A fast assembly of pentacyclic benz[f]indolo[2,3-a]quinolizidine core by tandem intermolecular formal Aza-[3 + 3] cycloaddition/Pictet-Spengler cyclization: A formal synthesis of (±)-tangutorine

Article abstract of DOI:10.1021/jo049459s

We have described a concise construction of the pentacyclic benz[f]indolo [2,3-a] quinolizidine intermediate 3 (with an overall yield of 54% for three steps), featuring a tandem intermolecular formal aza-[3 + 3] cycloaddition/Pictet-Spengler cyclization. The present work can be considered as a formal synthesis of β-carboline alkaloid (±)-tangutorine. Our strategy disclosed herein constitutes a new effective general synthetic approach toward the indoloquinolizidine family of alkaloids.

Full text of DOI:10.1021/jo049459s

CHART 1
A F a st Assem bly of P en ta cyclic
Ben z[f]in d olo[2,3-a ]qu in olizid in e Cor e by
Ta n d em In ter m olecu la r F or m a l Aza -[3 + 3]
Cycloa d d ition /P ictet-Sp en gler
Cycliza tion : A F or m a l Syn th esis of
(()-Ta n gu tor in e
Shengjun Luo,† J ingrui Zhao, and Hongbin Zhai*
CHART 2
Laboratory of Modern Synthetic Organic Chemistry and
State Key Laboratory of Bio-Organic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai, China 200032
zhaih@mail.sioc.ac.cn
Received April 1, 2004
SCHEME 1. Syn th esis of In ter m ed ia te 3
Abstr a ct: We have described a concise construction of the
pentacyclic benz[f]indolo[2,3-a]quinolizidine intermediate 3
(with an overall yield of 54% for three steps), featuring a
tandem intermolecular formal aza-[3 + 3] cycloaddition/
Pictet-Spengler cyclization. The present work can be con-
sidered as a formal synthesis of â-carboline alkaloid (()-
tangutorine. Our strategy disclosed herein constitutes a new
effective general synthetic approach toward the indoloquino-
lizidine family of alkaloids.
Nitraria tangutorum L., available in the Northwest
region of China, is among the approximately 15 species
comprising the genus Nitraria (Zygophyllaceae). The
leaves of this species have long been prescribed in
traditional Chinese medicine (TCM) as antispasmodic,
antineuropathic, and antiarrhythmic agents. Che and
colleagues disclosed in 1999 the isolation from the leaves
of N. tangutorum L. and structural determination of (()-
tangutorine (1, Chart 1), a novel benz[f]indolo[2,3-a]-
quinolizidine alkaloid.1 As the sole known â-carboline
natural product of this type, tangutorine has emerged
as an attractive target for synthetic organic chemists.2
J okela2a,b accomplished the first total synthesis of 1
starting from 7,8-dihydroquinoline-5(6H)-one, by taking
advantage of the classic Pictet-Spengler cyclization
strategy commonly employed in constructing monoter-
penoid indole alkaloids. More recently, Hsung and co-
workers2c published a novel and practical synthesis of 1,
featuring an intramolecular formal aza-[3 + 3] cycload-
dition,3 as well as a Heck coupling for establishing the
C2-C3 bond. Because the indolo[2,3-a]quinolizidine-type
natural products might be derived biosynthetically from
tryptophan, the commercially available tryptamine was
chosen as the starting point for the stereoselective route.2c
We noticed that in Hsung’s synthesis2c considerable
endeavor (11 steps) was devoted to constructing the key
pentacyclic Boc-protected intermediate 3, from which
tangutorine (1) was obtained in another eight steps
(Chart 2).
As a result of our interest in efficiently assembling
structurally complex and biologically active natural
products, we recently embarked on a novel expeditious
three-step synthesis of the pentacycle 3, the useful inter-
mediate for constructing tangutorine (1). As outlined in
Scheme 1, our synthetic strategy for constructing 3 relied
† Current address: Unilever Research China, 3/F, Xinmao Building,
99 Tianzhou Road, Shanghai, China 200233.
(1) For the isolation of tangutorine, see: Duan, J .-A.; Williams, I.
D.; Che, C.-T.; Zhou, R.-H.; Zhao, S.-X. Tetrahedron Lett. 1999, 40,
2593.
(2) For the previous syntheses of tangutorine, see: (a) Putkonen,
T.; Tolvanen, A.; J okela, R. Tetrahedron Lett. 2001, 42, 6593. (b)
Putkonen, T.; Tolvanen, A.; J okela, R.; Caccamese, S.; Parrinello, N.
Tetrahedron 2003, 59, 8589. (c) Luo, S.; Zificsak, C. A.; Hsung, R. P.
Org. Lett. 2003, 5, 4709.
(3) For intramolecular formal aza-[3 + 3] cycloaddition, see: (a) Wei,
L.-L.; Hsung, R. P.; Sklenicka, H. M.; Gerasyuto, A. I. Angew. Chem.,
Int. Ed. 2001, 40, 1516; Angew. Chem. 2001, 113, 1564. For intermo-
lecular formal aza-[3 + 3] cycloaddition, see: (b) Sklenicka, H. M.;
Hsung, R. P.; Wei, L.-L.; McLaughlin, M. J .; Gerasyuto, A. I.; Degen,
S. J . Org. Lett. 2000, 2, 1161. (c) Sklenicka, H. M.; Hsung, R. P.;
McLaughlin, M. J .; Wei, L.-L.; Gerasyuto, A. I.; Brennessel, W. B. J .
Am. Chem. Soc. 2002, 124, 10435.
10.1021/jo049459s CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/20/2004
4548
J . Org. Chem. 2004, 69, 4548-4550

upon combining the three basic components: tryptamine
(2), 1,3-cyclohexanedione, and acrolein. Heating trypt-
amine with 1 equiv of 1,3-cyclohexanedione in refluxing
toluene for 1 h brought on complete condensation to
afford ketoenamine 4 as colorless crystals in 95% yield.
Despite its high polarity, this compound was found to be
slightly soluble in tetrahydrofuran (THF). Next, a solu-
tion of ketoenamine 4 and freshly distilled acrolein (2.5
equiv) in THF was subjected to a boron trifluoride diethyl
etherate promoted tandem intermolecular formal aza-[3
+ 3] cycloaddition/Pictet-Spengler cyclization. Indeed,
the pentacycle 5 with the newly formed B and C rings
was produced after the reaction proceeded at room
temperature for 18 h. Note that sufficiently slow intro-
duction of BF3‚OEt2 to the system was crucial to this
transformation. The reaction sequence presumably con-
sisted of (i) the initial intermolecular formal aza-[3 + 3]
cycloaddition, via the enamine-to-acrolein Michael addi-
tion (generating 5A) followed by dehydrative iminium
formation (generating 5B), and (ii) the subsequent Pic-
tet-Spengler cyclization. For the aza-[3 + 3] cycloaddi-
tion, a head-to-tail orientation is assumed with regard
to the carbonyl groups of vinylogous amides and acrolein.
The regioselectivity that we adopted is coincident with
those reported previously by Hickmott,4 Greenhill,5 and
Stille6 but is opposite of the head-to-head orientation
proposed by Hsung.3c Either regiochemistry should be
possible,7 and appropriate mechanistic studies remain to
be conducted to reveal the exact reaction pathway.
The intermediate 5 was not sufficiently soluble in most
common organic solvents, which posed an obstacle in the
substance purification while ensuring reasonably high
yield. Therefore, the pentacycle 5, as a crude product,
was directly treated with excess di-tert-butyl dicarbonate
(Boc2O) and a catalytic amount of 4-(N,N-dimethylami-
no)pyridine (DMAP) in dichloromethane at room tem-
perature to realize the Boc protection at the indolyl
nitrogen. The addition of Boc2O in batches was found to
be vital in achieving better conversion (see Experimental
Section). The key pentacyclic benz[f]indolo[2,3-a]quino-
lizidine intermediate 3 (shown in Hsung’s synthesis of
(()-tangutorine2c) was obtained as a colorless oil in a
combined yield of 57% for the last two steps (i.e., the
tandem reaction and the Boc protection step). The
physical properties and the spectroscopic data of 3 were
in agreement with those reported in the literature.2c
In summary, we have described a concise construction
of the pentacyclic benz[f]indolo[2,3-a]quinolizidine inter-
mediate 3 (with an overall yield of 54% over three steps),
featuring a tandem intermolecular formal aza-[3 + 3]
cycloaddition/Pictet-Spengler cyclization. The present
work can be considered as a formal synthesis of â-car-
boline alkaloid (()-tangutorine, since 3 could be manipu-
lated to give rise to 1 in eight more steps.2c Our strategy
disclosed herein constitutes a new effective general
synthetic approach toward the indoloquinolizidine family
of alkaloids.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. NMR
spectra were recorded in CDCl3 or DMSO-d6 (1H at 300 MHz
and 13C at 75 MHz) using TMS as the internal standard. Column
chromatography was performed on silica gel. Dichloromethane
was distilled over calcium hydride under N2. THF and toluene
were distilled over sodium benzophenone ketyl under N2.
3-[2-(1H-3-In d olyl)eth yla m in o]-2-cycloh exen -1-on e (4).
A mixture of tryptamine (5.00 g, 31.2 mmol) and 1,3-cyclohex-
anedione (3.50 g, 31.2 mmol) in toluene (170 mL) was refluxed
under N2, and the reaction reached completion within 1 h as
judged by TLC analysis. After the reaction mixture was allowed
to cool to room temperature, the solid mass was collected by
filtration and the product in the mother liquor was subjected to
recrystallization. The two crops of the solid were combined and
washed with a small amount of petroleum ether to give 4 (7.54
g, 95%) as colorless crystals: mp 158-160 °C; 1H NMR (CDCl3,
300 MHz) δ 1.93-2.00 (m, 2H), 2.25 (t, J ) 6.0 Hz, 2H), 2.34 (t,
J ) 6.5 Hz, 2H), 3.08 (t, J ) 6.6 Hz, 2H), 3.46 (dd, J ) 12.0, 6.6
Hz, 2H), 4.44 (br s, 1H), 5.25 (s, 1H), 7.07 (d, J ) 2.4 Hz, 1H),
7.16 (td, J ) 7.5, 1.2 Hz, 1H), 7.25 (td, J ) 7.5, 1.5 Hz, 1H), 7.42
(dt, J ) 7.8, 0.9 Hz, 1H), 7.60 (dt, J ) 7.8, 0.6 Hz, 1H), 8.19 (br
s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ 22.3, 24.2, 29.2, 37.1,
43.5, 95.2, 112.0 (possibly corresponding to two carbons, C-3 and
C-7 of indole moiety), 118.7, 118.9, 121.6, 123.5, 127.7, 136.8,
165.1, 195.1. MS (ESI): m/z (% relative intensity) 255 (M + H+,
(4) Hickmott, P. W.; Sheppard, G. J . Chem. Soc. C 1971, 2112.
(5) (a) Greenhill, J . V.; Mohamed, M. J . Chem. Soc., Perkin Trans.
1 1979, 1411. (b) Chaaban, J .; Greenhill, J . V.; Ramli, M. J . Chem.
Soc., Perkin Trans. 1, 1981, 3120. (c) Greenhill, J . V.; Moten, M. A. J .
Chem. Soc., Perkin Trans. 1, 1984, 287. (d) Heber, D.; Berghaus, Th.
J . Heterocycl. Chem. 1994, 31, 1353.
(6) (a) P. Benovsky, G. A. Stephenson, J . R. Stille, J . Am. Chem.
Soc. 1998, 120, 2493. (b) Paulvannan, K.; Schwarz, J . B.; Stille, J . R.
Tetrahedron Lett. 1993, 34, 215. (c) Paulvannan, K.; Schwarz, J . B.;
Stille, J . R. Tetrahedron Lett. 1993, 34, 6673. (d) Paulvannan, K.; Stille,
J . R. J . Org. Chem. 1992, 57, 5319.
100). Anal. Calcd for C16H18
N 2O: C, 75.56; H, 7.13; N, 11.01.
Found: C, 75.29; H, 7.20; N, 11.07.
11-(ter t-Bu toxyca r bon yl)- 2,3,4,5,6,11b,12,13-octa h yd r o-
1-oxo-11H-4b,11-d ia za in d en o[2,1-a ]p h en a n th r en e (3). To a
solution of 4 (762 mg, 3.00 mmol) in dry THF (65 mL) was added
freshly distilled acrolein (0.50 mL, 7.5 mmol) under N2. A
solution of BF3‚OEt2 (0.46 mL, 3.6 mmol) in THF (5 mL) was
added over 10 min, and the resulting mixture was stirred at
room temperature for 18 h. The reaction was complete as judged
by TLC analysis. Evaporation of the volatiles gave the crude
cyclization product of 5 as a solid, which could be used directly
for the next reaction. An analytical sample of 5 was obtained
by recrystallization (MeOH/MeCOMe/petroleum ether, 3/20/3.5)
as colorless crystals: mp 205-207 °C; 1H NMR (DMSO-d6, 300
MHz) δ 1.67 (tdd, J ) 11.9, 11.6, 2.7 Hz, 1H), 1.85-1.90 (m,
1H), 1.94-2.02 (m, 1H), 2.23 (t, J ) 11.9 Hz, 1H), 2.45-2.55
(m, 3H), 2.61-2.75 (m, 2H), 2.77-2.96 (m, 3H), 3.47 (td, J )
12.8, 3.8 Hz, 1H), 4.48 (d, J ) 11.7 Hz, 1H), 4.98 (d, J ) 8.4 Hz,
1H), 7.02 (t, J ) 7.4 Hz, 1H), 7.11 (t, J ) 7.5 Hz, 1H), 7.37 (d, J
) 7.8 Hz, 1H), 7.45 (d, J ) 7.5 Hz, 1H), 11.08 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ 18.1, 21.1, 21.7, 26.7, 27.3, 31.0, 47.9, 56.4,
106.4, 107.4, 111.8, 118.5, 119.4, 121.9, 126.5, 133.5, 136.8, 169.8,
184.7. MS (ESI): m/z (% relative intensity) 293 (M + H+, 100).
(7) Intermediate 5B could be alternatively formed by adopting a
head-to-head orientation with regard to the carbonyl groups of viny-
logous amides and acrolein. See the following:
J . Org. Chem, Vol. 69, No. 13, 2004 4549

Anal. Calcd for C19H20
C, 78.13; H, 6.84; N, 9.70.
N
2O: C, 78.05; H, 6.89; N, 9.58. Found:
29.2, 35.1, 42.9, 55.7, 84.1, 107.2, 115.3, 116.6, 117.7, 122.7,
124.3, 128.0, 134.8, 136.7, 149.6, 158.7, 194.2. MS (ESI): m/z
(% relative intensity) 393 (M + H+, 100), 337 (20), 293 (10). Anal.
To a suspension of the above-mentioned crude 5 in dry
dichloromethane (190 mL) were added Boc2O (1.96 g, 8.98 mmol)
and DMAP (146 mg, 1.20 mmol). After the mixture was stirred
at room temperature for 18 h, the second batch of Boc2O (1.31
g, 6.00 mmol) was added. The resulting mixture was stirred for
another 20 min, and TLC analysis revealed the completion of
the reaction. Evaporation of the solvent resulted in a residue,
which was chromatographed (EtOAc/petroleum ether, gradient,
1/1 to 1/0) to give 3 (0.67 g, 57%) as a colorless oil: 1H NMR
(CDCl3, 300 MHz) δ 1.30-1.52 (m, 1H), 1.60 (s, 9H), 1.43-1.65
(m, 1H), 1.89-2.02 (m, 2H), 2.22-2.34 (m, 3H), 2.40-2.59 (m,
2H), 2.64-2.70 (m, 3H), 3.11-3.20 (m, 1H), 4.12 (d, J ) 13.2
Hz, 1H), 4.76 (d, J ) 10.5 Hz, 1H), 7.19 (t, J ) 7.2 Hz, 1H), 7.26
(t, J ) 7.2 Hz, 1H), 7.37 (d, J ) 7.5 Hz, 1H), 8.11 (d, J ) 7.8 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 20.3, 21.5, 22.3, 27.3, 27.9,
Calcd for C24H28
N 2O3: C, 73.44; H, 7.19; N, 7.14. Found: C,
73.55; H, 7.01; N, 7.11.
Ack n ow led gm en t. We thank National Natural
Science Foundation of China (no. 20372073), Science &
Technology Commission of Shanghai Municipality
(“Venus” Program), Bureau of Tobacco, PRC, and Chi-
nese Academy of Sciences (“Hundreds of Talent” Pro-
gram) for providing financial support. We are also
indebted to Professor Richard P. Hsung of University
of Minnesota for enlightening discussions.
J O049459S
4550 J . Org. Chem., Vol. 69, No. 13, 2004