Lateral lithiation-initiated annulations in the synthesis of 1-oxygenated carbazole alkaloids and a cycloheptacarbazole

Article abstract of DOI:10.1055/s-0031-1290380

Anionic [4+2] annulation of lithiated furoindolones with dimethyl maleate followed by selective demethoxycarbonylation provides an efficient synthetic route to 3-methoxycarbonylcarbazoles. The route has led to the straightforward synthesis of two natural

Full text of DOI:10.1055/s-0031-1290380

LETTER
▌1769
letter
Lateral Lithiation-Initiated Annulations in the Synthesis of 1-Oxygenated
Carbazole Alkaloids and a Cycloheptacarbazole
Synthesis of 1-Oxygenated Carbazole Alkaloids
Amit Kumar Jana,a Pallab Pahari,b Dipakranjan Mal*a
a
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
E-mail: dmal@chem.iitkgp.ernet.in
b
Synthetic Organic Chemistry Division, CSIR–North East Institute of Science and Technology, Jorhat, Assam 785006, India
Received: 31.03.2012; Accepted after revision: 23.04.2012
rayafoline A (14).7b However, the abundance of 1-
Abstract: Anionic [4+2] annulation of lithiated furoindolones with
oxygenated carbazole alkaloids featuring carboxylic acid
dimethyl maleate followed by selective demethoxycarbonylation
or ester group at C-3 positions prompted us to further ex-
plore the annulation and the demethoxycarbonylation.
provides an efficient synthetic route to 3-methoxycarbonylcarba-
zoles. The route has led to the straightforward synthesis of two nat-
ural products, namely clausine E, mukonine, and their 4-prenyl Hence, we planned to synthesize 3-carboxy carbazole al-
analogues. A new route to cyclohepta[d,e,f]carbazole was also un-
covered during the investigations.
kaloids using dimethyl maleate as a Michael acceptor. Re-
cently, we reported successful application of this strategy
Key words: annulation, selective demethoxycarbonylation, prenyl-
carbazole, cyclohepta[d,e,f]carbazole
for the convergent synthesis of prenylcarbazole
derivatives7c (2–5, Figure 1). Herein, we report a detailed
account of the annulation study that has led to the synthe-
sis of two natural products namely clausine E (16) and
Carbazoles are the key structural motifs of a variety of bi- mukonine (17). Both the compounds show antiprolifera-
ologically active alkaloids and some pharmaceuticals.1 tive activities against various cancer cell lines.10 To fur-
They are also important building scaffolds for functional ther broaden the scope of the strategy, we have studied the
materials with wide-ranging physical properties.2 Among reactivity of 3-prenyl-substituted furoindolones towards
the natural carbazoles, 1-hydroxycarbazoles (e.g., 1–17) annulations for the construction of 4-prenyl-1-hydroxy-
have figured prominently in the literature. These com- carbazole framework. In addition, we also report the for-
pounds are recognized as precursors for various quino- mation of an unusual ring system, that is,
noids and biscarbazole alkaloids. Recently, the prenyl- cyclohepta[d,e,f]carbazole.
substituted 1-hydroxycarbazoles3 (1–13) attracted atten-
Earlier studies from our group on the synthesis of 1-oxy-
tion for their profound activities against different cancer
genated carbazoles showed that the success of the annula-
cell lines.3c For example, clausamines C (4) and D (3) in-
tion depend on the stability of N-protecting group7 under
hibit EBV activation in Raji cells.3c Consequently, the
the strong basic conditions. Keeping this fact in mind, we
synthesis of this type of naturally occurring carbazoles has
prepared Boc-, MOM-, PMB-, and Bn-protected lactones
been of considerable attention.
(18a–d) from lactone 197a (Scheme 1). Each of the lac-
The synthetic approaches for the construction of carba- tones was subjected to annulation11 with dimethyl maleate
zole frameworks have been reviewed by Knölker et al.1g,4 in the presence of LDA in THF at –78 °C. While the reac-
In recent years, transition-metal-catalyzed C–C or C–N tion with N-Boc-protected furoindo lone 18a failed to give
bond-forming reactions,5 [2+2+2] cycloaddition,6 any product, N-MOM-protected furoindolone 18b and N-
benzannulation,7 Suzuki–Miyaura coupling,8 and ring- PMB-protected furoindolone 18c yielded the correspond-
closing metathesis9 have also been widely investigated. ing diesters 20b (38%) and 20c (30%), respectively, in
However, the problems of regiochemistry, efficacy, and low yields. Finally, N-benzylfuroindolone 18d7a was
generality for the synthesis of carbazoles continue to be found to undergo annulation most efficiently giving the
challenging. To circumvent some of these problems, we product 20d7c in 47% yield. For further improvement of
introduced anionic annulation of furoindolones for the re- the yield of the conversion of 18d, we explored various re-
gioselective construction of 1-hydroxycarbazole skele- action conditions. Ultimately, the yield could be increased
ton.7a,b It has been shown that 1-hydroxycarbazoles with to 68% with combined use of lithium tert-butoxide (LTB)
an electron-withdrawing substituent at the 2-position can and TMEDA.
readily be synthesized by the anionic [4+2] cycloaddition
After the standardization of the crucial annulation step
of furoindolones (e.g., 18) with suitably substituted
(18d to 20d), we undertook selective decarboxylation of
Michael acceptors. Annulation of acrylates as acceptors
the C-2 carboxy group and N-deprotection for the synthe-
followed by demethoxycarbonylation has led to the syn-
sis of 3-carboxy carbazoles, clausine E (16), and muko-
thesis of 3-unsubstituted carbazoles, for example, mur-
nine (17). To this end, diester 20d was first N-
debenzylated7c to carbazole 21 in the presence of AlCl3 in
SYNLETT 2012, 23, 1769–1774
Advanced online publication: 21.06.2012
CH2Cl2. It was then subjected to selective demethoxycar-
bonylation under different reaction conditions by varying
both base concentration and refluxing time. It was found
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290380; Art ID: ST-2012-D0291-L
© Georg Thieme Verlag Stuttgart · New York

1770
A. K. Jana et al.
LETTER
HO
O
O
R2
O
O
N
H
N
N
OR1
H
H
OR
OR
1: clausine D ( R1 = H, R2 = CHO)
2: clausine F (R1 = H, R2 = CO2Me)
3: clausamine D (R1 = Me, R2 = CO2Me)
4: clausamine C (R = Me)
5: clausevatine D (R = H)
6: clausamine A (R = H)
7: clausamine B (R = Me)
O
O
O
O
O
HO
O
O
O
OH
OOH
N
N
N
N
H
H
OH
OH
H
H
OMe
OMe
8: furoclausamine A
9: furoclausamine B
10: mafaicheenamine A
11: mafaicheenamine B
O
R4
R3
OH
R2
N
N
OR1
H
H
OMe
13: clausenapin (R1, R3 = Me; R2 = prenyl; R4 = H)
14: murrayafoline A (R1, R3 = Me; R2 = H; R4 = H)
15: clausine Z (R1, R2 = H; R3 = CHO; R4 = OH)
16: clausine E ( R1, R2, R4 = H; R3 = CO2Me)
17: mukonine (R1 = Me; R2, R4 = H, R3 = CO2Me)
12: mafaicheenamine C
Figure 1 Structures of some 1-oxygenated carbazole alkaloids
carbazole-3-carboxylic acid (22, Scheme 2). This acid,
without purification, was treated with DBU–MeI to fur-
nish clausine E (16, 58% over two steps). O-Methylation
of clausine E with K2CO3–MeI in acetone yielded muko-
nine (17) in 71% yield. The spectroscopic data of both the
compounds matched well with that of the reported val-
ues.12
CO2Me
LDA, LTB
CO2Me
–78 °C to r.t.
CO2Me
O
O
CO2Me
N
N
OH
PG
PG
20a (0%)a
20b (38%)a
20c (30%)a
18a (PG = Boc)
18b (PG = MOM)
18c (PG = PMB)
18d (PG = Bn)
19 (PG = H)
After successful synthesis of 3-carboxycarbazoles we de-
cided to extend the scope of the methodology towards the
synthesis of 4-prenylcarbazole natural products (e.g., 1–
10). Accordingly, we proposed that the annulation of the
3-prenyl lactone 23 with dimethyl maleate in presence of
a base would provide 4-prenyl carbazole diester 24. The
selective demethoxycarbonylation of the CO2Me group at
C-2 of diester 24 (Scheme 3) should produce compound
25, the N-protected analogue of clausine F (2) and claus-
amine D (3).
20d (47%a and 68%b)
Scheme 1 Annulation study with different furoindolones without 3-
prenyl substituent; a refers to yield with LDA and b refers to that with
lithium tert-butoxide and TMEDA in THF at –60 °C.
that the reaction proceeds most effectively only with 30%
aqueous KOH in methanol. Thus, the hydrolytic decar-
boxylation of 21 provided the corresponding 1-hydroxy-
30% aq KOH
CO2Me
CO2Me
CO2H
in MeOH
DBU, MeI
reflux, 3 h
CO2Me
58%
over two steps
N
N
H
N
H
H
OR
OH
OH
21
22
clausine E (16) (R = H)
K2CO3, MeI
acetone
71%
mukonine (17) (R = Me)
Scheme 2 Synthesis of clausine E (16) and mukonine (17)
Synlett 2012, 23, 1769–1774
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 1-Oxygenated Carbazole Alkaloids
1771
selective
demethoxy-
carbonylation
CO2Me
CO2Me
anionic [4+2]
cycloaddition
O
O
CO2Me
N
N
N
OH
OH
PG
PG
23
PG
25
24
PG = protecting group
Scheme 3 Initial plan for the synthesis of prenylcarbazoles
CO2Me
LDA,
OH
Br, In
THF, –78 °C to r.t.
65%
O
O
80%
CO2Me
O
O
OR
28: R = H
Et3N, AcCl
27
26
29: R = Ac
Scheme 4 Annulation of allylphthalide 26 with methyl crotonate
At the outset, we examined the annulation reactivity of Alternatively, furoindolone 30b was obtained in 70%
3-allylphthalide 2613 as a model. It was prepared by al- yield by allylation of 347a with LDA and allyl bromide at
lylation of phthalaldehydic acid (27) using allyl indium –78 °C in THF. It was then subjected to annulation reac-
bromide, prepared in situ from allyl bromide in the pres- tion with methyl crotonate, and allylcarbazole 35 was ob-
ence of In metal in DMF. The anionic [4+2] cycloaddition tained in 72% yield (Scheme 6).
of phthalide 26 with methyl crotonate in the presence of
LDA in THF at –78 °C produced 4-allylnaphthol 28 in
65% yield (Scheme 4). The product was fully character-
ized by the spectral data of its acetyl derivative 29.
Having established the annulation reactivity of allyl furo-
indolone 30, we focused our study on its prenyl analogue
36. Apprehending the difficulties in deprotection of the N-
methyl group (cf. 35), methoxymethyl (MOM) group was
Following the success with phthalide model, we extended selected as the N-protecting group. Thus, required furoin-
the strategy to furoindolone 30. Readily accessible indole dolone 18b was prepared in 80% yield from 19 by using
aldehyde 3114 was reacted with allyl indium bromide in NaH and methoxymethyl chloride in DMF (Scheme 7).
the manner described in Scheme 4. But the reaction result- But, attempted 3-prenylation of 18b using LDA and pre-
ed in the formation of an unexpected product, which could nyl bromide produced a considerable amount of diprenyl-
not be satisfactorily purified. The NMR data suggested an ated furoindolone 37 (15%) along with the desired 3-
open-chain structure like 32 (Scheme 5), which resisted prenylfuroindolone 36 (25%). Although, two compounds
cyclization to 30a with various acids. Similar was the re- were separable by column chromatography, the low yield
sult with N-methyl derivative 33,14 which was prepared in (25%) of the desired product 36 was a deterrent for its fur-
96% yield from 31 by using K2CO3–MeI in acetone ther study.
(Scheme 5).
Br
In,
CHO
OH
DMF
X
O
CO2Et
CO2Et
N
H
N
N
R
O
R
31: R = H
32
30a: R = H
30b: R = Me
K2CO3, MeI, 96%
33: R = Me
Scheme 5 Attempted preparation of furoindolone 30
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1769–1774

1772
A. K. Jana et al.
LETTER
Br
LDA,
–78 °C to r.t.
LDA,
–78 °C to r.t.
CO2Me
O
O
O
O
CO2Me
70%
72%
N
N
N
OH
Me
Me
Me
30
35
34
Scheme 6 Preparation of allylcarbazole 35 by annulation
Br
LDA,
NaH, MOMCl
THF
–78 °C to r.t.
DMF
O
O
O
O
O
O
+
80%
N
N
MOM
N
MOM
18b
N
O
H
O
MOM
19
36
(25%)
37
(15%)
Scheme 7 Preparation of N-MOM-protected 3-prenyl-substituted furoindolone 36
Fortunately, prenylation of N-benzylfuroindolone 18d The demethoxycarbonylation study was then successfully
provided N-benzylprenylfuroindolone 38 in an excellent applied to prenylcarbazole diester 39 to furnish 40 in two
yield (87%, Scheme 8). In this case, no diprenylated prod- steps.7c At this stage, it was evident that the removal of the
uct was observed. The contrasting reactivity of 18b and benzyl group would provide the intermediate of many im-
18d to prenylation was puzzling and beyond reasonable portant natural products including clausamine D (3). But,
explanation. We then examined the reactivity of 39 to- unfortunately, the projected deprotection turned out to be
wards annulation with dimethyl maleate. The reaction in more difficult than anticipated. The established methods15
the presence of LDA in THF at –78 °C provided the ex- for N-debenzylation such as O2/t-BuOK in DMSO, TFA–
pected carbazole diester 39. Contrary to our expectation, TfOH, and AlCl3 failed to give the expected product. With
the yield of the annulation was only 10%. The yield was O2/t-BuOK, the corresponding carboxylic acid 41 was ob-
slightly improved with the combined use of lithium tert- tained in 69% yield (Scheme 9). In refluxing TFA with a
butoxide and TMEDA. The reason of the low yield may catalytic amount of TfOH, the starting material decom-
be due to the base catalyzed competitive polymerization posed to give a mixture of compounds. But, during the re-
of dimethyl maleate.
action of 40 with AlCl3 in CH2Cl2, we encountered a novel
cyclization reaction, and the product 42 was obtained in
CO2Me
LDA,
Br
LDA,
CO2Me
–78 °C to r.t.
CO2Me
THF, –78 °C to r.t.
87%
O
O
CO2Me
10%
N
N
N
O
O
OH
Bn
Bn
Bn
18d
38
39
Scheme 8 Synthesis and annulation of N-benzylprenylfuroindolone 38
CO2Me
CO2Me
AlCl3
CH2Cl2
CO2R
67%
N
H
N
H
42
N
OH
OH
OMe
Bn
43
40: R = Me
41: R = H
Scheme 9 Prenylation and selective demethoxycarbonylation
Synlett 2012, 23, 1769–1774
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 1-Oxygenated Carbazole Alkaloids
1773
(3) (a) Maneerat, W.; Laphookhieo, S. Heterocycles 2010, 81,
1261. (b) Ito, C.; Itoigawa, M.; Aizawa, K.; Yoshida, K.;
Ruangrungsi, N.; Furukawa, H. J. Nat. Prod. 2009, 72, 1202.
(c) Ito, C.; Katsuno, S.; Itoigawa, M.; Ruangrungsi, N.;
Mukainaka, T.; Okuda, M.; Kitagawa, Y.; Tokuda, H.;
Nishino, H.; Furukawa, H. J. Nat. Prod. 2000, 63, 125; and
references therein.
(4) (a) Knölker, H.-J. Chem. Lett. 2009, 38, 8. (b) Knölker,
H.-J.; Reddy, K. R. The Alkaloids; Cordell, G. A., Ed.;
Academic Press: Amsterdam, 2008, Vol. 65 1–430; and
references therein. (c) Thomas, C.; Kataeva, O.; Knölker,
H.-J. Synlett 2011, 2663. (d) Muege, F.; Ronny, F.; Knölker,
H.-J. Synlett 2011, 2056.
(5) (a) Ackermann, L.; Althammer, A.; Mayer, P. Synthesis
2009, 3493. (b) Schmidt, M.; Knölker, H.-J. Synlett 2009,
2421. (c) Fuchsenberger, M.; Forke, R.; Knölker, H.-J.
Synlett 2011, 2056.
(6) Alaric, C.; Schollmeyer, D.; Witulski, B. Chem. Commun.
2009, 1464.
67% yield. The structure of the compound was assigned as
the cyclohepta[d,e,f]carbazole 42 on the basis of the con-
current spectral data.16 The formation of 42 can be ex-
plained by the intramolecular Friedel–Crafts intermediate
43. The occurrence of tetrahydrocycloheptacarbazole is
very uncommon in literature. The parent compound has
been synthesized as its carbazolium ion17 but not its de-
protonated form. It has been recently detected in crude
oil.18 In contrast, cycloocta[d,e,f]carbazoles19 are well
known.
In conclusion, anionic [4+2] annulation of indololactones
with dimethyl maleate in conjugation with selective de-
methoxycarbonylation allows a rapid synthesis of carba-
zole natural products, namely clausine E and mukonine.
Extension of this annulation strategy to different N-pro-
tected prenylfuroindolones yields prenylcarbazoles with
3-carboxymethyl groups. This study also discloses an un-
precedented cyclization leading to the formation of a cy-
cloheptacarbazole motif.
(7) (a) Mal, D.; Senapati, B.; Pahari, P. Tetrahedron 2007, 63,
3768. (b) Mal, D.; Senapati, B.; Pahari, P. Tetrahedron Lett.
2006, 47, 1071. (c) Jana, A. K.; Mal, D. Chem. Commun.
2010, 46, 4411.
(8) Kajiyama, D.; Inoue, K.; Ishikawa, Y.; Nishiyama, S.
Tetrahedron 2010, 66, 9779.
(9) Nishiyama, T.; Choshi, T.; Kitano, K.; Hibino, S.
Tetrahedron Lett. 2011, 52, 3876.
Acknowledgment
The authors are grateful to the Council of Scientific and Industrial
Research (CSIR) and University Grant Commission (UGC), New
Delhi for financial support.
(10) Liger, F.; Popowycz, F.; Besson, T.; Picot, L.; Galmarini,
C. M.; Joseph, B. Bioorg. Med. Chem. 2007, 15, 5615.
(11) General Procedure for the Annulation with LDA
In a flame-dried flask flushed with nitrogen, LDA (9 mmol)
was prepared by adding N,N-diisopropylamine (9 mmol) to
a solution of n-BuLi (9 mmol, 1.6 M in hexane) in THF (20
mL) at –78 °C under nitrogen atmosphere. After the solution
was stirred for 10 min at –78 °C, furoindolone (3 mmol) in
THF (10 mL) was added dropwise over 5 min. The reaction
mixture was stirred at the same temperature for 15 min, and
a solution of the appropriate Michael acceptor (3.6 mmol) in
THF (10 mL) was added dropwise. The reaction mixture was
further stirred and allowed to warm slowly to r.t. over 3 h.
The dark reddish brown solution was then quenched with a
sat. NH4Cl solution. The resulting mixture was concentrated
under reduced pressure, and the residue extracted with
EtOAc (3 × 100 mL). The combined extracts were washed
with brine (3 × 1/3 vol.), dried (Na2SO4), and concentrated
to provide crude product which was purified by column
chromatography.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
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Cyclohepta[d,e,f]carbazole 42
To a solution of compound 40 (20 mg, 0.05 mmol) in CH2Cl2
(8 mL) was added AlCl3 (32 mg, 0.25 mmol), and the
resulting mixture was stirred at r.t. for 3 h. After the
completion of the reaction, the solvent was evaporated and
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1769–1774

1774
A. K. Jana et al.
LETTER
(17) Freiermuth, B.; Wirz, J. Angew. Chem. 1988, 100, 589.
νmax (KBr): 2920, 1705, 1090, 804 cm–1. 1H NMR (200 MHz,
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H), 5.82 (br s, 1 H), 3.93 (s, 3 H), 3.73–3.65 (m, 2 H), 2.20–
2.12 (m, 2 H), 1.46 (s, 6 H). 13C NMR (50 MHz, CDCl3): δ
= 169.2, 147.7, 139.9, 138.0, 135.5, 131.7, 126.0, 125.2,
122.0, 119.3, 117.0, 112.8, 108.5, 52.0, 39.2, 38.6, 30.8,
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Synlett 2012, 23, 1769–1774
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