Facile construction of the pentacyclic framework of subincanadine B. Synthesis of 20-deethylenylated subincanadine B and 19,20-dihydrosubincanadine B

Article abstract of DOI:10.1021/ol0526367

(Chemical Equation Presented) We describe a facile approach for effectively constructing the pentacyclic framework of subincanadine B. The seven-step assembly of tetracyclic ketone 14 featured Michael addition, Pictet-Spengler cyclization, and Dieckmann condensation. From this key ketone intermediate, two analogues of subincanadine B, i.e., 20-deethylenylated subincanadine B (27) and 19,20-dihydrosubincanadine B (31), were synthesized in four steps, respectively.

Full text of DOI:10.1021/ol0526367

ORGANIC
LETTERS
2006
Vol. 8, No. 1
115-118
Facile Construction of the Pentacyclic
Framework of Subincanadine B.
Synthesis of 20-Deethylenylated
Subincanadine B and
19,20-Dihydrosubincanadine B
Yanqin Liu,† Shengjun Luo,† Xingnian Fu,† Fang Fang,† Zeyang Zhuang,†,‡
Wanting Xiong,† Xueshun Jia,‡ and Hongbin Zhai*,†
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai,
China 200032, and Department of Chemistry, Shanghai UniVersity,
Shanghai, China 200436
zhaih@mail.sioc.ac.cn
Received October 31, 2005
ABSTRACT
We describe a facile approach for effectively constructing the pentacyclic framework of subincanadine B. The seven-step assembly of tetracyclic
ketone 14 featured Michael addition, Pictet Spengler cyclization, and Dieckmann condensation. From this key ketone intermediate, two analogues
−
of subincanadine B, i.e., 20-deethylenylated subincanadine B (27) and 19,20-dihydrosubincanadine B (31), were synthesized in four steps,
respectively.
Indole alkaloids are an important class of biologically active
natural products that have tremendous potential for new drug
development.1 Kobayashi and co-workers described in 2002
the isolation of subincanadines A-F (1a-1c, 2a, 2b, and
3) from the bark of the Brazilian medicinal plant Aspi-
dosperma subincanum Mart (Figure 1).2 Subincanadines
A-C (1a-1c), three novel quaternary alkaloids, possess an
unprecedented 1-azoniatricyclo[4.3.3.01,5]undecane frame-
work. The remaining three subincanadines feature either a
1-azabicyclo[5.2.2]undecane [for subincanadines D-E (2a,
2b)] or a 1-azabicyclo[4.3.1]decane skeleton [for subinca-
nadine F (3)]. Preliminary biological experiments were
conducted on these compounds. For instance, it was found
that subincanadines E (2b) and F (3) were cytotoxic against
murine lymphoma L1210 cells (IC50: 2b, 0.3 µg/mL; 3, 2.4
µg/mL) and human epidermoid carcinoma KB cells (IC50:
2b, 4.4 µg/mL; 3, 4.8 µg/mL) in vitro.2 Surprisingly, no
reports have appeared so far addressing the synthesis of
subincanadines. Fascinated by their unique structural char-
acteristics and impressive pharmacological activity, we took
the initiative to tackle on assembling the subincanadine
family alkaloids.
Herein we wish to report our investigations centered at
the synthesis of the pentacyclic framework of subincanadine
B. The overall synthetic strategy is outlined in Figure 2.
Commercially available tryptamine (4) was chosen as the
starting material, from which tetrahydrocarboline 5 might
be obtained via Michael addition and Pictet-Spengler
† Shanaghai Institute of Organic Chemistry.
‡ Shanaghai University.
(1) Wright, C. W.; Phillipson, J. D. Phytother. Res. 1990, 4, 127.
(2) Kobayashi, J.; Sekiguchi, M.; Shimamoto, S.; Shigemori, H.;
Ishiyama, H.; Ohsaki, A. J. Org. Chem. 2002, 67, 6449.
10.1021/ol0526367 CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/10/2005

afforded in high yield (90%) the Michael adduct 8,4 which
was converted to diester 5 in 75% via Pictet-Spengler
reaction by reacting with methyl pyruvate in the presence
of trifluoroacetic acid in refluxing methanol for 4 days.
Dieckmann condensation of 5 (effected with t-BuOK)
followed by decarboxylative hydrolysis with HOAc and HCl
at reflux led to the formation of tetracyclic ketone 6 as a
white solid in 93% yield for the two steps.
To install ring E of subincanadine B, nucleophilic addition
to the carbonyl of ketone 6 was vigorously attempted. Direct
reaction of 6 with excess nucleophiles such as vinylmagne-
sium bromide and the lithium enolate of EtOAc (used for
model reactions), without prior nitrogen protection, could
not be accomplished. Moreover, protecting 6 as an N-Boc,
TBS, EE, or Ac derivative by standard protocols5 proved to
be unfruitful. It seemed that the nitrogen protection might
have to be performed at an earlier stage. Thus, 4 was
converted to N-benzyltryptamine6 (11) in high overall yield
by a three-step reaction sequence consisting of (i) phthala-
mide formation of the primary amine moiety by refluxing 4
with phthalic anhydride in toluene in a Dean-Stark ap-
paratus,7 (ii) indole nitrogen benzylation by treating 9 with
NaH and benzyl bromide in DMF at 55 °C, and (iii)
transamidation to release the primary amino group by heating
10 with excess hydrazine in refluxing ethanol (Scheme 2).8
Figure 1.
cyclization.3 Dieckmann condensation and decarboxylation
would transform 5 to tetracyclic ketone 6. Introducing a side
chain onto C-15 would allow the formation of the azonia-
cycle (i.e., ring E, see 7).
Scheme 2
Figure 2.
As described in Scheme 1, treatment of tryptamine (4)
with methyl acrylate (1 equiv) in EtOH at room temperature
Scheme 1
Michael addition of 11 with methyl acrylate (1 equiv) in
ethanol at room temperature provided 12 in 91% yield.
(3) For a review on the Pictet-Spengler reaction, see: (a) Cox, E. D.;
Cook, J. M. Chem. ReV. 1995, 95, 1797. For its recent, elegant applications,
see: (b) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.;
Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565. (c) Yu, J.; Wearing,
X.; Cook, J. M. J. Org. Chem. 2005, 70, 3963.
(4) Huizenga, R. H.; Pandit, U. K. Tetrahedron 1991, 47, 4155.
(5) ProtectiVe Groups in Organic Synthesis, 3rd ed.; Greene, T. W., Wuts,
P. G. M., Eds.; John Wiley: New York, 1999; Chapter 7; p 494 and
references therein.
(6) For preparation of 1-benzyltryptamine, see: Benson, S. C.; Lee, L.;
Yang, L.; Snyder, J. K. Tetrahedron 2000, 56, 1165.
(7) Luo, S. J.; Zificsak, C. A.; Hsung, R. P. Org. Lett. 2003, 5, 4709.
116
Org. Lett., Vol. 8, No. 1, 2006

Whereas refluxing 12 and methyl pyruvate with TFA in
methanol or with acetic acid in acetonitrile9 failed to generate
13, refluxing them with p-toluenesulfonic acid (TSA) in
benzene4 did furnish the product but only in very low yield.
Finally, tricycle 13 could be obtained via Pictet-Spengler
reaction in 84% yield by exposing 12 and methyl pyruvate
to TFA in benzene10 at reflux for 2 days. Diester 13 was
converted into N-protected tetracyclic ketone 14 in a similar
manner in 81% yield as described in Scheme 1.
With the N-protected tetracyclic ketone 14 in hand,
considerable efforts were devoted to attaching a side chain
onto ring D in order to generate the azoniacycle (i.e., ring
E) of subincanadine B. A variety of anionic nucleophiles of
different complexity (such as 15b-23b,11 generated from
15a-23a,12 respectively, Figure 3) were employed to react
15a), CH(OEt)2 (as in 16a), and CO2R (R ) Me, Et, and
But, as in 17a-23a) moieties would be converted to
methylenes with a leaving group for intramolecular am-
monium formation at a later stage. The hydroxyl (as in 21a)
and phenylselenyl (as in 22a and 23a) would be utilized to
form the carbon-carbon double bonds. As a matter of fact,
among the reagents listed in Figure 3, only the enolates 18b
and 19b could form adducts with 14 in good yields. Ketone
14 featured a rather rigid skeleton, and the limited steric
accessibility around the carbonyl has to be taken into
consideration. Thus, the fate of the nucleophilic addition to
14 might be dependent upon the overall reactivity and steric
hindrance of the attacking nucleophiles. Hence, we next
pursued the synthesis of the analogues of subincanadine B
as our immediate objective, by taking advantage of the
successful adduct formation of 14 with the lithium enolates
of ethyl acetate and ethyl butyrate.
As outlined in Scheme 3, aldol condensation of 14 with
the lithium enolate of ethyl acetate proceeded smoothly at
Scheme 3
Figure 3. Anionic nucleophiles.
with the carbonyl of 14 in the hope of fulfilling the goal. If
the side chains could be put in place, the CH2OTHP (as in
(8) Sheehan, J. C.; Bolhofer, W. A. J. Am. Chem. Soc. 1950, 72, 2786.
(9) Lu, Y.; Just, G. Tetrahedron 2000, 56, 4355.
(10) Kawate, T.; Yamanaka, M.; Nakagawa, M. Heterocycles 1999, 50,
1033.
(11) Generation of anion 16b: (a) Smith, A. B., III; Levenberg, P. A.;
Jerris, P. J.; Scarborough, R. M., Jr.; Wovkulich, P. M. J. Am. Chem. Soc.
1981, 103, 1501. (b) Anion 17b: Thibonnet, J.; Vu, V. A.; Berillon, L.;
Knochel, P. Tetrahedron 2002, 4787. (c) Anion 20b: Johnson, P. R.; White,
J. D. J. Org. Chem. 1984, 49, 4424. (d) Anion 21b: Swaren, P.; Massova,
I.; Bellettini, J. R.; Bulycher, A.; Maveyraud, L.; Kotra, L. P.; Miller, M.
J.; Mobashery, S.; Samama, J.-P. J. Am. Chem. Soc. 1999, 121, 5353.
(12) Preparation of compound 15a: (a) Ensley, H. E.; Buescher, R. R.;
Lee, K. J. Org. Chem. 1982, 47, 404. (b) Compound 22a: Guindon, Y.;
Faucher, A.-M.; Bourque, E.; Caron, V.; Jung, G.; Landry, S. R. J. Org.
Chem. 1997, 62, 9276. (c) Compound 23a: Dowd, P.; Kennedy, P. Synth.
Commun. 1981, 11, 935.
-78 °C and produced the pair of isomers 24a (84%) and
24b (6%). The configuration of C-15 relative to that of C-16
for the two diastereomers was elucidated with the aid of
NOESY analysis, as shown in the box in Scheme 3.13
NOESY correlation can be observed between the C-17
protons and one of the C-20 protons for aldol 24b, indicating
that the C-16-methyl and the C-15-(ethoxycarbonyl)methyl
(13) The numbering system adopted here is that for subincanadines A-C.
Org. Lett., Vol. 8, No. 1, 2006
117

groups are in a cis relation. Meanwhile, no NOESY cor-
relation is present between the C-17 and C-20 protons for
aldol 24a, which reveals that the methyl (C-17) is located
on the same side of the pyrrolidine ring as the hydroxyl at
C-15. The stereoselectivity of the nucleophilic addition could
be explained as the enolate approached the carbonyl from
the less hindered face, avoiding steric interaction with the
methyl residing at C-16. Complete reduction of ester 24a
with LiAlH4 in hot ether furnished 1,3-diol 25, which was
debenzylated with excess sodium in liquid ammonia at -33
°C to afford N-deprotected diol 26 in good overall yield (74%
yield over the two steps). Tosylation of the primary hydroxyl
of 26 with TsCl (120 mol %) in the presence of triethylamine
in CH2Cl2 at room temperature, followed by spontaneous
intramolecular ammonium formation, resulted in the genera-
tion of 20-deethylenylated subincanadine B (27) as colorless
crystals in 82% yield.
yields, respectively, as a result of the aldol condensation of
ketone 14 and the lithium enolate of ethyl butyrate (Scheme
4). The diastereomeric ratio was found to be approximately
1.7:1 in terms of C-20. Following the same protocol
developed for 24a, N-debenzylated 1,3-diol 30 was obtained
from the major aldol 28a in 70% yield. By treating diol 30
with TsCl (120 mol %) and excess triethylamine in dichlo-
romethane at room temperature, the sequential sulfonation/
cyclization (i.e., intramolecular ammonium formation) suc-
cessfully took place to afford in 64% overall yield 19,20-
dihydrosubincanadine B (31) as colorless crystals. The exact
three-dimensional structure was determined for 31 by X-ray
crystallographic analysis, which also confirmed the relative
configuration of aldol 28a proposed earlier. Subjecting the
minor isomeric aldol, 28b, to the same sequence of the
manipulations applied to 28a (consisting of ester reduction,
N-debenzylation, and primary hydroxyl tosylation), no desir-
able cyclized ammonium was isolable. This is presumably
because the final cyclization step of the monotosylate
produced from 28b might require a too high activation energy
as a result of the disfavored transition state for the intra-
molecular SN2 reaction. Nevertheless, 28b could be converted
back via a clean retro-aldol reaction to afford ketone 14 in
96% yield by the treatment with NaH (200 mol %) in THF
(16 mL for 0.79 mmol of 28b) at room temperature for 5 h.
Thus, the recycle of the seemingly less useful diastereomer
28b could be accomplished with ease.
In a similar manner, two major stereoisomers, tentatively
assigned14 as 28a and 28b, were produced in 51% and 30%
Scheme 4
In conclusion, we have described a facile approach for
effectively constructing the pentacyclic framework of sub-
incanadine B. The seven-step assembly of tetracyclic ketone
14 featured Michael addition, Pictet-Spengler cyclization,
and Dieckmann condensation. From this key ketone inter-
mediate, two analogues of subincanadine B, i.e., 20-deeth-
ylenylated subincanadine B (27) and 19,20-dihydrosubinca-
nadine B (31), were synthesized in four steps, respectively.
The total synthesis of subincanadines is ongoing in our
laboratory.
Acknowledgment. We thank NSFC (no. 20372073),
STCSM (“Post-Venus” Program, no. 05QMH1416), GCCP
of ECNU, and Ministry of Human Resources of PRC for
financial support.
Supporting Information Available: Experimental pro-
cedures and analytical data (including CIF file). This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0526367
(14) The relative configuration of 28a was subsequently confirmed by
the correlation to the X-ray crystallographic structure of 31 (see the main
text).
118
Org. Lett., Vol. 8, No. 1, 2006