Bronsted acid mediated cyclization of enaminones. Rapid and efficient access to the tetracyclic framework of the strychnos alkaloids

Article abstract of DOI:10.1021/np200759h

The development of an efficient diastereoselective method that permits rapid construction of the tetracyclic core 17 of the Strychnos-Aspidosperma alkaloids is described. Enaminone 16, synthesized in high yield, has been cyclized under the influence of a Bronsted acid to provide the core tetracyclic framework 17 of the Strychnos alkaloids in optically active form or alternatively to the β-ketoester tetrahydro-β-carboline (THBC) unit 18, by varying the equivalents of acid and the molar concentration. Attempts to utilize 18 to form the C(7)-C(16) bond of the akuammiline related alkaloids represented by strictamine (22), using metal-carbenoid chemistry, are also described.

Full text of DOI:10.1021/np200759h

Article
pubs.acs.org/jnp
Brønsted Acid Mediated Cyclization of Enaminones. Rapid and
Efficient Access to the Tetracyclic Framework of the Strychnos
Alkaloids
Rahul V. Edwankar,† Chitra R. Edwankar,† Ojas A. Namjoshi,† Jeffrey R. Deschamps,‡
and James M. Cook*,†
†Department of Chemistry & Biochemistry, University of WisconsinMilwaukee, Milwaukee, Wisconsin 53201, United States
‡Center for Biomolecular Science and Engineering, Naval Research Laboratory, Code 6930, Washington, D.C. 20375, United States
S
* Supporting Information
ABSTRACT: The development of an efficient diastereose-
lective method that permits rapid construction of the
tetracyclic core 17 of the Strychnos-Aspidosperma alkaloids is
described. Enaminone 16, synthesized in high yield, has been
cyclized under the influence of a Brønsted acid to provide the
core tetracyclic framework 17 of the Strychnos alkaloids in
optically active form or alternatively to the β-ketoester
tetrahydro-β-carboline (THBC) unit 18, by varying the
equivalents of acid and the molar concentration. Attempts to
utilize 18 to form the C(7)−C(16) bond of the akuammiline
related alkaloids represented by strictamine (22), using metal-
carbenoid chemistry, are also described.
he pentacyclic 3,5-ethano-3H-pyrrolo[2,3-d]carbazole
framework is common to a number of Strychnos alkaloids,
5, as well as other complex members of the Strychnos-
Aspidosperma class of indole alkaloids was explored. Herein, a
brief and rapid entry into this tetracyclic core 7 by a Brønsted
acid mediated cyclization of an enaminone 16 is described.
T
of which (−)-strychnine (1) and (−)-akuammicine (2) are the
most distinct members.1 This pentacyclic unit is also found in a
number of bisindoles including (−)-geissospermine (3),2
(+)-geissolosimine (4),3 and (+)-divaricine (5),4 as illustrated
in Figure 1. (+)-Geissoschizoline (6a),5 which has been
previously reported as a constituent of Geissospermum vellosii
(G. vellosii), is the pentacyclic strychnine-related monomer of
these dimeric indole alkaloids 3−5.
The stem bark extracts of G. vellosii commonly known as Pao
periera are used to treat malaria, poor digestion, constipation,
dizziness, and as a febrifuge and tonic or stimulant.6 In a study
carried out by Lima et al.7 this plant extract, rich in alkaloids,
exhibited potent anticholinesterase activity in vitro and memory
enhancing effects in vivo, in a model of cholinergic deficit that
has been validated for the development of drugs for the
symptomatic treatment of Alzheimer’s disease. The principal
alkaloid with anticholinesterase activity in the extract was
identified as geissospermine (3), which has also been known to
exhibit actions at the autonomic nervous system.8 Because of
their complex structural framework and important pharmaco-
logical activity coupled with the fact that the southern
hemisphere of bisindoles 3−5 had been synthesized in an
enantiospecific sense by us,9 efforts have been directed toward
the total synthesis of 6a,b as part of a doubly convergent
strategy.10 To this end a concise and rapid route via the
asymmetric Pictet−Spengler reaction11 to generate the core
tetracyclic framework 712 which contains rings ABCE, crucial to
the synthesis of the northern hemisphere of these bisindoles 3−
RESULTS AND DISCUSSION
■
The acid-catalyzed coupling of 6a with geissoschizine (8) or
vellosimine (9), respectively, to form 32d and 4,3 has been
documented and suggests a potential coupling of geissoschizo-
line Nb-oxide (6b) with vellosimine (9) to form 5. Since the
southern hemispheres 8 and 9 of the bisindoles 3−5 have been
synthesized from D-tryptophan,9 a doubly convergent strategy
could be employed for the synthesis of both the hemispheres of
the bisindoles 3−5. As illustrated in Scheme 1, retrosyntheti-
cally, the northern hemisphere 6a/6b might be obtained on
further functionalization of the tetracyclic Strychnos unit 17′
which in turn might arise from an α-diazo β-ketoester
tetrahydro-β-carboline unit 19 by making use of transition
metal mediated carbenoid chemistry.13 The nucleophilic attack
of the indole double bond onto the electrophilic center of the
carbene generated from 19 might lead to the tetracyclic core
17′. Formation of such a tetracyclic framework from an α-
ketocarbocation intermediate was originally studied by Takano
et al.,14 albeit in poor yields, in an approach toward
Aspidosperma alkaloids.15 In order to explore the diazonium
approach via 19, the stereoselective synthesis of the key β-
Received: September 20, 2011
Published: January 18, 2012
© 2012 American Chemical Society and
American Society of Pharmacognosy
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Figure 1. Strychnos-related indole alkaloids.
a
Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of C(1)-Substituted THBC
ketoester 18 (see Scheme 5) was required. The strategy was to
generate this intermediate 18 by carrying out C-acylation on an
acid moiety of a suitably substituted tetrahydro-β-carboline
(THBC) such as 11 (see Scheme 2), which in turn could be
synthesized from 1016 via the asymmetric Pictet−Spengler
reaction.
The synthesis began with the D-(+)-Nb-benzyltryptophan
methyl ester (10) which served as the starting material and the
chiral transfer agent. Based on the conditions developed by
Soerens et al.,17 the asymmetric Pictet−Spengler reaction of 10
with 3,3-dimethoxypropanoic acid 1318 under acidic conditions
or with commercially available oxaloacetic acid under thermal
conditions was carried out to form the 1-hydroxycarbonyl
THBC 11. In both the cases, however, no formation of the
target β-carboline 11 was observed. Instead, the trans isomer
12a was isolated under acidic conditions, and a mixture of cis
and trans diastereomers 12a,b was formed under thermal
nonacidic conditions (Scheme 2).19 Not unexpectedly, after
a
DST = Dean−Stark trap.
initial formation of the iminium ion I, the β-carboxylic acid,
presumably, underwent decarboxylation to give intermediate II,
which tautomerized to the iminium ion III, which cyclized to
provide the 1,3-disubstituted β-carboline 12a. Alternatively,
oxaloacetic acid could have undergone decarboxylation under
thermal conditions to generate CO2 and pyruvic acid, which on
condensation with 10 would provide 12a,b via intermediate IV.
182
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a
The spectroscopic data of 1-methylTHBC’s 12a,b was identical
to those of racemic cis/trans-1-methylTHBC’s.20
Scheme 4. Synthesis of Enaminone 16
Based on the above results, an alternate approach was
employed. The β-ketoester fragment 14 was synthesized first
followed by the Pictet−Spengler reaction of β-ketoester 14 with
10 in order to form the target β-carboline 18. The acid- and
base-sensitive β-ketoester 14 was thus synthesized via C-
acylation under the conditions developed by Brooks et al.21 As
illustrated in Scheme 3, the hydroxycarbonyl group in 13 was
Scheme 3. Synthesis of the Michael Acceptor 15
a
brsm: based on recovered starting material 10.
With the enaminone 16 in hand, the acid-mediated
cyclization of 16 to the THBC framework in 18 was attempted
(Scheme 5). Stirring the enaminone 16 in TFA/CH2Cl2
Scheme 5. Acid-Mediated Cyclization of Enaminone 16
activated as an imidazolide with N,N′-carboxyldiimidazole
(CDI) and condensed with the magnesium salt of methyl
malonate under essentially neutral conditions. Spontaneous
decarboxylation occurred during the acidic workup to afford the
methyl 5,5-dimethoxy-3-oxopentanoate (14) in 82% yield.22
Attempts to generate β-carboline 18, by condensation of 10
with 14 under the acid-mediated Pictet−Spengler reaction
conditions (TFA/CH2Cl2), failed. Addition of excess reagent,
continued stirring for extended periods at room temperature,
change of solvent to MeCN, and varying the temperature from
room temperature to 50 °C resulted in either no reaction or
decomposition of the starting material 10. The inability of
acetal 14 to react with 10 in the presence of TFA prompted the
use of a milder acid and the more reactive Michael acceptor 15,
synthesized in a single step from 14. The ability of trimethylsilyl
trifluoromethanesulfonate (TMSOTf), presumably, to bind to a
single heterofunctional group and to form a supercationic
species23a was utilized to synthesize β-ketoester 15 from the
dimethoxy-β-ketoester 14 in 87% yield.23b This represents an
important route to synthesize methyl (E)-5-methoxy-3-
oxopent-4-enoate (15) in an overall yield of 88% from methyl
3,3-dimethoxypropionate (Scheme 3).
When the β-ketoester 15 was stirred with 10 in the presence
of 20 equiv of HOAc in refluxing MeCN (Scheme 4),
cyclization to the β-carboline 18 was not observed; however,
the enaminone 16,24 present as the carbonyl tautomer, was
formed in 91% yield. Enaminones25 such as 16 have been
previously synthesized albeit in lower yield (34%) from L-
tryptophan methyl ester by Pandit et al.26 by using an aziridine-
based folate model and by Singh et al.24 in a moderate yield
(60%) by using oxazolidine-based folate models. The route
toward the synthesis of the synthetically useful enaminone26−28
16 utilized the readily accessible Michael acceptor 15 and is an
important improvement over the previous methods,24,26
especially in yield and scale-up. The reaction between 10 and
the β-ketoester 14 also furnished the enaminone 16 but
required longer reaction times with a considerable amount of
starting material 10 remaining.
resulted in no reaction, whereas treatment in HCl/MeOH28
gave a mixture of compounds. Analysis of this crude mixture by
NMR spectroscopy revealed the presence of a tetracyclic core
structure of the Strychnos alkaloids (17 or 17′), accompanied by
the THBC 18. Since both the cyclized products, 17/17′ and 18,
are potentially important intermediates in the doubly
convergent strategy to the total synthesis of indole
alkaloids,29,30 it was decided to pursue selectivity in this
process in order to obtain each exclusively. Methanesulfonic
acid (MeSO3H, pKa: 1.6 in DMSO),31 which was a stronger
acid than TFA but equivalent in strength to HCl (pKa: 1.8 in
DMSO)31 in an aprotic medium, presented an attractive option
to HCl/MeOH, the acidity of which was difficult to control.
The use of MeSO3H would permit one to achieve the exact
concentration of the acid in the reaction mixture unlike HCl
(g) whose solutions in aprotic media are less accurate and
cumbersome to generate.
Treatment of enaminone 16 with 8 or 10 equiv of MeSO3H
in CH2Cl2 (0.1 M) at 0 °C, followed by removal of the ice bath
immediately after the addition of the acid, gave a single spot at a
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Figure 2. ORTEP view of the crystal structures of 17 and 18.
higher Rf in 0.5 h. This indoline was isolated and identified as
the dihydroindole derivative 17. Encouraged by this result, the
amount of acid was altered in order to obtain the β-ketoester
THBC 18 as the sole product. It was found that addition of 4
equiv of MeSO3H and performing the reaction under more
dilute conditions (0.05 M) at 0 °C (0.5 h) gave the THBC 18,
exclusively in 86% yield, as shown in Scheme 5. Separate
recrystallization of analytical samples of tetracyclic 17 and the
THBC 18 from a mixture of CH2Cl2/hexanes afforded
crystalline material for single crystal X-ray analysis, as illustrated
in Figure 2. The X-ray analysis confirmed the structural
assignment and chirality of the ABCE Strychnos tetracyclic
structure as 17, which is opposite to the tetracyclic Strychnos
template 17′ (see Scheme 1).
Scheme 6. Possible Mechanism of the Acid-Mediated
Cyclization of the Enaminone 16
The stereochemistry of 17 and 18 obtained during the acid-
mediated cyclization of 16 suggested11a−c the formation of two
different spiroindolenine intermediates resulting from attack of
the indole double bond at C-3 from the Si-face to give the syn-
spiroindolenine B1 (syn to the ester function) and from the Re-
face to give the anti-spiroindolenine B2 (anti to the ester
function) of the iminium ion double bond (Scheme 6). It is
well-known that, in acidic medium wherein the enaminone is
protonated, the nucleophilic addition occurred preferentially at
the iminic sp2 carbon atom, thereby decreasing the possibility
of a direct Michael addition.32 Enaminones form stable salts
with strong acids, and these salts have been found to be
protonated at the oxygen atom, with only a few examples
suggesting C-protonation.33 Nevertheless, the five-atom π-
electron system of enaminone 16, in the presence of excess
acid, presumably results in a push−pull system wherein the
higher concentration of acid, higher temperature, and running
the reaction more concentrated results in O-protonation (see
A1) to generate the enol B1. In the presence of less acid (4
equiv), higher dilution, and lower temperature, the inherent
reactivity of the enamine was sufficient to give an intermediate
with C-protonation (see A2). The O-protonated intermediate
A1, presumably, facilitated the intramolecular attack from the
indole nucleus to the Si-face of the CN double bond to give
the syn spiroindolenine intermediate B1 wherein the stereo-
chemistry of the final product was irreversibly established. The
C(16)−C(2) bond in 17 was formed by attack of the enolate
carbon atom on the iminium ion bond, which resulted in the
formation of the tetracyclic Strychnos template 17 with rings C
and E fused in a cis-fashion.30 It is possible that hydrogen
bonding between the enolate double bond and the indole Na-H
group might have resulted in some stabilization of A1 in
contrast to that observed in intermediate A2. On the other
hand, the C-protonated intermediate A2 gave the classical
Pictet−Spengler product 18 with the targeted trans-stereo-
selectivity. Based on this hypothesis, the use of Nb-benzyl-L-
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Table 1. Diazo Decomposition of 19
temp
(°C)
time
(h)
entry
catalyst/reagent
solvent
product
%yield
1
2
3
4
5
6
7
8
9
Rh2(OAc)4 (10 mol %)
Rh2(OAc)4 (10 mol %)
Rh2(OAc)4 (10 mol %)
CuOTf (80 mol %)
CuOTf (40 mol %)
CuOTf (60−80 mol %)
HBF4 (4−8 equiv)
benzene
benzene
benzene
CH2Cl2
CH2Cl2
benzene
CH2Cl2
CH2Cl2
CCl4
rt
4
20
20
20
18
18
18
67%
67%
75%
51%
47%
51%
−
40
75
rt
1.5
2
1
reflux
rt
1
2
rt
>24
4
decomposition
decomposition
19 + baseline
HBF4 (4−8 equiv)
hυ (λ ≥ 254 nm)
reflux
rt
−
−
12
tryptophan methyl ester in the same process should provide the
framework (17′) with all the stereogenic centers in the correct
disposition. To confirm, whether the formation of 17 was not
via an acid-catalyzed rearrangement of 18, the β-carboline 18
was stirred at room temperature with 8 equiv of MeSO3H for
decomposition of 19 to provide the C(5)−C(16) bond was
next attempted. Initial trials (not shown) using catalytic
amounts (5−10 mol %) of CuOTf at room temperature or
under refluxing conditions gave only starting material 19. A
new product was obtained only after increasing the amount of
CuOTf39 to 40 mol % (at reflux) and 80 mol % at room
temperature to furnish the β-keto ester THBC 18 (Table 1,
entries 4 and 5). With the failure of the transition metal
mediated process to give the product with C(5)−C(16) bond
formation in 21, attention turned to the use of Brønsted acid
catalysis (Table 1, entries 7 and 8). Diazocarbonyl compounds
with suitably positioned internal nucleophilic sites permit
cyclizations to occur with new bond formation. Treatment of
the α-diazo β-keto ester 19 with 4 or 8 equiv of tetrafluoroboric
acid at room temperature provided only starting material 19
(TLC, silica gel) after 4 h. Continued stirring for prolonged
periods of time resulted in decomposition of 19 with no new
components observed by TLC. All attempts to heat the
solution also resulted in decomposition of 19. Photolysis
experiments on the diazo compound 19 also failed (Table 1,
entry 9). Based on these results it is apparent that the inability
to achieve the formation of the C(5)−C(16) bond in indole 21
presumably via a highly strained cyclopropane ring intermediate
followed by ring opening is less favorable, as a result of the
electrophilic carbene being inserted into the readily accessible
benzylic C−H bond thereby forming 20. In addition, formation
of a Strychnos tetracycle like 17′ presumably via the nucleophilic
attack of C-13 of the indole nucleus on the electrophilic
carbene followed by rearrangement was also not observed. This
suggests that the formed electrophilic carbenoid orients itself
relatively far from the indole double bond in the β-carboline
system 19.
1
24 h. Analysis of the crude reaction mixture by H NMR
spectroscopy after workup indicated the presence of only
starting 18. Any attempt to heat the reaction mixture resulted
in decomposition of the material.
With the important tetracyclic Strychnos template 17 and the
THBC unit 18 synthesized in just two steps from 10, the
diazonium approach via 18, to form the C(7)−C(16) bond
present in the akuammiline series, represented by strictamine
22,34 was attempted. The required diazo compound 19 was
readily obtained using standard diazo transfer conditions from
18. With the α-diazo β-keto ester 19 in hand, the efficiency of
transition metal salts as catalysts in diazo decompositions, to
effect the formation of the C(5)−C(16) bond in 19, was
explored (Table 1). Diazo decomposition13 of 19 in benzene in
the presence of 5−10 mol % of Rh2(OAc)4 at room
temperature, 40 °C, or 75 °C (Table 1, entries 1−3) gave
compound 20 (lower Rf) with complete consumption of the
starting material 19. Based on 2D NMR experiments on 20, it
appeared that the electrophilic Rh(II) carbene35 V, formed by
extrusion of nitrogen,36 had inserted into the electron-rich
tertiary C−H bond at the benzylic position35 via a single three-
centered transition state37 to form the cyclobutanone38 VI.
This was, presumably, followed by opening of the cyclo-
butanone ring and intramolecular proton transfer to provide
the olefinic THBC 20 as an E-isomer. This was confirmed by
analysis of the 1H NMR spectrum which showed the indole Na-
H proton at δ 13.8 because of hydrogen bonding with the C-15
carbonyl group. The effect of a CuOTf-mediated diazo
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min and then the flask was transferred to a preheated oil bath (70−75
°C). The reaction mixture was stirred at this temperature under argon
for 15 h, after which analysis by TLC (silica gel) indicated the
disappearance of the starting material 10 and a new component was
observed at a lower Rf. The reaction mixture was concentrated under
reduced pressure, diluted with CH2Cl2, and neutralized with ice cold
10% aqueous NH4OH. The two layers were separated, and the
aqueous layer was extracted with CH2Cl2. The combined organic
layers were washed with brine and dried (Na2SO4), and the solvent
was concentrated under reduced pressure. The brown colored residue
was purified by flash column chromatography (silica gel, hexanes/
EtOAc, 1:1), which provided enaminone 16 (2.3 g, 91%) as a light
brown solid. Rf 0.49 (silica gel, EtOAc/hexanes, 4:1); IR (KBr) νmax
In summary, an efficient, rapid synthesis of the highly
functionalized tetracyclic core 17 of the Strychnos alkaloids was
developed. This permits stereospecific formation of rings C and
E in a single step, which also generates the all important C-7
quaternary center in a stereospecific fashion. The tetracyclic
core 17 of the Strychnos alkaloids and the β-ketoester THBC
unit 18 were synthesized exclusively by simply varying the
equivalents of MeSO3H, molar concentration, and the reaction
temperature, from a common enaminone intermediate 16,
which in turn was obtained in high yield by making use of a
novel Michael acceptor 15. We believe that by employing L-
tryptophan as the starting material, stereospecific formation of
the tetracycle 17′ could be readily achieved. Further
functionalization of this core should provide ready access to
the northern hemispheres of bisindoles 3−5, as well as other
complex members of this series of alkaloids.
1
3403, 3303, 2951, 1740, 1653, 1558, 743 cm−1; H NMR (300 MHz,
CDCl3) δ 8.27 (1H, s), 7.88 (1H, d, J = 10.4 Hz), 7.39 (2H, d, J = 8.3
Hz), 7.22 (4H, m), 7.09 (1H, t, J = 7.5 Hz), 7.04−6.94 (3H, m), 5.30
(1H, d, J = 12.8 Hz), 4.36−4.21 (3H, m), 3.71 (3H, s), 3.65 (3H, s),
3.51 (1H, dd, J = 14.8, 6.5 Hz), 3.39 (2H, dd, J = 17.0, 14.4 Hz), 3.26
(1H, dd, J = 14.8, 8.8 Hz); 13C NMR (75 MHz, CDCl3) δ 189.0,
170.6, 169.0, 151.2, 136.1, 134.7, 128.5, 127.6, 127.2, 126.7, 123.4,
122.2, 119.6, 118.0, 111.3, 109.6, 97.6, 65.7, 53.4, 52.4, 52.0, 48.0, 27.1;
EIMS m/z 434 [M]+ (14), 361 (10), 334 (12), 319 (16), 305 (31),
275 (14), 243 (11), 234 (41), 201 (30), 170 (10), 130 (100), 91 (87);
anal. C 68.74, H 6.10, N 6.29%, calcd for C25H26N2O5, C 69.11, H
6.03, N, 6.45%.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Melting points were taken
on a Stuart melting point apparatus SMP3 manufactured by
Barloworld Scientific US Ltd. Optical rotations were measured on a
JASCO Model DIP-370 digital polarimeter. IR spectra were recorded
on a Thermo Nicolet Nexus 870 FT-IR or a Perkin-Elmer 1600 series
FT-IR spectrometer. Proton (1H NMR) and carbon high resolution
nuclear magnetic resonance spectra (13C NMR) were obtained on a
Bruker 300-MHz or a GE 500-MHz NMR spectrometer. The low
resolution mass spectra (LRMS) were obtained on electron impact
(EI, 70 eV) mass spectrometer, which were recorded on a Hewlett-
Packard 5985B gas chromatography−mass spectrometer, while high
resolution mass spectra (HRMS) were recorded on a VG Autospec
(Manchester England) mass spectrometer. HRMS recorded by
electrospray ionization (ESI) methods were performed on a API
QStar Pulsar model, manufactured by MDS Sciex. Flash and gravity
chromatography was performed using silica gel P60A, 40−63 μm
purchased from Silicycle. All reactions were carried out under an argon
atmosphere with dry solvents using anhydrous conditions unless
otherwise stated.
Brønsted Acid Mediated Cyclization of 16 To Provide
(2R, 3aR, 6S, 6aR, 11bR)-Dimethyl-3-benzyl-5-oxo-
2,3,3a,4,5,6,6a,7-octahydro-1H-pyrrolo[2,3-d]carbazole-2,6-di-
carboxylate (17). To a solution of enaminone 16 (725 mg, 1.7
mmol) in dry CH2Cl2 (15 mL), methanesulfonic acid (0.87 mL, 13.4
mmol) was added dropwise under an atmosphere of argon at 0 °C (ice
bath). After addition of the MeSO3H, the ice bath was removed
immediately and the reaction mixture was allowed to stir for 30 min, at
which point analysis by TLC indicated the disappearance of the
starting material 16 and a new spot at higher Rf. The reaction mixture
was brought to pH 8 with a saturated cold aqueous solution of
NaHCO3. The two layers were separated. The organic layer was
washed with brine and dried (Na2SO4), and the solvent was
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, EtOAc/hexanes) to furnish 17
(518 mg, 71% yield) as a light yellow solid, a portion of which was
recrystallized from a mixture of CH2Cl2/hexanes to give 17 as white
needle-shaped crystals for X-ray analysis. Rf 0.54 (silica gel, EtOAc/
(E)-Ethyl-5-methoxy-3-oxo-4-pentenoate (15). To a solution
of methyl 5,5-dimethoxy-3-oxopentanoate 14 (3.6 g, 19.1 mmol) in
dry CH2Cl2 (80 mL) was added 2,6-lutidine (6.1 g, 57.11 mmol). The
reaction flask was cooled to 0 °C with ice, followed by dropwise
addition of TMSOTf (8.5 g, 38.1 mmol). After 10 min, the ice bath
was removed and the reaction mixture was allowed to stir at rt for 3 h
or until analysis by TLC indicated disappearance of the starting
material 14 (silica gel, EtOAc/hexanes, 13:7; run the TLC on a longer
plate). After the acetal 14 was completely consumed (TLC), H2O was
added to the reaction mixture at rt, after which it was stirred for 5 min
and the two layers were separated. The aqueous layer was extracted
with CH2Cl2, and the combined organic layers were washed with brine
and dried (Na2SO4). The solvent was removed under reduced pressure
to afford the crude product 15, which was dried in vacuo to remove the
excess 2,6-lutidine before the crude oil was purified by flash
chromatography on silica gel (EtOAc/hexanes = 1:9) to provide the
enol ether 15 (2.6 g, 87%) as a pale yellow oil. IR (NaCl) νmax 2954,
1743, 1684, 1438 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.66 (1H, d, J
= 12.6 Hz), 5.68 (1H, d, J = 12.6 Hz), 3.75 (6H, s), 3.52 (2H, s)
(Proton NMR contains 4.8% of enol); 13C NMR (75 MHz, CDCl3) δ
190.7 (C), 167.9 (C), 164.2 (CH), 104.7 (CH), 57.7 (CH3), 52.3
(CH3), 47.8 (CH2); EIMS m/z 158 [M+] (100), 127 (17); HRESIMS
m/z 159.0654 [M + H]+ (calcd for C7H11O4, 159.0657).
hexanes, 3:5); mp 142−143 °C; [α]26 +81.64 (c 0.73, CHCl3); IR
D
1
(KBr) νmax 3383, 2951, 1738, 1723, 1608, 1203, 751 cm−1; H NMR
(300 MHz, CDCl3) δ 7.35−7.26 (3H, m), 7.23−7.20 (2H, m), 7.14−
7.06 (2H, m), 6.79 (1H, t, J = 7.4 Hz), 6.65 (1H, d, J = 7.5 Hz), 5.14
(1H, d, J = 2.0 Hz), 4.92 (1H, d, J = 3.2 Hz), 4.24 (1H, t, J = 2.0 Hz),
3.91−3.86 (4H, m), 3.62−3.54 (2H, m), 3.48 (3H, s), 2.90−2.82 (2H,
m), 2.55 (2H, ddd, J = 43.1, 18.6, 2.8 Hz), 2.09 (1H, dd, J = 14.4, 6.6
Hz) (Proton NMR contains 10.5% of enol); 13C NMR (75 MHz,
CDCl3) δ 202.9 (C), 174.0 (C), 170.9 (C), 149.9 (C), 135.8 (C),
131.1 (C), 129.4 (2 × CH), 128.8 (CH), 128.2 (2 × CH), 127.5
(CH), 122.8 (CH), 118.9 (CH), 109.5 (CH), 70.1 (CH), 67.2 (CH),
65.1 (CH), 55.9 (CH2), 54.6 (CH), 52.7 (C), 52.3 (CH3), 51.8
(CH3), 42.2 (CH2), 37.5 (CH2); EIMS m/z 434 [M+] (85), 403 (17),
375 (100), 343 (62), 319 (19), 284 (12), 259 (41), 242 (19), 204
(24), 154 (24), 143 (18), 130 (44), 91 (91); anal. C 68.76, H 6.19, N
6.28%, calcd for C25H26N2O5, C 69.11, H 6.03, N 6.45%.
Brønsted Acid Mediated Cyclization of 16 To Provide
(1S,3R)-Methyl-2-benzyl-1-(4-methoxy-2,4-dioxobutyl)-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (18). To a
solution of enaminone 16 (840 mg, 1.94 mmol) in dry CH2Cl2 (38
mL) was added dropwise methanesulfonic acid (0.50 mL, 7.74 mmol)
under an atmosphere of argon at 0 °C (ice bath). After stirring the
reaction mixture for 30 min at 0 °C, analysis by TLC indicated the
disappearance of the starting material 16 and a new spot at higher Rf.
The reaction mixture was neutralized with an ice cold saturated
solution of NaHCO3. The two layers were separated. The organic
layer was washed with brine and dried (Na2SO4), and the solvent was
Alkylation of 10 To Provide (R,E)-Methyl-5-((3-(1H-indol-3-
yl)-1-methoxy-1-oxo-propan-2-yl)(benzyl)amino)-3-oxopent-
4-enoate (16). The Nb-benzyl-D-trypthophan methyl ester 10 (1.8 g,
5.8 mmol) and the enol ether 15 (1.6 g, 9.9 mmol) were dissolved in
MeCN (65 mL). The mixture was cooled to 0 °C with ice, followed by
the dropwise addition of glacial acetic acid (7.0 g, 117 mmol). After
the reaction mixture was stirred for 15 min at 0 °C, the ice bath was
removed after which the reaction mixture was stirred for another 15
186
dx.doi.org/10.1021/np200759h | J. Nat. Prod. 2012, 75, 181−188

Journal of Natural Products
Article
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, EtOAc/hexanes) to furnish 18
(730 mg, 86% yield) as a light yellow solid, a portion of which was
recrystallized from a mixture of CH2Cl2/hexanes to give 18 as yellow
needle-shaped crystals for X-ray analysis. For subsequent batches, the
crude residue obtained after workup was directly subjected to the diazo
transfer reaction without any further purification. Rf 0.55 (silica gel,
226 (22), 209 (53), 195 (19), 181 (31), 154 (12); HREIMS m/z
432.1672 (calcd for C25H24N2O5, 432.1685).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures for compounds 12a,b, 13, 14 and
spectral data for all the compounds including X-ray data for 17
and 18 (CIF files). This material is available free of charge via
the Internet at http://pubs.acs.org.
EtOAc/hexanes, 2:3); mp 126−127 °C; [α]26 −10.71 (c 1.12,
D
CHCl3); IR (KBr) νmax 3335, 3034, 2949, 2880, 1757, 1732, 1359,
1048 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.42 (1H, s), 7.56 (1H, d, J
= 7.6 Hz), 7.39−7.25 (6H, m), 7.23−7.11 (2H, m), 4.38 (1H, dd, J =
9.4, 3.4 Hz), 4.01 (1H, dd, J = 9.5, 4.8 Hz), 3.94−3.77 (4H, m), 3.70
(3H, s), 3.62 (1H, d, J = 14.0 Hz), 3.45 (2H, s), 3.30−3.02 (4H, m);
13C NMR (75 MHz, CDCl3) δ 203.2 (C), 172.9 (C), 167.0 (C), 138.9
(C), 135.9 (C), 133.5 (C), 128.5 (2 × CH), 128.3 (2 × CH), 127.2
(CH), 126.5 (C), 121.9 (CH), 119.4 (CH), 118.0 (CH), 111.0 (CH),
106.8 (C), 57.7 (CH), 53.4 (CH2), 52.4 (CH3), 52.0 (CH3), 51.4
(CH), 49.8 (CH2), 49.2 (CH2), 20.8 (CH2); EIMS m/z 434 [M+]
(14), 375 (10), 343 (23), 319 (100), 257 (24), 183 (8), 169 (15), 156
(19), 91(84); anal. C 68.92, H 6.14, N 6.24%, calcd for C25H26N2O5, C
69.11, H 6.03, N 6.45%.
AUTHOR INFORMATION
Corresponding Author
*Tel: 414-229-5856. Fax: 414-229-5530. E-mail: capncook@
uwm.edu.
■
ACKNOWLEDGMENTS
■
We wish to acknowledge the NIMH (in part) and the Lynde
and Harry Bradley Foundation for support of this work. X-ray
crystallographic studies were supported by NIDA-NRL Inter-
agency Agreement Number Y1-DA1101.
Diazo Transfer Reaction of 18 To Provide (1S,3R)-Methyl-2-
benzyl-1-(3-diazo-4-methoxy-2,4-dioxobutyl)-2,3,4,9-tetrahy-
dro-1H-pyrido[3,4-b]indole-3-carboxylate (19). To the above
keto ester 18 (390 mg, 0.90 mmol) in MeCN (12 mL), Et3N (0.20
mL, 1.44 mmol) was added at rt. The solution which resulted was
allowed to stir for 15 min, at which time mesyl azide (192 mg, 1.8
mmol) was added, and the reaction mixture was allowed to stir at rt for
4 h. The reaction mixture was quenched with H2O, and the mixture
was partitioned between ether and H2O. The aqueous layer was
extracted with ether, and the combined organic layers were washed
with brine and dried (MgSO4), and the solvent was concentrated
under reduced pressure. The residue was subjected to flash silica gel
column chromatography to afford the diazo compound 19 as a yellow
solid (343 mg, 83%). Rf 0.61 (silica gel, EtOAc/hexanes, 2:3); IR
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1
(neat) νmax 3369, 2952, 2136, 1718, 1641, 1436, 741 cm−1; H NMR
(300 MHz, CDCl3) δ 8.48 (1H, s), 7.58 (1H, d, J = 7.4 Hz), 7.39−
7.28 (5H, m), 7.25−7.12 (3H, m), 4.34 (1H, t, J = 6.7 Hz), 4.15 (1H,
dd, J = 10.1, 5.2 Hz), 3.90−3.79 (7H, m), 3.52 (1H, d, J = 13.6 Hz),
3.33 (2H, ddd, J = 22.1, 14.3, 7.5 Hz), 3.17 (1H, dd, J = 16.0, 10.2 Hz),
3.08 (1H, dd, J = 16.0, 5.3 Hz); 13C NMR (75 MHz, CDCl3) δ 191.3
(C), 173.0 (C), 161.5 (C), 139.3 (C), 135.8 (C), 133.5 (C), 128.9 (2
× CH), 127.9 (2 × CH), 127.0 (CH), 126.7 (C), 121.8 (CH), 119.3
(CH), 118.1 (CH), 110.9 (CH), 107.2 (CH), 90.5 (C), 57.4 (CH),
53.1 (CH2), 52.2 (CH), 52.0 (2 × CH3), 46.8 (CH2), 20.4 (CH2);
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461.1825); anal. C 64.93, H 5.42, N 11.90%, calcd for C25H24N4O5,
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(R,E)-Methyl-2-benzyl-1-(4-methoxy-2,4-dioxobutylidene)-
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Procedure described for entry 1 (Table 1): To a solution of 19
(207 mg, 0.45 mmol) in dry benzene (6 mL) under nitrogen,
rhodium(II) acetate (20 mg, 0.045 mmol) was added. The mixture was
allowed to stir at rt for 4.0 h. The solution was then filtered through a
pad of Celite and washed with ether. The filtrate was concentrated
under reduced pressure, and the residue was subjected to flash silica
gel column chromatography (EtOAc/hexanes) to furnish 20 (130 mg,
67% yield) as a light yellow oil. Rf 0.41 (silica gel, EtOAc/hexanes,
2:3); IR (neat) νmax 2952, 1735, 1508, 1463, 733 cm−1; 1H NMR (300
MHz, CDCl3) δ 13.8 (1H, s), 7.58 (1H, d, J = 8.0 Hz), 7.50 (1H, d, J =
8.3 Hz), 7.44−7.31 (6H, m), 7.14 (1H, t, J = 7.7 Hz), 5.55 (1H, s),
5.13 (1H, d, J = 16.2 Hz), 4.42−4.40 (2H, m), 3.68−3.61 (7H, m),
3.50 (2H, t, J = 14.6 Hz), 3.39 (1H, dd, J = 16.5, 6.6 Hz); 13C NMR
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(2 × CH), 125.0 (CH), 124.6 (C), 119.9 (CH), 119.2 (CH), 113.0
(CH), 112.1 (C), 94.7 (CH), 62.4 (CH), 56.7 (CH2), 52.8 (CH3),
52.1 (CH3), 50.6 (CH2), 23.8 (CH2); EIMS m/z 432 [M+] (17), 373
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