Convergent formal synthesis of (±)-roseophilin

Article abstract of DOI:10.1021/jo201949x

A facile convergent synthesis of the tricyclic core 2 of roseophilin is described, which represents the shortest route so far for the formal synthesis of roseophilin. The key step was a tandem pyrrole acylation-Nazarov cyclization reaction to form the cyclopenta[b]pyrrole moiety 4.

Full text of DOI:10.1021/jo201949x

Note
pubs.acs.org/joc
Convergent Formal Synthesis of ( )-Roseophilin
Chuanjun Song,* Hui Liu, Meiling Hong, Yuanyuan Liu, Feifei Jia, Li Sun, Zhenliang Pan,
and Junbiao Chang*
Department of Chemistry, Zhengzhou University, 100 Science Avenue, Zhengzhou, Henan Province 450001, PR China
S
* Supporting Information
ABSTRACT: A facile convergent synthesis of the tricyclic
core 2 of roseophilin is described, which represents the
shortest route so far for the formal synthesis of roseophilin.
The key step was a tandem pyrrole acylation-Nazarov
cyclization reaction to form the cyclopenta[b]pyrrole moiety 4.
retrosynthetic analysis is shown in Scheme 1. A late-stage
intramolecular Tsuji−Trost reaction of 3 would eventually
close the 13-membered ring.
As shown in Scheme 2, 2-methoxycarbonyl-4-methylpente-
noic acid 5 was obtained in 92% overall yield as a mixture of Z/
E isomers in 3:2 ratio via Knoevenagel condensation19 between
tert-butyl methyl malonate and isobutyraldehyde, followed by
removal of the tert-butyl group with TFA.
oseophilin (1, Scheme 1), isolated from the culture broth
of Streptomyces griseoviridis by Seto et al. in 1992,1 has
R
Scheme 1. Retrosynthetic Analysis of Roseophilin
On the other hand, regioselective acylation of N-tosylpyrrole
with 6-heptenoic acid20 in the presence of TFAA delivered
acylpyrrole 8 in 56% isolated yield (Scheme 3).21 Reduction of
the carbonyl group in 8 with borane-t-butylamine complex in
the presence of aluminum trichloride22 gave 2-(6′-heptenyl)-
pyrrole 6. Longer reaction times or use of excess of the borane
complex resulted in the double bond being destroyed. After
some experiments, it was found that the optimized reaction
condition was to treat acylpyrrole 8 with 1.5 equiv of the
borane complex and 1 equiv of aluminum trichloride for 15 min
at 0 °C, which resulted in the formation of pyrrole 6 in 66%
isolated yield. With 5 and 6 in hand, we then attempted the key
tandem pyrrole acylation−Nazarov cyclization reaction. When
6 was subjected to 5 and TFAA, the reaction proceeded very
slowly and gave a variety of products. The desired cyclopenta-
[b]pyrrole derivative 4 could only be isolated in low yield after
prolonged reflux in DCE. Presumably, the inefficiency of the
acylation and subsequent Nazarov cyclization reaction was due
to the electron-withdrawing as well as the cation-destabilizing
nature of the methoxycarbonyl group at C-2 of 5.21,23,15 That
both pyrrole acylation and Nazarov cyclization reactions could
be catalyzed by Lewis acids promoted us to investigate their
effect in our tandem reaction. However, when Ti(OiPr)4 or
AlCl3 was used, little improvement was observed. Use of
Sc(OTf)3, which was found by Frontier to be the most reactive
catalyst for the Nazarov cyclization of pyrrolyl vinyl
ketones,24,16 resulted in hydration of the double bond. To
our delight, when FeCl3 was applied, the tandem pyrrole
acylation−Nazarov cyclization reaction proceeded smoothly
stimulated the synthetic effort of several research groups2−17
because of its highly promising antitumor property and
topologically interesting ansa-bridged azafulvene macrocyclic
core structural unit. Remarkably, Boger’s work indicated that
the unnatural enantiomer of roseophilin exhibits 2−10-fold
higher cytotoxicity than the naturally occurring enantiomer.11
There are three reported total syntheses of roseophilin to
date. Since Furstner reported the first total synthesis of racemic
̈
roseophilin,2,6 Boger11 and Tius12 have described the
asymmetric synthesis of ent-(−)-roseophilin and the natural
enantiomer, respectively. Formal synthesis of roseophi-
lin3−5,7−10,13−16 largely focused on the development of new
methodologies toward the construction of the macrotricyclic
core 2. Recently, Bitar and Frontier described a scandium(III)
triflate-catalyzed Nazarov cyclization reaction of pyrrolyl vinyl
ketone derivative to form the cyclopenta[b]pyrrole moiety as a
key step in their synthesis of 2.16,18 However, this otherwise
valuable approach required 17 steps to prepare the precursor
required for Nazarov cyclization. Herein, we report our strategy
to the synthesis of 2 featuring a tandem pyrrole acylation−
Nazarov cyclization reaction15 as the key step to form the
cyclopenta[b]pyrrole moiety (i.e., 5 + 6 → 4), and the
Received: September 21, 2011
Published: November 18, 2011
© 2011 American Chemical Society
704
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The Journal of Organic Chemistry
Note
Scheme 2. Synthesis of Compound 5
a
and 1.6 Hz), 4.91 (1H, d, J = 10.4 Hz), 2.66 (2H, t, J = 7.2 Hz), 2.37
(3H, s), 2.00 (2H, q, J = 7.2 Hz), 1.60 (2H, quint, J = 7.2 Hz), and
1.34 (2H, quint, J = 7.2 Hz); δC (100 MHz, CDCl3) 188.2, 144.7,
138.4, 135.9, 133.3, 130.0, 129.3, 128.3, 123.4, 114.6, 110.3, 39.2, 33.5,
28.3, 24.3, and 21.6; m/z (ESI) 354 ([M + Na]+, 100%) and 332 ([M
+ H]+, 10) [found [M + Na]+ 354.1160, C18H21NNaO3S requires
354.1140].
Scheme 3.
2-(6′-Heptenyl)-N-tosylpyrrole 6. A mixture of borane-tert-
butylamine complex (1.0 g, 11.76 mmol) and aluminum trichloride
(1.0 g, 7.84 mmol) in dry DCM (100 mL) was stirred at rt for 30 min
before being cooled to 0 °C. A solution of 2-(6′-heptenoyl)-N-
tosylpyrrole 8 (2.6 g, 7.84 mmol) dissolved in 80 mL of dry DCM was
added dropwise over 10 min. After addition, the resulting mixture was
stirred for a further 5 min and then quenched with ice water. The
separated aqueous phase was extracted with DCM (50 mL). The
combined organic phase was dried (Na2SO4), filtered, and evaporated.
The residue was purified by column chromatography on silica gel (5%
ethyl acetate in petroleum ether) to give pyrrole 6 (1.7 g, 66%) as a
colorless oil: νmax/cm−1 1597, 1367, 1175, and 1154; δH (400 MHz,
CDCl3) 7.66 (2H, d, J = 8.4 Hz), 7.31−7.29 (3H, m), 6.22 (1H, t, J =
3.4 Hz), 6.02 (1H, m), 5.82 (1H, ddt, J = 17.0, 10.0, and 6.8 Hz), 5.02
(1H, dd, J = 17.0 and 1.4 Hz), 4.97 (1H, d, J = 10.0 Hz), 2.69 (2H, t, J
= 7.6 Hz), 2.41 (3H, s), 2.05 (2H, q, J = 6.8 Hz), 1.58 (2H, quint, J =
7.4 Hz), and 1.43−1.34 (4H, m); δC (100 MHz, CDCl3) 144.8, 138.9,
136.6, 135.9, 130.0, 126.7, 122.2, 114.4, 111.8, 111.3, 33.7, 28.8, 28.7,
28.5, 27.1, and 21.6; m/z (ESI) 340 ([M + Na]+, 100%) [found [M +
Na]+ 340.1338, C18H23NNaO2S requires 340.1347].
trans-2-(6′-Heptenyl)-4-isopropyl-5-methoxycarbonyl-1-
tosylcyclopenta[b]pyrrol-6-one 4. To a solution of heptenylpyr-
role 6 (214 mg, 0.67 mmol), 2-methoxycarbonyl-4-methylpentenoic
acid 5 (230 mg, 1.35 mmol), and TFAA (0.3 mL) in dry DCE (30
mL) was added ferric trichloride (33 mg, 0.20 mmol). The resulting
mixture was heated to reflux for 10 h and then cooled to rt. The bulk
of solvent was evaporated in vacuo. The residue was partitioned
between ethyl acetate (50 mL) and water (50 mL). The separated
organic phase was dried (Na2SO4), filtered, and evaporated. The
residue was purified by column chromatography on silica gel (15%
ethyl acetate in petroleum ether) to give the title compound 4 (237
mg, 75%) as an orange oil: νmax/cm−1 1743, 1704, 1440, 1380, 1366,
and 1229; δH (400 MHz, CDCl3) 8.01 (2H, d, J = 8.4 Hz), 7.31 (2H,
d, J = 8.4 Hz), 6.08 (1H, s), 5.82 (1H, ddt, J = 17.2, 10.4, and 6.8 Hz),
5.03 (1H, dd, J = 17.2 and 1.6 Hz), 4.97 (1H, d, J = 10.4 Hz), 3.77
(3H, s), 3.57 (1H, d, J = 3.2 Hz), 3.26 (1H, dd, J = 5.8 and 3.2 Hz),
3.06−2.92 (2H, m), 2.42 (3H, s), 2.10−2.06 (2H, m), 1.92 (1H, m),
1.72−1.69 (2H, m), 1.46−1.44 (4H, m), 0.94 (3H, d, J = 6.6 Hz), and
0.89 (3H, d, J = 6.6 Hz); δC (100 MHz, CDCl3) 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, 28.8, 28.7, 28.6, 21.7, 19.8, and 19.7; m/z (ESI)
494 ([M + Na]+, 100%) and 472 ([M + H]+, 75) [found [M + Na]+
494.1980, C26H33NNaO5S requires 494.1977].
a
Reagents and conditions: (a) 6-heptenoic acid, TFAA, DCE, 80 °C,
24 h, 56%; (b) BH3·t-BuNH2, AlCl3, DCM, 0 °C, 15 min, 66%; (c) 5,
TFAA, FeCl3, DCE, 80 °C, 10 h, 75%; (d) allyl acetate, Grubbs 2nd
generation catalyst, DCM, 40 °C, 24 h, 79%; (e) NaH, Pd(OAc)2,
dppe, THF, reflux, 24 h, 38%.
and resulted in the formation of 4 in 75% isolated yield, solely
as the trans isomer. The stereochemical assignment was made
on the basis of NOE correlations of Ha with the methine as well
as the methyl protons of the isopropyl group. Next, cross olefin
metathesis reaction25 of 4 with allyl acetate gave 3 in 79%
isolated yield as a mixture of E/Z isomers in a ratio of 6.4:1.
Finally, a palladium-catalyzed intramolecular Tsuji−Trost
reaction26,27 delivered 9 in moderate yield, which could be
converted into 2 following known literature procedures by
hydrogenation of the double bond, detosylation, and Krapcho
dealkoxycarbonylation reaction.16
In summary, we have developed an eight-step synthesis of
the macrotricyclic core 2 of roseophilin starting from acylation
of N-tosylpyrrole with 6-heptenoic acid and TFAA. This
approach represents the shortest route so far for the formal
total synthesis of ( )-roseophilin. Future work will focus on
development of an asymmetric version of the tandem pyrrole
acylation−Nazarov cyclization reaction.
EXPERIMENTAL SECTION
■
Solvents were dried according to standard procedures where needed.
IR spectra were obtained using an IFS25 FT-IR spectrometer. H and
1
13C NMR spectra were obtained on a Bruker AV400 instrument. Mass
spectra were recorded on a Micromass Q-TOF mass spectrometer.
2-(6′-Heptenoyl)-N-tosylpyrrole 8. To a solution of N-
tosylpyrrole (5.0 g, 22.6 mmol) in DCE (50 mL) were added 6-
heptenoic acid (8.0 g, 62.4 mmol) and TFAA (14.2 mL). The resulting
mixture was refluxed for 24 h and cooled. Water was added carefully
until no bubbling was observed. The mixture was washed successively
with water (50 mL), saturated aqueous sodium bicarbonate (50 mL),
and brine (50 mL). The separated organic phase was dried (Na2SO4),
filtered, and evaporated. The residue was purified by column
chromatography on silica gel (10% ethyl acetate in petroleum ether)
to give acylpyrrole 8 (4.2 g, 56%) as a colorless oil: νmax/cm−1 1677,
1640, 1596, 1440, 1401, 1367, 1174, and 1145; δH (400 MHz, CDCl3)
7.88 (2H, d, J = 8.2 Hz), 7.78 (1H, dd, J = 2.8 and 1.6 Hz), 7.28 (2H,
d, J = 8.2 Hz), 7.03 (1H, dd, J = 3.6 and 1.6 Hz), 6.31 (1H, t, J = 3.2
Hz), 5.74 (1H, ddt, J = 17.2, 10.4, and 7.2 Hz), 4.96 (1H, dd, J = 17.2
trans-2-(8′-Acetoxy-6′-octenyl)-4-isopropyl-5-methoxycar-
bonyl-1-tosylcyclopenta[b]pyrrol-6-one 3. A mixture of 4 (110
mg, 0.23 mmol), allyl acetate (233 mg, 2.33 mmol), and Grubbs
second generation catalyst (20 mg, 0.02 mmol) in DCM (250 mL)
under nitrogen was refluxed for 24 h and cooled. The bulk of DCM
was removed in vacuo. The residue was purified by column
chromatography on silica gel (15% ethyl acetate in petroleum ether)
to give the title compound 3 (99 mg, 79%) as an orange oil: νmax/cm−1
1736, 1702, 1597, 1483, 1438, 1380, 1321, 1229, 1181, 1134, 1089,
and 1026; δH (400 MHz, CDCl3) 8.01 (2H, d, J = 8.4 Hz), 7.32 (2H,
d, J = 8.4 Hz), 6.08 (1H, s), 5.83−5.57 (2H, m), 4.65 (0.28H, d, J =
705
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The Journal of Organic Chemistry
Note
6.6 Hz), 4.54 (1.72H, d, J = 6.6 Hz), 3.78 (3H, s), 3.58 (1H, d, J = 3.0
Hz), 3.26 (1H, dd, J = 6.0 and 3.0 Hz), 3.06−2.92 (2H, m), 2.43 (3H,
s), 2.09 (5H, m), 1.92 (1H, m), 1.72 (2H, m), 1.46 (4H, m), 0.94 (3H,
d, J = 6.8 Hz), and 0.90 (3H, d, J = 6.8 Hz); m/z (ESI) 566 ([M +
Na]+, 100%), 552 (12) and 544 ([M + H]+, 10) [found [M + Na]+
566.2201, C29H37NNaO7S requires 566.2188].
(8) Bamford, S. J.; Luker, T.; Speckamp, W. N.; Hiemstra, H. Org.
Lett. 2000, 2, 1157−1160.
(9) Trost, B. M.; Doherty, G. A. J. Am. Chem. Soc. 2000, 122, 3801−
3810.
(10) Robertson, J.; Hatley, R. J. D.; Watkin, D. J. J. Chem. Soc., Perkin
Trans. 1 2000, 3389−3396.
Synthesis of Macrocycle 9. To a solution of 3 (529 mg, 0.97
mmol) in dry THF (10 mL) was added sodium hydride (60% w/w
dispersion in mineral oil; 50 mg, 1.17 mmol). The resulting mixture
(solution A) was stirred at ambient temperature for 0.5 h. A separate
flask was charged with palladium acetate (44 mg, 0.19 mmol), dppe
(194 mg, 0.49 mmol), and dry THF (30 mL). The mixture was heated
to reflux. Solution A was added dropwise over a period of 1 h. After
addition, the reaction was allowed to reflux for 23 h and then cooled
and quenched with water (60 mL). The separated aqueous phase was
extracted with ethyl acetate (60 mL). The combined organic extracts
were dried (MgSO4), filtered, and evaporated in vacuo. The residue
was dissolved in DCM (20 mL), which was added dropwise to a
solution of dimethyl maleate (100 mg) and aluminum trichloride (10
mg) in DCM (10 mL). The resulting mixture was stirred at ambient
temperature for 6 h. Water (20 mL) was added. The separated organic
phase was dried (MgSO4), filtered, and evaporated in vacuo. The
residue was purified by column chromatography on silica gel (15%
ethyl acetate in petroleum ether) to give macrocycle 9 (178 mg, 38%)
as an orange oil: νmax/cm−1 1736, 1701, 1640, 1597, 1484, 1433, 1386,
1214, 1192, and 1182; δH (400 MHz, CDCl3) 8.07 (2H, d, J = 8.0 Hz),
7.30 (2H, d, J = 8.0 Hz), 5.98 (1H, s), 5.21 (1H, dt, J = 15.6 and 6.4
Hz), 4.75 (1H, dt, J = 15.6 and 7.6 Hz), 3.77 (3H, s), 3.40 (1H, dt, J =
14.4 and 5.2 Hz), 2.76 (1H, d, J = 4.4 Hz), 2.75−2.57 (3H, m), 2.41
(3H, s), 1.99 (3H, m), 1.57 (1H, m), 1.07 (1H, m), 0.97 (3H, d, J =
6.8 Hz), 0.83 (2H, m), 0.64 (2H, m), and 0.57 (3H, d, J = 6.8 Hz); δC
(100 MHz, CDCl3) 185.5, 172.1, 158.2, 152.2, 145.7, 136.5, 136.3,
134.2, 130.0, 128.4, 124.3, 115.1, 70.2, 52.4, 51.0, 41.3, 30.7, 29.2, 28.9,
28.2, 27.7, 24.6, 23.1, 22.0, and 19.5; m/z (ESI) 506 ([M + Na]+,
100%) and 484 ([M + H]+, 40) [found [M + Na]+ 506.1979,
C27H33NNaO5S requires 506.1977].
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for compounds 3, 4, 6, 8, and 9. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chjsong@zzu.edu.cn (C.S.); changjunbiao@zzu.edu.cn
(J.C.).
■
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Young Scholarship to C.S., #20902085; Outstanding
Young Scholarship to J.C., #30825043) for financial support.
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