Synthesis of reported and revised structures of amathamide D and synthesis of convolutamine F, H and lutamide A, C

Article abstract of DOI:10.1021/jo3000173

Total synthesis of the published structure of amathamide D is described. Methyl 2,3,4-tribromo-5-hydroxybenzoate was selected as starting compound because it is readily accessible via acid-mediated Grob fragmentation- aromatization reaction of 1,4,5,6-tetrabromo-7,7-dimethoxybicyclo[2.2.1]hept-5- en-2-one. The aforementioned ester was transformed into the reported structure of amathamide D through methylation of a hydroxyl group and conversion of the ester moiety to a β-aminoethyl side chain. The NMR data of the synthetic compound did not conform to the reported natural product structure possessing contiguously positioned β-aminoethyl side chain, a set of three adjacent bromines, and a methyl ether linkage on the phenyl ring. This prompted us to redefine the natural product structure by synthesizing a product whose spectral data exactly matched with the reported data of amathamide D. The convolutamine H, with completely substituted phenyl ring adorned with an extra methyl ether functional group, has also been synthesized by application of Grob fragmentation-aromatization strategy to 3-(benzyloxy)-1,4,5,6-tetrabromo-7,7- dimethoxybicyclo[2.2.1]hept-5-en-2-one. This approach furnished directly methyl 2,3,4-tribromo-5,6-dimethoxybenzoate, which was converted straightforwardly into convolutamine H. Further, synthesis of convolutamine F and lutamide A and C is also described.

Full text of DOI:10.1021/jo3000173

Article
pubs.acs.org/joc
Synthesis of Reported and Revised Structures of Amathamide D and
Synthesis of Convolutamine F, H and Lutamide A, C
Faiz Ahmed Khan*,†,‡ and Saeed Ahmad‡
†Department of Chemistry, Indian Institute of Technology Hyderabad, Ordnance Factory Estate, Yeddumailaram-502205, India
‡Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016, India
S
* Supporting Information
ABSTRACT: Total synthesis of the published structure of amathamide D is
described. Methyl 2,3,4-tribromo-5-hydroxybenzoate was selected as starting
compound because it is readily accessible via acid-mediated Grob fragmentation−
aromatization reaction of 1,4,5,6-tetrabromo-7,7-dimethoxybicyclo[2.2.1]hept-5-en-
2-one. The aforementioned ester was transformed into the reported structure of
amathamide D through methylation of a hydroxyl group and conversion of the ester
moiety to a β-aminoethyl side chain. The NMR data of the synthetic compound did
not conform to the reported natural product structure possessing contiguously
positioned β-aminoethyl side chain, a set of three adjacent bromines, and a methyl
ether linkage on the phenyl ring. This prompted us to redefine the natural product
structure by synthesizing a product whose spectral data exactly matched with the
reported data of amathamide D. The convolutamine H, with completely substituted
phenyl ring adorned with an extra methyl ether functional group, has also been
synthesized by application of Grob fragmentation−aromatization strategy to 3-(benzyloxy)-1,4,5,6-tetrabromo-7,7-
dimethoxybicyclo[2.2.1]hept-5-en-2-one. This approach furnished directly methyl 2,3,4-tribromo-5,6-dimethoxybenzoate,
which was converted straightforwardly into convolutamine H. Further, synthesis of convolutamine F and lutamide A and C
is also described.
overall yield of 53%. Convolutamine H (11) is a nematocidal
brominated marine alkaloid.3c It was found to be more potent
than levamisole, a commercially available anthelmintic.
Convolutamine H might be a precursor in biosynthesis of
amathamide G, a tribrominated proline derived alkaloid. It was
also suggested that β-phenylethyl amine, isolated from Amathia
wilsoni, could be a biosynthetic precursor for various
amathamides.2c
The presence of three contiguous bromines on the phenyl
ring in some members of amathamides and convolutamines was
a particularly striking feature that attracted our attention. The
construction of aryl derivatives with three adjacent bromine
atoms poses a formidable challenge since a straightforward
installation through aromatic electrophilic substitution reac-
tions is not a viable method to access them. The presence of a
strong activating methoxy group is another major deterrent. A
very interesting and noteworthy strategy reported by Weinreb’s
group for the synthesis of chartelline A (12) involves an
indirect installation of three bromines,5 the most difficult
central bromine substituent being installed by utilizing an
amine group as surrogate for bromine via modified Sandmeyer
reaction. The activating amine functionality on the aryl ring in
which the para position is already blocked facilitated the ortho
bromination at two free adjacent positions. This strategy cannot
INTRODUCTION
■
The hunt for new structural entities as potential pharmaceutical
agents is a never ending endeavor, and marine organisms have
been one among the most promising sources of natural
products as a result of their wide ranging biological activity
profile. They are relatively less explored compared to other
traditional sources, though the number of new marine natural
products being discovered is continuously growing. Organo-
halogens constitute about 15−20% of all newly discovered
marine natural products.1 Amathamides are brominated
alkaloids and were isolated from the bryozoan Amathia genus
(1−8, Figure 1).2 The biological activities of isolated
amathamides were not investigated extensively, while ama-
thamide C and H were found to possess moderate antimalarial
and antitrypanosomal activity.
Convolutamines A−H were isolated from Floridian marine
bryozoan Amathia convoluta.3 They resemble amathamides in
having a β-nitrogen functionality and bromine(s) as well as a
methyl ether linkage on the aryl moiety. Convolutamine F (9)
displayed the biological activity against human epidermoid
carcinoma KB cells and its vincristine-resistant KB/VJ-300 cells
and also showed inhibitory effects for cell division of fertilized
sea urchin eggs.3b Until now, only one synthesis of convolut-
amine F is reported in the literature, which involves 7 steps
with 44% overall yield from 3-hydroxyphenylacetic acid.4 We
herein report a straightforward synthesis of convolutamine F
from readily available 3-hydroxybenzaldehyde in 5 steps with an
Received: January 4, 2012
Published: February 1, 2012
© 2012 American Chemical Society
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Figure 1. Structures of some marine-originated alkaloids.
Scheme 1. Synthesis of Amathamide D (8) (Structure As Published in the Literature) and Its Antipode (20)
be extended to amathamides and convolutamines due to lack of
a blocking para substituent. Second, the presence of a methoxy
unit is a further complicating factor. Recently, methods that
build up the aromatic ring starting from aliphatic precursors
(benzannulation methods) have been developed.6 These
methods, although offering better regiochemical control in
certain cases, are not completely unrestrictive.
In order to explore the synthetic efficacy of our previously
discovered methodology of synthesizing substituted bromo-
phenol derivatives starting from differently substituted 1,4,5,6-
tetrabromo-7,7-dimethoxy norbornene skeleton, we became
interested in synthesis of some of these brominated alkaloids of
marine origin. Herein we report synthesis and structure revision
of amathamide D along with the synthesis of some other
marine alkaloids.
RESULTS AND DISCUSSION
■
Methyl 2,3,4-tribromo-5-hydroxybenzoate 14 is easily acces-
sible via acid-mediated Grob fragmentation aromatization
reaction from 1,4,5,6-tetrabromo-7,7-dimethoxybicyclo[2.2.1]-
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hept-5-en-2-one 13 in quantitative yield by our previously
reported methodology.7 The ester group in 14 could be
conveniently converted in the desired substituted β-aminoethyl
side chain. First, hydroxyl group in 14 was methylated using
MeI. Since a direct conversion of ester to aldehyde group was
problematic due to over-reduction, a two-step procedure
involving a reduction (DIBAL-H)−oxidation (PCC) sequence
was used to obtain 16.8 Aldehyde 16 was converted into α,β-
unsaturated nitro compound 17 by refluxing with CH3NO2 in
presence of NH4OAc.8,9 Our initial attempts for the reduction
of nitroethylene moiety of 17 with reagents such as LiAlH4, Fe/
HCl, Pd−C/H2, PtO2/H2, and Na2S/NaHCO3 failed to yield
the desired saturated amine. Finally we succeeded in obtaining
the amine as hydrochloride salt 18 using BH3·SMe2.10 Because
the free amine was not stable, it was converted into
hydrochloride salt by using a saturated solution of anhydrous
HCl in dioxane. Coupling reaction between 18 and N-methyl-L-
proline11a was performed using DCC to get amide 8. Otherwise
when the Boc-protected amine 19 was utilized directly we
obtained the amide 8 with enhanced yield via a protocol
comprising deprotection with TFA, followed by coupling12
with N-methyl-L-proline. The product 8 (Scheme 1), thus
obtained should correspond to the published structure of
Scheme 2. Synthesis of Amathamide D (24) for Structure
Revision
The so obtained 2-(2,4,6-tribromo-3-methoxyphenyl)-
ethanamine 23 was coupled with N-methyl-L-proline using
DCC as a coupling reagent. The reaction proceeded slowly and
gave poor yield. Changing the coupling reagent to EDC·HCl
furnished 67% yield of the amide 24. The spectroscopic data
(1H and 13C NMR) of 24 was found to be in accordance with
the literature reported values of natural amathamide D. Figure 2
1
amathamide D. However, a comparison of H and 13C NMR
values revealed that it is not in conformity with published data,
indicating the need for a revision of the structure for
1
amathamide D. The most prominent difference in H NMR
was for Ar−H with a 0.93 ppm variation, while in 13C NMR,
peaks in the aromatic region displayed variations ranging
between 2 and 6 ppm. Since optical rotation data for
amathamide D was not reported in the literature, we
determined the specific rotation for 8. Further, we synthesized
its antipode 20 by coupling N-methyl-D-proline11b with Boc
amine 19 and measured its specific rotation as well. This
exercise was done keeping in mind the fact that the assignment
of absolute configuration for the published structure of
amathamide D was based on the extrapolation of circular
dichroism (CD) studies carried out for amathamide A and B.
In order to determine the correct structure for amathamide
D, we looked at some of the closely related aromatic derivatives
possessing bromine substituents at the 1,3,5-positions relative
to each other. The reported chemical shift value for Ar−H at δ
1
represents a H NMR comparison of published and revised
structures of amathamide D.
1
7.75 ppm in the H NMR spectrum strongly pointed out that
the three bromines could be symmetrically substituted instead
of being contiguous as proposed. In order to prove this
unambiguously, we thought of synthesizing the molecule with
symmetrically substituted bromines. For this purpose we chose
2,4,6-tribromo-3-methoxybenzaldehyde 21 (Scheme 2) as our
starting material for the structure revision of amathamide D,
which was prepared according to the literature method.13
Attempts to synthesize (E)-1,3,5-tribromo-2-methoxy-4-(2-
nitrovinyl)benzene 22 according to literature procedure using
CH3NO2 and AcOH/NH4OAc under reflux condition always
1
furnished, in our hands, a mixture of 21 and 22 (based on H
NMR). We then followed a two-step protocol for the synthesis
of 22 via Henry reaction followed by dehydration with conc
H2SO4.8 The requisite 2-(2,4,6-tribromo-3-methoxyphenyl)-
ethanamine 23 was obtained by the reduction of unsaturated
nitro compound 22 with BH3·THF (generated in situ with
BF3·OEt2 and NaBH4) at reflux temperature.10 Initially
observed moderate to poor yield could be substantially
improved to 82% on slight modification in workup procedure.
1
Figure 2. H NMR comparison of proposed structure of amathamide
D (8) and revised structure of (synthetic) amathamide D (24).
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Since convolutamine F (9) has three symmetrical bromines
on an aromatic system with methyl ether substituent and β-
aminoethyl moiety, 2,4,6-tribromo-3-methoxybenzaldehyde 21
is a suitable substrate for convolutamine F synthesis. One-
carbon homologation of 2,4,6-tribromo-3-methoxybenzalde-
hyde 21 via Wittig reaction followed by hydrolysis of vinyl
ether with MeSO3H furnished 2-(2,4,6-tribromo-3-
methoxyphenyl)acetaldehyde 25 (Scheme 3). Finally, aldehyde
selectively monomethylate one of the hydroxyl groups and then
oxidize the remaining hydroxyl group to ketone to set up Grob
fragmentation to obtain monomethylated catechol derivative.
Unfortunately, monomethylation of diol 26 was not successful
perhaps due to its instability under basic conditions. Therefore
we followed an indirect strategy for monoprotection. The diol
26 on treatment with benzaldehyde/p-TsOH16 under reflux
condition gave product 27 as 1.6:1 diastereomeric mixture
(diastereomeric ratio was determined by the integration of
benzylidene proton). A diastereomeric mixture of benzylidene
acetals 27 on hydrogenolysis with DIBAL-H17 in toluene
furnished monobenzyl ether 28. Compound 28 was oxidized
into monoketonorbornene 29 with pyridinium dichromate
(PDC).7
Scheme 3. Synthesis of Convolutamine F (9)
The monoketonorbornene 29 was subjected to Grob
fragmentation−aromatization reaction in refluxing toluene
using p-toluenesulfonic acid monohydrate (p-TsOH.H2O).
The crude phenolic product was methylated with diazomethane
to obtain the methyl ether of phenol. To our pleasant surprise,
we found that the benzyl ether group, present in the starting
material, was replaced by a methyl ether group in the product
obtained. A dimethylated catechol derivative 32 was obtained
instead of the expected 30, saving us from two extra steps. It
appears that in situ debenzylation of 30 is taking place during
the reaction. A literature search revealed that debenzylation of
ortho-substituted phenol would take place in acidic medium.18
A plausible mechanism via intermediate 31 is depicted in
Scheme 4. The ester 32 was converted into aldehyde 33 by
reduction with DIBAL-H followed by oxidation with PCC.
One-carbon homologation of aldehyde 33 was achieved by
Wittig reaction followed by acidic hydrolysis of vinyl ether with
MeSO3H. The homologated aldehyde 34 on reductive
amination with methylamine (40% aq)/NaBH4 gave title
compound convolutamine H (11). Synthetic 11 was confirmed
25 on reductive amination with methylamine (40% aq)/
NaBH4 gave the title compound convolutamine F (9) in
14
excellent yield. Synthetic 9 was found to be identical to the
1
natural convolutamine F as proved by H and 13C NMR data
and high-resolution mass spectrometry.
Our next target was to synthesize convolutamine H (11),
which is even more demanding. Indeed a pair of contiguous
methyl ether and a set of three adjoining bromines have to be
installed. For that purpose 1,4,5,6-tetrabromo-7,7-
dimethoxybicyclo[2.2.1]hept-5-ene-2,3-diol 26 was prepared
according to literature protocol.15 Our original plan was to
Scheme 4. Synthesis of Convolutamine H (11)
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1
to be identical to natural convolutamine H by H and 13C
organic layers were washed with brine, dried over Na2SO4, and
concentrated. The residue was purified by silica gel column
chromatography (20% EtOAc/hexane) to give methyl ether 15
(1.56 g, 96%) as a white crystalline solid. Mp 112−114 °C (lit.7a 116−
NMR data and high-resolution mass spectrometry.
In order to exploit the synthon 23 and 9, we focused our
attention on lutamide synthesis. Lutamides are another class of
formylated alkaloids and were isolated from a Floridian
bryozoan.4 Lutamide C showed cell growth inhibitory activity
against the human monocyte, such as lymphocytic leukemia
U937 cells. Phenylethylamine 23, synthesized during ama-
thamide D synthesis, was cleanly transformed into formylated
product 35 with ethyl formate19 at room temperature (Scheme
5). Compound 35 is lutamide A and has all spectroscopic data
1
118 °C). H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 3.95 (s, 3H),
3.93 (s, 3H).
2,3,4-Tribromo-5-methoxybenzaldehyde (16). To a cooled
(−78 °C) magnetically stirred solution of ester 15 (1.5 g, 3.73 mmol)
in CH2Cl2 (20 mL) was added a solution of DIBAL-H (8.76 mmol, 7.3
mL of 20 wt % solution in toluene) dropwise over a period of 10 min
under argon atmosphere. The resulting solution was allowed to warm
to room temperature and stirred for 70 h. After completion of starting
material (monitored by TLC) the reaction was taken at −78 °C and
quenched by dropwise addition of MeOH (2.5 mL) followed by
saturated aqueous Rochelle salt solution (2.5 mL). The mixture was
then allowed to warm to room temperature, diluted with EtOAc (20
mL), and subjected to vigorous stirring for 1 h. The resulting solidified
mass settled at the bottom, and the organic layer was decanted. The
solid residue was washed with EtOAc (3 × 5 mL). The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (60−80% EtOAc/hexane) to give
Scheme 5. Synthesis of Lutamide A (35) and C (36)
1
the alcohol (1.3 g, 92%) as a white solid. Mp 136−138 °C. H NMR
(400 MHz, CDCl3/DMSO-d6 = 3:1) δ 7.12 (s, 1H), 4.50 (s, 2H), 3.79
(s, 3H); 13C NMR (100 MHz, CDCl3/DMSO-d6 = 3:1) δ 156.0,
142.9, 128.3, 114.1, 113.2, 109.4, 64.6, 56.5; IR (KBr) 3300−2700
(OH), 1580, 1440, 1400, 1340, 1245, 1180, 1060 cm−1. Anal. Calcd for
C8H7Br3O2: C, 25.63; H, 1.88. Found: C, 25.69; H, 1.76.
To a cooled (0−5 °C) solution of the alcohol (obtained above) (1.2
g, 3.20 mmol) in CH2Cl2 (60 mL) was added PCC (702 mg, 3.26
mmol). The resulting solution was allowed to warm to room
temperature and stirred for 60 h. It was then filtered through a
small silica gel pad to remove the inorganic impurities and washed
with CH2Cl2 (10 mL). The filtrate was concentrated, and then the
residue was purified by silica gel column chromatography (30−50%
EtOAc/hexane) to give aldehyde 16 (1.12 g, 94%) as a white solid. Mp
in accordance with those reported. Convolutamine F (9) was
also formylated with ethyl formate to give product 36.
Formylation using HCO2NH4 in CH3CN under reflux
condition20 gave only 75% of the desired product. Compound
36 is lutamide C and has all spectroscopic data in accordance
with those reported.
1
138−140 °C. H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 7.38 (s,
1H), 3.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 191.8, 156.8,
134.5, 131.1, 123.6, 121.1, 109.6, 57.0; IR (KBr) 3070, 2878, 1685,
1566, 1365, 1064, 860 cm−1. Anal. Calcd for C8H5Br3O2: C, 25.77; H,
1.35. Found: C, 25.78; H, 1.26.
CONCLUSION
■
In conclusion, we have synthesized amathamide D according to
the published structure and redefined its structure via synthesis.
We found that natural amathamide D has symmetrical
substitution of bromines on the aromatic ring and not
contiguous as published. Convolutamine H, having a
completely substituted phenyl ring, has been synthesized via
an interesting pathway. We have also synthesized convolut-
amine F with improved overall yield as well as fewer steps.
Lutamide A and C have also been synthesized.
(E)-2,3,4-Tribromo-1-methoxy-5-(2-nitrovinyl)benzene (17).
To a solution of aldehyde 16 (900 mg, 2.41 mmol) in anhydrous
nitromethane (12 mL) was added ammonium acetate (185.8 mg, 2.41
mmol). The reaction was refluxed for 5 h. After completion of starting
material (monitored by TLC), the reaction was allowed to cool to
room temperature, and the solvent was evaporated in vacuo. The
residue was taken up in EtOAc (20 mL) and washed with water (7
mL). The aqueous phase was extracted again with EtOAc (3 × 8 mL).
The combined organic extracts were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (5−30% CH2Cl2/
hexane) to give 17 (734 mg, 73%) as a yellow solid. Mp 191−193 °C;
1H NMR (500 MHz, CDCl3) δ 8.38 (d, 1H, J = 13.4 Hz), 7.48 (d, 1H,
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed in oven-dried
apparatus. Commercial grade solvents were distilled before use.
Melting points were obtained in open capillary tubes and are
uncorrected. Infrared spectra were recorded as KBr pellets (solids)
or as thin films on NaCl flats (liquids). 1H NMR was recorded at 400
or 500 MHz. Proton decoupled 13C NMR was recorded at 100 or 125
MHz. HRMS were recorded using electron spray ionization (ESI) or
electron ionization (EI) mode. Optical rotations were measured using
J = 13.4 Hz), 6.95 (s, 1H), 3.95 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 156.6, 139.8, 138.7, 131.6, 131.4, 120.5, 120.1, 108.9, 57.1; IR (KBr)
3108, 1628, 1571, 1342, 1247, 1198, 1074, 967, 835 cm−1; HRMS
(ESI) calcd for C9H10Br3N2O3 (M + NH4), 430.8242; found,
430.8240.
2-(2,3,4-Tribromo-5-methoxyphenyl)ethanamine Hydro-
chloride (18). To a cooled (0 °C) solution of BH3·SMe2 (236.7
mg, 3.12 mmol) in anhydrous THF (1 mL) was added via cannula a
solution of compound 17 (216 mg, 0.52 mmol) dissolved in
anhydrous THF (5 mL). The reaction was stirred for 20 min at 0
°C and then allowed to warm to room temperature, and NaBH4 (5.2
mg, 0.14 mmol) was added. The mixture was stirred at room
temperature for 6.5 days, then distilled water ice (3 g) followed by
10% HCl solution (2.6 mL) was added, and the mixture was stirred at
60−65 °C for 2 h. All THF was removed in vacuo, and then water (8
mL) was added to the residue, which was extracted with Et2O (3 × 8
a 2-mL cell with a 1-dm path length and are reported as [α]22 (c g/
D
100 mL, solvent).
Methyl 2,3,4-Tribromo-5-methoxybenzoate (15). To a well-
stirred partially soluble mixture of methyl 2,3,4-tribromo-5-hydrox-
ybenzoate 14 (1.57 g, 4.04 mmol) in dry acetone (20 mL) was added
anhydrous K2CO3 (668.4 mg, 4.84 mmol, 1.2 equiv) followed by MeI
(1.3 mL, ∼5 equiv). The reaction was then stirred at room
temperature for 4 h. After completion of starting material (monitored
by TLC), the reaction mixture was concentrated under vacuo to
remove the volatiles. Water was added to the crude residue, and the
aqueous layer was extracted with EtOAc (3 × 20 mL). The combined
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mL). The aqueous phase was made basic to pH 9−10 with 25%
aqueous NH3 solution, and then solid NaCl was added until saturation
of the aqueous layer. The aqueous phase was then extracted with
CHCl3 (3 × 15 mL). The combined CHCl3 extracts were washed with
brine, dried over Na2SO4, and concentrated under reduced pressure.
The residue was then dissolved in CHCl3 (0.8 mL) and cooled to 0
°C, and then saturated dioxane/HCl was added dropwise until the
appearance of white precipitate. The obtained white solid was washed
with CHCl3 and dried in vacuum, to give amine hydrochloride salt 18
(103.1 mg, 47%) as a white crystalline solid. Mp 245−250 °C
(decomposed).
Synthesis of Amide 8 from Amine Hydrochloride Salt 18. To
a cooled (0 °C) solution of N-methyl-L-proline (6.2 mg, 0.048 mmol)
in anhydrous CH2Cl2 (1 mL) were added DCC (7.2 mg, 0.035 mmol)
and HOBT (5.6 mg, 0.04 mmol). The mixture was then stirred for 30
min at 0 °C, and then a solution of amine hydrochloride salt 18 (13.5
mg, 0.03 mmol) in anhydrous THF (0.5 mL) followed by i-Pr2NEt
(8.2 mg, 0.06 mmol) was added. The mixture was stirred for 20 min at
0 °C and then allowed to warm to room temperature. After stirring for
12 h at room temperature (monitored by TLC), the reaction was then
quenched with 5% citric acid (0.5 mL), and all volatiles were removed
under reduced pressure. EtOAc (10 mL) was added and the organic
phase was washed with saturated aqueous NaHCO3 solution (1 mL)
and brine (1 mL), dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (5−10% MeOH/EtOAc) to give 8 (8.7 mg, 55%) as
a light brown solid. Mp 134−136 °C. 1H NMR (400 MHz, CDCl3) δ
7.47 (br s, 1H), 6.82 (s, 1H), 3.88 (s, 3H), 3.56 (q, 2H, J = 6.7 Hz),
3.07 (t, 3H, J = 7.1 Hz), 2.90 (br s, 1H), 2.31 (br s, 4H), 2.21−2.19
(m, 1H), 1.76−1.71 (m, 3H).
175.0, 156.2, 140.2, 129.6, 118.5, 114.4, 112.5, 69.0, 56.9, 56.7, 41.9,
38.4, 38.2, 31.2, 24.4; IR (KBr) 3248, 3060, 2939, 1640, 1358, 1065,
900, 681 cm−1; HRMS (ESI) calcd for C15H20Br3N2O2 (M + H),
496.9075; found, 496.9073.
Synthesis of Amide 20. To a cooled (0 °C) solution of
compound 19 (35.3 mg, 0.07 mmol) in anhydrous CH2Cl2 (0.7 mL)
was added TFA (0.1 mL). The solution was then stirred for 25 min at
0 °C, and then all volatiles were removed in vacuum until the
appearance of yellowish solid. The obtained yellowish solid was
dissolved in anhydrous THF (1 mL). In another two-necked round-
bottom flask containing a solution of N-methyl-D-proline (11.2 mg,
0.087 mmol) in anhydrous CH2Cl2 (0.8 mL) at 0 °C were added
HOBT (15.6 mg, 0.12 mmol), EDC·HCl (19.4 mg, 0.10 mmol), i-
Pr2NEt (21.5 mg, 0.17 mmol), and 4 Å molecular sieves. The mixture
was then stirred for 30 min at 0 °C and to this was added via cannula a
solution of the TFA salt from compound 19. The mixture was then
allowed to warm to room temperature and stirred for 12 h. CH2Cl2
(10 mL) was added, and the reaction was quenched with 5% citric acid
(1 mL). The solution was then washed with saturated aqueous
NaHCO3 solution and brine, dried (Na2SO4), and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (1% MeOH/CHCl3) to give 20 (26.6 mg, 74%) as a
1
light yellow solid. Mp 141−143 °C; [α]22 +37.8 (c 0.9, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 7.43 (br s, 1H), 6.80 (s, 1H), 3.86 (s,
3H), 3.56−3.52 (m, 2H), 3.05 (t, 3H, J = 7.0 Hz), 2.88 (dd, 1H, J =
4.7, 9.6 Hz), 2.34−2.28 (m, 4H), 2.23−2.15 (m, 1H), 1.77−1.73 (m,
2H), 1.68−1.62 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 174.8,
156.1, 140.0, 129.5, 118.4, 114.2, 112.3, 68.8, 56.8, 56.6, 41.7, 38.2,
38.1, 31.0, 24.3; IR (KBr) 3249, 3060, 2939, 2775, 1640, 1358, 1065,
860, 681 cm−1; HRMS (ESI) calcd for C15H20Br3N2O2 (M + H),
496.9075; found, 496.9073.
Synthesis of Boc-Protected Amine 19. To a cooled (0 °C)
solution of amine hydrochloride salt 18 (65 mg, 0.15 mmol) in THF
(2.2 mL) were added di-tert-butyl dicarbonate (Boc)2O (40 mg, 0.18
mmol), i-Pr2NEt (29.6 mg, 0.23 mmol), and saturated aqueous
NaHCO3 solution (1 mL). The mixture was then allowed to warm to
room temperature and stirred overnight. All volatiles were removed
under reduced pressure, and the residue was taken up in EtOAc (10
mL), washed with water and brine, dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (15−25% EtOAc/hexane) to give 19 (64.2 mg, 86%)
(E)-1,3,5-Tribromo-2-methoxy-4-(2-nitrovinyl)benzene (22).
To a solution of aldehyde 21 (800 mg, 2.14 mmol) in anhydrous
nitromethane (6.4 mL) at 0 °C was added Et3N (216.6 mg, 2.14
mmol). The reaction was then stirred for 40 min at 0 °C, and then the
solvent was evaporated in vacuo. The residue was purified by silica gel
column chromatography (6−15% EtOAc/hexane) to furnish β-nitro
alcohol (901.6 mg, 97%) as a colorless sticky oil that solidified on
cooling. Mp 99−102 °C; 1H NMR (500 MHz, CDCl3) δ 7.82 (s, 1H),
6.24−6.20 (m, 1H), 5.17 (dd, 1H, J = 10.4, 13.2 Hz), 4.52 (dd, 1H, J =
3.2, 13.3 Hz), 3.88 (s, 3H), 3.36 (d, 1H, J = 8.2 Hz); 13C NMR (100
MHz, CDCl3) δ 154.7, 137.3, 135.6, 121.1, 119.2, 118.5, 72.6, 60.7,
53.4; IR (KBr) 3522, 2950, 1556, 1360, 1026, 897, 692 cm−1; HRMS
(ESI) calcd for C9H12Br3N2O4 (M + NH4), 448.8347; found,
448.8348.
1
as a white crystalline solid. Mp 112−114 °C; H NMR (500 MHz,
CDCl3) δ 6.77 (s, 1H), 4.61 (br s, 1H), 3.88 (s, 3H), 3.38 (q, 2H, J =
6.7 Hz), 3.03 (t, 2H, J = 6.9 Hz), 1.43 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 156.1, 156.0, 140.1, 129.6, 118.4, 114.2, 112.6, 79.6, 56.9,
39.9, 38.8, 28.5; IR (KBr) 3368, 3074, 2977, 1678, 1528, 1453, 1273,
1165, 1067, 850, 657 cm−1; HRMS (ESI) calcd for C14H19Br3NO3 (M
+ H), 485.8915; found, 485.8915.
To a solution of β-nitro alcohol (obtained above) (800 mg, 1.84
mmol) in 1,2-dichloroethane (7.2 mL) was added conc H2SO4 (541.9
mg, 5.53 mmol). The resulting solution was heated at 85−90 °C for 80
min (monitored by TLC). The reaction was then allowed to cool to
room temperature, and EtOAc (15 mL) was added. The organic phase
was washed with saturated aqueous NaHCO3 solution (5 mL), and the
aqueous phase was then extracted again with EtOAc (3 × 6 mL). The
combined organic phases were washed with brine, dried (Na2SO4),
and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (5−25% CH2Cl2/hexane) to give 22
(551 mg, 72%) as a yellow crystalline solid. Mp 112−114 °C (lit.13 93
Synthesis of Amide 8 from Boc-Protected Amine 19. To a
cooled (0 °C) solution of compound 19 (39 mg, 0.08 mmol) in
anhydrous CH2Cl2 (0.7 mL) was added TFA (0.1 mL). The resultant
solution was then stirred for 25 min at 0 °C, and then all volatiles were
removed in vacuum until the appearance of yellowish solid. The
obtained yellowish solid was dissolved in anhydrous THF (1 mL). In
another two-necked round-bottom flask containing a solution of N-
methyl-L-proline (12.4 mg, 0.096 mmol) in anhydrous CH2Cl2 (1 mL)
at 0 °C were added HOBT (17.3 mg, 0.13 mmol), EDC·HCl (21.5
mg, 0.11 mmol), i-Pr2NEt (23.7 mg, 0.18 mmol), and 4 Å molecular
sieves. The mixture was then stirred for 30 min at 0 °C, and to this was
added via cannula a solution of the TFA salt from compound 19. The
mixture was then allowed to warm to room temperature and stirred for
8 h. CH2Cl2 (10 mL) was added, and the reaction was quenched with
5% citric acid (1 mL). The solution was then washed with saturated
aqueous NaHCO3 solution and brine, dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (2% MeOH/CHCl3) to give 8 (27.7
1
°C); H NMR (500 MHz, CDCl3) δ 7.98 (d, 1H, J = 13.7 Hz), 7.88
(s, 1H), 7.56 (d, 1H, J = 13.7 Hz), 3.89 (s, 3H).
2-(2,4,6-Tribromo-3-methoxyphenyl)ethanamine (23). To a
cooled (0 °C) solution of the NaBH4 (238.6 mg, 6.28 mmol) in
anhydrous THF (8 mL) was added BF3·OEt2 (1.13 g, 7.93 mmol).
The resultant solution was then stirred for 10 min at 0 °C and for 15
min at room temperature. Then a solution of nitro compound 22 (550
mg, 1.32 mmol) in anhydrous THF (5.2 mL) was added via cannula.
The reaction was refluxed for 7.5 h and then allowed to cool to room
temperature. Water (17 mL) was added dropwise, followed by 1 N
HCl (17 mL). The reaction was heated again to 80−85 °C for 2 h.
After cooling at room temperature, the mixture was then extracted
with Et2O (2 × 10 mL). The aqueous layer was made basic with (20%
w/w) aqueous NaOH to pH 10, then solid NaCl was added, and the
mg, 70%) as a light brown solid. Mp 135−137 °C; [α]22 −38.9 (c
D
0.86, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.42 (br s, 1H), 6.80 (s,
1H), 3.86 (s, 3H), 3.56−3.52 (m, 2H), 3.06−3.02 (m, 3H), 2.85 (dd,
1H, J = 5.2, 10.3 Hz), 2.34−2.28 (m, 4H), 2.21−2.17 (m, 1H), 1.77−
1.75 (m, 2H), 1.67−1.65 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
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aqueous mixture was extracted with Et2O (3 × 20 mL). Previous Et2O
extracts also were basified with (20% w/w) aqueous NaOH to pH 10
and extracted with CH2Cl2 (3 × 15 mL). The combined organic
phases were dried over Na2SO4 and concentrated. The residue was
purified by column chromatography over silica gel (5−20% MeOH/
CHCl3) to give 23 (419.2 mg, 82%) as a colorless sticky liquid that
solidified on standing. Mp 56−58 °C; 1H NMR (500 MHz, CDCl3) δ
7.73 (s, 1H), 3.85 (s, 3H), 3.15−3.12 (m, 2H), 2.91 (t, 2H, J = 7.6
Hz), 1.42 (br s, 2H); 13C NMR (125 MHz, CDCl3) δ 154.0, 139.7,
135.4, 121.9, 120.0, 116.0, 60.6, 41.5, 40.7; IR (KBr) 3359, 3287, 3014,
2935, 1557, 1448, 1355, 1018, 930, 639 cm−1; HRMS (ESI) calcd for
C9H11Br3NO (M + H), 385.8391; found, 385.8398.
Synthesis of Amide 24. To a cooled (0 °C) solution of N-methyl-
L-proline (19.9 mg, 0.16 mmol) in anhydrous CH2Cl2 (1 mL) were
added HOBT (27.8 mg, 0.21 mmol), EDC·HCl (34.6 mg, 0.18
mmol), i-Pr2NEt (23.3 mg, 0.18 mmol), and 4 Å molecular sieves. The
mixture was then stirred for 30 min at 0 °C, and then a solution of
amine 23 (50 mg, 0.13 mmol) in anhydrous CH2Cl2 (0.6 mL) was
added. The reaction solution was then allowed to warm to room
temperature and stirred 12 h. After completion of starting material
(monitored by TLC), the reaction was diluted with CH2Cl2 (7 mL)
and quenched with 5% citric acid (0.8 mL). The solution was then
washed with saturated aqueous NaHCO3 solution and brine, dried
(Na2SO4), and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (5% MeOH/CHCl3) to
give 24 (43.2 mg, 67%) as a colorless liquid which solidified on
cooling. Mp 89−91 °C; [α]23D −39.8 (c 0.49, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.74 (s, 1H), 7.48 (br s, 1H), 3.85 (s, 3H), 3.54−3.50
(m, 2H), 3.24 (dt, 2H, J = 2.1, 7.3 Hz), 3.08−3.05 (m, 1H), 2.89 (dd,
1H, J = 4.9, 10.1 Hz), 2.33 (s, 4H), 2.20−2.14 (m, 1H), 1.83−1.76 (m,
1H), 1.74−1.69 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 174.8,
154.1, 139.0, 135.5, 122.2, 120.2, 116.5, 69.0, 60.6, 56.8, 42.0, 37.1,
37.0, 31.0, 24.5; IR (KBr) 3309, 2967, 2939, 1650, 1529, 1448, 1360,
1264, 1050, 861, 746 cm−1; HRMS (ESI) calcd for C15H20Br3N2O2 (M
+ H), 496.9075; found, 496.9078.
were dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (10−
25% MeOH/CHCl3) to give 9 (188 mg, 91%) as a colorless viscous
liquid. 1H NMR (500 MHz, CDCl3) δ 7.72 (s, 1H), 3.85 (s, 3H), 3.16
(t, 2H, J = 7.8 Hz), 2.76 (t, 2H, J = 7.9 Hz), 2.49 (s, 3H), 1.45 (s, 1H);
13C NMR (125 MHz, CDCl3) δ 154.0, 139.9, 135.4, 121.8, 120.0,
116.0, 60.6, 49.7, 37.7, 36.4; IR (Neat) 3331, 2934, 2842, 1558, 1451,
1358, 1075, 864 cm−1; HRMS (ESI) calcd for C10H13Br3NO (M + H),
399.8547; found, 399.8540.
Synthesis of Benzylidene Acetal 27. To a solution of diol 26
(13.45 g, 26.79 mmol) in anhydrous benzene (428 mL) were added p-
toluenesulfonic acid monohydrate (509 mg, 2.68 mmol) and
benzaldehyde (3.98 g, 37.55 mmol). The reaction was refluxed for
11 h with azeotropic removal of water with a Dean−Stark condenser
(monitored by TLC). The reaction was allowed to cool to room
temperature, poured into saturated aqueous NaHCO3 solution (60
mL), and then extracted with Et2O (3 × 70 mL). The combined
organic phases were washed with brine, dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (3% EtOAc/hexane) to give 27
(13.38 g, 85%) in 1.6:1 diastereomeric mixture as a white crystalline
solid. Mp 113−115 °C; 1H NMR (500 MHz, CDCl3) δ 7.50−7.48 (m,
2H), 7.39−7.34 (m, 8H), 6.01 (s, 1H), 5.81 (s, 1H), 5.07 (s, 2H), 4.98
(s, 2H), 3.65 (s, 3H), 3.62 (s, 3H), 3.60 (2 s, partially merged, due to
two -OMe, 6H); 13C NMR (125 MHz, CDCl3) δ 137.7, 134.1, 130.3,
129.6, 128.5, 128.4, 127.8, 126.2, 125.4, 124.8, 115.4, 113.7, 109.2,
107.7, 88.1, 87.1, 70.3, 69.8, 53.1, 52.1, 52.0; IR (KBr) 3039, 2946,
1608, 1461, 1187, 1039, 931, 702 cm−1; HRMS (ESI) calcd for
C16H18Br4NO4 (M + NH4), 603.7969; found, 603.7974.
3-(Benzyloxy)-1,4,5,6-tetrabromo-7,7-dimethoxybicyclo-
[2.2.1]hept-5-en-2-ol (28). To a cooled (−10 °C) solution of
benzylidene acetal 27 (12.6 g, 21.34 mmol) in anhydrous toluene (22
mL) was added DIBAL-H (25% in toluene, 36.4 g, 64.02 mmol). The
reaction was allowed to warm to room temperature and stirred for 14
h (monitored by TLC). The reaction was cooled to −20 °C, and
MeOH (30 mL) was added dropwise followed by 10% aq NaOH (30
mL). The mixture was then extracted with Et2O (5 × 30 mL). The
combined organic phases were washed with brine, dried (Na2SO4),
and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (2−5% EtOAc/hexane) to give 28
2-(2,4,6-Tribromo-3-methoxyphenyl)acetaldehyde (25). To a
cooled (0 °C) solution of methoxymethyltriphenylphosphonium
chloride (10.36 g, 30.23 mmol) in anhydrous THF (30 mL) was
added potassium tert-butoxide (3.30 g, 29.49 mmol). The mixture was
stirred for 20 min at 0 °C and then for 1.5 h at room temperature, and
a solution of aldehyde 21 (5.5 g, 14.74 mmol) in anhydrous THF (45
mL) was added via cannula at 0 °C. The reaction was allowed to warm
to room temperature and stirred overnight. The reaction was filtered
through a short silica pad, and the filtrate was then washed with water
(30 mL) and brine (40 mL), dried (Na2SO4), and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (3% EtOAc/hexane) as eluent to furnish the enol
ether, which was used as such in the next reaction.
1
(10.95 g, 87%) as a colorless viscous liquid; H NMR (500 MHz,
CDCl3) δ 7.37−7.33 (m, 5H), 4.87 (d, 1H, J = 11.5 Hz), 4.75 (d, 1H, J
= 11.5 Hz), 4.51 (t, 1H, J = 7.4 Hz), 4.40 (d, 1H, J = 7.4 Hz), 3.59 (s,
3H), 3.57 (s, 3H), 2.76 (d, 1H, J = 8.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 136.4, 128.5, 128.3, 128.0, 124.3, 110.1, 84.0, 78.1, 75.3,
73.0, 71.8, 53.1, 51.8; IR (Neat) 3501, 2948, 1571, 1455, 1139, 1105,
1030, 739 cm−1; HRMS (ESI) calcd for C16H20Br4NO4 (M + NH4),
605.8126; found, 605.8128.
To a cooled (0−10 °C) solution of the enol ether (obtained above)
in anhydrous CH2Cl2 (220 mL) was added methanesulphonic acid
(MeSO3H, 4.3 g, 44.8 mmol) dropwise. After 3 h, the reaction was
poured in saturated aqueous NaHCO3 solution (50 mL), and then
organic phase was separated and washed with brine, dried (Na2SO4),
and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (5% EtOAc/hexane) to give 25
(4.53 g, 79%) as a white solid. Mp 108−110 °C; 1H NMR (500 MHz,
CDCl3) δ 9.73 (s, 1H), 7.80 (s, 1H), 4.21 (s, 2H), 3.87 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 196.1, 154.2, 135.5, 134.1, 122.5, 120.5,
117.7, 60.7, 51.6; IR (KBr) 3073, 2939, 2850, 2724, 1714, 1561, 1452,
1038, 659 cm−1; HRMS (ESI) calcd for C9H8Br3O2 (M + H),
384.8074; found, 384.8091.
Convolutamine F (9). To a solution of aldehyde 25 (200 mg, 0.52
mmol) in anhydrous MeOH (3 mL) was added a 40% aqueous
solution of methylamine (100.1 mg, 1.29 mmol). The reaction was
stirred for 30 min at room temperatureand then cooled to 0 °C, and
NaBH4 (15.7 mg, 0.41 mmol) was added in three portions over a
period of 10 min. The reaction was stirred for 24 h at room
temperature, then water (2.5 mL) was added, and all MeOH was
removed under reduced pressure. The obtained aqueous phase was
extracted with CH2Cl2 (3 × 10 mL). The combined organic phases
3-(Benzyloxy)-1,4,5,6-tetrabromo-7,7-dimethoxybicyclo-
[2.2.1]hept-5-en-2-one (29). To a solution of pyridine (576.5 mg,
7.30 mmol) in CH2Cl2 (11.6 mL) was added CrO3 (365 mg, 3.65
mmol). The resultant solution was stirred at room temperature for
30−40 min, and then to this a solution of alcohol 28 (320 mg, 0.54
mmol) in CH2Cl2 (10 mL) was added and stirred for 90 h at room
temperature. The reaction solution was then filtered through a small
silica gel pad, and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (2%
EtOAc/hexane) to give 29 (267 mg, 84%) as a white crystalline solid.
1
Mp 94−96 °C; H NMR (400 MHz, CDCl3) δ 7.32−7.18 (m, 5H),
4.95 (d, 1H, J = 12.2 Hz), 4.85 (d, 1H, J = 12.2 Hz), 4.09 (s, 1H), 3.57
(s, 3H), 3.49 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 193.5, 136.6,
130.2, 128.4, 128.0, 127.8, 119.0, 112.4, 79.8, 74.4, 69.4, 53.4, 52.1; IR
(KBr) 2993, 1780, 1561, 1453, 1121, 1026, 745 cm−1; HRMS (ESI)
calcd for C16H15Br4O4 (M + H), 586.7704; found, 586.7701.
Methyl 2,3,4-Tribromo-5,6-dimethoxybenzoate (32). To a
solution of ketone 29 (2.0 g, 3.39 mmol) in anhydrous toluene (11.9
mL) was added p-toluenesulfonic acid monohydrate (322 mg, 1.69
mmol). The resultant solution was refluxed for 3.5 h and then allowed
to cool to room temperature. The reaction was poured into saturated
aqueous NaHCO3 solution (8 mL) and then extracted with EtOAc (3
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The Journal of Organic Chemistry
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× 25 mL). The combined organic phases were washed with water and
brine, dried (Na2SO4), and concentrated. The residue was dissolved in
MeOH (3 mL) and then treated with diazomethane at 0 °C. All
volatiles were removed under reduced pressure, and the residue was
purified by silica gel column chromatography (2% EtOAc/hexane) to
2877, 1738, 1651, 1454, 1026, 871 cm−1; HRMS (ESI) calcd for
C10H11Br3NO2 (M + H), 413.8340; found, 413.8340.
Lutamide C (36). Experimental procedure is similar to that for
compound 35. After column purification the product 36 (44.6 mg,
1
93%) was obtained as a colorless oil. H NMR (400 MHz, CDCl3) δ
1
give 32 (1.22 g, 83%) as a white crystalline solid. Mp 77−78 °C; H
8.04 (s, 1H), 7.78 and 7.76 (each s, due to geometrical isomer, 1H),
3.88 and 3.87 (each s, due to geometrical isomer, 3H), 3.55−3.51 and
3.44−3.40 (each m, due to geometrical isomer, 2H), 3.27−3.23 (m,
2H), 3.00 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 162.6 and 162.4
(due to geometrical isomer), 154.2 and 154.0 (due to geometrical
isomer), 138.5 and 137.4 (due to geometrical isomer), 135.6 and 135.4
(due to geometrical isomer), 121.9 and 121.8 (due to geometrical
isomer), 119.9 and 119.8 (due to geometrical isomer), 116.9 and 116.5
(due to geometrical isomer), 60.6 and 60.5 (due to geometrical
isomer), 47.2 and 42.2 (due to geometrical isomer), 36.6, 34.9, 34.6,
30.1; IR (Neat) 2935, 2849, 1678, 1452, 1075, 865 cm−1; HRMS
(ESI) calcd for C11H13Br3NO2 (M + H), 427.8496; found, 427.8496.
NMR (400 MHz, CDCl3) δ 3.96 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 165.3, 151.0, 149.8, 132.6, 123.8,
123.6, 116.5, 61.9, 60.7, 53.0; IR (KBr) 2943, 2860, 1746, 1550, 1455,
1280, 1029, 656 cm−1; HRMS (EI) calcd for C10H9Br3O4, 429.8051;
found, 429.8055.
2,3,4-Tribromo-5,6-dimethoxybenzaldehyde (33). To a
cooled (−78 °C) solution of ester 32 (910 mg, 2.10 mmol) in
anhydrous toluene (12.6 mL) was added DIBAL-H (1.0 M in toluene,
6.3 mL, 6.30 mmol). The resulting solution was allowed to warm to
−20 °C in 2 h (monitored by TLC). The reaction solution was cooled
again to −78 °C, and MeOH (1.5 mL) was added dropwise followed
by saturated aqueous Rochelle salt solution (1.5 mL). The mixture was
then allowed to warm to room temperature, diluted with EtOAc (15
mL), and subjected to vigorous stirring for 1 h. The resulting solidified
mass settled at the bottom, and the organic layer was decanted. The
solid residue was washed with EtOAc (2 × 5 mL). The combined
organic phases were washed with brine, dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (15−30% EtOAc/hexane as eluent)
to furnish the alcohol, which was used as such for the next reaction.
To a cooled (0 °C) solution of PCC (476.6 mg, 2.21 mmol) in
anhydrous CH2Cl2 (2 mL) was added a solution of alcohol (obtained
above) in anhydrous CH2Cl2 (12 mL). The resulting solution was
allowed to warm to room temperature and stirred for 44 h. It was then
filtered through a small silica gel pad to remove the inorganic
impurities and washed with CH2Cl2, and the filtrate was concentrated.
The residue was purified by silica gel column chromatography (2−4%
EtOAc/hexane) to furnish aldehyde 33 (759.3 mg, 90%) as a white
crystalline solid. Mp 105−107 °C (lit.2d 102−104 °C). 1H NMR (400
MHz, CDCl3) δ 10.18 (s, 1H), 3.96 (s, 3H), 3.91 (s, 3H).
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H NMR, 13C NMR, and HRMS spectra for
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: faiz@iith.ac.in.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
F.A.K. gratefully acknowledges DST and CSIR for financial
support. S.A. thanks CSIR for a fellowship.
■
2-(2,3,4-Tribromo-5,6-dimethoxyphenyl)acetaldehyde (34).
Experimental procedure is similar to that for compound 25. After
column purification the compound 34 (579.6 mg, 76%) was obtained
as a white solid. Mp 112−114 °C; 1H NMR (400 MHz, CDCl3) δ 9.76
(s, 1H), 4.06 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 197.2, 151.7, 150.6, 129.3, 123.3, 123.0, 121.8, 61.1, 60.5,
46.9; IR (KBr) 2976, 2838, 2731, 1713, 1455, 1370, 1061, 897 cm−1;
HRMS (ESI) calcd for C10H10Br3O3 (M + H), 414.8180; found,
414.8184.
REFERENCES
■
(1) Gribble, G. W. Naturally Occurring Organohalogen Compounds−A
Comprehensive Update, Progress in the Chemistry of Organic Natural
Products; Springer: Wien, New York, 2010; Vol. 91, see ref 107 and
references therein.
(2) For isolation of amathamides A−H, see: (a) Blackman, A. J.;
Matthews, D. J. Heterocycles 1985, 23, 2829−2833. (b) Blackman, A. J.;
Green, R. D. Aust. J. Chem. 1987, 40, 1655−1662. (c) Blackman, A. J.;
Fu, S. L. J. Nat. Prod. 1989, 52, 436−438. (d) Blackman, A. J.;
Eldershaw, T. P. D; Garland, S. M. Aust. J. Chem. 1993, 46, 401−405.
(e) Carroll, A. R.; Duffy, S.; Sykes, M.; Avery, V. M. Org. Biomol.
Chem. 2011, 9, 604−609.
Convolutamine H (11). Experimental procedure is similar to that
for compound 9. After column purification the product 11 (24.7 mg,
1
72%) was obtained as a colorless oil. H NMR (500 MHz, CDCl3) δ
3.88 (s, 3H), 3.84 (s, 3H), 3.07 (t, 2H, J = 7.7 Hz), 2.76 (t, 2H, J = 7.7
Hz), 2.49 (s, 3H), 1.79 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ
151.4, 150.7, 135.5, 123.1, 122.8, 120.2, 61.1, 60.4, 50.6, 36.2, 32.7; IR
(Neat) 3350, 2936, 2851, 1623, 1449, 1388, 1009, 750 cm−1; HRMS
(ESI) calcd for C11H15Br3NO2 (M + H), 429.8653; found, 429.8654.
Lutamide A (35). A solution of amine 23 (52 mg, 0.13 mmol) in
ethyl formate (0.5 mL) was stirred at room temperature for 10 h. The
excess ethyl formate was removed under reduced pressure, and the
residue was purified by silica gel column chromatography (60−70%
EtOAc/hexane) to give product 35 (53.4 mg, 96%) as a white solid.
Mp 100−101 °C (lit.4 105 °C); 1H NMR (400 MHz, CDCl3) δ 8.17,
7.99, and 7.96 (each s, due to geometrical isomer, 1H), 7.78 and 7.76
(each s, due to geometrical isomer, 1H), 5.85 (br s, 1H), 3.87 (s, 3H),
3.57 and 3.47 (each q, due to geometrical isomer, 2H, J = 6.6 and 7.0
Hz), 3.26 (t, 2H, J = 7.0 Hz); 13C NMR (125 MHz, CDCl3) δ 164.2
and 161.3 (due to geometrical isomer), 154.2 and 154.0 (due to
geometrical isomer), 138.4 and 137.3 (due to geometrical isomer),
135.6 and 135.5 (due to geometrical isomer), 122.0 and 121.9 (due to
geometrical isomer), 120.0 and 119.9 (due to geometrical isomer),
117.0 and 116.6 (due to geometrical isomer), 60.6 and 60.5 (due to
geometrical isomer), 39.6 and 38.7 (due to geometrical isomer), 36.7
and 36.2 (due to geometrical isomer); IR (KBr) 3268, 3067, 2936,
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