Synthesis of an advanced intermediate of the macrotricyclic core of roseophilin

Article abstract of DOI:10.1055/s-0031-1289882

A facile approach for the preparation of a cyclopenta[b]pyrrole derivative, the key precursor in Frontiers synthesis of the macrotricyclic core of roseophilin, was developed. The key steps involved two successive pyrrole acylations and a Sc(OTf)₃

Full text of DOI:10.1055/s-0031-1289882

LETTER
2995
Synthesis of an Advanced Intermediate of the Macrotricyclic Core of
Roseophilin
A
dvancedIntermediate
e
of the Ma
i
crotric
y
l
clic Co
i
re of
R
n
oseophilin g Hong, Hui Liu, Li Sun, Feifei Jia, Yuanyuan Liu, Qingwei Jiang, Chuanjun Song,* Junbiao Chang*
Department of Chemistry, Zhengzhou University, 100 Science Avenue, Zhengzhou, Henan Province 450001, P. R. of China
E-mail: chjsong@zzu.edu.cn; E-mail: changjunbiao@zzu.edu.cn
Received 11 September 2011
Herein, we report our approach to the synthesis of 8,
which was realized in six steps and >10% overall yield
starting from a TFAA-mediated regioselective acylation
of N-tosylpyrrole previously developed by one of us.5
Abstract: A facile approach for the preparation of a cyclopen-
ta[b]pyrrole derivative, the key precursor in Frontier’s synthesis of
the macrotricyclic core of roseophilin, was developed. The key
steps involved two successive pyrrole acylations and a Sc(OTf)3-
catalyzed Nazarov cyclization reaction.
As shown in Scheme 2, acylation of N-tosylpyrrole with
6-heptenoic acid6 in the presence of TFAA, followed by
reduction of the carbonyl group in the acylation product
with borane-tert-butylamine complex in the presence of
aluminum trichloride7 delivered 4 in 37% isolated yield
over two steps. A second acylation with monomethyl
malonate and TFAA gave acylpyrrole 58 in 61% yield.
Knoevenagel condensation9 between 5 and isobutyralde-
hyde provided 610 as a mixture of Z- and E-isomers in a
ratio of 1.7:1. Scandium(III)-catalyzed Nazarov
cyclization2l of compound 6 gave cyclopenta[b]pyrrole
711 in good yield, solely as the trans isomer. The stereo-
chemical assignment of 7 was made on the basis of NOE
correlations of Ha with both the methine and the methyl
protons of the isopropyl group. Finally, cross olefin meta-
thesis reaction12 of 7 with allyl acetate gave 813 in 79%
isolated yield, as a mixture of E- and Z-isomers in a ratio
of 6.4:1. Compound 8 could then be converted into 2 fol-
Key words: pyrrole acylation, Knoevenagel reaction, Nazarov
cyclization, olefin cross-metathesis, scandium triflate
Roseophilin (1, Scheme 1), isolated from the culture broth
of Streptomyces griseoviridis by Seto et al. in 1992, ex-
hibits potent cytotoxicity against K562 human erythroid
leukemia and KB human epidermoid carcinoma cell lines
in the submicromolar range.1 This alkaloid possesses a
unique ansa-bridged cyclopenta[b]pyrrole skeleton incor-
porated with a conjugated pyrrolylfuran moiety. These
properties render roseophilin an ideal target for total syn-
thesis.2,3 Quite unexpectedly, Boger’s work showed that
the unnatural enantiomer of roseophilin exhibits 2–10-
fold higher cytotoxicity than the naturally occurring enan-
tiomer.2d
OMe
MeO
c
a,b
N
MeO
O
N
Ts
O
+
N
N
O
Ts
Ts
Cl
O
RN
N
H
4
5
O
Cl
NH
2
3
1
e
d
MeO2C
Ha
MeO
Scheme 1
N
N
O
O
Ts
O
Ts
The reported total syntheses of roseophilin to date2a–d are
based on the same disconnection that includes the conden-
sation of the macrotricyclic core 2 with the conjugated
pyrrolylfuran portion 3. Formal synthesis of roseophilin2e–l
largely focused on development of new methodologies to-
wards the construction of the tricyclic core 2. Recently,
Bitar and Frontier2l reported their synthesis of the tricyclic
core 2, and the precursor 8 for the palladium-catalyzed in-
tramolecular Tsuji–Trost reaction4 to form the 13-mem-
bered macrocyclic ring in 18 steps and <4% overall yield.
6
7
AcO
ref. 2l
f
MeO2C
N
O
N
O
H
Ts
8
2
Scheme 2 Reagents and conditions: (a) 6-heptenoic acid, TFAA,
DCE, 80 °C, 24 h, 56%; (b) BH3·t-BuNH2, AlCl3, CH2Cl2, r.t., 15 min,
66%; (c) monomethyl malonate, TFAA, CH2Cl2, r.t., 30 h, 61%; (d)
pyrrolidine, AcOH, 4 Å MS, CH2Cl2, 0 °C, 5 min, then isobutyralde-
hyde, 0 °C to r.t., 16 h, 73%; (e) Sc(OTf)3, LiClO4, DCE, reflux, 1 h,
81%; (f) Grubbs II catalyst, CH2Cl2, 40 °C, 24 h, 79%.
SYNLETT 2011, No. 20, pp 2995–2996
x
x
.x
x
.2
0
1
1
Advanced online publication: 11.11.2011
DOI: 10.1055/s-0031-1289882; Art ID: W20011ST
© Georg Thieme Verlag Stuttgart · New York

2996
M. Hong et al.
LETTER
4 H). 13C NMR (100 MHz, CDCl3): d = 181.8, 167.8, 147.2,
144.9, 138.8, 136.5, 135.1, 129.6, 127.6, 123.5, 114.5,
111.5, 52.4, 47.3, 33.6, 28.9, 28.8, 28.6, 21.7. MS (ESI):
m/z (%) = 440 (100) [M + Na]+, 424 (5), 418 (6) [M + H]+.
HRMS-ESI: m/z [M + Na]+ calcd for C22H27NNaO5S:
440.1508; found: 440.1521.
lowing Frontier’s procedure by palladium-catalyzed in-
tramolecular Tsuji–Trost reaction to close the 13-
membered macrocyclic ring, followed by double bond re-
duction, detosylation and Krapcho dealkoxycarbonyla-
tion.2l
(9) Ranu, B. C.; Jana, R. Eur. J. Org. Chem. 2006, 3767; and
references cited therein.
In summary, we have developed a facile synthesis of
cyclopenta[b]pyrrole moiety 8, which represents a valu-
able approach for the formal synthesis of roseophilin.
(10) IR (neat): 1724, 1662, 1597, 1557, 1480, 1435, 1371, 1330,
1294, 1247, 1191, 1175, 1103. 1H NMR (400 MHz, CDCl3):
d = 8.04 (m, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 6.84 (d, J = 11.2
Hz, 0.63 H), 6.78 (d, J = 3.6 Hz, 0.63 H), 6.62 (d, J = 3.6 Hz,
0.37 H), 6.60 (d, J = 10.4 Hz, 0.37 H), 6.08 (d, J = 3.6 Hz,
0.63 H), 6.02 (d, J = 3.6 Hz, 0.37 H), 5.80 (ddt, J = 16.8,
10.4, 6.4 Hz, 1 H), 5.01 (d, J = 16.8 Hz, 1 H), 4.95 (d, J =
10.4 Hz, 1 H), 3.80 (s, 1.11 H), 3.68 (s, 1.89 H), 3.01 (t, J =
7.6 Hz, 1.26 H), 2.84 (t, J = 7.6 Hz, 0.74 H), 2.51 (m, 1 H),
2.43 (s, 3 H), 2.05 (m, 2 H), 1.68 (m, 1.26 H), 1.59 (m, 0.74
H), 1.36–1.44 (m, 4 H), 1.10 (d, J = 6.4 Hz, 2.22 H), 0.96 (d,
J = 6.4 Hz, 3.78 H). 13C NMR (100 MHz, CDCl3): d = 182.5,
180.5, 166.3, 165.5, 157.5, 154.7, 148.3, 145.0, 144.9,
144.8, 138.8, 136.8, 136.3, 135.8, 134.8, 133.9, 131.3,
129.7, 129.5, 125.7, 122.3, 114.5, 114.4, 111.1, 110.9, 52.2,
52.1, 33.6, 29.5, 29.2, 28.9, 28.9, 28.7, 28.6, 28.3, 22.0, 21.8,
21.7. MS (ESI): m/z (%) = 494 (100) [M + Na]+, 472 (10) [M
+ H]+. HRMS-ESI: m/z [M + Na]+ calcd for C26H33NNaO5S:
494.1977; found: 494.1986.
(11) IR (neat): 1743, 1704, 1639, 1597, 1483, 1440, 1380, 1366,
1229, 1192, 1182, 1133, 1087, 1027, 970 cm–1. 1H NMR
(400 MHz, CDCl3): d = 8.01 (d, J = 8.4 Hz, 2 H), 7.31 (d,
J = 8.4 Hz, 2 H), 6.08 (s, 1 H), 5.82 (ddt, J = 17.2, 10.4, 6.8
Hz, 1 H), 5.03 (dd, J = 17.2, 1.6 Hz, 1 H), 4.97 (d, J = 10.4
Hz, 1 H), 3.77 (s, 3 H), 3.57 (d, J = 3.2 Hz, 1 H), 3.26 (dd,
J = 5.8, 3.2 Hz, 1 H), 2.99 (m, 2 H), 2.42 (s, 3 H), 2.08 (m, 2
H), 1.92 (m, 1 H), 1.69–1.72 (m, 2 H), 1.44–1.46 (m, 4 H),
0.94 (d, J = 6.6 Hz, 3 H), 0.89 (d, J = 6.6 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): d = 180.7, 170.3, 159.3, 152.2, 145.5,
138.8, 135.8, 132.5, 130.0, 127.8, 114.5, 109.0, 61.8, 52.6,
44.4, 33.6, 31.2, 28.8, 28.7, 28.6, 28.5, 21.7, 19.8, 19.7. MS
(ESI): m/z (%) = 494 (100) [M + Na]+, 472 (75) [M + H]+.
HRMS-ESI: m/z [M + Na]+ calcd for C26H33NNaO5S:
494.1977; found: 494.1980.
(12) (a) Schuster, M.; Blechert, S. Angew. Chem. Int. Ed. 1997,
36, 2036. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2001, 34, 18. (c) Connon, S. J.; Blechert, S. Angew. Chem.
Int. Ed. 2003, 42, 1900. (d) Schrock, R. R.; Hoveyda, A. H.
Angew. Chem. Int. Ed. 2003, 42, 4592. (e) Chatterjee, A.
K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem.
Soc. 2003, 125, 11360. (f) Hoveyda, A. H.; Zhugralin, A. R.
Nature (London) 2007, 450, 243.
(13) IR (neat): 1736, 1702, 1597, 1483, 1438, 1380, 1321, 1229,
1181, 1134, 1089, 1026 cm–1. 1H NMR (400 MHz, CDCl3):
d = 8.01 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 2 H), 6.08
(s, 1 H), 5.57–5.83 (m, 2 H), 4.65 (d, J = 6.6 Hz, 0.28 H),
4.54 (d, J = 6.6 Hz, 1.72 H), 3.78 (s, 3 H), 3.58 (d, J = 3.0
Hz, 1 H), 3.26 (dd, J = 6.0, 3.0 Hz, 1 H), 2.99 (m, 2 H), 2.43
(s, 3 H), 2.09 (m, 5 H), 1.92 (m, 1 H), 1.72 (m, 2 H), 1.46 (m,
4 H), 0.94 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 180.7, 170.9, 170.3, 159.4,
152.1, 145.5, 136.1, 135.7, 132.5, 129.9, 127.7, 124.0,
109.1, 65.2, 61.7, 52.6, 44.4, 32.0, 31.2, 28.8, 28.8, 28.6,
28.5, 21.7, 21.0, 19.8, 19.6. MS (ESI): m/z (%) = 566 (100)
[M + Na]+, 552 (12), 544 (10) [M + H]+. HRMS-ESI: m/z
[M + Na]+ calcd for C29H37NNaO7S: 566.2188; found:
566.2201.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
C. Song is grateful to the National Natural Science Foundation of
China (Young Scholarship, #20902085) for financial support.
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