 2, the α-hydroxyketone 14a was prepared using an
irregular Wittig reaction.9 (1-Methoxyethyl)triphenylphos-
phonium ylide was generated in situ from Wittig salt 129,10
and n-BuLi at −40 °C. Then, addition of this ylide to
benzaldehyde 13a11 at −78 °C, followed by quenching at −78
°C with saturated aqueous NH4Cl, afforded 14a in 82% yield.
Coupling 14a with isocyanate 15 furnished 16a, as a mixture of
diastereomers (dr 1:1), in 90% yield. This mixture was then
treated with BF3·OEt2 at −78 °C to induce cyclization, followed
In order to prepare ( )-3, a slightly different strategy was
used in the initial stage of the synthesis. As illustrated in
B
DOI: 10.1021/acs.joc.6b02024
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Note
Scheme 2. Synthesis of 6a-Methyl Aporphines 18a and 18b
by silyl deprotection with TBAF, which gave anti-isomer 17a in
80% yield. Intermediate 17a was then subjected to ortho-phenol
arylation with the XPhos precatalyst at 110 °C for 20 min.
Surprisingly, this substrate furnished not only the desired
arylated products 18a but also the oxidized derivative 19a in a
ratio of 53:47 and a combined yield of 96%. Heating the
reaction for a longer time favored formation of 19a. For
instance, 1 h of heating generated 18a and 19a in a ratio of
23:77. The electron donating benzyloxy (OBn) group appeared
to have facilitated oxidation of the tetrahydroisoquinoline ring
since this type of product was not observed during the ortho-
phenol arylation of 9.
To evaluate this structure−reactivity relationship in more
detail, the OBn substituent was replaced with nitro (NO2), a
strong electron withdrawing group that could be subsequently
converted to a hydroxy present in natural product 3. Following
a similar procedure from commercially available aldehyde 13b,
anti-isomer 17b was obtained in 37% yield over three steps. As
anticipated, ortho-phenol arylation of 17b favored formation of
the desired product 18b with only trace amounts of oxidized
product 19b (18b:19b = 95:5 and combined yield of 56%)
being observed.
As shown in Scheme 3, demethylation of 18b with BBr3
furnished catechol 20 in 98% yield. Treatment of this material
with CH2I2, followed by reduction of the nitro with iron,
generated 22 in 76% yield over two steps. A Sandmeyer
reaction of the aniline in the presence of sulfuric acid gave 24,12
which is a precursor to ( )-3, in 89% yield.
The benzyloxy derivative 18a was also converted to
precursor 24. Dealkylation of both the methyl and benzyl
groups in 18a with BBr3 at room temperature for 30 min
generated catechol 23 in 87% yield. In addition, 23 was
obtained from 19a in 79% yield after dealkylation of the methyl
and benzyl groups and hydrogenation of the alkene.
Intermediate 23 was converted to 24 in 69% yield upon
treatment with CH2I2. However, intermediate 24 had very poor
solubility, making subsequent reactions difficult. Consequently,
the phenol was reprotected as 25 and reduced with DIBAL-H
to give 7-hydroxyaporphine 26. Oxidation of 26 with DMP
generated 7-oxoaporphine 27 in 94% yield, which, upon
hydrogenolysis, furnished ( )-3 in 96% yield.13
In summary, the strategy of utilizing an acid-mediated
cyclization, followed by palladium-catalyzed ortho-phenol
arylation as key steps, has been successfully extended to the
synthesis of ( )-3 and derivative 4. This study has also
confirmed the structure of 3 as a rarely encountered 6a-alkyl
aporphine alkaloid. Finally, the electronic property of
substituents on the aryl halide portion of the ortho-phenol
arylation substrates (e.g., OBn vs NO2) was shown to
significantly influence the formation of an oxidized side
product. This methodology should allow for the synthesis of
additional 6a-alkyl aporphines and exploration of their
pharmacology.
EXPERIMENTAL SECTION
■
General Experimental Procedures. All reactions involving air-
sensitive reagents were carried out with magnetic stirring and in oven-
dried glassware with rubber septa under argon unless otherwise stated.
All commercially available chemicals and reagent grade solvents were
used directly without further purification unless otherwise specified.
XPhos precatalyst was used as received from commercial suppliers
without further purification. Reactions were monitored by thin-layer
chromatography (TLC) on silica gel plates (IB2-F) using UV-light
(254 and 365 nm) detection or visualizing agents (e.g., ninhydrin or
phosphomolybdic acid stain). Flash chromatography was conducted
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DOI: 10.1021/acs.joc.6b02024
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Note
Scheme 3. Synthesis of ( )-3
on a silica gel (40−60 μm). Melting points were measured using a
capillary melting point apparatus. NMR spectra were recorded at room
temperature (1H NMR at 500 MHz and 13C NMR at 125 MHz) with
tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ)
are given in parts per million (ppm) with reference to solvent signals
[1H NMR: CDCl3 (7.26 ppm), CD3OD (3.31 ppm), DMSO-d6 (2.50
ppm); 13C NMR: CDCl3 (77.0 ppm), CD3OD (49.15 ppm), DMSO-
d6 (39.51 ppm)]. Signal patterns are reported as s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), and br (broad).
Coupling constants (J) are given in Hz. Nuclear Overhauser
enhancement spectroscopy (NOESY) spectra were obtained to
observe correlations between proton signals. High-resolution mass
spectra (HRMS) were measured using TOF-MS with a DART
ionization source and reported as m/z (relative intensity) for the
molecular ion [M].
was purified by column chromatography on silica gel (EtOAc/hexane,
15:85 to 20:80) to afford 8 (1.26 g, 80%) as a white solid; mp 143−
145 °C; 1H NMR (CDCl3, 500 MHz) 7.57 (1 H, dd, J = 8.0, 1.2 Hz),
7.41 (1 H, dd, J = 8.0, 1.7 Hz), 7.36 (1 H, td, J = 8.0, 1.2 Hz), 7.22 (1
H, td, J = 8.0, 1.7 Hz), 6.71−6.69 (2 H, m), 6.62 (1 H, dd, J = 8.0, 1.7
Hz), 5.70 (1 H, s), 3.78 (3 H, s), 3.52−3.40 (2 H, m), 3.02−2.96 (1 H,
m), 2.92−2.87 (1 H, m), 1.55 (3 H, s), 0.98 (9 H, s), 0.10 (3 H, s),
0.09 (3 H, s); 13C NMR (CDCl3, 125 MHz) 156.3, 151.0, 143.7,
133.1, 133.0, 132.1, 130.5, 128.6, 127.7, 123.1, 121.1, 120.8, 112.9,
88.3, 82.9, 55.5, 41.9, 34.3, 25.7 (3 ×), 25.2, 18.4, −4.7 (2 ×); HRMS
(DART-TOF) m/z calculated for C25H35BrNO5Si [M + H]+:
536.1468; found: 536.1481.
rel-(1S,10bS)-1-(2-Bromophenyl)-9-hydroxy-8-methoxy-
10b-methyl-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a]isoquino-
lin-3-one (9). To a solution of 8 (480 mg, 0.9 mmol) in anhydrous
CH2Cl2 (10 mL) was added BF3·OEt2 (330 μL, 2.7 mmol) at 0 °C
under argon, and the mixture was stirred at room temperature for 28 h.
After being quenched with H2O (10 mL), the aqueous layer was
extracted with EtOAc (2 × 10 mL). The combined organic extracts
were washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 30:70 to 40:60) to afford 9 (360 mg, 99%)
as a white solid; mp 174−175 °C; 1H NMR (CDCl3, 500 MHz) 7.64
(1 H, d, J = 8.0 Hz), 7.45−7.39 (2 H, m), 7.29−7.25 (2 H, m), 6.57 (1
H, s), 6.03 (1 H, s), 5.74 (1 H, s, OH), 4.09−4.06 (1 H, m), 3.88 (3 H,
s), 3.27−3.19 (2 H, m), 2.58−2.56 (1 H, m), 1.21 (3 H, s); 13C NMR
(CDCl3, 125 MHz) 158.7, 146.0, 144.4, 135.9, 133.1, 132.9, 130.3,
128.6, 127.8, 124.8, 123.0, 111.7, 111.1, 84.4, 64.0, 55.9, 37.0, 25.9,
5-(2-Bromophenyl)-3-(4-((tert-butyldimethylsilyl)oxy)-3-
methoxyphenethyl)oxazolidine-2,4-dione (7). 7 was prepared
according to the previously reported method.7
rel-(4R,5S)-5-(2-Bromophenyl)-3-(4-((tert-butyldimethyl-
silyl)oxy)-3-methoxyphenethyl)-4-hydroxy-4-methyloxazoli-
din-2-one (8). To a solution of MeMgCl (3.0 M in anhydrous THF,
2 mL, 5.9 mmol) was added a solution of 7 (1.5 g, 2.9 mmol) in
anhydrous THF (5 mL) at −30 °C under argon, and the temperature
was slowly allowed to rise from −30 to 0 °C over 1 h. The reaction
was then quenched by the addition of saturated aqueous NH4Cl,
evaporated in vacuo to remove THF, and partitioned between H2O
and CH2Cl2. The combined organic extracts were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated. The residue
D
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Note
24.9; HRMS (DART-TOF) m/z calculated for C19H19BrNO4 [M +
H]+: 404.0497; found: 404.0509.
CH2Cl2, 5:95 to 10:90 to 15:85) to afford 5 (48 mg, 65%) as a white
solid; mp 201−202 °C; 1H NMR (CDCl3, 500 MHz) 8.08−8.07 (1 H,
m), 7.69 (1 H, d, J = 6.9 Hz), 7.37−7.32 (2 H, m), 6.56 (1 H, s), 6.08
(1 H, d, J = 1.7 Hz), 5.95 (1 H, d, J = 1.7 Hz), 5.06 (1 H, s), 3.56−3.51
(1 H, m), 3.09−2.99 (2 H, m), 2.53 (3 H, s), 2.50−2.45 (1 H, m), 1.16
(3 H, s); 13C NMR (CDCl3, 125 MHz) 146.8, 142.7, 137.8, 128.6,
127.9, 127.8, 127.0, 126.5, 125.6, 124.1, 116.0, 108.2, 100.7, 71.2, 59.9,
46.1, 36.2, 22.3, 19.5; HRMS (DART-TOF) m/z calculated for
C19H20NO3 [M + H]+: 310.1443; found: 310.1458.
rel-(31S,12bS)-8-Hydroxy-7-methoxy-31-methyl-31,4,5,12b-
tetrahydro-2H-dibenzo[de,g]oxazolo[5,4,3-ij]quinolin-2-one
(6). To a mixture of 9 (176 mg, 0.44 mmol), Cs2CO3 (424 mg, 1.3
mmol), and XPhos precatalyst (30 mg, 0.04 mmol) was added
anhydrous DMA (1 mL) under argon. The reaction was stirred at
room temperature for 5 min and then put into a preheated oil bath
(110 °C) for another 40 min. After being quenched by the addition of
1 M HCl(aq), the aqueous layer was extracted with EtOAc (2 × 50
mL). Following neutralization with saturated aqueous NaHCO3, the
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography on silica gel (EtOAc/hexane,
25:75 to 30:70) to afford 6 (109 mg, 77%) as a pale yellow solid; mp
180−182 °C; 1H NMR (CDCl3, 500 MHz) 8.36 (1 H, d, J = 8.0 Hz),
7.41 (2 H, t, J = 8.0 Hz), 7.34 (1 H, t, J = 8.0 Hz), 6.67 (1 H, s), 6.33
(1 H, s, OH), 5.04 (1 H, s), 3.93 (3 H, s), 3.90−3.85 (1 H, m), 3.63−
3.57 (1 H, m), 2.97 (2 H, t, J = 6.3 Hz), 0.98 (3 H, s); 13C NMR
(CDCl3, 125 MHz) 157.2, 147.0, 143.0, 132.2, 130.9, 129.4, 128.3,
127.6 (2 ×), 121.8, 119.6, 115.5, 109.5, 84.4, 56.4, 56.3, 36.2, 26.4,
16.7; HRMS (DART-TOF) m/z calculated for C19H18NO4 [M + H]+:
324.1236; found: 324.1236.
7,7a-Dimethyl-5,6,7,7a-tetrahydro-8H-[1,3]dioxolo-
[4′,5′:4,5]benzo[1,2,3-de]benzo[g]quinolin-8-one (4). To a
mixture of 5 (15 mg, 0.048 mmol) and Dess−Martin periodinane
(47 mg, 0.11 mmol) was added anhydrous CH2Cl2 (2 mL) under
argon. The reaction was stirred at room temperature for 4 h. After
being quenched by the addition of 1 M Na2S2O3(aq), the aqueous layer
was extracted with CH2Cl2 (2 × 10 mL). Following neutralization with
saturated aqueous NaHCO3, the combined organic extracts were
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated. The residue was purified by column chromatography on
silica gel (CH3OH/CH2Cl2, 1:99 to 2:98) to afford 4 (13 mg, 88%) as
1
a pale yellow solid; mp 167−169 °C; H NMR (CDCl3, 500 MHz)
8.35 (1 H, d, J = 8.0 Hz), 8.06 (1 H, d, J = 7.5 Hz), 7.63 (1 H, t, J = 8.0
Hz), 7.40 (1 H, t, J = 7.5 Hz), 6.61 (1 H, s), 6.11 (1 H, d, J = 1.2 Hz),
6.02 (1 H, d, J = 1.2 Hz), 3.52−3.46 (1 H, m), 3.13−3.01 (2 H, m),
2.58 (1 H, dd, J = 15.5, 6.9 Hz), 2.40 (3 H, s), 1.54 (3 H, s); 13C NMR
(CDCl3, 125 MHz) 199.8, 147.0, 143.5, 134.2, 134.0, 129.3, 128.6,
127.9, 127.7, 127.3, 127.2, 114.1, 109.0, 100.9, 66.5, 45.7, 38.5, 27.6,
24.1; HRMS (DART-TOF) m/z calculated for C19H18NO3 [M + H]+:
308.1287; found: 308.1294.
rel-(31S,12bS)-7,8-Dihydroxy-31-methyl-31,4,5,12b-tetra-
hydro-2H-dibenzo[de,g]oxazolo[5,4,3-ij]quinolin-2-one (10).
To a solution of 6 (79 mg, 0.24 mmol) in anhydrous CH2Cl2 (5
mL) was added BBr3 (1.0 M in CH2Cl2, 590 μL, 0.59 mmol) under
argon, and the mixture was stirred at room temperature for 2 h. After
being quenched with saturated aqueous NaHCO3, the aqueous layer
was extracted with EtOAc (2 × 20 mL). The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 40:60 to 50:50) to
(1-Methoxyethyl)triphenylphosphonium Tetrafluoroborate
(12). To a solution of acetaldehyde dimethyl acetal (9.6 mL, 90 mmol)
and PPh3 (15.8 g, 60 mmol) in toluene (100 mL) was added BF3·OEt2
(10 mL, 81 mmol) at 0 °C under argon, and the mixture was stirred at
room temperature for 16 h. The residue was filtered and washed with
toluene and dried under reduced pressure to afford 12 (25 g, 98%) as a
white solid. The spectral data of the Wittig salt correspond with the
literature data.9,10 The crude product was used in the next step without
further purification.
1
afford 10 (69 mg, 91%) as a white solid; mp 245−247 °C; H NMR
(CD3OD, 500 MHz) 8.44 (1 H, d, J = 8.0 Hz), 7.40−7.37 (1 H, m),
7.34−7.30 (2 H, m), 6.66 (1 H, s), 5.07 (1 H, s),3.78−3.73 (1 H, m),
3.63−3.58 (1 H, m), 2.98−2.86 (2 H, m), 0.93 (3 H, s); 13C NMR
(CD3OD, 125 MHz) 159.8, 147.1, 144.9, 133.6, 133.4, 131.0, 128.7,
128.3, 128.1, 122.4, 120.9, 117.2, 114.8, 86.6, 58.1, 37.8, 27.1, 17.1;
HRMS (DART-TOF) m/z calculated for C18H16NO4 [M + H]+:
310.1079; found: 310.1060.
5-Benzyloxy-2-bromobenzaldehyde (13a).11 To a solution of
2-bromo-5-hydroxybenzaldehyde (2.05 g, 10 mmol) and K2CO3 (1.66
g, 12 mmol) in anhydrous DMF (5 mL) was added BnBr (1.4 mL, 12
mmol) under argon, and the mixture was stirred at room temperature
for 16 h. After being quenched by the addition of 1 M HCl(aq), the
aqueous layer was extracted with EtOAc (2 × 50 mL). The combined
organic extracts were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was purified by
column chromatography on silica gel (EtOAc/hexane, 0:100 to 5:95)
rel-(4bS,4b1S)-4b1-Methyl-4b,4b1,8,9-tetrahydro-6H-[1,3]-
dioxolo[4′,5′:4,5]benzo[1,2,3-de]benzo[g]oxazolo[5,4,3-ij]-
quinolin-6-one (11). To a solution of 10 (125 mg, 0.4 mmol) and
Cs2CO3 (260 mg, 0.8 mmol) in anhydrous DMF (1 mL) was added
CH2Br2 (42 μL, 0.6 mmol) under argon, and the mixture was stirred at
room temperature for 18 h. After being quenched by the addition of 1
M HCl(aq), the aqueous layer was extracted with EtOAc (2 × 30 mL).
The combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography on silica gel (EtOAc/hexane,
10:90 to 15:85) to afford 11 (120 mg, 93%) as a white solid; mp 213−
215 °C; 1H NMR (CDCl3, 500 MHz) 8.01 (1 H, d, J = 7.5 Hz), 7.44
(1 H, d, J = 6.9 Hz), 7.42−7.35 (2 H, m), 6.63 (1 H, s), 6.10 (1 H, d, J
= 1.2 Hz), 5.99 (1 H, d, J = 1.2 Hz), 5.07 (1 H, s), 3.89−3.84 (1 H,
m), 3.62−3.57 (1 H, m), 2.95 (2 H, t, J = 6.3 Hz), 1.02 (3 H, s); 13C
NMR (CDCl3, 125 MHz) 157.0, 148.2, 143.5, 132.0, 129.7, 128.3,
128.2, 128.0, 127.8, 122.4, 122.1, 112.8, 107.7, 101.2, 84.2, 56.4, 36.3,
26.6, 17.1; HRMS (DART-TOF) m/z calculated for C19H16NO4 [M +
H]+: 322.1079; found: 322.1052.
rel-(7aS,8S)-7,7a-Dimethyl-6,7,7a,8-tetrahydro-5H-[1,3]-
dioxolo[4′,5′:4,5]benzo[1,2,3-de]benzo[g]quinolin-8-ol (5). To
a solution of 11 (80 mg, 0.24 mmol) in anhydrous CH2Cl2 (1 mL)
was added dropwise a solution of DIBAL-H (25% in toluene, 320 μL,
0.48 mmol) at −10 °C under argon. The mixture was stirred at −10
°C for 30 min and then quenched by the addition of saturated aqueous
NaHCO3 (20 mL). The aqueous layer was extracted with CH2Cl2 (2 ×
30 mL), and the combined organic extracts were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated. The residue
was purified by column chromatography on silica gel (CH3OH/
1
to afford 13a (2.82 g, 96%) as a colorless oil; H NMR (CDCl3, 500
MHz) 10.31 (1 H, s), 7.53 (1 H, d, J = 8.5 Hz), 7.51 (1 H, d, J = 2.5
Hz), 7.44−7.35 (5 H, m), 7.10 (1 H, d, J = 2.5 Hz), 5.09 (2 H, s); 13C
NMR (CDCl3, 125 MHz) 191.6, 158.2, 135.8, 134.6, 133.9, 128.6 (2
×), 128.2, 127.5 (2 ×), 123.6, 118.1, 113.7, 70.3; HRMS (DART-
TOF) m/z calculated for C14H12BrO2 [M + H]+: 291.0021; found:
290.9988.
1-(5-(Benzyloxy)-2-bromophenyl)-1-hydroxypropan-2-one
(14a). To a solution of 12 (1.23 g, 3 mmol) in anhydrous THF (10
mL) was added n-BuLi (2.5 M in hexane, 1.2 mL, 3 mmol) at −40 °C
under argon. After being stirred at −40 °C for 10 min, 13a (587 mg, 2
mmol) in anhydrous THF (2 mL) was added to the dark red ylide
solution at −78 °C, and the resulting mixture was stirred at −78 °C for
1 h. The reaction was then quenched at −78 °C by the addition of
saturated aqueous NH4Cl and evaporated in vacuo to remove the
THF. The remaining aqueous layer was extracted with EtOAc (3 × 10
mL), and the combined organic extracts were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography on silica gel (EtOAc/hexane, 5:95
1
to 10:90) to afford 14a (550 mg, 82%) as a colorless oil; H NMR
(CDCl3, 500 MHz) 7.49 (1 H, d, J = 8.5 Hz), 7.40−7.33 (5 H, m),
6.87−6.83 (2 H, m), 5.56 (1 H, d, J = 4.0 Hz), 5.04−4.98 (2 H, m),
4.41 (1 H, d, J = 4.0 Hz), 2.14 (3 H, s); 13C NMR (CDCl3, 125 MHz)
E
DOI: 10.1021/acs.joc.6b02024
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
206.2, 158.5, 138.2, 136.1, 133.9, 128.6 (2 ×), 128.1, 127.5 (2 ×),
117.3, 114.7, 114.1, 78.5, 70.2, 25.4; HRMS (DART-TOF) m/z
calculated for C16H16BrO3 [M + H]+: 335.0283; found: 335.0258.
tert-Butyl(4-(2-isocyanatoethyl)-2-methoxyphenoxy)-
dimethylsilane (15).7 A suspension of 4-hydroxy-3-methoxyphen-
ethylamine hydrochloride (2.1 g, 10.3 mmol) and imidazole (2.4 g, 40
mmol) in anhydrous CH2Cl2 (20 mL) was stirred at room
temperature for 10 min, and then TBSCl (1.7 g, 11 mmol) was
added under argon. The resulting mixture was stirred at room
temperature for 3 h and then quenched by the addition of saturated
aqueous NH4Cl. The aqueous layer was extracted with CH2Cl2 (2 ×
50 mL). After neutralization with saturated aqueous NaHCO3, the
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography on silica gel (CH3OH/CH2Cl2,
1:99 to 5:95) to afford the O-silylated phenethylamine product (2.8 g,
97%) as a colorless oil, and the spectral data correspond with the
literature data.7 To a solution of triphosgene (1.1 g, 3.75 mmol) in
anhydrous toluene (10 mL) was added a solution of the O-silylated
phenethylamine (1.5 g, 5.33 mmol) in anhydrous toluene (5 mL)
under argon. The mixture was stirred at room temperature for 30 min
and heated to 100 °C for another 1 h. After being quenched by the
addition of saturated aqueous NH4Cl, the aqueous layer was extracted
with EtOAc (2 × 30 mL). The combined organic extracts were washed
with brine, dried over anhydrous Na2SO4, filtered, and concentrated to
70.2, 55.5, 42.2, 34.8, 25.7 (3 ×), 22.0, 18.4, −4.7 (2 ×); HRMS
(DART-TOF) m/z calculated for C32H41BrNO6Si [M + H]+:
642.1887; found: 642.1878.
rel-(1S,10bS)-1-(5-(Benzyloxy)-2-bromophenyl)-9-hydroxy-
8-methoxy-10b-methyl-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-
a]isoquinolin-3-one (17a). To a solution of 16a (106 mg, 0.165
mmol) in anhydrous CH2Cl2 (10 mL) was added BF3·OEt2 (60 μL,
0.49 mmol) at −78 °C under argon, and the mixture was stirred at
−78 °C for 1 h. After being quenched with saturated aqueous
NaHCO3 (10 mL) at −78 °C, the mixture was slowly allowed to warm
to room temperature and extracted with EtOAc (2 × 10 mL). The
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography on silica gel (EtOAc/hexane,
10:90 to 15:85) to afford cyclized intermediate TBS-17a (85 mg,
82%). To a solution of TBS-17a (85 mg, 0.136 mmol) in anhydrous
CH2Cl2 (3 mL) was added TBAF (1.0 M in THF, 140 μL, 0.14 mmol)
under argon. The resulting mixture was stirred at room temperature
for 5 min and then concentrated. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 25:75 to 35:65) to
afford 17a (67 mg, 98%).
1
TBS-17a. Pale yellow solid; mp 150−151 °C; H NMR (CDCl3,
500 MHz) 7.49 (1 H, d, J = 9.0 Hz), 7.43−7.30 (5 H, m), 7.21 (1 H,
s), 6.98 (1 H, d, J = 2.5 Hz), 6.89 (1 H, dd, J = 9.0, 2.5 Hz), 6.52 (1 H,
s), 5.93 (1 H, s), 5.12−5.05 (2 H, m), 4.05−3.99 (1 H, m), 3.78 (3 H,
s), 3.24−3.14 (2 H, m), 2.57−2.50 (1 H, m), 1.10 (3 H, s), 1.00 (9 H,
s), 0.16 (3 H, s), 0.15 (3 H, s); 13C NMR (CDCl3, 125 MHz) 158.6,
158.2, 150.4, 143.7, 136.9, 136.1, 133.7, 132.4, 128.6 (2 ×), 128.1,
127.5 (2 ×), 126.3, 118.2, 117.5, 114.8, 113.3, 112.3, 84.3, 70.2, 63.9,
55.4, 37.1, 25.7 (4 ×), 24.8, 18.4, −4.6, −4.7; HRMS (DART-TOF)
m/z calculated for C32H39BrNO5Si [M + H]+: 624.1781; found:
624.1779.
1
afford 15 (1.6 g, 98%) as a light yellow oil; H NMR (CDCl3, 500
MHz) 6.81 (1 H, d, J = 8.0 Hz), 6.70 (1 H, d, J = 2.0 Hz), 6.67 (1 H,
dd, J = 8.0, 2.0 Hz), 3.81 (3 H, s), 3.48 (2 H, t, J = 7.0 Hz), 2.84 (2 H,
t, J = 7.0 Hz), 1.00 (9 H, s), 0.16 (6 H, s); 13C NMR (CDCl3, 125
MHz) 150.9, 144.0, 131.1, 122.6, 121.0, 120.9, 112.8, 55.4, 44.4, 37.4,
25.7 (3 × ), 18.4, −4.7 (2 ×). The isocyanate product was freshly
prepared and used in the next step.
1
17a. White solid; mp 212−213 °C; H NMR (CDCl3, 500 MHz)
5-(5-(Benzyloxy)-2-bromophenyl)-3-(4-((tert-butyldimethyl-
silyl)oxy)-3-methoxyphenethyl)-4-hydroxy-4-methyloxazoli-
din-2-one (16a): A Mixture of rel-(4R,5S)-16a and rel-(4S,5S)-
16a. A suspension of 14a (330 mg, 0.98 mmol) and triethylamine
(270 μL, 1.9 mmol) in anhydrous CH2Cl2 (20 mL) was stirred at
room temperature for 10 min, and then 15 (600 mg, 1.95 mmol) was
added under argon. After being stirred at room temperature for 2 days,
the reaction mixture was quenched by the addition of saturated
aqueous NH4Cl, extracted with EtOAc (2 × 30 mL), and neutralized
with saturated aqueous NaHCO3. The combined organic extracts were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 10:90 to 15:85) to afford diastereomers rel-
(4R,5S)-16a and rel-(4S,5S)-16a (570 mg, dr 1:1) in a combined yield
of 90%. Analytical samples were obtained by additional column
chromatography on silica gel (EtOAc/hexane, 10:90 to 15:85), and
relative configurations of these two diastereomers were confirmed by
2D-NOESY.
7.49 (1 H, d, J = 9.0 Hz), 7.42−7.30 (5 H, m), 7.24 (1 H, s), 6.99 (1
H, d, J = 2.5 Hz), 6.89 (1 H, dd, J = 9.0, 2.5 Hz), 6.54 (1 H, s), 5.94 (1
H, s), 5.74 (1 H, s, OH), 5.12−5.05 (2 H, m), 4.06−3.99 (1 H, m),
3.86 (3 H, s), 3.24−3.14 (2 H, m), 2.57−2.52 (1 H, m), 1.12 (3 H, s);
13C NMR (CDCl3, 125 MHz) 158.5, 158.1, 146.0, 144.4, 136.7, 136.1,
133.7, 132.8, 128.6 (2 ×), 128.0, 127.5 (2 ×), 124.7, 117.5, 114.8,
113.4, 111.7, 111.1, 84.3, 70.2, 63.9, 55.9, 37.0, 25.8, 24.7; HRMS
(DART-TOF) m/z calculated for C26H25BrNO5 [M + H]+: 510.0916;
found: 510.0907.
Preparation of 18a and 19a. To a mixture of 17a (52 mg, 0.1
mmol), Cs2CO3 (98 mg, 0.3 mmol), and XPhos precatalyst (8 mg,
0.01 mmol) was added anhydrous DMA (500 μL) under argon. The
reaction was stirred at room temperature for 5 min and then put into a
preheated oil bath (110 °C) for another 20 min. After being quenched
by the addition of 1 M HCl(aq), the aqueous layer was extracted with
EtOAc (2 × 10 mL). Following neutralization with saturated aqueous
NaHCO3, the combined organic extracts were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated. The residue
was purified by column chromatography on silica gel (EtOAc/hexane,
20:80 to 30:70 to 40:60) to afford 18a (22 mg, 51%) and 19a (19 mg,
45%).
1
rel-(4R,5S)-16a. White solid; mp 165−166 °C; H NMR (CDCl3,
500 MHz) 7.44 (1 H, d, J = 9.5 Hz), 7.38−7.31 (6 H, m), 6.86 (1 H,
dd, J = 9.5, 3.0 Hz), 6.74 (1 H, d, J = 8.0 Hz), 6.69 (1 H, d, J = 2.0
Hz), 6.63 (1 H, dd, J = 8.0, 2.0 Hz), 5.65 (1 H, s), 5.04 (1 H, d, J =
12.0 Hz), 4.96 (1 H, d, J = 12.0 Hz), 3.75 (3 H, s), 3.54−3.48 (1 H,
m), 3.45−3.39 (1 H, m), 2.92−2.89 (2 H, m), 1.47 (3 H, s), 0.99 (9 H,
s), 0.12 (3 H, s), 0.12 (3 H, s); 13C NMR (CDCl3, 125 MHz) 158.3,
156.9, 150.9, 143.7, 136.2, 133.7, 133.5, 132.1, 128.6 (2 ×), 128.1,
127.6 (2 ×), 121.1, 120.8, 118.0, 115.1, 113.3, 112.8, 88.8, 83.2, 70.4,
55.4, 42.2, 34.6, 25.7 (3 ×), 24.6, 18.4, −4.7 (2 ×); HRMS (DART-
TOF) m/z calculated for C32H41BrNO6Si [M + H]+: 642.1887; found:
642.1879.
rel-(31S,12bS)-11-(Benzyloxy)-8-hydroxy-7-methoxy-31-methyl-
31,4,5,12b-tetrahydro-2H-dibenzo[de,g]oxazolo[5,4,3-ij]quinolin-2-
1
one (18a). White solid; mp 225−226 °C; H NMR (CDCl3, 500
MHz) 8.29 (1 H, d, J = 8.5 Hz), 7.48−7.33 (5 H, m), 7.09 (1 H, d, J =
2.0 Hz), 6.98 (1 H, dd, J = 8.5, 2.0 Hz), 6.63 (1 H, s), 6.27 (1 H, s,
OH), 5.13 (2 H, s), 5.00 (1 H, s), 3.92 (3 H, s), 3.89−3.84 (1 H, m),
3.62−3.57 (1 H, m), 2.96 (2 H, t, J = 7.0 Hz), 1.00 (3 H, s); 13C NMR
(CDCl3, 125 MHz) 158.1, 157.1, 147.0, 142.3, 136.5, 134.0, 130.8,
128.6 (2 ×), 128.0, 127.6, 127.5 (2 ×), 123.4, 119.6, 115.6, 113.2,
109.1, 108.7, 84.2, 70.0, 56.4, 56.3, 36.3, 26.4, 16.6; HRMS (DART-
TOF) m/z calculated for C26H24NO5 [M + H]+: 430.1654; found:
430.1632.
1
rel-(4S,5S)-16a. Light yellow oil; H NMR (CDCl3, 500 MHz)
7.44−7.29 (6 H, m), 6.85−6.81 (6 H, m), 6.44 (1 H, s), 6.71 (1 H, d, J
= 8.0 Hz), 6.69 (1 H, d, J = 2.0 Hz), 6.63 (1 H, dd, J = 8.0, 2.0 Hz),
5.76 (1 H, s), 5.07−5.01 (2 H, m), 4.33 (1 H, s, br, OH), 3.74 (3 H,
s), 3.44 (2 H, t, J = 8.0 Hz), 2.96−2.82 (2 H, m), 0.97 (9 H, s), 0.93 (3
H, s), 0.09 (3 H, s), 0.09 (3 H, s); 13C NMR (CDCl3, 125 MHz)
158.3, 157.2, 150.9, 143.6, 136.5, 136.1, 133.7, 132.1, 128.6 (2 ×),
128.2, 127.5 (2 ×), 121.1, 120.8, 116.7, 113.5, 113.1, 112.8, 90.0, 85.7,
rel-(31S,12bS)-11-(Benzyloxy)-8-hydroxy-7-methoxy-31-methyl-
31,12b-dihydro-2H-dibenzo[de,g]oxazolo[5,4,3-ij]quinolin-2-one
(19a). Light yellow oil; 1H NMR (CDCl3, 500 MHz) 8.33 (1 H, d, J =
9.0 Hz), 7.47−7.33 (5 H, m), 7.09 (1 H, d, J = 3.0 Hz), 6.98 (1 H, dd,
F
DOI: 10.1021/acs.joc.6b02024
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
J = 9.0, 3.0 Hz), 6.64 (1 H, d, J = 7.5 Hz), 6.60 (1 H, s), 6.39 (1 H, s,
OH), 5.82 (1 H, d, J = 7.5 Hz), 5.50 (1 H, s), 5.13 (2 H, s), 3.93 (3 H,
s), 1.02 (3 H, s); 13C NMR (CDCl3, 125 MHz) 158.3, 154.7, 147.2,
143.6, 136.4, 133.7, 130.9, 128.6 (2 ×), 128.1, 127.5 (2 ×), 124.3,
123.1, 119.1, 118.3, 115.6, 113.2, 109.6, 109.3, 106.2, 85.3, 70.0, 57.5,
56.5, 16.1; HRMS (DART-TOF) m/z calculated for C26H22NO5 [M +
H]+: 428.1497; found: 428.1508.
1-(2-Bromo-5-nitrophenyl)-1-hydroxypropan-2-one (14b).
The same procedure as 14a was used to synthesize 14b starting
from 2-bromo-5-nitrobenzaldehyde (13b) to afford 14b in 64% yield.
Pale yellow solid; mp 93−94 °C; 1H NMR (CDCl3, 500 MHz) 8.14 (1
H, d, J = 3.0 Hz), 8.06 (1 H, dd, J = 8.5, 3.0 Hz), 7.82 (1 H, d, J = 8.5
Hz), 5.63 (1 H, d, J = 3.0 Hz), 4.55 (1 H, d, J = 3.0 Hz, OH), 2.20 (3
H, s); 13C NMR (CDCl3, 125 MHz) 204.6, 147.7, 139.5, 134.4, 130.4,
124.5, 124.0, 78.2, 25.6; HRMS (DART-TOF) m/z calculated for
C9H9BrNO4 [M + H]+: 275.9695; found: 275.9689.
5-(2-Bromo-5-nitrophenyl)-3-(4-((tert-butyldimethylsilyl)-
oxy)-3-methoxyphenethyl)-4-hydroxy-4-methyloxazolidin-2-
one (16b). A suspension of 14b (400 mg, 1.46 mmol) and
triethylamine (420 μL, 3 mmol) in anhydrous CH2Cl2 (15 mL) was
stirred at room temperature for 15 min, and then 15 (820 mg, 3
mmol) was added under argon. After being stirred at room
temperature for 16 h, the reaction mixture was quenched by the
addition of saturated aqueous NH4Cl, extracted with CH2Cl2 (2 × 20
mL), and neutralized with saturated aqueous NaHCO3. The combined
organic extracts were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated. The crude mixture was used
directly for the next step. One diastereomer was purified by column
chromatography on silica gel (EtOAc/hexane, 10:90 to 20:80) and
determined to be rel-(4R,5S)-16b by 2D-NOESY.
5.63 (1 H, s, OH), 4.13−4.06 (1 H, m), 3.89 (3 H, s), 3.27−3.19 (2 H,
m), 2.62−2.55 (1 H, m), 1.24 (3 H, s); 13C NMR (CDCl3, 125 MHz)
157.7, 147.6, 146.2, 144.5, 138.2, 134.4, 132.0, 129.9, 125.0, 124.8,
123.8, 111.4, 111.3, 83.6, 63.8, 56.0, 37.2, 25.9, 24.9; HRMS (DART-
TOF) m/z calculated for C19H18BrN2O6 [M + H]+: 451.0330; found:
451.0362.
Preparation of 18b and 19b. To a mixture of 17b (209 mg,
0.465 mmol), Cs2CO3 (456 mg, 1.4 mmol), and XPhos precatalyst (34
mg, 0.046 mmol) was added anhydrous DMA (5 mL) under argon.
The reaction was stirred at room temperature for 5 min and then put
into a preheated oil bath (110 °C) for another 20 min. After being
quenched by the addition of 1 M HCl(aq), the aqueous layer was
extracted with EtOAc (2 × 20 mL). Following neutralization with
saturated aqueous NaHCO3, the combined organic extracts were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 30:70 to 40:60) to afford 18b (91 mg, 53%)
and 19b (5 mg, 3%).
rel-(31S,12bS)-8-Hydroxy-7-methoxy-31-methyl-11-nitro-
31,4,5,12b-tetrahydro-2H-dibenzo[de,g]oxazolo[5,4,3-ij]quinolin-2-
one (18b). Yellow solid; mp > 250 °C (decomposed); 1H NMR
(CDCl3, 500 MHz) 8.57−8.55 (1 H, m), 8.29−8.27 (2 H, m), 6.76 (1
H, s), 6.49 (1 H, s, OH), 5.05 (1 H, s), 3.97 (3 H, s), 3.93−3.88 (1 H,
m), 3.65−3.59 (1 H, m), 3.00 (2 H, t, J = 7.0 Hz), 1.01 (3 H, s); 13C
NMR (CDCl3, 125 MHz) 156.5, 147.2, 146.3, 143.9, 137.6, 133.8,
130.1, 128.3, 123.2, 120.1, 117.3, 113.8, 111.1, 83.2, 56.6, 55.9, 36.2,
26.3, 17.1; HRMS (DART-TOF) m/z calculated for C19H17N2O6 [M
+ H]+: 369.1087; found: 369.1105.
rel-(31S,12bS)-8-Hydroxy-7-methoxy-31-methyl-11-nitro-31,12b-
dihydro-2H-dibenzo[de,g]oxazolo[5,4,3-ij]quinolin-2-one (19b).
rel-(4R,5S)-16b. White solid; mp 207−208 °C; 1H NMR (DMSO-
d6, 500 MHz) 8.28 (1 H, d, J = 3.0 Hz), 8.14 (1 H, dd, J = 9.0, 3.0 Hz),
7.98 (1 H, d, J = 9.0 Hz), 6.88 (1 H, d, J = 2.0 Hz), 6.76 (1 H, d, J =
8.0 Hz), 6.69 (1 H, dd, J = 8.0, 2.0 Hz), 6.20 (1 H, s, OH), 5.70 (1 H,
s), 3.76 (3 H, s), 3.44−3.39 (1 H, m), 3.30−3.24 (1 H, m), 2.82 (2 H,
t, J = 7.5 Hz), 1.40 (3 H, s), 0.95 (9 H, s), 0.10 (6 H, s); 13C NMR
(DMSO-d6, 125 MHz) 155.9, 150.4, 146.7, 142.7, 135.8, 134.2, 132.7,
129.7, 124.9, 124.8, 121.0, 120.3, 113.1, 87.9, 81.9, 55.4, 41.7, 34.3,
25.6 (3 ×), 24.6, 18.2, −4.7 (2 ×); HRMS (DART-TOF) m/z
calculated for C25H34BrN2O7Si [M + H]+: 583.1302; found: 583.1317.
rel-(1S,10bS)-1-(2-Bromo-5-nitrophenyl)-9-hydroxy-8-me-
thoxy-10b-methyl-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a]-
isoquinolin-3-one (17b). To a solution of crude 16b in anhydrous
CH2Cl2 (10 mL) was added BF3·OEt2 (660 μL, 5.4 mmol) at −78 °C
under argon, and the mixture was stirred at −78 °C for 1 h. After being
quenched with saturated aqueous NaHCO3 (10 mL) at −78 °C, the
mixture was slowly allowed to warm to room temperature and
extracted with EtOAc (2 × 20 mL). The combined organic extracts
were washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 5:95 to 10:90) to afford cyclized
intermediate TBS-17b (488 mg, 59% over 2 steps). To a solution of
TBS-17b (143 mg, 0.254 mmol) in anhydrous CH2Cl2 (5 mL) was
added TBAF (1.0 M in THF, 250 μL, 0.25 mmol) under argon. The
resulting mixture was stirred at room temperature for 10 min and then
concentrated. The residue was purified by column chromatography on
silica gel (CH3OH/CH2Cl2, 2:98 to 5:95) to afford 17b (114 mg,
99%).
1
Yellow solid; mp > 250 °C (decomposed); H NMR (CDCl3, 500
MHz) 8.62−8.60 (1 H, m), 8.31−8.29 (2 H, m), 6.73 (1 H, s), 6.68 (1
H, d, J = 7.5 Hz), 6.58 (1 H, s, OH), 5.86 (1 H, d, J = 7.5 Hz), 5.59 (1
H, s), 3.98 (3 H, s), 1.04 (3 H, s); 13C NMR (CDCl3, 125 MHz)
154.0, 147.4, 146.5, 145.0, 137.3, 133.5, 130.2, 124.9, 123.4, 119.7,
118.7, 117.3, 113.7, 109.3, 108.5, 84.3, 57.2, 56.7, 16.6; HRMS
(DART-TOF) m/z calculated for C19H15N2O6 [M + H]+: 367.0930;
found: 367.0946.
rel-(31S,12bS)-7,8-Dihydroxy-31-methyl-11-nitro-31,4,5,12b-
tetrahydro-2H-dibenzo[de,g]oxazolo[5,4,3-ij]quinolin-2-one
(20). To a solution of 18b (90 mg, 0.24 mmol) in anhydrous CH2Cl2
(20 mL) was added BBr3 (1.0 M in CH2Cl2, 490 μL, 0.49 mmol)
under argon, and the reaction was stirred at room temperature for 20
min. After being quenched by the addition of CH3OH (1 mL) and
NaHCO3(s) (10 mg), the mixture was stirred for another 5 min. Then,
the solid was separated by filtration, and the combined filtrates were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by column chromatography on
silica gel (CH3OH/CH2Cl2, 0:100 to 5:95) to afford 20 (85 mg, 98%)
1
as a yellow solid; mp > 250 °C (decomposed); H NMR (DMSO-d6,
500 MHz) 8.61 (1 H, d, J = 9.0 Hz), 8.33 (1 H, dd, J = 9.0, 2.0 Hz),
8.00 (1 H, d, J = 2.0 Hz), 6.77 (1 H, s), 5.19 (1 H, s), 3.69−3.64 (1 H,
m), 3.58−3.53 (1 H, m), 2.92−2.84 (2 H, m), 0.88 (3 H, s); 13C NMR
(DMSO-d6, 125 MHz) 156.0, 145.8, 145.3, 144.2, 138.8, 133.8, 130.1,
126.5, 123.0, 119.6, 116.0, 115.6, 114.0, 82.5, 55.3, 36.3, 25.3, 17.3;
HRMS (DART-TOF) m/z calculated for C18H15N2O6 [M + H]+:
355.0930; found: 355.0938.
rel-(4bS,4b1S)-4b1-Methyl-3-nitro-4b,4b1,8,9-tetrahydro-6H-
[1,3]dioxolo[4′,5′:4,5]benzo[1,2,3-de]benzo[g]oxazolo[5,4,3-ij]-
quinolin-6-one (21). To a solution of 20 (50 mg, 0.14 mmol) and
K2CO3 (40 mg, 0.28 mmol) in anhydrous DMF (1 mL) was added
CH2I2 (20 μL, 0.25 mmol) under argon, and the mixture was stirred at
70 °C for 1 h. After being quenched with H2O (5 mL), the aqueous
layer was extracted with EtOAc (2 × 10 mL). The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated. The crude mixture containing 21 was used
directly for the next step. A sample for characterization was purified by
column chromatography on silica gel (EtOAc/hexane, 20:80 to 30:70)
to afford 21 as a yellow solid; mp > 250 °C (decomposed); 1H NMR
(CDCl3, 500 MHz) 8.32−8.27 (2 H, m), 8.20 (1 H, d, J = 8.5 Hz),
1
TBS-17b. Pale yellow solid; mp 167−168 °C; H NMR (CDCl3,
500 MHz) 8.26 (1 H, d, J = 3.0 Hz), 8.12 (1 H, dd, J = 8.5, 3.0 Hz),
7.85 (1 H, d, J = 8.5 Hz), 7.10 (1 H, s), 6.55 (1 H, s), 6.01 (1 H, s),
4.12−4.05 (1 H, m), 3.79 (3 H, s), 3.27−3.18 (2 H, m), 2.61−2.55 (1
H, m), 1.20 (3 H, s), 0.99 (9 H, s), 0.16 (3 H, s), 0.15 (3 H, s); 13C
NMR (CDCl3, 125 MHz) 157.8, 150.6, 147.6, 143.8, 138.4, 134.3,
131.4, 129.6, 126.5, 124.8, 123.7, 117.9, 112.4, 83.7, 63.8, 55.4, 37.2,
25.8, 25.7 (3 × ), 25.0, 18.4, −4.6, −4.7; HRMS (DART-TOF) m/z
calculated for C25H32BrN2O6Si [M + H]+: 565.1197; found: 565.1171.
1
17b. White solid; mp > 250 °C (decomposed); H NMR (CDCl3,
500 MHz) 8.27 (1 H, d, J = 3.0 Hz), 8.13 (1 H, dd, J = 9.0, 3.0 Hz),
7.86 (1 H, d, J = 9.0 Hz), 7.13 (1 H, s), 6.58 (1 H, s), 6.04 (1 H, s),
G
DOI: 10.1021/acs.joc.6b02024
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
6.74 (1 H, s), 6.17 (1 H, d, J = 1.0 Hz), 6.06 (1 H, d, J = 1.0 Hz), 5.10
(1 H, s), 3.92−3.87 (1 H, m), 3.65−3.59 (1 H, m), 2.99 (2 H, t, J = 7.0
Hz), 1.05 (3 H, s); 13C NMR (CDCl3, 125 MHz) 156.3, 148.6, 146.9,
144.6, 136.3, 133.6, 128.7, 128.3, 123.4, 122.6, 117.9, 110.9, 109.5,
101.8, 83.1, 56.1, 36.2, 26.6, 17.5; HRMS (DART-TOF) m/z
calculated for C19H15N2O6 [M + H]+: 367.0930; found: 367.0951.
rel-(4bS,4b1S)-3-Amino-4b1-methyl-4b,4b1,8,9-tetrahydro-
6H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2,3-de]benzo[g]oxazolo-
[5,4,3-ij]quinolin-6-one (22). To a solution of crude 21 and NH4Cl
(40 mg, 0.28 mmol) in a mixture of EtOH/H2O/THF (2:1:1, 2 mL)
was added Fe powder (80 mg), and the mixture was vigorously stirred
at 100 °C for 1 h. After the mixture was allowed to cool to room
temperature, the solid was removed by filtration through a Celite pad
and the filtrate was concentrated. The residue was purified by column
chromatography (CH3OH/CH2Cl2, 1:99 to 5:95) to afford 22 (36 mg,
was stirred at 70 °C for 1 h. After being quenched with H2O (5 mL),
the aqueous layer was extracted with EtOAc (2 × 20 mL). The
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography on silica gel (CH3OH/CH2Cl2,
1:99 to 2:98) to afford 24 (65 mg, 69%).
rel-(4bS,4b1S)-3-Hydroxy-4b1-methyl-4b,4b1,8,9-tetrahydro-6H-
[1,3]dioxolo[4′,5′:4,5]benzo[1,2,3-de]benzo[g]oxazolo[5,4,3-ij]-
quinolin-6-one (24). Pale yellow solid; mp > 250 °C (decomposed);
1
NMR data were collected from material prepared by Method A: H
NMR (DMSO-d6, 500 MHz) 10.07 (1 H, s, OH), 7.78 (1 H, d, J = 8.5
Hz), 6.81−6.76 (3 H, m), 6.12 (1 H, s), 6.03 (1 H, s), 5.08 (1 H, s),
3.68−3.63 (1 H, m), 3.57−3.52 (1 H, m), 2.94−2.86 (2 H, m), 0.91 (3
H, s); 13C NMR (DMSO-d6, 125 MHz) 157.7, 156.2, 147.6, 142.0,
133.9, 129.4, 127.1, 122.7, 119.8, 113.9, 112.4, 109.8, 106.7, 101.0,
83.1, 55.8, 36.3, 26.0, 17.0; HRMS (DART-TOF) m/z calculated for
C19H16NO5 [M + H]+: 338.1028; found: 338.1047.
1
76% over 2 steps) as a white solid; mp > 250 °C (decomposed); H
NMR (DMSO-d6, 500 MHz) 7.62 (1 H, d, J = 8.0 Hz), 6.68 (1 H, s),
6.59 (1 H, s), 6.54 (1 H, dd, J = 8.0, 2.0 Hz), 6.08 (1 H, s), 6.01 (1 H,
s), 5.70 (2 H, s, NH2), 5.01 (1 H, s), 3.67−3.62 (1 H, m), 3.56−3.51
(1 H, m), 2.91−2.85 (2 H, m), 0.92 (3 H, s); 13C NMR (DMSO-d6,
125 MHz) 156.4, 149.2, 147.5, 141.4, 133.3, 129.0, 126.8, 122.6, 115.8,
113.3, 111.5, 107.7, 105.7, 100.8, 83.4, 55.9, 36.3, 26.1, 16.9; HRMS
(DART-TOF) m/z calculated for C19H17N2O4 [M + H]+: 337.1188;
found: 337.1204.
rel-(4bS,4b1S)-3-(Benzyloxy)-4b1-methyl-4b,4b1,8,9-tetra-
hydro-6H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2,3-de]benzo[g]-
oxazolo[5,4,3-ij]quinolin-6-one (25). To a solution of 24 (58 mg,
0.17 mmol) and K2CO3 (29 mg, 0.2 mmol) in anhydrous DMF (0.5
mL) was added BnBr (24 μL, 0.2 mmol) under argon, and the mixture
was stirred at room temperature for 3 h. After being quenched by the
addition of 1 M HCl(aq), the aqueous layer was extracted with EtOAc
(2 × 10 mL). The combined organic extracts were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated. The residue
was purified by column chromatography on silica gel (EtOAc/hexane,
20:80) to afford 25 (51 mg, 70%) as a white solid; mp 197−198 °C;
1H NMR (CDCl3, 500 MHz) 7.93 (1 H, d, J = 8.5 Hz), 7.46−7.33 (5
H, m), 7.10−7.09 (1 H, m), 6.96 (1 H, dd, J = 8.5, 2.0 Hz), 6.59 (1 H,
s), 6.07 (1 H, d, J = 2.0 Hz), 5.97 (1 H, d, J = 2.0 Hz), 5.12 (2 H, s),
5.01 (1 H, s), 3.87−3.83 (1 H, m), 3.61−3.56 (1 H, m), 2.94 (2 H, t, J
= 6.0 Hz), 1.03 (3 H, s); 13C NMR (CDCl3, 125 MHz) 158.7, 156.9,
148.1, 142.8, 136.3, 133.8, 129.4, 128.6 (2 ×), 128.1, 127.5 (2 ×),
122.1, 122.0 (2 ×), 113.5, 112.8, 109.5, 106.8, 101.1, 84.0, 70.0, 56.4,
36.3, 26.6, 16.9; HRMS (DART-TOF) m/z calculated for C26H22NO5
[M + H]+: 428.1498; found: 428.1521.
rel-(7aS,8S)-10-(Benzyloxy)-7,7a-dimethyl-6,7,7a,8-tetra-
hydro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2,3-de]benzo[g]-
quinolin-8-ol (26). To a solution of 25 (42 mg, 0.098 mmol) in
anhydrous CH2Cl2 (5 mL) was added dropwise a solution of DIBAL-
H (25% in toluene, 200 μL, 0.3 mmol) under argon. The mixture was
stirred at room temperature for 20 min and then quenched by the
addition of saturated aqueous potassium sodium tartrate (Rochelle’s
salt) (5 mL). The mixture was stirred for another 1 h until two layers
separated; then the aqueous layer was extracted with CH2Cl2 (2 × 5
mL). The combined organic extracts were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography on silica gel (CH3OH/CH2Cl2,
5:95 to 10:90) to afford 26 (38 mg, 93%) as a white solid; mp 159−
160 °C; 1H NMR (CDCl3, 500 MHz) 8.01 (1 H, d, J = 8.5 Hz), 7.48−
7.32 (6 H, m), 6.93 (1 H, dd, J = 8.5, 3.0 Hz), 6.52 (1 H, s), 6.06 (1 H,
d, J = 2.0 Hz), 5.93 (1 H, d, J = 2.0 Hz), 5.17−5.11 (2 H, m), 5.03 (1
H, s), 3.58−3.51 (1 H, m), 3.09−2.99 (2 H, m), 2.53 (3 H, s), 2.48−
2.45 (1 H, m), 1.18 (3 H, s); 13C NMR (CDCl3, 125 MHz) 158.8,
146.8, 142.0, 139.9, 136.9, 128.5 (2 ×), 128.0, 127.9, 127.6 (2 ×),
127.0, 125.5, 121.5, 115.9, 113.3, 110.5, 107.3, 100.6, 71.2, 69.9, 60.1,
46.2, 36.1, 22.3, 19.4; HRMS (DART-TOF) m/z calculated for
C26H26NO4 [M + H]+: 416.1862; found: 416.1834.
10-(Benzyloxy)-7,7a-dimethyl-5,6,7,7a-tetrahydro-8H-[1,3]-
dioxolo[4′,5′:4,5]benzo[1,2,3-de]benzo[g]quinolin-8-one (27).
To a solution of 26 (32 mg, 0.077 mmol) and Dess−Martin
periodinane (68 mg, 0.16 mmol) was added anhydrous CH2Cl2 (3
mL) under argon. The reaction was stirred at room temperature for 1
h. After being quenched by the addition of 1 M Na2S2O3(aq), the
aqueous layer was extracted with CH2Cl2 (2 × 10 mL). Following
neutralization with saturated aqueous NaHCO3, the combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by column
chromatography on silica gel (CH3OH/CH2Cl2, 1:99 to 2:98) to
Preparation of 23. Method A. To a solution of 18a (150 mg,
0.35 mmol) in anhydrous CH2Cl2 (5 mL) was added BBr3 (1.0 M in
CH2Cl2, 1.75 mL, 1.75 mmol) under argon, and the reaction was
stirred at room temperature for 30 min. After being quenched by the
addition of saturated aqueous NaHCO3, the aqueous layer was
extracted with CH2Cl2 (2 × 10 mL). The combined filtrates were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by column chromatography on
silica gel (CH3OH/CH2Cl2, 1:99 to 5:95) to afford 23 (99 mg, 87%).
Preparation of 23. Method B. To a solution of 19a (25 mg,
0.058 mmol) in anhydrous CH2Cl2 (1 mL) was added BBr3 (1.0 M in
CH2Cl2, 300 μL, 0.3 mmol) under argon, and the reaction was stirred
at room temperature for 30 min. After being quenched by the addition
of saturated aqueous NaHCO3, the aqueous layer was extracted with
CH2Cl2 (2 × 10 mL). The combined filtrates were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated to afford a
crude intermediate. To a solution of the intermediate in CH3OH (10
mL) was added 10% Pd/C (5 mg), and the mixture was vigorously
stirred under an atmosphere of H2 at room temperature for 1 h. The
solid was removed by filtration through a Celite pad, and the filtrate
was concentrated. The residue was purified by column chromatog-
raphy (CH3OH/CH2Cl2, 1:99 to 5:95) to give 23 (15 mg, 79%) over
two steps.
rel-(31S,12bS)-7,8,11-Trihydroxy-31-methyl-31,4,5,12b-tetra-
hydro-2H-dibenzo[de,g]oxazolo[5,4,3-ij]quinolin-2-one (23). Pale
yellow solid; mp > 250 °C (decomposed); NMR data were collected
from material prepared by Method A: 1H NMR (CD3OD, 500 MHz)
8.27 (1 H, d, J = 8.5 Hz), 6.81−6.76 (2 H, m), 6.60 (1 H, s), 5.02 (1
H, s), 3.77−3.72 (1 H, m), 3.63−3.58 (1 H, m), 2.96−2.87 (2 H, m),
0.95 (3 H, s); 13C NMR (CD3OD, 125 MHz) 159.8, 158.1, 146.9,
144.0, 135.3, 132.5, 127.4, 124.4, 120.8, 117.7, 114.5, 113.7, 110.2,
86.6, 58.1, 37.9, 27.1, 17.0; HRMS (DART-TOF) m/z calculated for
C18H16NO5 [M + H]+: 326.1028; found: 326.1018.
Preparation of 24. Method A. To a solution of 22 (10 mg, 0.03
mmol) in 50% H2SO4 (0.5 mL) was added a cool solution of NaNO2
(4 mg, 0.06 mmol) in H2O (0.5 mL) at 0 °C, and the mixture was
stirred at 0 °C for 30 min. Then, the resulting mixture was poured into
boiling water (20 mL) and refluxed for 10 min. After being quenched
by slow addition of saturated aqueous NaHCO3, the aqueous layer was
extracted with EtOAc (2 × 20 mL). The combined organic extracts
were washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by column chromatography on
silica gel (CH3OH/CH2Cl2, 0:100 to 1:99) to afford 24 (9 mg, 89%).
Preparation of 24. Method B. To a solution of 23 (91 mg, 0.28
mmol) and K2CO3 (116 mg, 0.84 mmol) in anhydrous DMF (1 mL)
was added CH2I2 (25 μL, 0.31 mmol) under argon, and the mixture
H
DOI: 10.1021/acs.joc.6b02024
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
afford 27 (30 mg, 94%) as a pale yellow solid; mp 170−171 °C; H
NMR (CDCl3, 500 MHz) 8.31 (1 H, d, J = 8.5 Hz), 7.68 (1 H, d, J =
3.0 Hz), 7.47−7.33 (5 H, m), 7.26 (1 H, dd, J = 8.5, 3.0 Hz), 6.57 (1
H, s), 6.08 (1 H, d, J = 1.0 Hz), 6.01 (1 H, d, J = 1.0 Hz), 5.15 (2 H,
s), 3.55−3.50 (1 H, m), 3.11−3.02 (2 H, m), 2.59−2.54 (1 H, m),
2.39 (3 H, s), 1.55 (3 H, s); 13C NMR (CDCl3, 125 MHz) 199.6,
158.3, 146.9, 142.8, 136.3, 130.6, 128.9, 128.6 (2 ×), 128.1, 127.9,
127.6 (2 ×), 127.5, 127.1, 122.2, 114.0, 111.1, 108.2, 100.8, 70.2, 66.6,
45.6, 38.3, 28.0, 23.8; HRMS (DART-TOF) m/z calculated for
C26H24NO4 [M + H]+: 414.1705; found: 414.1687.
Modak, B.; Sobarzo-Sanchez, E. Curr. Top. Med. Chem. 2016, 16,
1906−1909.
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Rasamizafy, S.; Cave, A.; Moretti, C. J. Nat. Prod. 1983, 46, 335−341.
(c) Rabelo, D. d. M.; Pinheiro, M. L. B.; Barison, A.; Salome, K. S.;
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A. Tetrahedron 1982, 38,
́
́
́
Costa, E. V.; Araujo da Silva, F. M.; Chaves, Y. O.; Bastos, I. d. S.
Quim. Nova 2014, 37, 1453−1458.
( )-N-Methylguattescidine (3).5,13 To a solution of 27 (20 mg,
0.048 mmol) in CH3OH (10 mL) was added 10% Pd/C (4 mg), and
the mixture was vigorously stirred under an atmosphere of H2 at room
temperature for 2 h. The solid was removed by filtration through a
Celite pad, and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (CH3OH/CH2Cl2, 2:98 to 5:95)
to give ( )-3 (15 mg, 96%) as a pale yellow solid; mp > 250 °C
(5) Alias, A.; Hazni, H.; Jaafar, F. M.; Awang, K.; Ismail, N. H.
Molecules 2010, 15, 4583−4588.
(6) Sindhu, T.; Rajamanikandan, S.; Durgapriya, D.; Anitha, J. R.;
Akila, S.; Gopalakrishnan, V. K. Asian J. Pharm. Clin. Res. 2011, 4, 67−
71.
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(8) Galliani, G.; Rindone, B.; Suarez-Bertoa, R.; Saliu, F.; Terraneo,
A. Synth. Commun. 2013, 43, 749−757.
1
(decomposed); H NMR (CD3OD, 500 MHz) 8.27 (1 H, d, J = 8.5
Hz), 7.36 (1 H, d, J = 3.0 Hz), 7.12 (1 H, dd, J = 8.5, 3.0 Hz), 6.62 (1
H, s), 6.09 (1 H, d, J = 1.0 Hz), 6.02 (1 H, d, J = 1.0 Hz), 3.54−3.47 (1
H, m), 3.12−3.04 (1 H, m), 2.99−2.95 (1 H, m), 2.67−2.62 (1 H, m),
2.36 (3 H, s), 1.51 (3 H, s); 13C NMR (DMSO-d6, 125 MHz) 199.5,
157.3, 146.6, 142.1, 131.0, 128.7, 127.5, 127.4, 124.7, 121.4, 113.6,
112.6, 107.7, 100.9, 66.1, 45.4, 38.3, 26.2, 24.3; HRMS (DART-TOF)
m/z calculated for C19H18NO4 [M + H]+: 324.1236; found: 324.1232.
(9) Okada, H.; Mori, T.; Saikawa, Y.; Nakata, M. Tetrahedron Lett.
2009, 50, 1276−1278.
(10) Tuckmantel, W.; Oshima, K.; Utimoto, K. Tetrahedron Lett.
̈
1986, 27, 5617−5618.
́ ́ ́
(11) Kesȩ ru, G. M.; Mezey-Vandor, G.; Nogradi, M.; Vermes, B.;
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Kajtar-Peredy, M. Tetrahedron 1992, 48, 913−922.
(12) (a) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 1633−1635.
(b) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 2650−2653.
1
ASSOCIATED CONTENT
* Supporting Information
(13) The H NMR data of ( )-3 corresponded with the reported
■
natural product given a correction of two protons in the range of
3.12−2.95 ppm instead of three protons as previously reported (Dr.
Nor Hadiani Ismail, personal communication).
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b02024.
1
Copies of H and 13C spectra for reaction products and
2D NMR spectra for 8, rel-(4R,5S)-16a, rel-(4S,5S)-16a,
rel-(4R,5S)-16b, and 17a (PDF)
X-ray crystallographic data of 6 (CCDC 1495290) (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: gdcuny@central.uh.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to thank Dr. Charles L. Anderson for
assisting with the 2D NMR analyses, Dr. James D. Korp for
assisting with the X-ray crystallographic analysis, Dr. Nor
Hadiani Ismail for additional spectra information, and the
University of Houston for financial support.
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DOI: 10.1021/acs.joc.6b02024
J. Org. Chem. XXXX, XXX, XXX−XXX