Towards total synthesis of communesins and perophoramidine: Unexpected cascade reaction of Michael-Mannich-Mannich additions

Article abstract of DOI:10.1055/s-0030-1259705

A new type of chiral amidinobenzodiene 5 was prepared from isatin in ten steps. While attempting to prepare the core structure from 5 and tryptamine derivative 17 via a hetero Diels-Alder reaction for the total synthesis of communesin and perophoramidine, we observed an unexpected three-step, one-pot cascade reaction of Michael-Manich-Manich additions. The cascade reaction between 5 and 17 yielded diasteromers 21a and 21b with a complex polycyclic skeleton of 2,3,4,5-diindolinohexahydropyrrole in 76% yield and a ratio of 3:1. The stereochemistry of 21a was confirmed by X-ray crystal-structural analysis. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1259705

LETTER
907
Towards Total Synthesis of Communesins and Perophoramidine:
Unexpected Cascade Reaction of Michael–Mannich–Mannich Additions
Total
S
ynthesis of
a
Communes
o
ins and
P
ero
x
phoramidineing Wu, Xue Xiao, Yong Qin*
Department of Medicinal Natural Products, Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education,
West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. of China
Fax +86(28)85503842; E-mail: yongqin@scu.edu.cn
Received 12 October 2010
Dedicated to Professors Lixin Dai and Prof. Xiyan Lu of the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
The intriguing structure and interesting biological activity
Abstract: A new type of chiral amidinobenzodiene 5 was prepared
of communesins and perophoramidine have attracted in-
from isatin in ten steps. While attempting to prepare the core struc-
ture from 5 and tryptamine derivative 17 via a hetero Diels–Alder
tense interest among synthetic chemists wishing to recre-
ate the core structure.4 Their efforts have led to two total
reaction for the total synthesis of communesin and perophorami-
dine, we observed an unexpected three-step, one-pot cascade reac- syntheses of racemic (dehalo)perophoramidine5 and two
total syntheses of racemic communesin F.6 Recently, the
tion of Michael–Manich–Manich additions. The cascade reaction
between 5 and 17 yielded diasteromers 21a and 21b with a complex
absolute configuration of these alkaloids has been deter-
polycyclic skeleton of 2,3,4,5-diindolinohexahydropyrrole in 76%
mined by asymmetric total syntheses of (–)-communesin
yield and a ratio of 3:1. The stereochemistry of 21a was confirmed
F from Ma’s group7 and an asymmetric total synthesis of
by X-ray crystal-structural analysis.
(+)-perophoramidine by our group.8
Key words: communesin, perophoramidine, cascade reaction,
Michael addition, Mannich addition
In our total synthesis of (+)-perophoramidine,8 we carried
out an asymmetric intermolecular hetero Diels–Alder re-
action between the in situ generated trans,trans-benzodi-
ene 3 and indole 2 to assemble the chiral core structures
Since communesins A and B were isolated from a Penicil-
lium mold by Numata in 1993,1 six additional members
(C–H) of this indole alkaloid family have been identified
during the past two decades (Figure 1).2 Among commu-
nesins, communesin B is the most active in vitro cytotox-
icity against the lymphocytic leukemia cell line P388
(ED50: 0.45 mg/mL). In 2002, perophoramidine, a biosyn-
thetically related alkaloid and with opposite stereochem-
istry at the two adjacent quaternary stereocenters related
to communesin B, was isolated by Ireland from the marine
ascidian Perophora Namei (Figure 1). This compound
showed low cytotoxicity against the colon carcinoma cell
line HCT116 (IC50 of 60 mg/mL).3
4a and 4b. In this reaction, the chirality of adducts 4a and
4b was induced by a chiral auxiliary pre-installed on the
amide nitrogen (Scheme 1).
During our further explorations of the efficiency and
scope of this type of in situ generated benzodiene on
asymmetric hetero Diels–Alder reaction, we observed an
unexpected cascade reaction of Michael–Mannich–
Mannich additions to yield a new chiral skeleton when a
chiral auxiliary attached to the carbon of a benzodiene 5
rather than to the nitrogen of the benzodiene 3
(Scheme 1). In this letter, we report the unusual cascade
reaction.
Preparation of chloroimidate 14, a precursor of benzodi-
ene 5, is shown in Scheme 2. By adapting our previous
procedure,8 aldehyde 7 was prepared in 65% yield in three
steps from isatin (6). After reduction of the aldehyde
group in 7, the resulting hydroxyl group was converted to
bromide to give compound 8 in 84% yield. Treatment of
8 with NaI, K2CO3, and (S)-a-methylbenzylamine in
DMF for 10 hours at 90 °C led to the formation of a mix-
ture of diastereomers 11 in 83% yield. The reaction most
likely proceeded through a three-step reaction of iodo ex-
change (9), ring closure (10), and nucleophilic attack of
the imidate group by (S)-a-methylbenzylamine. Selective
protection of the indole nitrogen with MeCO2Cl under
weak basic conditions resulted in ring opening of the in-
doline to give imidate 12 in 87% yield. Removal of TBS
in 12 with TBAF provided alcohol 13. Chlorination of 13
with SOCl2 in pyridine at 0 °C afforded chloride 14 in
90% yield. Because of its instability under chromatogra-
phy conditions, chloride 14 was used directly in the next
step without purification.
O
Me
N
R2
X
N
N
N
S
R
R
R
Cl
S
R
R
N
N
Br
H
N
N
Cl
H
R1
communesins
perophoramidine
R1 = H, Me, CHO
2 = Me, Et, Pr, 1,3-pentadienyl
X = O, double bond
R
Figure 1 Structures of communesins and perophoramidine (com-
munesin B: R1 = Me, R2 = 1,3-pentadienyl, X = O; communesin F:
R1 = R2 = Me, X = double bond)
SYNLETT 2011, No. 7, pp 0907–0910
Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1259705; Art ID: W31610ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

908
H. Wu et al.
LETTER
Ph
N
Me
Me
O
R
Cl
1
Ph
Ag+
exo
N
R
+
88%
N
O
Me
Br
NHBoc
Br
N
N
2
Me
Boc
2
3
Me
O
Me
Ph
Ph
O
N
N
N
N
N
O
O
O
+
O
O
Me
N
N
Ph
CO2Me
N
N
Br
N
Br
Me
Me
Boc
Boc
4a
4b
5
Scheme 1 Asymmetrically intermolecular Diels–Alder reaction
TBSO
TBSO
O
Br
O
ref. 8
a, b
c
– NaBr
N
O
N
H
O
N
O
H
H
7
8
6
OTBS
Me
Ph
TBSO
I
H2N
OTBS
O
– KI
N
H
NH
O
N
OK
N
Ph
9
10
11
TBSO
HO
Cl
O
N
O
N
O
d
e
f
Me
Ph
Me
Ph
Me
Ph
N
NH
NH
NH
CO2Me
CO2Me
CO2Me
12
13
14
Scheme 2 Reagents and conditions: a) NaBH4, THF, 0 °C, 1 h, 93%; b) Ph3P, NBS, CH2Cl2, r.t., 12 h, 90%; c) NaI, K2CO3, (S)-a-methyl-
benzylamine, DMF, 90 °C, 10 h, 83%; d) ClCO2Me, NaHCO3, THF, r.t., 5 h, 87%; e) TBAF, THF, r.t., 12 h, 90%; f) SOCl2, pyridine, CH2Cl2,
0 °C, 15 min.
The tryptamine derivative 17 with a 4-benzyloxy substit- skeleton of communesins and perophoramidine
uent was prepared from 3-(4-benzyloxyindolo)carbox- (Scheme 4). Unfortunately, when the benzodiene 5, gen-
aldehyde 159 (Scheme 3). Methylation with MeI and erated in situ with 2 equivalents of AgBF4, reacted with 17
condensation with nitromethane provided nitroolefin 16 at –78 °C in CH2Cl2 for 2 hours, the diastereomers 21a
in 81% yield in two steps. After simultaneous reduction of and 21b10 instead of 18 were generated. These diastereo-
the double bond and nitro group in 16 with LiAlH4, the re- mers, which have a complex polycyclic skeleton of
sulting amine was protected with the phthalic group to 2,3,4,5-diindolinohexahydropyrrole, were produced in
give 17 with 62% yield in two steps.
76% yield and a ratio of 1:3. The formation of 21a and
21b was explained through a three-step, one-pot cascade
reaction of Michael–Mannich–Mannich additions. We
hypothesize that the attack of indole 17 on the benzodiene
We originally envisioned that benzodiene 5 might react
with 17 through an intermolecular hetero Diels–Alder re-
action to give a chiral intermediate 18 possessing the basic
O
OBn
OBn
NO2
OBn
CHO
N
a, b
c, d
O
N
N
N
H
Me
Me
15
16
17
Scheme 3 Reagents and conditions: a) MeI, K2CO3, THF, r.t., 10 h; b) NH4OAc, MeNO2, 100 °C, 30 min, 81% in 2 steps; c) LiAlH4, THF,
0–60 °C, 3 h, 79%; d) phthalic anhydride, toluene, 90 °C, 12 h, 78%.
Synlett 2011, No. 7, 907–910 © Thieme Stuttgart · New York

LETTER
Total Synthesis of Communesins and Perophoramidine
909
R1
Me
R2
Ph
N
O
N
OBn
OBn
O
O
X
N
+
N
O
N
N
N
N
Ph
Me
Me
MeOOC
Me
CO2Me
17
18
5
Ag+
OBn
Cl
O
O
O
N
Ag+
N
Me
N
+
O
N
NH
Ph
N
Ph
Me
MeOOC
CO2Me
Me
14
5
17
R2
R2
R1
R1
N
N
OBn
OBn
O
HN
O
N
N
N
N
N
H
H
COOMe
Me
Me
COOMe
Ph
Ph
Me
19
Me
20
R2
R2
R1
R1
N
N
OBn
OBn
+
O
O
N
N
N
N
Me
N
N
Me
COOMe
COOMe
Ph
Ph
Me
21a
Me
21b
1:3
R1, R2 = phth
Scheme 4 Reagents and conditions: AgBF4, CH2Cl2, –78 °C, 2 h, 76%.
5 gave indolinium 19, which was susceptible to addition
of the imidate group in 19 to afford the iminium interme-
diate 20. A final Mannich addition of the amide group in
20 to the iminium moiety provided 21a and 21b. X-ray
crystal-structural analysis of 21a11 firmly established the
stereochemistry of 21a and 21b. Efforts to carry out an
acid-catalyzed rearrangement to convert 21a and 21b to
18, a potentially useful intermediate for the total synthesis
of communesins and perophoramidine, failed because of
the easy decomposition of 21a and 21b under a variety of
acidic conditions.
In conclusion, two chiral compounds 21a (Figure 2) and
21b with a polycylic skeleton of 2,3,4,5-diindolino-
hexahydropyrrole were prepared through a three-step,
one-pot cascade reaction of Michael–Mannich–Mannich
additions involving tryptamine derivative 17 and benzodi-
ene 5. Although we failed to prepare 18 with a skeleton of
communesins and perophoramidine from 21a and 21b,
this work demonstrates the usefulness of the new benzo-
diene 5 for preparing a complex ring system.
Figure 2 ORTEP diagram of 21a
Synlett 2011, No. 7, 907–910 © Thieme Stuttgart · New York

910
H. Wu et al.
LETTER
(10) Analytical Data
Acknowledgment
Compound 21a: 1H NMR (400 MHz, CDCl3): d = 0.32 (br,
1 H), 1.60–1.64 (m, 1 H), 1.74 (d, J = 7.6 Hz, 3 H), 2.04–
2.12 (m, 1 H), 2.64–2.72 (m, 1 H), 2.69 (s, 3 H), 3.18–3.33
(m, 2 H), 3.72–3.79 (m, 1 H), 3.94 (s, 3 H), 4.25–4.29 (m, 1
H), 4.74–4.81 (m, 2 H), 5.16 (br, 1 H), 5.40 (s, 1 H), 5.62–
5.67 (m, 2 H), 6.50 (t, J = 6.8 Hz, 1 H), 6.61 (t, J = 8.0 Hz, 1
H), 6.71 (d, J = 6.8 Hz, 1 H), 6.92 (t, J = 7.6 Hz, 2 H), 7.17
(t, J = 7.6 Hz, 2 H), 7.31–7.34 (m, 1 H), 7.39–7.43 (m, 2 H),
7.53–7.56 (m, 5 H), 7.65–7.74 (m, 4 H). 13C NMR (100
MHz, CDCl3): d = 21.74, 29.32, 29.33, 30.55, 34.19, 34.20,
36.04, 52.09, 52.10, 54.70, 69.23, 72.65, 92.73, 99.60,
99.73, 112.95, 113.43, 121.13, 122.66, 122.67, 123.75,
124.77, 126.83, 127.48, 127.50, 127.51 127.78, 127.79,
127.85, 128.11, 128.17, 128.43, 128.44, 128.45, 128.46,
129.50, 130.86, 132.19, 133.42, 133.48, 137.03, 144.82,
151.73, 153.36, 154.89, 167.61. HRMS: m/z [M + H+] calcd
for C46H43N4O6: 747.3183; found: 747.3142. IR (KBr):
3463, 2950, 2875, 1712, 1608, 1446, 1393, 1208, 716 cm–1.
[a]D20 +1.98 (c 1.0, CHC13).
This work was supported by grants from NSFC (20825207,
21021001), PCSIRT (IRT0846), the National Basic Research Pro-
gram of China (973 program, 2010CB833200), the National S & T
Major Project of China (2009ZX09310-002), and the State Key La-
boratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry.
References and Notes
(1) Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.;
Usami, Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa, T.
Tetrahedron Lett. 1993, 34, 2355.
(2) (a) Dalsgaard, P. W.; Blunt, J. W.; Munro, M. H. G.; Frisvad,
J. C.; Christophersen, C. J. Nat. Prod. 2005, 68, 258.
(b) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.;
Schaumann, K.; Wray, V.; Steube, K.; Proksch, P. J. Nat.
Prod. 2004, 67, 78. (c) Hayashi, H.; Matsumoto, H.;
Akiyama, K. Biosci. Biotechnol. Biochem. 2004, 68, 753.
(3) Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion,
G. P.; Ireland, C. M. J. Org. Chem. 2002, 67, 7124.
(4) (a) Evans, M. A.; Sacher, J. R.; Weinreb, S. M. Tetrahedron
2009, 65, 6712. (b) George, J. H.; Adlington, R. M. Synlett
2008, 2093. (c) Siengalewicz, P.; Gaich, T.; Mulzer, J.
Angew. Chem. Int. Ed. 2008, 47, 8170. (d) Crawley, S.;
Funk, R. L. Org. Lett. 2006, 8, 3995. (e) Seo, J. H.; Artman,
G. D.; Weinreb, S. M. J. Org. Chem. 2006, 71, 8891.
(f) Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett.
2006, 8, 2187. (g) May, J. A.; Stoltz, B. M. Tetrahedron
2006, 62, 5262; and references cited therein. (h) Crawley,
S.; Funk, R. L. Org. Lett. 2003, 5, 3169. (i) Artman, G. D.;
Weinreb, S. M. Org. Lett. 2003, 5, 1523. (j) May, J. A.;
Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003, 44,
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(5) (a) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Chem. 2004, 126,
5068. (b) Sabahi, A.; Novikov, A.; Rainier, J. D. Angew.
Chem. Int. Ed. 2006, 45, 4317.
(6) (a) Yang, J.; Wu, H. X.; Shen, L. Q.; Qin, Y. J. Am. Chem.
Soc. 2007, 129, 13794. (b) Liu, P.; Seo, J. H.; Weinreb,
S. M. Angew. Chem. Int. Ed. 2010, 49, 2000. (c) Seo, J. H.;
Liu, P.; Weinreb, S. M. J. Org. Chem. 2010, 75, 2667.
(7) Zuo, Zh. W.; Xie, W. Q.; Ma, D. W. J. Am. Chem. Soc. 2010,
132, 13226.
Compound 21b: 1H NMR (400 MHz, CDCl3): d = 1.57 (s, 3
H), 1.71 (d, J = 6.8 Hz, 3 H), 1.80–1.84 (m, 1 H), 2.05–2.12
(m, 1 H), 2.60–2.68 (m, 1 H), 2.87–2.94 (m, 1 H), 3.48–3.55
(m, 1 H), 3.73–3.79 (m, 1 H), 3.80–3.96 (m, 1 H), 3.96 (s, 3
H), 4.31–4.35 (m, 1 H), 5.15 (d, J = 11.6 Hz, 1 H), 5.29 (d,
J = 11.6 Hz, 1 H), 5.30–5.36 (m, 2 H), 5.32 (br, 1 H), 5.49
(d, J = 7.6 Hz, 1 H), 6.07 (d, J = 8.4 Hz, 1 H), 6.55–6.57 (m,
1 H), 6.75 (t, J = 8.0 Hz, 1 H), 6.89–6.93 (m, 1 H), 6.93–6.97
(m, 1 H), 7.24–7.28 (m, 1 H), 7.33–7.43 (m, 6 H), 7.65–7.67
(m, 2 H), 7.72–7.74 (m, 2 H), 7.75–7.78 (m, 2 H), 7.85–7.89
(m, 2 H). 13C NMR (100 MHz, CDCl3): d = 20.05, 29.42,
29.66, 31.15, 35.40, 36.97, 52.39, 53.18, 54.40, 69.79,
72.49, 72.92, 93.04, 99.56, 100.00, 113.03, 113.25, 121.26,
123.13, 123.14, 124.53, 125.04, 127.08, 127.10, 127.71,
127.72, 127.86, 127.88, 128.12, 128.15, 128.35, 128.47,
129.14, 129.15, 129.88, 131.15, 132.27, 133.80, 133.82,
137.68, 141.41, 144.51, 151.69, 153.57, 155.46, 168.06.
HRMS: m/z [M + H+] calcd for C46H43N4O6: 747.3183;
found: 747.3141. IR (KBr): 3464, 2951, 2868, 1709, 1606,
1445, 1389, 1189, 719 cm–1. [a]D20 –0.43 (c 1.0, CHC13).
(11) The crystallographic data of 21a (C46H42N4O6) have been
deposited with the Cambridge Crystallographic Data Centre;
the entry CCDC 776462 contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
(8) Wu, H. X.; Xue, F.; Xiao, X.; Qin, Y. J. Am. Chem. Soc.
2010, 132, 14052.
(9) Somei, M.; Yamada, F.; Kunimoto, M.; Kaneko, C.
Heterocycles 1984, 22, 797.
Synlett 2011, No. 7, 907–910 © Thieme Stuttgart · New York