Synthesis of the indolizino[7,6- c ]quinoline alkaloid isaindigotidione

Article abstract of DOI:10.1021/ol101890t

The first synthesis of isaindigotidione has been developed utilizing a reaction sequence including an asymmetric rhodium-catalyzed 1,4-conjugate addition, an intramolecular aldol reaction, and a lactamization.

Full text of DOI:10.1021/ol101890t

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4628-4631
Synthesis of the
Indolizino[7,6-c]quinoline Alkaloid
Isaindigotidione
Malik Hellal and Gregory D. Cuny*
Laboratory of Drug DiscoVery in Neurodegeneration, HarVard NeuroDiscoVery
Center, Brigham & Women’s Hospital and HarVard Medical School,
65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
gcuny@rics.bwh.harVard.edu
Received August 18, 2010
ABSTRACT
The first synthesis of isaindigotidione has been developed utilizing a reaction sequence including an asymmetric rhodium-catalyzed 1,4-
conjugate addition, an intramolecular aldol reaction, and a lactamization.
Isaindigotidione (1) is a indolizino[7,6-c]quinoline alkaloid
isolated from the roots of herbaceous Isatis indigotica
indigenous to China’s Changjiang river valley used in
traditional Chinese medicine for treating a wide variety of
ailments, including influenza and encephalitis. Furthermore,
the ethanolic extracts of this plant, from which 1 was
obtained, were found to exhibit effective antiendotoxin
activity.1
Herein we report the first synthesis of 1 along with several
analogues. On the basis of the observations of Poon and
Chiu,3 a strategy was sought that would avoid strong basic
conditions during the final stage of tetracyclic carboskeleton
formation. The approach we employed utilizes an asymmetric
rhodium-catalyzed 1,4-conjugate addition of arylboronic
acids to construct a key chiral intermediate, an intramolecular
aldol reaction to obtain the substituted quinolin-2(1H)-one,
and a lactamization to generate the indolizino[7,6-c]quinoline
(Scheme 1).
Rhodium-catalyzed 1,4-conjugate addition of organome-
tallic reagents is a convenient means for the stereoselective
construction of C-C bonds.4 This methodology has been
successfully applied to a variety of electron-deficient olefins,
including R,ꢀ-unsaturated ketones,5 esters,6 and amides.7 In
particular, Frost and co-workers recently used this approach
with pyrrolidine substrates for a stereoselective route to
Alkaloid 1 appears to be the first reported indolizino[7,6-
c]quinoline found in nature.2 A synthesis of the tetracyclic
carboskeleton has recently been reported using a bis-
cyclization strategy under basic conditions (NaOMe in
MeOH).3 However, the (S,S) diastereoisomer, which is found
in the natural product, was only obtained as the minor isomer
(<10%). The authors attributed this result to equilibration to
the more thermodynamically stable (S,R) diastereoisomer in
agreement with density functional theory calculations.
(4) For reviews, see: (a) Hayashi, T. Synlett 2001, 879. (b) Hayashi, T.;
Yamasaki, K. Chem. ReV. 2003, 103, 2829. (c) Fagnou, K.; Lautens, M.
Chem. ReV. 2003, 103, 169. (d) Darses, S.; Geneˆt, J.-P. Eur. J. Org. Chem.
2003, 4313. (e) Yoshida, K.; Hayashi, T. In Modern Rhodium-Catalyzed
Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, Germany,
2005; Chapter 3.
(1) Wu, X.; Qin, G.; Cheung, K. K.; Cheng, K. F. Tetrahedron 1997,
53, 13323.
(2) For a review of quinoline alkaloids, see: Michael, J. P. Nat. Prod.
Rep. 1999, 16, 697.
(3) Poon, C. Y.; Chiu, P. Tetrahedron Lett. 2004, 45, 2985.
10.1021/ol101890t  2010 American Chemical Society
Published on Web 09/16/2010

very similar to those previously reported.8 The diastereose-
lectivity of the reaction was dependent on the chirality of
the substrate and the ligand. For example, (S)-BINAP as well
as dppp afforded the (R,S)-diastereoisomer in excellent yield
and high diastereoselectivity (entries 1 and 2). However, (R)-
BINAP gave (S,S)-8a (the required isomer for 1) in both
lower yield and diastereoselectivity (entry 3). Interestingly,
chiral dienes have been reported to be superior to other types
of chiral ligands, such as bisphosphines, in terms of both
catalytic activity and enantioselectivity for rhodium-catalyzed
asymmetric 1,4-conjugate additions.9,10 (R,R,R)-DOLEFIN,
a commercially available chiral diene developed by Carreira
and co-workers, was found to improve both the yield of (S,S)-
8a to 90% and the diastereoselectivity to 90:10 (entry 4).11
This ligand proved superior in terms of conversion and
selectivity compared to several other chiral diene ligands
(entries 5-9).10c Next, this reaction was extended to phe-
nylboronic acids containing electron-donating substituents.
As expected, (R,R,R)-DOLEFIN was again more efficient
than (R)-BINAP (entries 10-13). Importantly for the syn-
thesis of 1, the presence of the 4-benzyloxy did not adversely
affect the yield or selectivity of the reaction. (S,S)-8c was
obtained in 70% yield and 93:7 diastereoselectivity (entry
13).
Scheme 1. Synthetic Strategy
functionalized pyrrolizidinones.8 Our synthesis of 1 likewise
takes advantages of the versatility of the rhodium-catalyzed
1,4-conjugate addition for the diastereoselective construction
of diversely substituted indolizino[7,6-c]quinolines.
Initial efforts focused on synthesizing the chiral amino
ester 8 (Table 1). The optimal reaction conditions, using
Transformation of (R,S)-8a to indolizino[7,6-c]quinolines
using methodology recently developed by our group was
explored (Scheme 2).12 After quantitative ester hydrolysis
Table 1. Asymmetric 1,4-Conjugate Addition of Boronic Acids
to Pyrrolidine 7
Scheme 2
entry
ligand
yield (%) dr (S,S):(R,S) product
1
dppp
92
97
6:94
5:95
(R,S)-8a
(R,S)-8a
(S,S)-8a
(S,S)-8a
(S,S)-8a
(S,S)-8a
(S,S)-8a
(S,S)-8a
(S,S)-8a
(S,S)-8b
(S,S)-8b
(S,S)-8c
(S,S)-8c
2
(S)-BINAP
3
(R)-BINAP
66
87:13
90:10
70:30
55:45
63:37
ndc
4
(R,R,R)-DOLEFIN
L1, R ) CO2Me
L2, R ) CH2OH
L3, R ) CH2OMe
L4, R) CMe2OH
L5, R) CMe2OMe
(R)-BINAP
90
5
51b
22b
34b
<10b
<10b
46
6
7
8
9
ndc
10
11
12
13
91:9
(R,R,R)-DOLEFIN
(R)-BINAP
71
92:8
39
90:10
93:7
(R,R,R)-DOLEFIN
70
a Reaction conditions:
7
(1.0 equiv), ArB(OH)2 (4.0 equiv),
Rh(C2H4)2Cl]2 (3 mol %), ligand (7 mol %), Cs2CO3 (1.0 equiv),
b
1
1,4-dioxane/H2O (10:1), 60 °C, 24 h. Conversion based on H NMR of
the crude product. c Not determined.
of (R,S)-8a, N-acylation of isatin was accomplished using
EDCI. The N-acylated isatin 9, which is unstable and used
without purification, was hydrolyzed in alkaline conditions
to give the R-oxoacetic acid 10 in 84% yield over three steps.
This material was then subjected to an intramolecular aldol
[Rh(C2H4)2Cl]2 as catalyst (3 mol %), a ligand (7 mol %),
Cs2CO3 (1 equiv), and a phenylboronic acid (4 equiv) in a
mixture of 1,4-dioxane:H2O (10:1) at 60 °C for 24 h, were
Org. Lett., Vol. 12, No. 20, 2010
4629

reaction to give 2-quinolinone 11 in 56% yield. Either direct
treatment of this material with SOCl2 or a two-step process
(Boc deprotection with HCl/MeOH followed by EDCI-
mediated coupling) produced indolizino[7,6-c]quinoline 12
in good yields.
Table 2. Optimization of the Lactamization
Attempts were then made to extend this strategy to the
synthesis of 1 (Scheme 3). Ester hydrolysis of (S,S)-8c
Scheme 3
entry
conditionsa
ratio 14/15/16
yield (%)
1
2
3
4
5
6
A
B
C
D
E
F
39/61/0
12/88/0
35/0/65
-
100/0/0
100/0/0
83
90
80
0
21
54
a Reaction conditions. Condition A: (1) MeOH, HCl, rt, 2 h; (2) EDCI,
NEt3, DMF, rt, 24 h. Condition B: (1) MeOH, HCl, rt, 2 h; (2) HBTU,
DIEA, DMF, rt, 24 h. Condition C: SOCl2, 80 °C, 1 h. Condition D: SOCl2
(1.1 equiv), toluene, 100 °C, 24 h. Condition E: SOCl2 (2.2 equiv), toluene,
100 °C, 24 h. Condition F: (1) MeOH, HCl, rt, 2 h; (2) SOCl2 (2.2 equiv),
toluene, 80 °C, 2 h.
that the relative stereochemistry influences formation of the
tautomeric product and not the presence of the electron-
donating substituents in 2. Parenthetically, it appears that
the stereochemistry of the intermediate deprotected 2-quino-
linone most likely is responsible for formation of the
tautomeric product and not intermediacy of the indolizino[7,6-
c]quinoline.13
Given the difficulties encountered with the initial depro-
tection/lactamization method, the direct conversion of 2 in
the presence of neat SOCl2 was investigated. The desired
cyclization was observed, but concomitant chlorination of
the electron-rich pendent aromatic ring also occurred leading
to 16 as the major product (entry 3).14 When the reaction
was conducted with only 1.1 equiv of SOCl2 in toluene, no
followed by N-acylation of 4 and ring opening of N-acylated
isatin 13 gave the expected product 3 in 61% yield over three
steps. The intramolecular aldol reaction was performed in 55%
yield generating 2. However, deprotection and lactamization
of 2 was problematic and required optimization.
Initial attempts to remove the Boc protecting group and
to induce lactam formation with either EDCI or HBTU gave
only minor amounts of the desired product 14 along with
15 as the major product (Table 2, entries 1 and 2).
Surprisingly, tautomerization was not observed with the (R,S)
diastereoisomer 11. However, the same type of byproduct
was observed when (S,S)-11 was subjected to identical
deprotection/coupling conditions. These observations suggest
(8) Zoute, L.; Kociok-Ko¨hn, G.; Frost, C. G. Org. Lett. 2009, 11, 2491.
(9) For reviews, see: (a) Defieber, C.; Grutzmacher, H.; Carreira, E. M.
Angew. Chem., Int. Ed. 2008, 47, 4482. (b) Shintani, R.; Hayashi, T.
Aldrichchimica Acta 2009, 42, 31.
(5) (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura,
N. J. Am. Chem. Soc. 1998, 120, 5579. (b) Tokunaga, N.; Yoshida, K.;
Hayashi, T. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5445. (c) Amengual,
R.; Michelet, V.; Geneˆt, J.-P. Synlett 2002, 1791. (d) Itooka, R.; Iguchi,
Y.; Miyaura, N. J. Org. Chem. 2003, 68, 6000. (e) Boiteau, J.-G.; Imbos,
R.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 681.
(6) (a) Moss, R. J.; Wadsworth, K. J.; Chapman, C. J.; Frost, C. G.
Chem. Commun. 2004, 1984. (b) Takaya, Y.; Senda, T.; Kurushima, H.;
Ogasawara, M.; Hayashi, T. Tetrahedron: Asymmetry 1999, 10, 4047. (c)
Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org. Chem. 2000, 65,
5951. (d) Navarre, L.; Darses, S.; Geneˆt, J.-P. Angew. Chem., Int. Ed. 2004,
43, 719.
(10) For selected examples of the asymmetric reaction using chiral
dienes, see: (a) Nishimura, T.; Wang, J.; Nagaosa, M.; Okamoto, K.;
Shintani, R.; Kwong, F.-Y.; Yu, W.-Y.; Chan, A. S. C.; Hayashi, T. J. Am.
Chem. Soc. 2010, 132, 464. (b) Paquin, J.-F.; Stephenson, C. R. J.; Defieber,
C.; Carreira, E. M. Org. Lett. 2005, 7, 3821. (c) Okamoto, K.; Hayashi, T.;
Rawal, V. H. Org. Lett. 2008, 10, 4387. (d) Gendrineau, T.; Chuzel, O.;
Eijsberg, H.; Geneˆt, J.-P.; Darses, S. Angew. Chem., Int. Ed. 2008, 47, 7669.
(11) Fisher, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem.
Soc. 2004, 126, 1628.
(7) (a) Senda, T.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66,
6852. (b) Sakuma, S.; Miyaura, N. J. Org. Chem. 2001, 66, 8944. (c)
Pucheault, M.; Michaut, V.; Darses, S.; Geneˆt, J.-P. Tetrahedron Lett. 2004,
45, 4729.
(12) Hellal, M.; Cuny, G. D. J. Org. Chem. 2010, 75, 3465.
(13) Indolizino[7,6-c]quinolines (S,S)- or (R,S)-12 in DMF in the
presence of NEt3 (2 equiv) were stirred at room temperature for 24 h. No
tautomeric product was observed.
4630
Org. Lett., Vol. 12, No. 20, 2010

cyclization was observed due to lack of Boc deprotection
(entry 4). However, 14 was obtained in 21% yield with no
detectable production of 16 when 2.2 equiv of SOCl2 was
used (entry 5). Encouraged by these results, a two-step
sequence was explored. Deprotection of the Boc with HCl
in MeOH followed by cyclization in the presence of SOCl2
(2.2 equiv) produced indolizino[7,6-c]quinoline 14 in 54%
yield over two steps with no observed formation of 15 or
16 (entry 6). Finally, removal of the benzyloxy protecting
group from 14 using standard hydrogenation conditions
agreement with those previously reported for the isolated
natural product.1
In summary, a synthesis of isaindigotidione (1) from the
enantiopure pyrrolidine 7 using a concise route involving
an asymmetric rhodium-catalyzed 1,4-conjugate addition of
an arylboronic acid, an intramolecular aldol reaction, and
lactamization has been achieved. In addition, this synthetic
route provides diastereoselective access to indolizino[7,6-
c]quinolines.
Acknowledgment. The authors appreciate financial sup-
port from the Harvard NeuroDiscovery Center and the
Chemistry Department at Brandies University for use of a
polarimeter.
1
furnished 1 in 86% yield. The H and 13C NMR spectral
data and optical rotation for the synthetic material were in
(14) For examples of chlorination of electron-rich aromatic rings with
thionyl chloride, see: (a) Huazhou, Y.; Yongzhou, H.; Qiaojun, H.; Runping,
L.; Bo, Y. Eur. J. Med. Chem. 2007, 42, 226. (b) Xiao, X.; Morrell, A.;
Fanwick, P. E.; Cushman, M. Tetrahedron 2006, 62, 9705. (c) Kunihiko,
M.; Yuki, Y.; Takako, A.; Yoshiaki, T.; Kimiaki, I. Heterocycles 2001, 55,
1779.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL101890T
Org. Lett., Vol. 12, No. 20, 2010
4631