Enantioselective total synthesis of desbromoarborescidines A-C and the formal synthesis of (S)-deplancheine

Article abstract of DOI:10.1021/jo401079v

Starting from Boc-protected tryptamine and (S)-tetrahydro-5-oxo-2- furancarboxylic acid, facile enantioselective total synthesis of desbromoarborescidines A-C and the formal synthesis of (S)-deplancheine have been accomplished via a common intermediate (S

Full text of DOI:10.1021/jo401079v

Note
pubs.acs.org/joc
Enantioselective Total Synthesis of Desbromoarborescidines A−C
and the Formal Synthesis of (S)‑Deplancheine
Pravat Mondal and Narshinha P. Argade*
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411 008, India
S
* Supporting Information
ABSTRACT: Starting from Boc-protected tryptamine and (S)-tetrahydro-5-oxo-2-furancarboxylic acid, facile enantioselective
total synthesis of desbromoarborescidines A−C and the formal synthesis of (S)-deplancheine have been accomplished via a
common intermediate (S)-indolo[2,3-a]quinolizine. Synthesis of enantiomerically pure (S)-acetoxyglutarimide, stereoselective
reductive intramolecular cyclization, hydroxyl group-assisted in situ N-Boc-deprotection, selective deoxygenation of the xanthate
ester, and lactam hydrolysis followed by an appropriate exchange of nitrogen regioselectivity in intramolecular cyclization were
the decisive steps.
he indole alkaloids have been imperative targets due to
their novel structural architectures, wide range of
escidines A−C have been known32,33 and based on synthesis of
proposed arborescidine D, a revision of structural assignment
has been recommended.32 Rawal and co-workers reported the
enantioselective total synthesis of antipodes of arborescidines
A−C and confirmed the assigned absolute stereochemistry of
these natural products.34 In continuance of our efforts to
synthesize structurally interesting and biologically important
natural and unnatural products from cyclic anhydrides and
derivatives as the potential precursors,35−38 we herein report
the enantioselective convergent access to desbromoarboresci-
dines A−C and (S)-deplancheine from (S)-acetoxyglutarimide
(Schemes 1−3).
A careful scrutiny of desbromoarborescidines A−C structures
and their retrosynthetic analysis revealed that they are the
analogous indole alkaloids containing skeletonal 15-carbon and
2-nitrogen atoms (Scheme 1). We reasoned that (S)-
acetoxyglutarimide has similar 15-carbon skeleton along with
appropriately placed 2-nitrogens and it would be a suitable
precursor for the synthesis of target compounds, namely, (i)
the (S)-acetoxy function would serve as best detachable handle
to embark the stereoselectivity, (ii) regioselective reduction of
an imide carbonyl to the lactamol followed by an intramolecular
stereoselective cyclization would provide an access to
desbromoarborescidine A and (iii) hydrolytic cleavage of δ-
lactam unit in the advanced intermediate (S)-indolo[2,3-
a]quinolizine followed by an alternate intramolecular cycliza-
tion utilizing the indole nitrogen atom would constitute a path
to desbromoarborescidines B and C.
T
promising biological activities and the current clinical
applications.1−6 More specifically, the indolo[2,3-a]quinolizine
template is of great significance due to its presence in several
exotic alkaloids such as ajmalicine, corynantheidine, magni-
florine, reserpine, vellosimine and vincamine.7−12 In 1966,
Johns and Lamberton isolated the analogous (S)-desbromoar-
borescidine A from the leaves of Dracontomelum mangife-
rum.13−16 In 1993, Pais and co-workers isolated another four
̈
new brominated alkaloids of the tetrahydro-β-carboline family,
the arborescidines A−D from a marine tunicate Pseudodistoma
arborescens (Figure 1).17,18 Arborescidines, desbromoarboresci-
Figure 1. Bioactive arborescidine alkaloids.13−18
dines and their analogs have been recently tested against human
gastric adenocarcinoma (AGS), lung cancer (SK-MES-1),
bladder carcinoma (J82) and leukemia (HL-60) cells, and
they exhibited antiproliferative activity (IC50, 9 to >100 μM).19
A few racemic and some well-designed asymmetric synthesis of
desbromoarborescidine A have been reported in the
literature.20−31 A straightforward racemic synthesis of arbor-
The enantiomerically pure starting material (S)-tetrahydro-5-
oxo-2-furancarboxylic acid (2) was prepared from (S)-glutamic
acid by using known procedure.39 EDCI induced dehydrative
Received: May 20, 2013
Published: June 12, 2013
© 2013 American Chemical Society
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Note
Scheme 1. Retrosynthetic Analysis of
Desbromoarborescidines A and C
Table 1. Base Catalyzed Rearrangement of (S)-
Amidolactone to (S)-Hydroxyglutarimide
a
b
entry t-BuOK (equiv)
temp. °C
time (h) % yield
% ee
1
2
3
4
5
6
0.60
0.50
0.50
0.45
0.45
−78 to −40
−78 to −40
−78 to −40
−78 to −50
−78 to −50
−78 to −50
3.00
3.00
2.00
2.00
1.50
2.00
82
72
68
66
65
56
68
80
89
91
96
92
0.40
b
a
Isolated yields. Determined by chiral HPLC.
the desired cyclized product 7 in very good yield with high
stereoselectivity (79%, 23:2 dr), via the N-acyliminium ion
intermediate.43 The present reaction was chemoselective as the
Boc-protection remained intact with the use of two equivalents
of TFA at lower temperature. In the transformation of 6 to 7,
the distinct enhancement in diastereoselectivity is attributed to
the formation of flat iminium ion intermediate followed by the
stereoselective intramolecular nucleophilic attack from the less
hindered β-side. However, the repetition of the above
experiment at −78 to 0 °C did not show any further refinement
in diastereoselectivity and/or yield. The mixture of diaster-
eoisomers 7 was quantitatively separated by using flash column
chromatography and the required major isomer retained 94%
enantiopurity (by HPLC). The major isomer 7 on treatment
with K2CO3/MeOH underwent both one-pot deacylation and
N-Boc-deprotection44 in four hours to exclusively provide the
product 9 in 92% yield. In the conversion of 7 to 9, tlc-
monitoring of the reaction progress indicated that one of the
intermediate formed has a sufficient life span and its isolation
would be feasible. Hence, the above-mentioned reaction was
arrested after one hour time and immediate silica gel column
chromatography of the reaction mass was performed. We could
successfully isolate the intermediate 8 in almost 26% yield along
with some amounts of both starting material and final product.
Thus, mechanistically the deacylation followed by an in situ
coupling reaction of Boc-protected tryptamine 1 with
enantiomerically pure acid 2 furnished the desired product 3
in 86% yield with 96% ee (by HPLC) (Scheme 2). Control
experiments on base-catalyzed rearrangement of amidolactone
3 to the desired (S)-hydroxyglutarimide 4 revealed that the
starting material is very much prone to racemize. Hence, the
yield and enantiomeric purity of formed ring expansion product
are highly dependent on molar amount of base used, reaction
temperature and time.40,41 The results obtained on the basis of
systematic studies on conversion of compound 3 to 4 have
been summarized in Table 1. The use of 0.45 equivalents of t-
BuOK at −78 to −50 °C in 1.50 h time furnished the product 4
in 65% yield with 96% enantiomeric purity (Table 1, entry 5).
The (S)-hydroxyl group in compound 4 was transformed to the
corresponding acetate 5 in 98% yield by using acetic anhydride
and triethylamine. The regioselective sodium borohydride
reduction of more reactive imide carbonyl group in compound
5 provided product 6 in 84% yield with ∼2:1 diastereomeric
1
ratio (by H NMR). Such type of lactamol units is known to
display the ring−chain tautomerism42 and hence to keep the
complete control on diastereoselectivity is a difficult task.
However, under controlled reaction conditions, the chemo-
selective trifluoroacetic acid induced intramolecular cyclization
of a masked aldehyde in compound 6 at −10 to 0 °C furnished
Scheme 2. Stereoselective Synthesis of Pivotal Intermediate (S)-Indolo[2,3-a]quinolizine: Formal Synthesis of (S)-
Deplancheine
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Note
Scheme 3. Synthesis of Enantiomerically Pure Desbromoarborescidines A−C from (S)-Indolo[2,3-a]quinolizine
intramolecular N-Boc-group migration to the proximal hydroxyl
oxygen function takes place to form the intermediate 8, which
on methanolysis provides product 9. The observed intra-
molecular 1,5-Boc migration is attributed to the geometrical
features and the unusual carbamate to carbonate transformation
is significant from a basic chemistry point of view. Finally, the
absolute and relative stereochemistry of product (−)-9 was
confirmed by using single crystal X-ray crystallographic data.
We feel that our present protocol will mirror to provide (+)-9
from the corresponding (R)-glutamic acid. At this stage, the
detachment of stereoselectivity handle, the (S)-hydroxyl group
in compound 9 was decided to obtain the product (S)-11. In
our hands, the preparation of mesylate derivative of compound
9 followed by its displacement by iodide resulted mostly in
elimination product owing to the higher acidity of an adjacent
methine proton. Alternatively, the chemoselective reaction of
compound 9 with excess of phenyl chlorothionoformate in the
presence of diisopropylethylamine exclusively provided the
xanthate ester 10 in 92% yield. The xanthate ester 10 was not
very stable and hence it was quickly filtered through the silica
gel column and immediately used for the next step. The
xanthate ester 10 on Barton−McCombie deoxygenation45
using tributyltin hydride in the presence of AIBN gave the
desired common chiral building block 11 in 54% yield (94% ee,
by HPLC). The analytical and spectral data obtained for
compound 11 were in complete agreement with the reported
data.30 Thus, the desired common intermediate 11 was
obtained in 8-steps with 15% overall yield. A seven-step
synthetic protocol to transform the compound 11 to (S)-
deplancheine (12, antipode) in very good overall yield is
known.30,46,47
In the next part of studies, syntheses of desbromoarbor-
escidines A−C were planned from an advanced intermediate 11
(Scheme 3). Aluminum hydride reduction of δ-lactam carbonyl
in compound 11 provided the natural product (S)-desbro-
moarborescidine A (13) in 82% yield. The exchange of
nitrogen regioselectivity in intermediate 11 was then envisioned
for synthesis of desbromoarborescidines B and C. The
hydrolytic cleavage of δ-lactam unit in compound 11 was
specifically intended under basic conditions to avoid
racemization issues.48 Compound 11 on hydrolysis with
aqueous KOH followed by an acidification provided product
14 in 85% yield. At this stage, a selective carbomethoxy
protection of piperidine nitrogen in compound 14 was
undertaken, as initially it would serve as a protecting group
and later on the source of essential methyl group. The
regioselective reaction of more reactive piperidine nitrogen with
methyl chloroformate in the presence of KOH gave the
corresponding carbamate derivative 15 in 72% yield. Com-
pound 15 on treatment with diazomethane formed the required
ester 16 in 86% yield (99% ee, by HPLC).49 DIBAL reduction
of ester 16 furnished the corresponding alcohol 17 in 73%
yield. The Dess−Martin periodinane oxidation of alcohol 17
formed aldehyde 18. However, all our attempts to isolate
aldehyde 18 in pure form were met with failure and it was
always contaminated with the further cyclized product 19 (by
1H NMR). The above mixture of products on stirring in
chloroform at room temperature for 18 h underwent the
smooth stereoselective intramolecular cyclization to exclusively
yield the desired trans-aminol (+)-19 in 72% yield. The
catalytic amount of hydrochloric acid present in the chloroform
was responsible for the above-mentioned intramolecular
cyclization. On the basis of NMR data, all four products 15−
19 were designated as the rotameric mixtures and are in
accordance with literature precedent.33 The conversion of
(+)-aminol 19 to (+)-desbromoarborescidines C and B has
been known in the literature.19 Similarly, alane reduction of
carbomethoxy group in compound (+)-19 to the methyl group
furnished the desired (3S,17S)-desbromoarborescidine C (20)
in 95% yield. (3S,17S)-Desbromoarborescidine C (20) on
treatment with Burgess reagent provided the corresponding
dehydration product (S)-desbromoarborescidine B (21) in 81%
yield. The analytical and spectral data obtained for
desbromoarborescidines A−C were in complete agreement
with reported data.17,18,32,33 Starting from Boc-protected
tryptamine 1,50 the desbromoarborescidines A/C/B (13/20/
21) were respectively obtained in 9/15/16 steps with 13/4/3%
overall yields.
In summary, we have demonstrated enantioselective
convergent approach to deplancheine and desbromoarboresci-
dines A−C from the corresponding (S)-acetoxyglutarimide. All
three different oxygen functions present in (S)-acetoxyglutar-
imide were rationally utilized in a remarkable chemo-, regio-
and stereoselective fashion to design these four desired
tantamount targets in very good overall yields and high
enantiomeric purities, using an appropriate protecting groups.
The present practical approach to these products is general in
nature and would be useful to synthesize their potential
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Note
2.25 (m, 2H), 2.20 (s, 3H), 2.58−2.78 (m, 1H), 2.78−2.98 (m, 3H),
3.89−4.13 (m, 2H), 5.45 (dd, J = 10 and 6 Hz, 1H), 7.18 (dt, J = 8 and
2 Hz, 1H), 7.24 (dt, J = 8 and 2 Hz, 1H), 7.36 (s, 1H), 7.63 (dd, J = 6
and 2 Hz, 1H), 8.04 (d, J = 8 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ
20.7, 23.1, 23.4, 28.1, 30.4, 40.3, 68.6, 83.4, 115.1, 117.0, 119.1, 122.5,
123.4, 124.4, 130.3, 135.4, 149.6, 169.1, 169.8, 170.6; ESIMS (m/z)
437 [M + Na]+; HRMS (ESI) calcd for C22H26N2O6Na 437.1683,
found 437.1675; IR (CHCl3) νmax 1734, 1686 cm−1.
analogues and congeners for SAR studies. The witnessed in situ
intramolecular Boc-group migration-deprotection is notable
from mechanistic point of view. The chiral intermediate
(1S,12R)-1-hydroxy-1,2,3,6,7,12b-hexahydroindolo[2,3-a]-
quinolizin-4(12H)-one (9) is noteworthy and it will serve as an
important synthon to design several other bioactive indole
alkaloids.
tert-Butyl 3-(2-((3S)-3-Acetoxy-2-hydroxy-6-oxopiperidin-1-yl)-
ethyl)-1H-indole-1-carboxylate (6). To a stirred solution of (S)-
acetoxyglutarimide 5 (2.00 g, 4.83 mmol) in MeOH/CH2Cl2 (2:1, 30
mL) was added NaBH4 (550 mg, 14.5 mmol) at −10 °C over 5 min.
The reaction mixture was stirred at 0 °C for 1 h and quenched with
saturated aq. NaHCO3 (5 mL). It was extracted with CH2Cl2 (75 mL
× 3) and the combined organic layer was washed with water, brine and
dried over Na2SO4. Concentration of organic layer in vacuo and silica
gel (60−120 mesh) column chromatographic purification of residue
using ethyl acetate−petroleum ether (8:2) as an eluent afforded
lactamol 6 (2:1 dr) as a thick oil (1.69 g, 84%). 1H NMR (CDCl3, 500
MHz) δ 1.66 (s, 9H), 2.01 (s, 1H), 2.08 (s, 2H), 2.10−2.35 (m, 2H),
2.40−2.64 (m, 2H), 2.93−3.08 (m, 2H), 3.50−3.63 (m, 1H), 3.75−
3.94 (m, 1H), 4.83−5.00 (m, 2H), 7.20−7.27 (m, 1H), 7.27−7.35 (m,
1H), 7.41 (s, 1H), 7.58−7.65 (m, 1H), 8.10 (br s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 20.4, 20.5, 20.9, 21.0, 23.7, 23.8, 27.4, 28.2, 29.3,
29.7, 45.9, 46.4, 69.5, 70.0, 79.8, 81.4, 83.5, 115.3, 117.8, 119.0, 119.1,
122.49, 122.53, 123.07, 123.11, 124.4, 130.3, 135.4, 149.7, 169.4,
169.9, 170.4; ESIMS (m/z) 439 [M + Na]+; HRMS (ESI) calcd for
C22H28N2O6Na 439.1840, found 439.1836; IR (CHCl3) νmax 3384,
1734, 1635 cm−1.
tert-Butyl (1S,12bR)-1-Acetoxy-4-oxo-1,3,4,6,7,12b-
hexahydroindolo[2,3-a]quinolizine-12(2H)-carboxylate (7). To a
stirred solution of lactamol 6 (3.50 g, 8.40 mmol) in CH2Cl2 (50
mL) at −10 °C was added TFA (1.36 mL, 16.8 mmol) and it was
stirred at −10 to 0 °C for 3.50 h. The reaction was quenched with
saturated aq. NaHCO3 (5 mL) and extracted with CH2Cl2 (75 mL ×
3). The combined organic layer was washed with brine and dried over
Na2SO4. Concentration of the organic layer in vacuo and silica gel
(230−400 mesh) column chromatographic purification of the residue
using ethyl acetate−petroleum ether (7:3) as an eluent afforded the
minor diastereomer (200 mg, 6%) and the required major
EXPERIMENTAL SECTION
■
General Description. Melting points are uncorrected. Mass
spectra were taken on MS-TOF mass spectrometer. HRMS (ESI)
were taken on Orbitrap (quadrupole plus ion trap) and TOF mass
analyzer. The IR spectra were recorded on an FT-IR spectrometer.
Commercially available starting materials and reagents were used.
tert-Butyl (S)-3-(2-(5-Oxotetrahydrofuran-2-carboxamido)ethyl)-
1H-indole-1-carboxylate (3). Solution of compound 150 (5.50 g, 21.13
mmol) in CH2Cl2 (40 mL) was added to a stirred suspension of acid 2
(2.75 g, 21.13 mmol) and EDCI (8.10 g, 42.26 mmol) in CH2Cl2 (80
mL) at 0 °C. To the reaction mixture was added Et3N (8.80 mL, 63.40
mmol) and stirred at rt for 24 h. The reaction was quenched with
water (25 mL) and extracted with CH2Cl2 (100 mL × 3). The extract
was washed with brine and dried over Na2SO4. Concentration of the
organic layer in vacuo and silica gel (60−120) column chromato-
graphic purification of residue using ethyl acetate−petroleum ether
(3:2) as an eluent gave product 3 (6.76 g, 86% yield; 96% ee). Mp
100−102 °C; [α]25 −13.6 (c 0.10 CHCl3); H NMR (CDCl3, 200
1
D
MHz) δ 1.67 (s, 9H), 2.17−2.40 (m, 1H), 2.43−2.68 (m, 3H), 2.94 (t,
J = 8 Hz, 2H), 3.63 (q, J = 8 Hz, 2H), 4.81 (t, J = 8 Hz, 1H), 6.59 (br
t, J = 4 Hz, 1H), 7.24 (dt, J = 8 and 2 Hz, 1H), 7.33 (dt, J = 8 and 2
Hz, 1H), 7.41 (s, 1H), 7.53 (dd, J = 6 and 2 Hz, 1H), 8.13 (d, J = 8
Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 24.9, 25.6, 27.4, 28.1, 38.9,
77.3, 83.6, 115.3, 117.1, 118.7, 122.5, 123.1, 124.5, 130.2, 135.5, 149.5,
169.4, 175.6; ESIMS (m/z) 395 [M + Na]+; HRMS (ESI) calcd for
C20H24N2O5Na 395.1577, found 395.1571; IR (CHCl3) νmax 3431,
3020, 1789, 1727, 1677 cm−1.
tert-Butyl (S)-3-(2-(3-Hydroxy-2,6-dioxopiperidin-1-yl)ethyl)-1H-
indole-1-carboxylate (4). Suspension of t-BuOK in THF (0.45 M,
5.35 mL) was added to a stirred solution of lactone 3 (2.00 g, 5.36
mmol) in THF (30 mL) at −78 °C over 10 min under argon
atmosphere. The reaction mixture was stirred at −50 °C for 30 min.
The reaction was quenched with saturated aq. NH4Cl (5 mL) and
concentrated in vacuo. To the residue was added ethyl acetate (150
mL) and the organic layer was washed with water, brine and dried over
Na2SO4. Concentration of the organic layer in vacuo and silica gel
(230−400 mesh) column chromatographic purification of the residue
using petroleum ether−ethyl acetate (1:1) as an eluent yielded (S)-
diastereomer 7 (2.44 g, 73% yield; 94% ee). Major isomer 7: Mp
1
63−65 °C; [α]25 −136.1 (c 0.10 CHCl3); H NMR (CDCl3, 200
D
MHz) δ 1.68 (s, 9H), 1.70−1.85 (m, 1H), 1.95−2.10 (m, 1H), 2.15 (s,
3H), 2.33−2.50 (m, 1H), 2.50−3.00 (m, 4H), 4.98−5.17 (m, 1H),
5.30−5.38 (m, 1H), 5.41−5.50 (m, 1H), 7.21−7.40 (m, 2H), 7.46 (dd,
J = 8 and 2 Hz, 1H), 8.00 (dd, J = 8 and 2 Hz, 1H); 13C NMR
(CDCl3, 50 MHz) δ 21.0, 21.4, 23.4, 27.3, 27.9, 40.6, 59.9, 70.6, 84.6,
115.2, 118.2, 120.7, 122.9, 124.8, 128.5, 131.8, 136.7, 150.2, 169.5,
169.6; ESIMS (m/z) 421 [M + Na]+; HRMS (ESI) calcd for
C22H26N2O5Na 421.1739, found 421.1724; IR (Nujol) νmax 1733,
1652 cm−1.
hydroxyglutarimide 4 (1.30 g, 65% yield; 96% ee). Mp 136−138 °C;
1
[α]25 −47.9 (c 0.108 CHCl3); H NMR (CDCl3, 200 MHz) δ 1.67
D
(s, 9H), 1.89 (dq, J = 12 and 6 Hz, 1H), 2.28−2.43 (m, 1H), 2.55−
2.75 (m, 1H), 2.83−3.00 (m, 1H), 2.93 (t, J = 6 Hz, 2H), 3.58 (br s,
1H), 3.93−4.28 (m, 3H), 7.28 (dt, J = 8 and 2 Hz, 1H), 7.34 (dt, J = 8
and 2 Hz, 1H), 7.45 (s, 1H), 7.70 (dd, J = 8 and 2 Hz, 1H), 8.13 (d, J
= 8 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 23.4, 25.2, 28.1, 30.7,
40.2, 68.2, 83.5, 115.2, 116.9, 119.0, 122.5, 123.3, 124.4, 130.3, 135.4,
149.6, 171.1, 175.1; ESIMS (m/z) 395 [M + Na]+; HRMS (ESI) calcd
for C20H24N2O5Na 395.1577, found 395.1571; IR (CHCl3) νmax 3517,
1730, 1679 cm−1.
(1S,12bR)-1-Hydroxy-2,3,6,7,12,12b-hexahydroindolo[2,3-a]-
quinolizin-4(1H)-one (9). Anhydrous K2CO3 (666 mg, 4.82 mmol)
was added to a stirred solution of acetate 7 (2.40 g, 6.02 mmol) in
MeOH (30 mL) at 0 °C. The reaction mixture was stirred for 4 h at rt
and concentrated in vacuo. The obtained residue on silica gel (230−
400 mesh) column chromatographic purification using ethyl acetate−
methanol (98:2) as an eluent afforded product 9 (1.42 g, 92%). Mp
1
247−249 °C; [α]25 −169.4 (c 0.10 MeOH); H NMR (DMSO-d6,
tert-Butyl (S)-3-(2-(3-Acetoxy-2,6-dioxopiperidin-1-yl)ethyl)-1H-
indole-1-carboxylate (5). To a stirred solution of hydroxyimide 4
(4.20 g, 11.28 mmol) in CH2Cl2 (50 mL) at 0 °C was added Et3N
(1.88 mL, 13.54 mmol), Ac2O (1.60 mL, 16.92 mmol) and DMAP (20
mg). The reaction mixture was stirred at rt for 4 h and quenched with
water (10 mL). It was extracted with CH2Cl2 (50 mL × 3) and the
combined organic layer was washed with saturated aq. NaHCO3, brine
and dried over Na2SO4. Concentration of the organic layer in vacuo
and silica gel (60−120 mesh) column chromatographic purification of
the residue using petroleum ether−ethyl acetate (6:4) as an eluent
afforded acetoxyimide 5 (4.60 g, 98%). Mp 104−106 °C; [α]25D −30.5
(c 0.106 CHCl3); 1H NMR (CDCl3, 200 MHz) δ 1.64 (s, 9H), 1.97−
D
500 MHz) δ 1.80−1.87 (m, 2H), 2.25−2.34 (m, 1H), 2.43 (td, J = 20
and 5 Hz, 1H), 2.57−2.70 (m, 2H), 2.79 (dt, J = 15 and 5 Hz, 1H),
3.90 (quintet, J = 5 Hz, 1H), 4.57 (d, J = 10 Hz, 1H), 4.80 (dd, J = 15
and 5 Hz, 1H), 5.90 (d, J = 5 Hz, 1H), 6.96 (t, J = 10 Hz, 1H), 7.04 (t,
J = 10 Hz, 1H), 7.38 (d, J = 10 Hz, 1H), 7.42 (d, J = 10 Hz, 1H), 10.38
(s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 21.0, 28.2, 29.7, 40.6,
60.0, 68.6, 108.0, 112.2, 118.1, 119.1, 121.5, 126.4, 133.8, 136.4, 168.7;
ESIMS (m/z) 279 [M + Na]+; HRMS (ESI) calcd for C15H17N2O2
257.1285, found 257.1281; IR (Nujol) νmax 3292, 1715, 1612 cm−1.
tert-Butyl ((1S,12bR)-4-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo-
[2,3-a]quinolizin-1-yl) carbonate (8). The above reaction was
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Note
performed on a 100 mg scale and arrested after 1 h. Similar work up
127.4, 135.1, 135.9; ESIMS (m/z) 227 [M + H]+; IR (CHCl3) νmax
3476, 1599 cm−1.
and column chromatographic purification afforded intermediate 8 (23
1
mg, 26%). Mp 74−76 °C; [α]25 −42.8 (c 0.50 CHCl3); H NMR
(S)-4-(2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)butanoic
Acid (14). Aqueous KOH (10%, 20 mL) was added to a stirred
solution of lactam 11 (300 mg, 1.25 mmol) in THF (4 mL) at rt. The
reaction mixture was heated at 100 °C for 36 h. It was neutralized by
addition of 2 N HCl at 0 °C. The product precipitated in between pH
8 to 7 was filtered and dried to obtain acid 14 (274 mg, 85%). Mp
D
(CDCl3, 500 MHz) δ 1.57 (s, 9H), 2.00−2.10 (m, 1H), 2.15−2.24 (m,
1H), 2.50−2.58 (m, 1H), 2.67−2.94 (m, 4H), 4.87 (d, J = 5 Hz, 1H),
4.98−5.04 (m, 1H), 5.09−5.18 (m, 1H), 7.14 (t, J = 10 Hz, 1H), 7.22
(t, J = 10 Hz, 1H), 7.37 (d, J = 10 Hz, 1H), 7.52 (d, J = 10 Hz, 1H),
8.58 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 20.9, 24.8, 27.8, 28.8,
40.8, 58.1, 74.6, 83.9, 110.9, 111.1, 118.4, 119.8, 122.5, 126.5, 130.5,
136.1, 152.8, 168.8; ESIMS (m/z) 357 [M + H]+; HRMS (ESI) calcd
for C20H25N2O4 357.1809, found 357.1806; IR (CHCl3) νmax 3473,
1746, 1635 cm−1.
1
198−200 °C; H NMR (D2O, 200 MHz) δ 1.69 (t, J = 6 Hz, 1H),
1.76 (t, J = 8 Hz, 1H), 1.91 (q, J = 8 Hz, 1H), 2.00−2.25 (m, 1H), 2.44
(t, J = 8 Hz, 2H), 2.90−3.04 (m, 2H), 3.20−3.38 (m, 1H), 3.65 (td, J
= 12 and 6 Hz, 1H), 4.45−4.57 (m, 1H), 7.13 (dt, J = 8 and 2 Hz,
1H), 7.24 (dt, J = 8 and 2 Hz, 1H), 7.43 (d, J = 8 Hz, 1H), 7.54 (d, J =
8 Hz, 1H); 13C NMR (D2O, 50 MHz) δ 20.3, 22.3, 33.2, 35.7, 44.0,
55.5, 108.6, 114.1, 120.9, 122.3, 125.2, 128.1, 131.4, 138.8, 180.5;
HRMS (ESI) calcd for C15H19N2O2 259.1441, found 259.1439; IR
(Nujol) νmax 3350, 1791, 1623 cm−1. NMR data of 14 was collected as
monohydrochloride for solubility reasons.
(1S,12bR)-4-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]-
quinolizin-1-yl phenyl carbonate (10). Anhydrous DIPEA (1.02 mL,
5.85 mmol) was added to a stirred solution of alcohol 9 (500 mg, 1.95
mmol) and DMAP (71.5 mg, 0.59 mmol) in CH2Cl2 (30 mL) at −40
°C under argon atmosphere and stirred for 10 min. To the reaction
mixture was added o-phenyl chlorothionoformate (0.81 mL, 5.85
mmol) and stirred at −15 to 0 °C for 4 h. Concentration of reaction
mixture in vacuo and silica gel (60−120 mesh) column chromato-
graphic purification of residue using petroleum ether−ethyl acetate
(6:4) as an eluent afforded xanthate 10 (704 mg, 92%). Mp 82−84 °C;
[α]25D −48.1 (c 0.104 CHCl3); 1H NMR (CDCl3, 500 MHz) δ 2.20−
2.40 (m, 2H), 2.58−2.68 (m, 1H), 2.73−2.88 (m, 2H), 2.88−3.05 (m,
2H), 5.10−5.30 (m, 2H), 5.78 (s, 1H), 7.13−7.60 (m, 9H), 8.55 (s,
1H); 13C NMR (CDCl3, 125 MHz) δ 21.0, 23.7, 28.3, 41.3, 58.0, 80.2,
111.2, 111.6, 118.5, 120.0, 121.7, 122.7, 126.6, 127.0, 129.7, 129.8,
136.2, 153.0, 168.4, 193.9; ESIMS (m/z) 415 [M + Na]+; HRMS
(ESI) calcd for C22H20N2O3SNa 415.1087, found 415.1082; IR
(CHCl3) νmax 3361, 1714, 1652 cm−1.
(S)-2,3,6,7,12,12b-Hexahydroindolo[2,3-a]quinolizin-4(1H)-one
(11). To a stirred solution of ester 10 (500 mg, 1.27 mmol) and AIBN
(21 mg, 0.13 mmol) in dry toluene (20 mL) was added n-Bu3SnH
(0.55 mL, 2.05 mmol) at rt for 15 min under argon atmosphere. The
reaction mixture was heated at 80 °C for 2 h and toluene was distilled
off in vacuo. The obtained residue was dissolved in acetonitrile (40
mL) and washed with hexane (15 mL × 3). Concentration of the
acetonitrile layer in vacuo and silica gel (230−400 mesh) column
chromatographic purification of the residue using ethyl acetate as an
(S)-4-(2-(Methoxycarbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-
indol-1-yl)butanoic Acid (15). Solution of KOH (117 mg, 2.09
mmol) in water (2 mL) was added at 0 °C to a stirred suspension of
amine 14 (270 mg, 1.05 mmol) in acetone:water (1:1, 8 mL).
Reaction mixture was stirred for 10 min and methyl chloroformate
(0.09 mL, 1.15 mmol) was added. It was stirred for 2 h at 0 °C and
neutralized with 2 N HCl. Acetone was removed in vacuo and residue
was extracted with ethyl acetate (20 mL × 3). Combined organic layer
was washed with brine and dried over Na2SO4. Concentration of
organic layer in vacuo and silica gel (60−120 mesh) column
chromatographic purification of residue using petroleum ether−ethyl
acetate (1:9) as an eluent provided carbamate 15 (238 mg, 72%). Mp
56−58 °C; [α]25 +77.0 (c 0.48 CHCl3); 1H NMR (CDCl3, 400
D
MHz) δ 1.80 (br s, 3H), 1.90 (br s, 1H), 2.41 (br s, 2H), 2.64 (s,
0.35H), 2.68 (s, 0.65H), 2.79 (br s, 1H), 3.16 (br d, J = 12 Hz, 1H),
3.71 (s, 1.05H), 3.75 (s, 1.95H), 4.30 (d, J = 12 Hz, 0.65H), 4.48 (d, J
= 8 Hz, 0.35H), 5.16 (s, 0.35H), 5.34 (s, 0.65H), 6.95−7.15 (m, 2H),
7.25 (d, J = 8 Hz, 1H), 7.43 (d, J = 8 Hz, 1H), 8.32 (s, 0.35H), 8.57 (s,
0.65H), 8.50−9.50 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 21.0,
21.1, 21.4, 33.4, 33.7, 34.0, 38.3, 38.5, 51.1, 52.9, 53.0, 107.8, 108.5,
111.0, 117.9, 118.1, 119.3, 121.7, 126.6, 133.6, 134.0, 136.0, 156.4,
156.9, 178.4; ESIMS (m/z) 339 [M + Na]+; HRMS (ESI) calcd for
C17H21N2O4 317.1496, found 317.1494; IR (CHCl3) νmax 3333,
2700−2500, 1700, 1685 cm−1.
eluent afforded product 11 (165 mg, 54% yield; 94% ee). Mp 194−196
1
°C; [α]25 −220.2 (c 0.10 CHCl3); H NMR (CDCl3, 500 MHz) δ
D
1.70−2.00 (m, 3H), 2.35−2.55 (m, 2H), 2.55−2.65 (m, 1H), 2.72−
2.95 (m, 3H), 4.80 (dd, J = 10 and 5 Hz, 1H), 5.13−5.24 (m, 1H),
7.13 (t, J = 10 Hz, 1H), 7.19 (t, J = 10 Hz, 1H), 7.35 (d, J = 10 Hz,
1H), 7.52 (d, J = 10 Hz, 1H), 8.30 (br s, 1H); 13C NMR (CDCl3, 125
MHz) δ 19.4, 21.0, 29.0, 32.4, 40.2, 54.4, 109.5, 110.9, 118.4, 119.8,
122.1, 126.8, 133.3, 136.2, 169.3; ESIMS (m/z) 241 [M + H]+; HRMS
(ESI) calcd for C15H17N2O 241.1335, found 241.1332; IR (CHCl3)
νmax 3283, 1733, 1623 cm−1.
Methyl (S)-1-(4-Methoxy-4-oxobutyl)-1,3,4,9-tetrahydro-2H-
pyrido[3,4-b]indole-2-carboxylate (16). Diazomethane in ether was
added at 0 °C to a stirred solution of acid 15 (230 mg, 0.73 mmol) in
ether and THF (1:1, 6 mL) until persistence of a yellow color.
Reaction mixture was stirred at 0 °C for 30 min and concentrated in
vacuo. Silica gel (60−120 mesh) column chromatographic purification
of the residue using petroleum ether−ethyl acetate (6:4) as an eluent
afforded ester 16 as a gum (206 mg, 86% yield; 99% ee). [α]25D +91.0
1
(S)-1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizine (Des-
bromoarborescidine A, 13). To a stirred slurry of AlCl3 (22 mg,
0.16 mmol) in THF (4 mL) was added suspension of LiAlH4 (21 mg,
0.55 mmol) in THF (2 mL) at 0 °C under argon atmosphere. After
stirring for 10 min, a solution of lactam 11 (44 mg, 0.18 mmol) in
THF (2 mL) was added to the reaction mixture. It was stirred for 30
min at rt and quenched with saturated aq. NH4Cl (2 mL). The
reaction mixture was filtered through Celite and the residue was
washed with ethyl aceatate (10 mL × 3). The filtrate was dried over
Na2SO4 and concentrated in vacuo. Silica gel (230−400 mesh) column
chromatographic purification of the residue using chloroform−
(c 0.14 CHCl3); H NMR (CDCl3, 200 MHz) δ 1.85 (quintet, J = 6
Hz, 4H), 2.43 (t, J = 8 Hz, 2H), 2.60−3.00 (m, 2H), 3.05−3.30 (m,
1H), 3.69 (s, 3H), 3.75 (s, 3H), 4.25−4.60 (br m, 1H), 5.19 (br s,
0.35H), 5.33 (br s, 0.65H), 7.09 (t, J = 8 Hz, 1H), 7.16 (t, J = 8 Hz,
1H), 7.32 (d, J = 8 Hz, 1H), 7.47 (d, J = 8 Hz, 1H), 8.08 (br s, 0.35H),
8.18 (br s, 0.65H); 13C NMR (CDCl3, 100 MHz) δ 21.0, 21.3, 33.5,
33.9, 34.2, 38.3, 38.5, 51.0, 51.6, 52.8, 107.9, 108.6, 110.9, 117.9, 119.3,
121.6, 126.7, 133.7, 134.1, 136.0, 156.3, 156.6, 174.1; ESIMS (m/z)
353 [M + Na]+; HRMS (ESI) calcd for C18H23N2O4 331.1652, found
331.1648; IR (CHCl3) νmax 3331, 1735, 1685, 1623 cm−1.
Methyl (S)-1-(4-Hydroxybutyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-
b]indole-2-carboxylate (17). DIBAL solution (1 M in cyclohexane,
0.60 mL) was added at −78 °C to a stirred solution of ester 16 (200
mg, 0.60 mmol) in THF (8 mL) under argon atmosphere. The
reaction mixture was stirred for 4 h to reach rt. It was quenched with
saturated aq. potassium sodium tartrate (4 mL), stirred for 1 h and
concentrated in vacuo. The obtained residue was extracted with
CH2Cl2 (25 mL × 3) and the combined organic layer was washed with
brine and dried over Na2SO4. Concentration of the organic layer in
vacuo and silica gel (230−400 mesh) column chromatographic
methanol (9:1) as an eluent afforded desbromoarborescidine A (13)
1
(34 mg, 82%). Mp 148−150 °C; [α]25 −80.5 (c 0.10 CHCl3); H
D
NMR (CDCl3, 400 MHz) δ 1.42−1.57 (m, 1H), 1.60 (dq, J = 12 and
4 Hz, 1H), 1.70−1.85 (m, 2H), 1.91 (d, J = 12 Hz, 1H), 2.06 (dd, J =
12 and 4 Hz, 1H), 2.41 (dt, J = 12 and 4 Hz, 1H), 2.60−2.78 (m, 2H),
2.98−3.09 (m, 2H), 3.10 (t, J = 4 Hz, 1H), 3.24 (d, J = 8 Hz, 1H), 7.11
(t, J = 8 Hz, 1H), 7.15 (t, J = 8 Hz, 1H), 7.30 (d, J = 8 Hz, 1H), 7.50
(d, J = 8 Hz, 1H), 7.80 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ
21.5, 24.3, 25.7, 29.9, 53.5, 55.7, 60.2, 108.0, 110.7, 118.1, 119.3, 121.2,
6806
dx.doi.org/10.1021/jo401079v | J. Org. Chem. 2013, 78, 6802−6808

The Journal of Organic Chemistry
Note
purification of residue using ethyl acetate−petroleum ether (8:2) as an
escidine B (21) (38 mg, 81%). Mp 98−100 °C; [α]25 +62.1 (c 0.36
D
1
eluent afforded alcohol 17 (134 mg, 73%). Mp 56−58 °C; [α]25
CHCl3); H NMR (CDCl3, 400 MHz) δ 1.91 (dq, J = 12 and 4 Hz,
D
+89.9 (c 0.50 CHCl3); 1H NMR (CDCl3, 200 MHz) δ 1.40−1.75 (m,
4H), 1.75−2.07 (m, 2H), 2.60−3.00 (m, 2H), 3.05−3.35 (m, 1.30H),
3.35−3.55 (m, 0.70H), 3.55−3.75 (m, 2H), 3.83 (s, 3H), 4.38 (dd, J =
10 and 2 Hz, 0.70H), 4.54 (d, J = 10 Hz, 0.30H), 5.21 (br s, 0.30H),
5.40 (br s, 0.70H), 7.05−7.24 (m, 2H), 7.32 (dd, J = 8 and 2 Hz, 1H),
7.51 (dd, J = 8 and 2 Hz, 1H), 8.81 (br s, 0.30H), 9.26 (br s, 0.70H);
13C NMR (CDCl3, 100 MHz) δ 21.0, 21.4, 22.3, 22.5, 32.1, 34.1, 34.4,
1H), 2.34−2.50 (m, 2H), 2.50−2.63 (m, 1H), 2.57 (s, 3H), 2.70−2.80
(m, 2H), 2.90−3.02 (m, 1H), 3.18 (dd, J = 12 and 4 Hz, 1H), 3.45 (d,
J = 12 Hz, 1H), 5.07 (td, J = 8 and 4 Hz, 1H), 6.95 (d, J = 12 Hz, 1H),
7.15 (t, J = 8 Hz, 1H), 7.22 (t, J = 8 Hz, 1H), 7.35 (d, J = 8 Hz, 1H),
7.49 (d, J = 8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.6, 28.0,
29.9, 42.4, 52.8, 62.5, 109.1, 109.2, 110.0, 118.2, 120.2, 121.8, 122.0,
126.9, 136.1, 137.1; ESIMS (m/z) 239 [M + H]+; IR (Nujol) νmax
1674 cm−1.
38.3, 38.4, 51.4, 51.7, 52.6, 52.9, 62.2, 107.3, 108.0, 110.9, 117.8, 118.0,
119.0, 119.1, 121.3, 121.5, 126.5, 134.0, 134.5, 136.0, 156.4, 156.8;
ESIMS (m/z) 325 [M + Na]+; IR (CHCl3) νmax 3405, 3468, 1684,
1623 cm−1.
ASSOCIATED CONTENT
■
S
* Supporting Information
Methyl (3aS,7S)-7-Hydroxy-1,3a,4,5,6,7-hexahydro-3,7a-diaza-
cyclohepta[jk]fluorene-3(2H)-carboxylate (19). To a stirred solution
of alcohol 17 (130 mg, 0.43 mmol) in CH2Cl2 (6 mL) at 0 °C was
added Dess−Martin periodinane (274 mg, 0.65 mmol) and pyridine
(0.05 mL, 0.65 mmol). It was stirred for 30 min and quenched with a
mixture of aq. sodium thiosulphate (40%, 2 mL) plus saturated aq.
NaHCO3 (2 mL). It was extracted with CH2Cl2 (20 mL × 3) and the
combined organic layer was washed with brine and dried over Na2SO4.
Concentration of the organic layer in vacuo and silica gel (60−120
mesh) column chromatographic purification of the residue using ethyl
acetate−petroleum ether (1:1) as an eluent resulted in the mixture of
1H NMR, 13C NMR and DEPT spectra of compounds 3−11,
13−17 and 19−21. HPLC data for the enantiomeric purity of
the compounds 3, 4, 7, 11 and 16. X-ray crystallographic data
(CIF), and the ORTEP diagram for compound 9. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: np.argade@ncl.res.in
1
aldehyde 18 and further cyclized product 19 as a thick oil (by H
Notes
NMR). The mixture of products was stirred in chloroform (8 mL) at rt
for 18 h. Concentration of the chloroform solution in vacuo and silica
gel (60−120 mesh) column chromatographic purification of the
residue using petroleum ether−ethyl acetate (6:4) as an eluent
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
afforded product 19 as a gum (93 mg, 72%). [α]25 +110.4 (c 0.25
D
Dedicated to Professor K. N. Ganesh, IISER, Pune on the
occasion of his 60th birthday. N.P.A. thanks Department of
Science and Technology, New Delhi for financial support. P.M.
thanks CSIR, New Delhi, for the award of research fellowship.
We thank Mrs. S. S. Kunte from NCL, Pune, for the HPLC
data. We thank Mr. Arijit Mallick from NCL, Pune, for the X-
ray data.
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.62 (t, J = 12 Hz, 1H), 1.80
(d, J = 8 Hz, 2H), 2.00−2.14 (m, 1H), 2.25−2.50 (m, 2H), 2.60−2.82
(m, 2H), 3.04 (t, J = 12 Hz, 1.50H), 3.28 (br s, 0.50H), 3.72 (s,
1.50H), 3.74 (s, 1.50H), 4.31 (d, J = 12 Hz, 0.50H), 4.49 (d, J = 12
Hz, 0.50H), 5.31 (d, J = 12 Hz, 0.50H), 5.41 (d, J = 12 Hz, 0.50H),
6.23 (d, J = 4 Hz, 1H), 7.11 (t, J = 8 Hz, 1H), 7.19 (t, J = 8 Hz, 1H),
7.32 (d, J = 8 Hz, 1H), 7.45 (d, J = 8 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 19.5, 21.3, 21.6, 33.3, 33.9, 38.8, 39.1, 52.4, 52.7, 52.8, 76.1,
108.4, 108.9, 109.6, 118.2, 118.3, 119.47, 119.53, 121.55, 121.64,
126.3, 135.7, 136.5, 155.7, 156.0; ESIMS (m/z) 323 [M + Na]+; IR
(CHCl3) νmax 3384, 1683, 1615 cm−1.
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■
(3aS,7S)-3-Methyl-1,2,3,3a,4,5,6,7-octahydro-3,7a-diazacyclo-
hepta[jk]fluoren-7-ol (Desbromoarborescidine C, 20). To a stirred
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was added a solution of AlH3 (1.55 M, 0.40 mL, 0.60 mmol) and the
reaction mixture was stirred for 2 h under an argon atmosphere. It was
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escidine C (20) (73 mg, 95%). Mp 140−142 °C; [α]25 +3.2 (c 0.25
D
1
CHCl3); H NMR (CDCl3, 400 MHz) δ 1.51 (dq, J = 12 and 4 Hz,
1H), 1.66 (qt, J = 12 and 4 Hz, 1H), 1.80−1.90 (m, 1H), 2.20 (tq, J =
12 and 4 Hz, 1H), 2.30−2.41 (m, 2H), 2.56 (s, 3H), 2.73−2.88 (m,
1H), 2.81 (d, J = 4 Hz, 2H), 3.11 (quintet, J = 8 Hz, 1H), 3.80 (d, J =
8 Hz, 1H), 6.24 (dd, J = 8 and 4 Hz, 1H), 7.11 (dt, J = 8 and 4 Hz,
1H), 7.19 (dt, J = 8 and 4 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.48 (d, J =
8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 19.8, 20.1, 32.0, 34.2, 42.2,
50.4, 61.4, 76.4, 108.4, 108.6, 118.3, 119.4, 121.4, 126.5, 136.1, 136.7;
ESIMS (m/z) 257 [M + H]+; IR (Nujol) νmax 3365, 1612 cm−1.
(S)-3-Methyl-1,2,3,3a,4,5-hexahydro-3,7a-diazacyclohepta[jk]-
fluorene (Desbromoarborescidine B, 21). Burgess reagent (95 mg,
0.40 mmol) was added at rt to a stirred solution of aminol 20 (50 mg,
0.20 mmol) in benzene (10 mL) under an argon atmosphere. The
reaction mixture was refluxed for 8 h and diluted with ethyl acetate (25
mL). The organic layer was washed three times with brine and dried
over Na2SO4. Concentration of the organic layer in vacuo and silica gel
(230−400 mesh) column chromatographic purification of the residue
using CH2Cl2−methanol (95:5) as an eluent afforded desbromoarbor-
6807
dx.doi.org/10.1021/jo401079v | J. Org. Chem. 2013, 78, 6802−6808

The Journal of Organic Chemistry
Note
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