Synthetic applications of a three-component Mannich reaction. Total synthesis of IL-6 inhibitor (+)-madindoline A and B

Article abstract of DOI:10.1016/j.tetlet.2006.07.083

A three-component Mannich reaction of 3a-hydroxyfuroindoline (3), β-ketoester and formaldehyde was employed as an efficient and concise method to synthesize naturally-occurring (+)-Madindolines A (1) and B (2). The scope and limitations of the Mannich rea

Full text of DOI:10.1016/j.tetlet.2006.07.083

Tetrahedron Letters 47 (2006) 6761–6764
Synthetic applications of a three-component Mannich reaction.
Total synthesis of IL-6 inhibitor (+)-madindoline A and B
Tomoyasu Hirose, Toshiaki Sunazuka, Daisuke Yamamoto,
ꢀ
Eisuke Kaji and Satoshi Omura*
The Kitasato Institute and Kitasato Institute for Life Sciences and Pharmaceutical Sciences, Kitasato University,
5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
Received 27 June 2006; accepted 17 July 2006
Available online 8 August 2006
Abstract—A three-component Mannich reaction of 3a-hydroxyfuroindoline (3), b-ketoester and formaldehyde was employed as an
efficient and concise method to synthesize naturally-occurring (+)-Madindolines A (1) and B (2). The scope and limitations of the
Mannich reaction with 3 are described.
ꢀ 2006 Elsevier Ltd. All rights reserved.
In 1996, we reported the isolation of two novel indole
alkaloids from a culture broth of Streptomyces nitro-
sporeus K93-0711, (+)-madindolines A (1) and B (2)
(Fig. 1), both proved selective inhibitors of interleukin-
6 (IL-6).1,2 Both (+)-1 and 2 specifically inhibited the
growth of the IL-6 dependent MH60 cell line; impor-
tantly the response was dose-dependent, without any
cytotoxicity.3 More detailed biological studies revealed
oral administration of (+)-1 to ovariectomized mice
significantly suppressed the decrease in bone mass and
increase in serum Ca2+ level after ovariectomy.3
other groups7–10 since the original source, Streptomyces
nitrosporeus K93-0711, no longer produces these antibi-
otics. We have been involved in the first4,6 and second
generation5,6 of total synthesis and determination of
the absolute configurations of (+)-1 and 2, as well as
the SAR studies of madindolines.11 In the course of
the continuation of these studies, we were interested in
the application of a three-component Mannich reac-
tion12 to build b-aminocarbonyl moieties of madindo-
lines. Mannich’s methodology for the construction of
b-aminocarbonyls has been a very useful tool of the syn-
thetic organic chemistry. Indeed, the Mannich reactions,
including asymmetric versions, have been investigated
and applied to natural products synthesis by several re-
search groups.13–17 We present here a very quick synthe-
sis of the title compounds as well as the limitation and
scope for the Mannich reaction of sensitive amines, such
as 3a-hydroxyfuroindoline (ꢀ)-3.
The design and development of practical and efficient
strategies for (+)-madindolines (1) and (2) synthesis
have been an important objective in our group4–6 and
HO
HO
3aR
3aR
Our synthetic strategy for madindolines after second
generation synthesis feature three-component coupling
(ꢀ)-3, b-ketoester and formaldehyde (Scheme 1). Stereo-
chemistry of the quaternary carbon of cyclopentenedi-
one is not important to supply madindolines for
bioassay, because both (+)-madindolines A and B show
selective inhibitory activity of IL-6.
8aS
8aS
O
O
N
N
H
H
Me
Me
β-aminocarbonyl
2'R
2'S
moiety
O
O
O
O
Me
Me
Me
Me
(+)-Madindoline A (+)-1
(+)-Madindoline B (+)-2
Figure 1. Structure of (+)-madindolines A (1) and B (2).
Before we embarked upon the synthesis of (+)-1 and 2
via a third generation strategy, it was necessary to exam-
ine the general applicability of the Mannich reaction
of acid-sensitive (ꢀ)-3 with formaldehyde and ethyl
*
Corresponding author. Tel.: +81 3 5791 6101; fax: +81 3 5791
6380; e-mail: omura-s@kitasato.or.jp
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.083

6762
T. Hirose et al. / Tetrahedron Letters 47 (2006) 6761–6764
HO
HO
N
O
H
N
H
O
H
Me
(–)- 3 (99% ee)
Mannich
Reaction
Madindolines
((+)-1 and (+)-2)
HCHO
Me
O
CO2Me
O
CO2Me
TMS
TMS
Me
Me
5
4
Scheme 1. Synthetic strategy of madindolines.
Table 1. Results and scope of Mannich reaction of 3a-hydroxyfuroindoline, nucleophiles and formaldehyde
HO
HO
O
3aR
Nucleophiles
N
8aS
H
6 (R1 = H, R2 = CO2Et)
7 (R1 = Me, R2 = CO2Et)
8 (R1 = H, R2 = H)
O
37wt% formalin
R1
N
H
H
O
R2
(–)-3
Me
9 (R1 = H, R2 = COMe)
Entrya
1
Nucleophiles
Conditions (acids, solvents)
AcOH (1.0 equiv), EtOH
Temperature; time
Results (yield%)
Decomposed
O
EtO2C
0 ꢁC; 1 h
0 ꢁC; 1 h
Me
O
EtO2C
EtO2C
2
3
Without acid, EtOH
Decomposed
Me
O
Yb(DS)3 (0.1 equiv), H2O
0 ꢁC; 3 h
0 ꢁC; 3 h
6 (78%)b,c
Me
Me
O
4
Yb(DS)3 (0.1 equiv), H2O
7 (Trace)
EtO2C
Me
Me
No reactiond
No reactiond
OTMS
5
6
Yb(DS)3 (0.1 equiv), H2O
Sc(DS)3 (0.1 equiv), H2O
rt; 1 day
rt; 1 day
EtO2C
EtO2C
Me
Me
OTMS
Me
Me
7 (52%)b,c
7 (97%)b,c
OTMS
7
8
Sc(OTf)3 (0.1 equiv) + Yb(DS)3 (0.2 equiv), H2O
Sc(OTf)3 (0.1 equiv) + Sc(DS)3 (0.2 equiv), H2O
rt; 1 day
rt; 1 day
EtO2C
EtO2C
Me
Me
OTMS
Me
OMe
Me
9
Yb(DS)3 (0.1 equiv), H2O
Yb(DS)3 (0.1 equiv), H2O
0 ꢁC; 3 h
0 ꢁC; 3 h
8 (98%)b
9 (Trace)
O
O
10
Me Me
a All the runs were carried out by using 3.0 equiv of nucleophiles and 1.0 equiv of 37 wt % formalin.
b Isolated yields.
c As a diastereomixture of the quaternary carbon center.
d Starting material was recovered.

T. Hirose et al. / Tetrahedron Letters 47 (2006) 6761–6764
6763
acetoacetate or ethyl 2-methylacetoacetate. A series of
experiments were carried out to identify appropriate
reaction conditions and the results are listed in Table
1. When the reaction was carried out with or without
AcOH in EtOH, (ꢀ)-3 was quickly decomposed, and
no desired product was observed (entries 1 and 2). Next,
we tried to use a lanthanide-catalyzed Mannich reaction
in aqueous media, which was developed by Kobayashi’s
group.18,19 The reaction of (ꢀ)-3 and acetoacetyl ester in
the presence of 10 mol % of ytterbium tridodecylsulfate
(Yb(DS)3) proceeded smoothly at 0 ꢁC to afford the de-
sired 6 in satisfactory yield (entry 3). Though good yield
was obtained in the case of acetoacetyl ester, the use of
2-methylacetoacetyl ester led to very low yield (entry 4).
Thus, TMS enol ether of 2-methylacetoacetyl ester20 was
employed instead of 2-methylacetoacetyl ester in the
presence of Yb(DS)3 or scandium tridodecylsulfate
(Sc(DS)3). However, the reaction did not proceed com-
pletely (entries 5 and 6). The reaction was further carried
out in the presence of 20 mol % of Yb(DS)3 with
another 10 mol % of Sc(OTf)3, and comparable yield
was obtained (entry 7). Moreover, the combination of
10 mol % of Sc(OTf)3 and 20 mol % of Sc(DS)3 led to
desired 7 in almost quantitative yield (entry 8).21 The
other simple nucleophiles were also examined under
the condition of 10% Yb(OTf)3 in H2O, and though
excellent yield was obtained in the case of 2-methoxy-
propene as a nucleophile (entry 9), 2,4-pentadione was
not produced under this condition (entry 10).
steps.5,6 Therefore, allylsilane b-ketoester (4) was pre-
pared from 11 by C-acylation with lithium enolate of
methyl propionate in 67% yield (Scheme 2).
We next tried a three-component Mannich reaction of
(ꢀ)-3 and TMS enolate of 4 under suitable conditions,
as shown in Table 1, entry 8. At first, TMS enolate
(12) was prepared by using LDA and TMSCl, then sub-
jected to the next reaction without purification. Man-
nich reaction of (ꢀ)-3, formaldehyde and 12 in the
presence of 10 mol % of Sc(OTf)3 and 20 mol % of
Sc(DS)3 led to Mannich adduct (5) in 11% yield.22
Though many examinations of this reaction condition
were carried out, we could not improve this yield. We
suspect that this is caused by instability of 12 against
Lewis acids, and high hydrophobicity of 12 may be
difficult to approach scandium atom as the active center
of the micelle complex of Sc(DS)3 and Sc(OTf)3. Finally,
an intramolecular endo cyclization of allylsilane (5)
using tris(dimethylamino)sulfur(trimethylsilyl)difluoride
(TAS-F), directly led to (+)-madindolines A (1) and B
(2) in 39% and 38% yields, respectively (Scheme 3).23
Synthetic (+)-1 and (+)-2 were very easy to separate
and purify by standard separation conditions (Prepara-
tive TLC; hexane–ethyl acetate = 1:1) from the crude
reaction mixture and identical in all respects with
authentic (+)-1 and (+)-2.
In conclusion, the third generation synthesis of (+)-
madindolines A and B, has been achieved via a conver-
gent strategy involving a three-component Mannich
reaction (two linear steps from optically active (ꢀ)-3a-
hydroxyfuroindoline (99% ee) (3) or eight linear steps
from commercially available 10). This synthetic route
not only provides quick access to madindolines, but also
broadens the chemical diversity of madindoline libraries.
We believe that chemical diversity of madindolines will
accelerate biological evaluation and lead to the discov-
ery of a more potent IL-6 inhibitor.
After achieving satisfactory yields for the Mannich reac-
tion of (ꢀ)-3 and 2-methylacetoacetate, we turned our
attention to the applicability of the construction of
b-amino carbonyl moiety of madindolines. We have
already reported a practical method to prepare acid
chloride (11) from commercially available 10 in four
Me
Cl
O
a
b
CO2Et
P(O)(OEt)2
O
CO2Me
TMS
n-Bu
Acknowledgements
TMS
n-Bu
10
11
4
This work was supported by a Grant from the 21st Cen-
tury COE Program, Ministry of Education, Culture,
Sports, Science and Technology. We also thank Ms.
Scheme 2. Preparation of b-ketoester ether 4: (a) Refs. 5,6; (b) methyl
propionate, LDA, THF, ꢀ78 ꢁC, 10 min, 67%.
4
a
HO
N
Me
TMSO
TMS
CO2Me
O
H
Me
n-Bu
c
(+)-1 and (+)-2
CO2Me
12
b
(–)-3
O
ratio
1
:
1
TMS
n-Bu
5
Scheme 3. Mannich reaction of (ꢀ)-3 and 12, and final cyclization. Reagents and conditions: (a) TMSCl, LDA, Et3N, THF, ꢀ78 ꢁC, 30 min; (b) 12,
37 wt % formalin, Sc(OTf)3, Sc(DS)3, H2O, rt, 24 h, 11%; (c) TAS-F, DMF, rt, 20 min, 39% for (+)-1, 38% for (+)-2.

6764
T. Hirose et al. / Tetrahedron Letters 47 (2006) 6761–6764
solution (2.0 mL) and extracted with EtOAc (·3). The
combined organic layers were washed with brine (·1),
dried over Na2SO4, filtered and concentrated. The crude
product was purified by preparative TLC (CHCl3–acetone
2:1) to afford Mannich adduct 7 (94.1 mg, 97%) as a light
brown oil; Rf 0.57 (CHCl3–acetone 2:1); IR (KBr) 3436
(OH), 1737 (–OC@O), 1710 (C@O), 1612, 1487, 1462
(arom.) cmꢀ1; NMR data for one of the diastereomer of 7,
1H NMR (270 MHz, CDCl3) d 7.22 (1H, d, J = 7.3 Hz, 4-
H), 7.12 (1H, dd, J = 7.9, 7.6 Hz, 6-H), 6.70 (1H, dd,
J = 7.6, 7.3 Hz, 5-H), 6.40 (1H, d, J = 7.9 Hz, 7-H), 5.03
(1H, s, 8a-H), 4.17 (2H, q, J = 7.3 Hz, OCH2CH3), 4.11
(1H, d, J = 14.8 Hz, 10-H), 3.85 (1H, m, 2-H), 3.68 (1H, d,
J = 14.8 Hz, 10-H), 2.84 (1H, m, 2-H), 2.84 (1H, br s, OH),
2.34, 2.24 (each 1H, m, 3-H2), 2.17 (3H, s, 40-H3), 1.39
(3H, s, 20-CH3), 1.25 (3H, t, J = 7.3 Hz, OCH2CH3); 13C
NMR (6.75 MHz, CDCl3) d 205.2 (C-30), 172.1 (20-
COOCH2CH3) 151.1 (C-7a), 130.0 (C-3b), 130.0 (C-6),
123.8 (C-4), 118.4 (C-5), 106.5 (C-7), 104.5 (C-8a), 87.6 (C-
3a), 66.9 (C-2), 61.6 (OCH2CH3), 60.4 (C-20), 47.9 (C-10),
41.2 (C-3), 26.5 (C-40), 18.6 (20-CH3) 13.9 (OCH2CH3);
HR-MS (FAB, NBA matrix) m/z: 333.1600 [M]+, calcd
for C18H23O5N: 333.1576 [M].
A. Nakagawa, Ms. C. Sakabe and Ms. N. Sato for var-
ious instrumental analyses.
References and notes
1. Hayashi, M.; Kim, Y.-P.; Takamatsu, S.; Enomoto, A.;
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Sunazuka, T.; Hirose, T.; Komiyama, K.; Omura, S. Proc.
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22. Mannich adduct 5 as a light brown oil; Rf 0.53 (CHCl3–
acetone 5:1); IR (KBr) 3438 (OH), 1740 (OC@O), 1728
(C@C–C@O), 1661 (C@C), 1616, 1487, 1464
(arom.) cmꢀ1; NMR data for one of the diastereomer of
5, 1H NMR (270 MHz, CDCl3) d 7.16 (1H, d, J = 7.3 Hz,
4-H), 7.13 (1H, dd, J = 7.9, 7.3 Hz, 6-H), 6.69 (1H, dd,
J = 7.3, 7.3 Hz, 5-H), 6.44 (1H, d, J = 7.9 Hz, 7-H), 6.28
(1H, t, J = 7.3 Hz, 50-H), 5.08 (1H, s, 8a-H), 4.13 (1H, d,
J = 15.2 Hz, 10-H), 3.97 (1H, m, 2-H), 3.63 (3H, s, OCH3),
3.61 (1H, d, J = 15.2 Hz, 10-H), 3.38 (1H, m, 2-H), 2.44,
2.25 (each 1H, m, 3-H2), 2.14 (2H, m, 60-H2), 1.84, 1.73
(each 1H, d, J = 13.5 Hz, CH2Si(CH3)3), 1.61 (3H, s, 20-
CH3), 1.36 (4H, m, 70-, 80-H2), 0.93 (3H, t, J = 6.9 Hz,
90-H3), 0.86 (9H, s, Si[(CH3)2]C(CH3)3), 0.00 (9H, s,
Si(CH3)3), ꢀ0.12, ꢀ0.16 (each 3H, s, Si[(CH3)2]C(CH3)3);
13C NMR (67.5 MHz, CDCl3) d: 199.3 (C-30), 175.2 (20-
COOCH3), 153.0 (C-7a), 140.5 (C-50), 138.8 (C-40), 131.6
(C-3b), 130.7 (C-6), 125.4 (C-4), 119.0 (C-5), 107.5 (C-7),
103.6 (C-8a), 90.6 (C-3a), 67.6 (C-2), 58.5 (C-20), 54.1 (C-
10), 53.2 (20-COOCH3), 44.9 (C-3), 31.8 (C-70), 30.5 (C-60),
26.6 (Si[(CH3)2]C(CH3)3), 23.4 (C-80), 22.6 (20-CH3), 18.9
(Si[(CH3)2]C(CH3)3), 17.6 (CH2Si(CH3)3), 14.8 (C-90), 0.0
(Si(CH3)3), ꢀ2.3, ꢀ2.9 (Si[(CH3)2]C(CH3)3); HR-MS
(FAB, NBA matrix) m/z: 496.25 [M+Na]+, calcd for
C26H39O5NSiNa: 496.2495 [M+Na].
23. Experimental procedure of preparation of (+)-madindo-
lines A (1) and B (2): At room temperature, a solution of 5
(4.3 mg, 9.08 lmol) in DMF (0.91 ml) was treated with
tris(dimethylamino)sulfur(trimethylsilyl)difluoride (12.5
mg, 0.0455 mmol). The reaction mixture was stirred for
20 min, and then quenched with H2O (2 ml), extracted
with hexane–EtOAc (1:1) solution (·3), and the combined
extracts were washed with brine (·1), dried over Na2SO4,
filtered and concentrated. Preparative TLC (hexane–
EtOAc 1:1) furnished (+)-madindoline A (+)-1 (1.3 mg,
39%) as a light yellow crystal and (+)-madindoline B (+)-2
(1.1 mg, 38%) also as a light yellow crystal: All physical
data for (+)-1 and (+)-2 were matched with the data of
synthetic (+)-madindolines in our previous papers (Refs.
4–6).
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21. Experimental procedure of preparation of (3aR,8aS)-3a-
hydroxy-8-(2-methoxycarbonyl-2-methyl-3-oxobutyl)-3,3a,
8,8a-tetrahydro-2H-furo[2,3-b]indole (7): (ꢀ)-3 (51.6 mg,
0.291 mmol) was dissolved in a solution of Sc(DS)3
(49.0 mg, 0.0582 mmol), Sc(OTf)3 (14.3 mg, 0.0291 mmol),
37 wt % formalin (24 lL, 0.291 mmol) and 2-methyl-3-
trimethylsilyloxy)-2-butenoic acid ethyl ester (188.9 mg,
0.873 mmol) in H2O (1.8 mL) at room temperature. The
resulting reaction mixture was stirred for 24 h. The
reaction mixture was quenched with satd aq NaHCO3