Total synthesis of the monoterpenoid alkaloid (±)-tangutorine

Article abstract of DOI:10.1039/c1ob06539d

A novel approach to a formal total synthesis of the monoterpenoid indole alkaloid (±)-tangutorine has been developed starting from an α,β-unsaturated cyclic dehydroamino ester. Synthesis of the rather unusual trans-substituted 2,3-indoloquinolizidine substructure was accomplished via Cu(ii)-mediated conjugate addition and organozinc/copper coupling as the key steps, thereby setting the stage for ring-closing metathesis to produce the quinolone substructure. Finally, Bischler-Napieralski cyclization gave rise to the pentacyclic system of (±)-tangutorine thereby realizing a formal synthesis in an overall yield of 5.2% in eight consecutive steps.

Full text of DOI:10.1039/c1ob06539d

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PAPER
Total synthesis of the monoterpenoid alkaloid ( )-tangutorine†
Sebastiaan (Bas) A. M. W. van den Broek, Jaap G. H. Lemmers, Floris L. van Delft and Floris P. J. T. Rutjes*
Received 7th September 2011, Accepted 10th November 2011
DOI: 10.1039/c1ob06539d
A novel approach to a formal total synthesis of the monoterpenoid indole alkaloid ( )-tangutorine has
been developed starting from an a,b-unsaturated cyclic dehydroamino ester. Synthesis of the rather
unusual trans-substituted 2,3-indoloquinolizidine substructure was accomplished via Cu(II)-mediated
conjugate addition and organozinc/copper coupling as the key steps, thereby setting the stage for
ring-closing metathesis to produce the quinolone substructure. Finally, Bischler–Napieralski cyclization
gave rise to the pentacyclic system of ( )-tangutorine thereby realizing a formal synthesis in an overall
yield of 5.2% in eight consecutive steps.
Tangutorine (1) shows interesting biological effects on the
regulation of cell cycle and cellular morphology and therefore
Introduction
might serve as a lead compound for the design of new drugs.5
Since its isolation in 1999, several syntheses of ( )-tangutorine (1)
have been published,6–10 one of which describes the synthesis of
both optical antipodes.11
Following-up on previously developed methodology from our
group on ring-closing metathesis (RCM) of (sterically hindered)
enamides,12,13 and its application in the synthesis of substituted
piperidines,14,15 we herewith describe a novel approach to racemic
tangutorine (1) starting from key building block 7.16 As de-
picted in Scheme 1, a first disconnection of the pentacyclic
Monoterpenoid alkaloids are widespread in nature and possess
diverse structures with often relevant biological properties.1 b-
Carbolines (e.g. 1–3, Fig. 1) belong to this class and form one of
the principal alkaloid groups in nature that are biosynthetically
derived from tryptophan.2 This class contains some of the most
important alkaloids used in medicine such as reserpine (3).3 In
1999, a novel racemic b-carboline named tangutorine (1) was
isolated by Duan and colleagues from the leaves of the Chinese
medical plant Nitraria tangutorine.4 Although tangutorine (1)
is structurally related to the more common yohimbine skeleton
(viz. 2), it is the only known b-carboline alkaloid containing an
indoloquinolizidine substructure.
Fig. 1 Monoterpenoid indole alkaloids.
Radboud University Nijmegen, Institute for Molecules and Materials,
Heyendaalseweg 135, NL-6525 AJ Nijmegen, The Netherlands. E-mail:
F.Rutjes@science.ru.nl
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob06539d
Scheme 1 Retrosynthesis of ( )-tangutorine (1).
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tangutorine framework would involve a Bischler–Napieralski
cyclization, followed by reduction giving rise to bicyclic pre-
cursor 4. Subsequently, hexahydroquinolone 4 could be derived
via RCM from the trans-5,6-disubstituted lactam 5. We were
hopeful that the primary iodide 6 would serve as a suitable
precursor to deliver 5 via organozinc/copper-mediated coupling
with ethyl 2-(bromomethyl)acrylate. Finally, diastereoselective
copper-catalyzed 1,4-addition onto 7, followed by some further
functionalization was anticipated to lead to iodide 6.
Results and discussion
Recently, we have shown that the unsaturated lactam 7 can
be readily prepared from a linear enamide precursor through
RCM.15 Having lactam 7 thus available, diastereoselective copper-
catalyzed 1,4-addition of vinylmagnesium bromide in the presence
of CuI at -20 ◦C provided the trans-5,6-disubstituted lactam 8 in
72% yield as a single diastereoisomer (Scheme 2).17 Next, conver-
sion of the ester functionality into the corresponding primary
iodide was aimed to provide a handle for introduction of the
second double bond, thereby setting the stage for RCM formation
of the second ring. Disappointingly, reduction with DIBAL-H at
-78 ◦C was unproductive, and starting material was recovered.
Use of LiAlH4 also gave no product, but instead led to reduction
of both the alcohol and the amide. Gratifyingly, reduction with
LiEt3BH at 0 ◦C was efficient and yielded the desired alcohol
9 in 88%. Subsequent conversion into primary iodide 6 was
accomplished with iodine in the presence of triphenylphosphine
and imidazole in 78% yield. To prepare RCM precursor 10,
initially Grignard-mediated substitution of the iodide and the
corresponding tosylate was investigated. In either case, however,
no reaction was observed and only starting material was recovered.
We then turned to an organozinc/copper coupling strategy to
introduce the second olefin (Scheme 2).18 Reaction of iodide 6
with activated zinc and ethyl 2-(bromomethyl)acrylate did result
in the desired RCM-precursor 10 in 42% yield together with the
undesired ring-opened product 11 (39%).
Scheme 3 Toward quinolone precursor 5.
12 with Boc-protected tryptophyl bromide (14). To this end,
the amide group had to be deprotected. PMB-deprotection of
12 proved to be somewhat less trivial than expected, however.
Oxidation with ceric ammonium nitrate (CAN) in MeCN led
to long reaction times despite using a large excess of reagents,
eventually resulting in multiple products. Alternatively, treatment
with DDQ in H2O/CH2Cl2 mixtures did not show any conversion
at all. Treatment with TFA at elevated temperatures on the
other hand proceeded smoothly resulting in 13 in 72% yield.
Unfortunately, alkylation of lactam 13 with bromide 14 and
DIPEA at elevated temperature only resulted in degradation of the
starting material.19 Disappointingly, reaction with sodium hydride
in DMF in the presence of 14 (and additional TBAI or KI) did
not lead to any product either.
Introduction of the indole group was therefore envisioned to
occur starting from the cyclic dehydroamino ester 7 (Scheme 4).
PMB-deprotection of 7 using TFA yielded lactam 15 in 85% yield.
Scheme 2 Organozinc/copper coupling strategy.
Having RCM-precursor 10 in hand, treatment with the Grubbs’
◦
second generation catalyst (G2, 10 mol%, toluene, 80 C) led to
hexahydroquinolone 12 in 89% yield (Scheme 3). To introduce the
indole moiety, we initially turned to N-alkylation of quinolizidine
Scheme 4 Bischler–Napieralski cyclization.
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Alkylation with Boc-protected tryptophyl bromide (14) in the
presence of sodium hydride now resulted in the desired N-alkylated
product, but the isolated yield never exceeded 10%. When sodium
hydride was added portionwise (5 times 0.25 equiv) the yield
was raised to an acceptable 53%. With 16 successfully synthe-
sized, trans-selective 1,4-addition with vinylmagnesium bromide,
followed by Bischler–Napieralski cyclization was thought to lead
to the desired pentacycle.20 Indeed, diastereoselective conjugate
addition, and subsequent treatment of 17 with POCl3 in DMF
at elevated temperatures led to iminium-salt 18, which was then
reduced with sodium borohydride in ethanol to give an inseparable
mixture of diastereoisomers 19 (86 : 14). Unfortunately, the Boc-
group was cleaved during the cyclization so that reprotection was
necessary to complete the synthesis.
overall yield of 45%. Its spectral data were in agreement with values
reported in literature.4
Conclusions
In conclusion, we have demonstrated the synthetic value of
the dehydroamino ester building block 7 through application
in the synthesis of ( )-tangutorine in eight consecutive steps in
an overall yield of 5.2%. The pathway is characterized by a
diastereoselective copper-catalyzed 1,4-addition onto the cyclic
dehydroamino ester, an organozinc/copper coupling followed
by ring-closing metathesis of the diolefin for the construction
of the quinolone substructure and a diastereoselective Bischler–
Napieralski cyclization.
To avoid the reprotection step, a slightly different strategy was
pursued, in which the quinolizidine substructure was constructed
from dehydroamino ester 17 in four consecutive steps (Scheme 5).
The reduction/iodination protocol first yielded iodide 21 in 69%
yield over two steps. Then, the organozinc/copper coupling af-
fordedRCMprecursor5 inamoderate yieldof52%, againtogether
with the undesired 1,4-diene (34%) as described previously. Finally,
RCM proceeded uneventfully to give quinolone structure 4 in a
near quantitative conversion. En route to completion of the syn-
thesis, pentacycle 23 was produced in diastereomerically pure form
via Bischler–Napieralski cyclization of lactam 4. Surprisingly,
the Boc-group was only partially removed during this reaction.
Separation of both products and subsequent Boc-deprotection
of 22 with TFA resulted in the known carboxylic ester 23 in an
Experimental
General
1H-NMR spectra were recorded on a 400 MHz NMR spec-
trometer. 13C-NMR spectra were recorded on a 75 MHz NMR
spectrometer. Chemical shifts (d) are reported in ppm and relative
to a residual solvent peak (1H-NMR: 7.26 in CDCl3, 13C-
NMR: 77.0 in CDCl3). IR spectra were recorded on an ATR
IR-spectrometer. Rf values are obtained using thin layer chro-
matography (TLC) on silica gel-coated plates with the indicated
eluents and compounds were detected with UV-light, potassium
permanganate, p-anisaldehyde or ninhydrin.
1-[2-(1-tert-Butoxycarbonyl-1H-indol-3-yl)ethyl]-2-oxo-1,2,3,
4,4a,5,6,8a-octahydroquinoline-7-carboxylic acid ethyl ester (4)
Compound 5 (28 mg, 0.056 mmol) was dissolved in toluene (1 mL)
and argon was flushed through the solvent. The second generation
Grubbs’ catalyst (5 mg, 0.005 mmol) was added and the solution
was heated to 80 ◦C. After 1 h, the solution was cooled to
room temperature and concentrated in vacuo. The residue was
purified by flash column chromatography (EtOAc/heptane 1 : 1)
affording compound 4 (26 mg, 98%) as a colorless oil. Rf 0.38
(EtOAc/heptane 2 : 1). FTIR (ATR) 2922, 1728, 1639, 1450, 1369,
1256, 1157 cm-1.1H NMR (CDCl3, 400 MHz): d 8.12 (d, J = 7.0
Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.43 (s, 1H), 7.35–7.22 (m, 2H),
6.70 (d, J = 1.1 Hz, 1H), 4.21 (q, J = 6.9 Hz, 2H), 3.84–3.68 (m,
2H), 3.14 (ddd, J = 12.1, 9.7, 2.2 Hz, 1H), 3.09–3.00 (m, 1H), 2.83–
2.73 (m, 1H), 2.69–2.53 (m, 3H), 2.46–2.36 (m, 2H), 2.34–2.23 (m,
1H), 2.04–1.96 (m, 1H), 1.67 (s, 9H), 1.63–1.50 (m, 2H), 1.31 (t, J =
7.1 Hz, 3H).13C NMR (CDCl3, 300 MHz): d 170.2, 166.1, 149.3,m
138.7, 135.0, 130.0, 129.7, 128.5, 127.7, 124.8, 124.0, 122.4, 122.1,
118.7, 117.5, 114.8, 83.0, 60.2, 58.1, 42.3, 39.6, 32.5, 27.8, 26.8,
26.0, 24.1, 23.7, 13.8. HRMS (ESI) m/z calcd for C27H34N2O5
(M + Na)+: 489.2368, found: 489.2365.
3-{2-[2-(3-Ethoxycarbonylbut-3-enyl)-6-oxo-3-vinylpiperidin-1-
yl]ethyl}indole-1-carboxylic acid tert-butyl ester (5)
Zinc dust (42 mg, 0.65 mmol) was weighed into a Schlenk flask,
which was flame dried and flushed with argon. 1,2-Dibromoethane
(2.8 mL, 0.03 mmol) in dry DMF (0.2 mL) was added and the flask
was heated to 60 ◦C for 1 h. Me3SiCl (0.41 mL, 0.0031 mmol)
was added and the mixture was stirred at 60 ◦C for 30 min.
Scheme 5 Completion of tangutorine (1).
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Compound 21 (55 mg, 0.11 mmol) was dissolved in DMF (0.3 mL),
added to the mixture and stirred for 10 min at 60 ◦C. CuCN
(10 mg, 0.11 mmol) and LiCl (9.2 mg, 0.22 mmol) were heated to
150 ◦C under vacuum for 2 h and cooled to room temperature.
Addition of DMF (0.3 mL) formed a soluble CuCN·2LiCL
complex. After cooling, the organozinc reagent was cooled to
-55 ◦C, the Cu-complex was added and the solution was warmed
to 0 ◦C. After stirring for 10 min at 0 ◦C, the solution was
cooled to -55 ◦C and ethyl 2-(bromomethyl)acrylate (18.2 mL,
0.13 mmol) was added. The solution was slowly warmed to room
temperature and stirred overnight. The mixture was filtered over
Celite, diluted with EtOAc (10 mL), washed with aqueous NH4Cl
(50 mL) and brine (50 mL), dried (MgSO4) and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (EtOAc/heptane 1 : 1) affording lactam 5 (28 mg,
52%) as a viscous oil. Rf 0.27 (EtOAc/heptane 1 : 1). FTIR (ATR)
2977, 1728, 1637, 1454, 1372, 1158 cm-1.1H NMR (CDCl3, 400
MHz): d 8.13 (d, J = 7.0 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.41 (s,
1H), 7.35–7.22 (m, 2H), 6.15 (s, 1H), 5.71 (ddd, J = 17.3, 10.3, 7.2
Hz, 1H), 5.51 (s, 1H), 5.16–5.06 (m, 2H), 4.19 (q, J = 6.9 Hz, 2H),
4.21–4.12 (m, 1H), 3.19–3.13 (m, 1H), 3.09–2.93 (m, 3H), 2.54–
2.44 (m, 2H), 2.40–2.16 (m, 3H), 2.07–1.96 (m, 1H), 1.88–1.68
(m, 4H), 1.66 (s, 9H), 1.28 (t, J = 7.2 Hz, 3H).13C NMR (CDCl3,
300 MHz): d 169.5, 166.3, 149.2, 139.3, 138.5, 135.0, 130.0, 124.8,
123.9, 122.8, 122.0, 118.7, 117.3, 115.6, 114.8, 82.9, 61.1, 60.3,
45.5, 38.4, 31.3, 28.6, 27.9, 27.8, 22.6, 22.2, 13.7. HRMS (ESI)
m/z calcd for C29H38N2O5 (M + Na)+: 517.2681, found: 517.2678.
(EtOAc/heptane 1 : 1) affording compound 8 (0.95 g, 72%) as a
viscous oil. Rf 0.41 (EtOAc/heptane 1 : 1). FTIR (ATR) 2940,
1
1738, 1649, 1511 cm-1. H NMR (CDCl3, 400 MHz): d 7.16 (d,
J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 5.69–5.59 (m, 1H), 5.35
(d, J = 7.4 Hz, 1H), 5.08–4.91 (m, 2H), 4.22–4.12 (m, 2H), 3.89
(dd, J = 3.9, 1.0 Hz, 1H), 3.79 (s, 3H), 3.69 (d, J = 14.7, 1H), 2.83–
2.77 (m, 1H), 2.54–2.47 (m, 2H), 2.00–1.90 (m, 1H), 1.78–1.71 (m,
1H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 75 MHz): d 170.9,
169.3, 158.7, 136.2, 129.8, 127.9 116.3, 113.4, 61.9, 61.2 54.8, 48.1
38.6 28.3 22.9 13.7. HRMS (ESI) m/z calcd for C18H23NO4Na
(M + Na)+: 340.1537, found: 340.1525.
6-Hydroxymethyl-1-(4-methoxybenzyl)-2-oxo-5-vinylpiperidine (9)
To a cooled solution (0 ◦C) of compound 8 (0.95 g, 3.0 mmol) in
THF (30 mL) LiEt3BH (9.0 mL, 9.0 mmol, 1 M solution in THF)
was added. After 1.5 h of stirring at 0 ◦C another equivalent
of LiEt3BH (1.0 mL, 1.0 mmol) was added and the reaction
was stirred for 2 h. The reaction was then quenched with ice-
water and the product was extracted with CH2Cl2 (2 ¥ 40 mL),
dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography (EtOAc/heptane 1 : 1
to CH2Cl2/MeOH 9 : 1) affording compound 9 (0.78 g, 95%) as
a colorless oil. Rf 0.41 (CH2Cl2/MeOH 9 : 1). FTIR (ATR) 3376,
1
2948, 1613, 1512 cm-1. H NMR (CDCl3, 400 MHz): d 7.20 (d,
J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.64–5.54 (m, 1H),
5.07–5.00 (m, 3H), 4.25 (d, J = 7.4 Hz, 1H), 3.79 (s, 3H), 3.79–3.73
(m, 1H), 3.64–3.56 (m, 1H), 3.21–3.16 (m, 1H), 2.72–2.63 (m, 1H),
2.58–2.37 (m, 2H), 2.05–1.95 (m, 2H), 1.72–1.60 (m, 1H).13C NMR
(CDCl3, 75 MHz): d 171.0, 158.5, 138.5, 129.2, 128.9, 116.0, 113.6,
61.1, 60.6, 54.8, 46.9, 38.3, 30.0, 23.8. HRMS (ESI) m/z calcd for
C16H21NO3Na (M + Na)+: 298.1421, found: 298.1419.
6-Iodomethyl-1-(4-methoxybenzyl)-2-oxo-5-vinylpiperidine (6)
To a solution of compound 9 (105 mg, 0.38 mmol) in THF (4 mL),
PPh3 (120 mg, 0.46 mmol) and imidazole (39 mg, 0.57 mmol) were
added. The reaction was heated to 70 ◦C and iodine (116 mg,
0.46 mmol) was added. After 30 min the reaction was cooled to
room temperature and concentrated in vacuo. The residue was
purified by flash column chromatography (EtOAc/heptane 1 : 1)
affording compound 6 (140 mg, 67%) as a viscous oil. Rf 0.82
(CH2Cl2/MeOH 9 : 1). FTIR (ATR) 2948, 1642, 1512, 1244, 519
4-[1-(4-Methoxybenzyl)-6-oxo-3-vinylpiperidin-2-yl]-2-
methylenebutyric acid ethyl ester (10)
Zinc dust (52.3 mg, 0.81 mmol) was weighed into a Schlenk flask,
which was evacuated under flame drying and flushed with argon.
1,2-Dibromoethane (3.3 mL, 0.04 mmol) in dry DMF (0.3 mL)
was added and the flask was heated to 60 ◦C for 1 h. Me3SiCl
(0.5 mL, 0.004 mmol) was added and the mixture was stirred
at 60 ◦C for 30 min. Compound 6 (50 mg, 0.13 mmol) was
dissolved in DMF (0.4 mL), added to the mixture and stirred
for 10 min at 60 ◦C. CuCN (11.6 mg, 0.13 mmol) and LiCl (11 mg,
0.26 mmol) were heated to 150 ◦C under vacuum for 2 h and
cooled to room temperature. Addition of DMF (0.5 mL) formed
a soluble CuCN·2LiCL complex. After cooling the organozinc
reagent to -55 ◦C the Cu-complex was added and the solution
was warmed to 0 ◦C. After stirring for 10 min at 0 ◦C the solution
was cooled to -55 ◦C and ethyl 2-(bromomethyl)acrylate (21.8 mL,
0.156 mmol) was added. The solution was slowly warmed to room
temperature and stirred for 16 h. The mixture was filtered over
celite, diluted with EtOAc, washed with aqueous NH4Cl and brine,
dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography (EtOAc/heptane 1 : 1)
affording compound 10 (43 mg, 42%) as a viscous oil. Rf 0.25
(EtOAc/heptane 1 : 1). FTIR (ATR) 2936, 1712, 1635, 1512, 1245
cm-1. 1H NMR (CDCl3, 400 MHz): d 7.18 (d, J = 8.6 Hz, 2H), 6.83
(d, J = 8.7 Hz, 2H), 6.16 (d, J = 1.2 Hz, 1H), 5.60–5.50 (m, 1H),
1
cm-1. H NMR (CDCl3, 400 MHz): d 7.16 (d, J = 8.4 Hz, 2H),
6.86 (d, J = 8.7 Hz, 2H), 5.59–5.49 (m, 1H), 5.51 (d, J = 15.0 Hz,
1H), 5.14–5.04 (m, 2H), 3.80 (s, 3H), 3.75 (d, J = 15.1 Hz, 1H),
3.36–3.33 (m, 2H), 2.94–2.89 (m, 1H), 2.68–2.60 (m, 1H), 2.60–
2.41 (m, 2H), 1.95–1.86 (m, 1H), 1.78–1.66 (m, 1H). 13C NMR
(CDCl3, 75 MHz): d 169.9, 158.6, 137.8, 129.1, 127.9, 116.9, 113.7,
57.8, 54.8, 45.4, 41.4, 30.0, 23.2, 9.4. HRMS (ESI) m/z calcd for
C16H20INO2Na (M + Na)+: 408.0439, found: 408.0436.
1-(4-Methoxybenzyl)-6-oxo-3-vinylpiperidine-2-carboxylic acid
ethyl ester (8)
To a cooled solution (-30 ◦C) of CuI (3.15 g, 16.6 mmol) in
Et2O (30 mL), a 1 M vinylmagnesium bromide solution in THF
(8.3 mL, 8.3 mmol) was added. The solution was stirred for 20 min
and was cooled to -70 ◦C. Then compound 7 (1.20 g, 4.15 mmol)
dissolved in Et2O (10 mL) was added and the temperature was
slowly warmed to -10 ◦C. The reaction was quenched with 0.1 M
HCl and washed with aqueous Na2S2O3 (2 ¥ 40 mL), NaHCO3
(40 mL) and H2O (40 mL), dried over MgSO4 and concentrated in
vacuo. The residue was purified by flash column chromatography
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5.50 (d, J = 1.2 Hz, 1H), 5.42 (d, J = 14.6 Hz, 1H), 5.01–4.92 (m,
2H), 4.23 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 3.76 (d, J = 14.6 Hz,
1H), 3.18–3.13 (m, 1H), 2.58–2.45 (m, 2H), 2.44–2.34 (m, 1H),
2.33–2.17 (m, 2H), 2.06–1.95 (m, 1H), 1.90–1.63 (m, 3H), 1.32
(t, J = 7.1 Hz, 3H).13C NMR (CDCl3, 75 MHz): d 169.7, 166.3,
158.4, 139.4, 138.4, 129.4, 128.9, 124.8, 115.6, 113.4, 60.3, 58.0,
54.8, 46.0, 39.3, 30.1, 28.9, 27.5, 22.5, 13.8. HRMS (ESI) m/z
calcd for C22H29NO4Na (M + Na)+: 394.1997, found: 394.1994.
3-[2-(6-Ethoxycarbonyl-2-oxo-3,4-dihydro-2H-pyridin-1-
yl)ethyl]indole-1-carboxylic acid tert-butyl ester (16)
Lactam 15 (121 mg, 0.72 mmol) was dissolved in DMF (8 mL) and
Boc-protected 3-(2-bromoethyl)indole (14, 347 mg, 1.07 mmol)
was added. NaH (45 mg, 0.9 mmol) was gradually added to the
mixture over 2.5 h. The reaction was then stirred overnight at room
temperature, diluted with EtOAc/heptane 1 : 1 (10 mL), cooled to
0 ◦C and quenched with H2O (10 mL). The organic layer was ex-
tracted with EtOAc (3 ¥ 10 mL), dried (MgSO4) and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (EtOAc/heptane 1 : 1) affording compound 16
(155 mg, 53%) as a viscous oil. Rf 0.40 (EtOAc/heptane 1 : 1).
FTIR (ATR) 2977, 1724, 1678, 1367, 1255, 1157 cm-1.1H NMR
(CDCl3, 400 MHz): d 8.11 (d, J = 6.1 Hz, 1H), 7.62 (d, J = 7.7
Hz, 1H), 7.36 (s, 1H), 7.32–7.20 (m, 2H), 6.27 (t, J = 5.0 Hz, 1H),
4.11 (dq, J = 7.1, 0.5 Hz, 2H), 4.10–4.04 (m, 2H), 3.01–2.95 (m,
2H), 2.50 (t, J = 7.6 Hz, 2H), 2.35–2.26 (m, 2H), 1.66 (s, 9H), 1.25
(dt, J = 7.1, 0.5 Hz, 3H).13C NMR (CDCl3, 75 MHz): d 170.1,
162.1, 149.2, 135.1, 134.5, 130.0, 123.8, 122.8, 121.9, 119.9, 118.7,
117.2, 114.7, 82.9, 60.9, 42.9, 30.4, 27.8, 23.9, 19.4, 13.6. HRMS
(ESI) m/z calcd for C23H28N2O5Na (M + Na)+: 435.1898, found:
435.1896.
4-Vinylhex-5-enoic acid 4-methoxybenzylamide (11)
Compound 11 (31 mg, 46%) was isolated as a side product
from the organozinc/copper coupling with compound 6. Rf 0.43
(EtOAc/heptane 1 : 1). FTIR (ATR) 3282, 3073, 2930, 1641, 1512,
1246 cm-1.1H NMR (CDCl3, 400 MHz): d 7.20 (d, J = 8.6 Hz, 2H),
6.86 (d, J = 8.7 Hz, 2H), 5.75–5.64 (m, 2H), 5.62 (br s, 1H), 5.05–
4.96 (m, 4H), 4.36 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H), 2.71 (q, J = 7.4
Hz, 1H), 2.19 (t, J = 7.4 Hz, 2H), 1.79 (dt, J = 7.8, 7.4 Hz, 2H).
13C NMR (CDCl3, 75 MHz): d 171.9, 158.6, 139.9, 129.9, 128.8,
114.5, 113.6, 54.8, 46.9, 42.6, 33.8, 29.3. HRMS (ESI) m/z calcd
for C16H21NO2Na (M + Na)+: 282.1472, found: 282.1470.
3-[2-(2-Ethoxycarbonyl-6-oxo-3-vinylpiperidin-1-yl)ethyl]indole-1-
carboxylic acid tert-butyl ester (17)
1-(4-Methoxybenzyl)-2-oxo-1,2,3,4,4a,7,8,8a-octahydroquinoline-
6-carboxylic acid ethyl ester (12)
To a cooled solution (-30 ◦C) of CuI (0.3 g, 1.75 mmol) in Et2O
(2 mL), a 1 M vinylmagnesium bromide solution in THF (0.87
mL, 0.87 mmol) was added. The solution was stirred for 20 min
Compound 10 (40 mg, 0.11 mmol) was dissolved in toluene (4 mL)
and argon was flushed through the solvent. The second generation
Grubbs’ catalyst (◦9.2 mg, 0.01 mmol) was added and the solution
was heated to 80 C. After 1 h, the solution was cooled to room
temperature and concentrated in vacuo. The residue was purified
by flash column chromatography (EtOAc/heptane 1 : 1 to 2 : 1)
affording compound 12 (34 mg, 86%) as a colorless oil. Rf 0.16
(EtOAc/heptane 1 : 1). FTIR (ATR) 2933, 1708, 1639, 1512, 1244
cm-1. 1H NMR (CDCl3, 400 MHz): d 7.13 (d, J = 8.8 Hz, 2H), 6.84
(d, J = 8.8 Hz, 2H), 6.67 (d, J = 1.3 Hz, 1H), 5.06 (d, J = 15.4 Hz,
1H), 4.42 (d, J = 15.4 Hz, 1H), 4.17 (q, J = 7.1, 7.0 Hz, 2H), 3.79
(s, 3H), 3.08 (ddd, J = 12.2, 9.8, 2.5 Hz, 1H), 2.76—2.59 (m, 2H),
2.55—2.31 (m, 3H), 2.23—2.09 (m, 1H), 2.05—1.97 (m, 1H), 1.60
(m, 1H), 1.42 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3,
75 MHz): d 170.5, 166.1, 158.1, 138.7, 129.3, 127.9, 126.7, 113.5,
60.1, 57.6, 54.8, 44.5, 39.5, 32.4, 26.4, 25.9, 24.0, 13.7. HRMS
(ESI) m/z calcd for C20H25NO4Na (M + Na)+: 366.1684, found:
366.1681.
◦
and cooled to -70 C. Then compound 16 (120 mg, 0.29 mmol)
dissolved in Et2O (1 mL) was added and the temperature was
slowly warmed to -10 ◦C. The reaction was diluted with Et2O,
quenched with 0.1 M HCl (10 mL), washed with aqueous
Na2S2O3 (2 ¥ 10 mL), NaHCO3 (10 mL) and H2O (10 mL),
dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography (EtOAc/heptane 1 : 1)
affording compound 17 (0.95 g, 72%) as a viscous oil. Rf 0.26
(EtOAc/heptane 1 : 1). FTIR (ATR) 2977, 1731, 1650, 1454, 1373,
1158 cm-1.1H NMR (CDCl3, 400 MHz): d 8.12 (d, J = 7.8 Hz, 1H),
7.63 (d, J = 7.7 Hz, 1H), 7.39 (s, 1H), 7.28 (m, 2H), 5.71 (ddd, J =
17.3, 10.4, 7.0 Hz, 1H), 5.19–5.10 (m, 2H), 4.22 (dq, J = 7.1, 0.6
Hz, 2H), 4.18–4.12 (m, 1H), 3.91 (d, J = 4.1 Hz, 1H), 3.10–2.86
(m, 3H), 2.85–2.77 (m, 1H), 2.56–2.38 (m, 2H), 1.98–1.87 (m,
1H), 1.78–1.69 (m, 1H), 1.66 (s, 9H), 1.27 (dt, J = 7.1, 0.7 Hz,
3H).13C NMR (CDCl3, 75 MHz): d 171.0, 169.4, 149.2, 136.4,
135.0, 129.9, 123.9, 122.8, 122.1, 118.6, 117.1, 116.4, 114.8, 83.0,
65.0, 61.3, 47.3, 39.2, 28.5, 27.8, 23.2, 22.4, 13.8. HRMS (ESI) m/z
calcd for C25H32N2O5Na (M + Na)+: 463.2211, found: 463.2209.
6-Oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid ethyl
ester (15)
Compound 7 (1.04 g, 3.6 mmol) was dissolved in a TFA/CH2Cl2
mixture (1 : 4, 36 mL) and stirred overnight at 50 ◦C. The reaction
was quenched with NaHCO3 and the organic compound was
extracted with CH2Cl2 (2 ¥ 40 mL), dried over Na2SO4 and
concentrated in vacuo. The residue was purified by flash column
chromatography (EtOAc/heptane 1 : 1) affording compound 15
(516 mg, 85%). Rf 0.14 (EtOAc/heptane 1 : 1). 1H NMR (CDCl3,
400 MHz): d 7.58 (s, 1H), 6.29–6.26 (m, 1H), 4.29 (q, J = 7.1 Hz,
2H), 2.53–2.50 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H).13C NMR (CDCl3,
75 MHz): d 169.2, 161.2, 128.4, 113.5, 61.4, 28.7, 20.3, 13.7.
3-Vinyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine-4-
carboxylic acid ethyl ester (19)
Compound 17 (20 mg, 0.045 mmol) was dissolved in toluene
(1 mL) and POCl3 (42 mL, 0.45 mmol) was added. The solution
was stirred at 70 ◦C for 2 h. The reaction was concentrated
under reduced pressure, the residue was dissolved in EtOH
(1 mL) and cooled to 0 ◦C. NaBH4 (3.4 mg, 0.09 mmol) was
added and the reaction was stirred for 10 min at 0 ◦C, diluted
with CH2Cl2 (10 mL) and quenched with aqueous NaHCO3
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(10 mL). The organic layer was washed with H2O (2 ¥ 10 mL),
dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography (EtOAc/heptane 1 : 2)
affording compound 19 (13.0 mg, 68%) as a colorless oil. Rf 0.48
(EtOAc/heptane 1 : 1). FTIR (ATR) 3342, 2916, 1717, 1455, 611
cm-1. 1H NMR (CDCl3, 400 MHz): d 7.69 (br s, 1H), 7.46 (d, J =
7.8 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.11 (ddt, J = 15.9, 7.1, 1.2
Hz, 2H), 5.68 (m, 1H), 5.04 (dd, J = 10.2, 1.7 Hz, 1H), 4.30–4.20
(m, 2H), 3.40 (br d, J = 11.4 Hz, 1H), 3.06–2.97 (m, 2H), 2.95
(d, J = 10.3 Hz, 1H), 2.76–2.68 (m, 1H), 2.68–2.54 (m, 2H), 2.19–
2.11 (m, 1H), 2.03–1.96 (m, 1H), 1.87–1.75 (m, 1H), 1.56–1.44 (m,
1H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 75 MHz): d 167.7,
137.9, 135.5, 133.5, 121.0, 119.0, 117.7, 116.1, 110.2, 108.0, 105.7,
72.6, 60.3, 58.8, 50.7, 44.6, 29.7, 28.3, 21.4, 13.9. HRMS (ESI)
m/z calcd for C20H25N2O2 (M + H)+: 325.1918, found: 325.1916.
22.6, 9.3. HRMS (ESI) m/z calcd for C23H29IN2O3Na (M + Na)+:
531.1123, found: 531.1121.
2,4a,5,6,11b,12,13,13a-Octahydro-1H-4b,11-diazaindeno[2,1-
a]phenanthrene-3,11-dicarboxylic acid 11-tert-butyl ester 3-ethyl
ester (22)
Compound 4 (26 mg, 0.056 mmol) was dissolved in toluene (1 mL)
and POCl3 (52 mL, 0.56 mmol) was added. The solution was
stirred at 70 ◦C for 2 h, after which additional POCl3 (27 mL,
0.27 mmol) was added and stirring was continued for another
hour at 70 ◦C. The reaction was concentrated under reduced
pressure, the residue was dissolved in EtOH (1 mL) and cooled
to 0 ◦C. NaBH4 (4.2 mg, 0.11 mmol) was added, the reaction
was stirred for 10 min at 0 ◦C, diluted with CH2Cl2 (50 mL) and
quenched with aqueous NaHCO3 (50 mL). The organic layer was
extracted, dried (MgSO4) and concentrated in vacuo. The residue
was purified by flash column chromatography (EtOAc/heptane
1 : 2) affording compound 22 (11.5 mg, 46%) as a viscous oil. Rf
0.63 (EtOAc/heptane 2 : 1). FTIR (ATR) 2933, 1725, 1477, 732
cm-1.1H NMR (CDCl3, 400 MHz): d 8.16 (d, J = 8.0 Hz, 1H), 7.41
(d, J = 7.2 Hz, 1H), 7.29–7.19 (m, 2H), 6.70 (s, 1H), 4.51 (d, J =
10.9 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.08–2.95 (m, 2H), 2.87–
2.71 (m, 3H), 2.62 (dd, J = 15.8, 4.2 Hz, 1H), 2.39 (t, J = 10.7 Hz,
2H), 2.10–1.97 (m, 3H), 1.90–1.76 (m, 2H), 1.65 (s, 9H), 1.53–1.40
(m, 1H), 1.31 (t, J = 7.1 Hz, 3H).13C NMR (CDCl3, 75 MHz): d
166.9, 149.6, 141.8, 136.4, 136.0, 129.4, 128.8, 123.4, 122.1, 117.4,
115.3, 114.5, 83.1, 63.3, 60.0, 58.2, 36.3, 33.3, 30.8, 27.8, 26.8, 25.8,
25.3, 21.7, 13.8. HRMS (ESI) m/z calcd for C27H34N2O4 [M + H]+:
451.2599, found: 451.2597.
3-[2-(2-Hydroxymethyl-6-oxo-3-vinylpiperidin-1-yl)ethyl]indole-1-
carboxylic acid tert-butyl ester (20)
To a cooled solution (0 ◦C) of compound 17 (93 mg, 0.21 mmol)
in THF (2.5 mL) LiEt3BH (0.63 mL, 0.63 mmol, 1 M solution
in THF) was added. After stirring for 2.5 h at 0 ◦C, the
reaction was quenched with ice-water (25 mL) and the product
was extracted with CH2Cl2 (2 ¥ 40 mL), dried over MgSO4
and concentrated in vacuo. The residue was purified by flash
chromatography (EtOAc/heptane 1 : 1 to CH2Cl2/MeOH 9 : 1)
affording compound 20 (74 mg, 88%) as a viscous oil. Rf 0.35
(CH2Cl2/MeOH 9 : 1). FTIR (ATR) 3322, 1731, 1615, 1455, 1370
cm-1.1H NMR (CDCl3, 400 MHz): d 8.11 (d, J = 6.7 Hz, 1H),
7.69–7.60 (m, 1H), 7.39 (d, J = 3.3 Hz, 1H), 7.33–7.19 (m, 2H),
5.73–5.55 (m, 1H), 5.16–5.00 (m, 2H), 4.11–4.00 (m, 1H), 4.00–
3.64 (m, 2H), 3.32–3.14 (m, 2H), 3.08–2.85 (m, 2H), 2.53–2.40 (m,
2H), 2.39–2.23 (m, 1H), 2.07–1.84 (m, 1H), 1.68–1.57 (m, 10H).
13C NMR (CDCl3, 75 MHz): d 170.7, 170.4, 149.2, 138.5, 138.3,
135.0, 130.0, 130.0, 124.0, 123.9, 122.7, 122.1, 118.8, 118.6, 117.4,
117.3, 115.8, 115.7, 115.5, 114.8, 83.0, 82.9, 62.9, 62.0, 62.0, 61.9,
61.6, 46.0, 45.9, 45.8, 37.8, 37.7, 37.4, 29.4, 29.2, 29.0, 27.8, 23.1,
22.8, 22.7, 22.6. HRMS (ESI) m/z calcd for C23H30N2O4Na (M +
Na)+: 421.2106, found: 421.2103.
1,2,4a,5,6,11,11b,12,13,13a-Decahydro-4b,11-diazaindeno[2,1-
a]phenanthrene-3-carboxylic acid ethyl ester (23)
Compound 23 (4 mg, 20%) was isolated as a side product of
the Bischler–Napieralski reaction with compound 4. Rf 0.54
(EtOAc/heptane 2 : 1). FTIR (ATR) 2919, 1700, 1648, 1255, 736
cm-1.1H NMR (CDCl3, 400 MHz): d 7.70 (s, 1H), 7.39 (d, J =
7.9 Hz, H), 7.21 (d, J = 7.9 Hz, H), 7.16–7.06 (m, 2H), 6.68 (s,
1H), 4.21 (q, J = 7.2, 7.1 Hz, 2H), 3.62 (ddd, J = 10.4, 4.8, 2.1
Hz, 1H), 3.48 (d, J = 11.4 Hz, 1H), 2.98–2.88 (m, 1H), 2.79 (d,
J = 15.5 Hz, 1H), 2.62 (dd, J = 16.1, 5.2 Hz, 1H), 2.45–2.27 (m,
4H), 2.25–2.14 (m, 2H), 2.09–2.02 (m, 1H), 1.82 (dq, J = 12.2, 3.6
Hz, 1H), 1.62–1.33 (m, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR
(CDCl3, 75 MHz): d 167.2, 141.6, 136.0, 135.1, 129.5, 127.3, 121.4,
119.4, 118.2, 110.7, 108.4, 64.0, 60.5, 60.4, 45.7, 40.7, 30.3, 30.0,
26.0, 25.0, 22.1, 14.3. HRMS (ESI) m/z calcd for C22H26N2O2
[M + H]+: 351.2074, found: 351.2073.
3-[2-(2-Iodomethyl-6-oxo-3-vinyl-piperidin-1-yl)ethyl]-indole-1-
carboxylic acid tert-butyl ester (21)
Compound 20 (20 mg, 0.125 mmol) was dissolved in THF (2 mL)
and PPh3 (50 mg, 0.19 mmol), imidazole (13 mg, 0.19 mmol)
and iodine (48 mg, 0.19 mmol) were added and stirred at room
temperature for 4 h. The reaction was diluted with CH2Cl2, washed
with Na2S2O3 (20 mL) and H2O (20 mL), dried over Na2SO4
and concentrated in vacuo. The residue was purified by flash
column chromatography (heptane → EtOAc/heptane 1 : 3 to 1 : 2)
affording compound 21 (50 mg, 78%). Rf 0.80 (CH2Cl2/MeOH
9 : 1). FTIR (ATR) 1975, 1731, 1646, 1455, 1373, 1157 cm-1.1H
NMR (CDCl3, 400 MHz): d 8.13 (d, J = 7.0 Hz, 1H), 7.66 (d,
J = 7.7 Hz, 1H), 7.35–7.23 (m, 3H), 5.67–5.56 (m, 1H), 5.23–
5.10 (m, 2H), 4.20–2.11 (m, 1H), 3.43–3.37 (m, 1H), 3.36–3.29
(m, 1H), 3.16–2.91 (m, 4H), 2.72–2.64 (m, 1H), 2.55–2.36 (m,
2H), 1.95–1.85 (m, 1H), 1.75–1.63 (m, 10H).13C NMR (CDCl3,
75 MHz): d 169.8, 149.2, 137.8, 135.0, 129.9, 124.0, 122.7, 122.1,
118.6, 117.2, 116.8, 114.8, 83.0, 60.9, 44.9, 40.9, 29.7, 27.8, 22.9,
Deprotection of 2,4a,5,6,11b,12,13,13a-octahydro-1H-4b,11-
diazaindeno[2,1-a]phenanthrene-3,11-dicarboxylic acid
11-tert-butyl ester 3-ethyl ester (23)
Compound 22 (28 mg, 0.056 mmol) was dissolved in a mixture of
TFA/CH2Cl2 (1 : 4) and stirred at room temperature. After 64 h
the solution was concentrated in vacuo. The residue was purified
by flash column chromatography (EtOAc/heptane 1 : 1) affording
compound 23 (13 mg, 55%). Rf 0.21 (EtOAc/heptane 1 : 1).
950 | Org. Biomol. Chem., 2012, 10, 945–951
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11 T. Nemoto, E. Yamamoto, R. Franzen, T. Fukuyama, R. Wu, T.
Fukamachi, H. Kobayashi and Y. Hamada, Org. Lett., 2010, 12, 872–
875.
12 S. S. Kinderman, J. H. van Maarseveen, H. E. Schoemaker, H. Hiemstra
and F. P. J. T. Rutjes, Org. Lett., 2001, 3, 2045–2047.
13 For an excellent overview of formation of cyclic compounds using
RCM, see: Metathesis in Natural Product Synthesis, J. Cossy, S.
Arseniyadis and C. Meyer, (ed.); Wiley-VCH, Weinheim, 2010.
14 M. Arisawa, H. Terada, M. Nakagawa and A. Nishida, Angew. Chem.,
Int. Ed., 2002, 41, 4732–4735.
Notes and references
1 W. A. Creasey in The Monoterpenoid Indole Alkaloids, A. J. E. Saxton
(Ed.); Wiley, Chichester, 1983, vol. 4, 783.
2 G. Blasko´, H. Knight, K. Honty and C. Sza´ntey, Liebigs Ann. Chem.,
1986, 655–663.
3 G. Stork, P. C. Tang, M. Casey, B. Goodman and M. Toyota, J. Am.
Chem. Soc., 2005, 127, 16255–16262.
4 J.-A. Duan, I. D. Williams, C.-T. Che, R.-H. Zhou and S.-X. Zhao,
Tetrahedron Lett., 1999, 40, 2593–2596.
5 B. P. L. Liu, E. Y. Y. Chong, F. W. K. Cheung, J.-A. Duan,
C.-T. Che and W. K. Liu, Biochem. Pharmacol., 2005, 70, 287–
299.
6 T. Putkonen, A. Tolvanen and R. Jokela, Tetrahedron Lett., 2001, 42,
6593–6594.
15 K. F. W. Hekking, L. Lefort, A. H. M. de Vries, F. L. van Delft, H.
E. Schoemaker, J. G. de Vries and F. P. J. T. Rutjes, Adv. Synth. Catal.,
2008, 350, 95–106.
16 S. A. M. W. van den Broek, P. G. W. Rensen, F. L. van Delft and F. P.
J. T. Rutjes, Eur. J. Org. Chem., 2010, 5906–5912.
7 T. Putkonen, A. Tolvanen, R. Jokela, S. Caccamese and N. Parrinello,
Tetrahedron, 2003, 59, 8589–8595.
8 S. Luo, C. A. Zificsak and R. P. Hsung, Org. Lett., 2003, 5, 4709–
4712.
9 T.-L. Ho and C.-K. Chen, Helv. Chim. Acta, 2006, 89, 122–
126.
17 N. Toyooka, Z. Dejun, H. Nemoto, H. M. Garraffo, T. F. Spande and
J. W. Daly, Tetrahedron Lett., 2006, 47, 581–582.
18 P. Knochel and R. D. Singer, Chem. Rev., 1993, 93, 2117–2188.
19 J. Leonard, D. Appleton and S. P. Fearnley, Tetrahedron Lett., 1994,
35, 1071–1074.
20 (a) G. Fodor, J. Gal and B. A. Philips, Angew. Chem., Int. Ed. Engl.,
1972, 11, 6593–6594; (b) E. D. Cox and J. M. Cook, Chem. Rev., 1995,
95, 1797–1842.
10 R. Salame, E. Gravel, K. Leblanc and E. Poupon, Org. Lett., 2009, 11,
1891–1994.
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