Development of novel pyrrole synthesis for the preparation of intermediates of bioactive pyrrole alkaloids

Article abstract of DOI:10.1016/j.tetlet.2009.06.012

We have developed a novel method for the synthesis of 3,4-diarylpyrrole-2,5-dicarboxylates via α-diazo esters, which are easily obtained from phenylalanine derivatives. Utilizing this method, intermediates of bioactive compounds having the structure of 3,

Full text of DOI:10.1016/j.tetlet.2009.06.012

Tetrahedron Letters 50 (2009) 4762–4765
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Development of novel pyrrole synthesis for the preparation
of intermediates of bioactive pyrrole alkaloids
*
Eiko Yasui, Masao Wada, Norio Takamura
Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a novel method for the synthesis of 3,4-diarylpyrrole-2,5-dicarboxylates via a-diazo
Received 1 May 2009
Revised 3 June 2009
Accepted 5 June 2009
Available online 7 June 2009
esters, which are easily obtained from phenylalanine derivatives. Utilizing this method, intermediates of
bioactive compounds having the structure of 3,4-diarylpyrrole-2,5-dicarboxylates were synthesized.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
3,4-Diarylpyrrole-2,5-dicarboxylates,
Piloty-Robinson pyrrole synthesis
a-Diazo ester
Hydrazone
Polycitone
Storniamide
O
In our series of investigations on the reactivity and the utility of
-diazo esters 1, which are easily available from corresponding a-
a
CO2R'
NH2
R
O
R
amino acid esters1,2, we found that the terminal nitrogen of 1 was
readily attacked by nucleophiles, such as aryllithiums, hydride re-
agents, and phosphines. The addition of aryllithiums to 1 gave aryl
hydrazones 2, the precursor for the Fisher indole synthesis.2 Aryl
hydrazones 2 were converted into indoles 3 under acidic condi-
tions in good yields. Hydride reagents also reacted with 1 to yield
hydrazones 4.3 Hydrazones 4 in turn could yield 1,3,4-oxadiazin-6-
ones 5, the substrate for the Diels–Alder reaction. The terminal
nitrogen of 1 also reacted with phosphines to give aza-ylides 6 that
were easily hydrolyzed to furnish 4 (Fig. 1). In this Letter, we report
a novel method for the synthesis of 3,4-diarylpyrrole-2,5-dicarbox-
ylates 7 via 4 that were easily obtained from phenylalanine
derivatives.
N
N
5
R''
Ref. 1)
AcOH,
ONO
CO2R'
CO2R'
CO2R'
H
ArLi
R
R
R
R
N
N2
N
Ref. 3)
4
2
1
H2N
ArHN
Ref. 2)
P(n-Bu)3
H
H
H2O
CO2R'
R
R
R
N
N
N
H
CO2R'
P(n-Bu)3
6
R'O2C
CO2R'
N
3
H
Several 3,4-diarylpyrrole-2,5-dicarboxylates are known for
their unique biological activities. For example, polycitone A (8) is
a natural product that inhibits the activity of retroviral reverse
transcriptases and cellular DNA polymerases.4 Storniamide A (10)
and permethyl storniamide A (11) have multidrug resistance
(MDR) reversal activity5 (Fig. 2). The synthesis of these compounds
has been performed by some groups.6–10 The Piloty–Robinson pyr-
7
Figure 1.
role synthesis is a conventional method for the synthesis of pyr-
roles under vigorous reaction conditions.11 The condensation of
two carbonyl compounds and hydrazine gives azine 12. It is con-
sidered that the isomerization of 12 and its subsequent cyclization
furnish pyrrole 7 (Fig. 3). We speculated that hydrazones 4 ob-
* Corresponding author. Tel./fax: +81 424 68 9278.
tained by our methodology from a-diazo esters 1 could be precur-
E-mail address: noritaka@musashino-u.ac.jp (N. Takamura).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.012

E. Yasui et al. / Tetrahedron Letters 50 (2009) 4762–4765
4763
Br
Br
OH
Br
HO
OR OR
RO RO
Br
OR
RO
Br
Br
Br
Br
H
N
H
N
OH
HO
N
N
R
O
O
O
O
OR
RO
R = CH2CH2C6H4OH: Polycitone A (8)
R = H: Polycitone B (9)
R = H: Storniamide A (10)
R = Me: Permethyl Storniamide A (11)
OR
Figure 2.
Table 1
Piloty-Robinson pyrrole synthesis
R1
R1
R2
R1
R2
R1
R2
R1
R2
R2
2 x
Ar
Ar
CO2R
SOCl2, ROH
O
Ar
N
N
H
7
N
N
90 ºC
RO2C
CO2R
N
H
7
H2N
NH2NH2
(in a sealed tube)
12
4
Entry
1
Ar
Ph
R
Yield (%)
L-Selectride®
CO2R'
CO2R'
R
R
(4a)
Et
94 (7a)
or
N2
N
P(n-Bu)3; H2O
H2N
2
3
(4b)
(4c)
Me
Me
79 (7b)
79 (7c)
1
4
HO
Figure 3.
MeO
MeO
sors for the synthesis of azine 12. Thus, first, we exposed (E)-hydra-
zone 4a prepared from -diazo ester 1a derived from ethyl phe-
a
nylalaninate to acidic conditions (heating in a sealed tube with
10 mol equiv of thionyl chloride in ethanol at 90 °C for 45 min)
to give azine 12a. However, the reaction proceeded quickly and
pyrrole 7a was obtained in 94% yield instead of azine 12a (Scheme
1).12 (Z)-Hydrazone 4a0 or a mixture of both stereoisomers also
gave pyrrole 7a in good yield under the same reaction conditions.
As pyrrole 7a was obtained in good yield, we examined other
substrates (Table 1). Hydrazones 4b–e derived from tyrosine deriv-
atives gave pyrroles 7b–e (entries 2–5). Protection of the hydroxyl
group was not necessary for a series of reactions (diazotization,
reduction, and cyclization). Although hydrazone 4f derived from
4-chloro phenylalanine gave pyrrole 7f in good yield, 4g derived
from 4-nitro phenylalanine failed to produce a pyrrole. Hydrazones
containing 5-membered heteroaromatic compounds 4h and 4i
were prepared from corresponding amino acid esters13 and sub-
jected to cyclization. Unfortunately, no pyrroles could be obtained
from these compounds.
4
(4d)
Me
66 (7d)
MeO
MeO
5
6
7
8
9
(4e)
(4f)
(4g)
(4h)
(4i)
Et
74 (7e)
BnO
Cl
Me
Me
Me
Me
80 (7f)
0
0
0
O2N
Bn
N
N
Then, we examined the synthesis of intermediates that can
lead to bioactive compounds 8, 9, and 11 (Scheme 2). 4-Methoxy
S
Ph
Ph
CO2Et
N
EtO2C
N
CO2Et
CO2Et
12a
i)
ii)
N2
1a
N
H2N
4a
Ph
EtO2C
Ph
CO2Et
CO2Et
94%
ii)
Ph
H2N
CO2Et
NH2
N
ii)
90%
N
H
7a
93%
N
4a'
4a + 4a'
Scheme 1. Reagents and conditions: (i) P(n-Bu)3, IPE, 93%; and (ii) SOCl2, EtOH, 90 °C (in a sealed tube).

4764
E. Yasui et al. / Tetrahedron Letters 50 (2009) 4762–4765
MeO
OMe
CO2Me
CO2Me
NH2
i) 93%
iii) 79%
known
known
8, 9
N
N
ii) 82%
iv) 100%
MeO
H2N
MeO
HO2C
CO2H
N
H
4c
13c
MeO MeO OMe OMe
MeO
OMe
MeO
MeO
CO2Me
iii) 66%
MeO
MeO
CO2Me
NH2
i) 92%
11
v) 89%
H2N
MeO2C
CO2Me
N
H
7d
MeO
MeO
4d
Scheme 2. Reagents and conditions: (i) isoamyl nitrite, AcOH, CHCl3, 70 °C; (ii) P(n-Bu)3, IPE; (iii) SOCl2, EtOH, 90 °C (in a sealed tube); (iv) aq KOH, MeOH; and (v) L-
selectrideÒ, THF.
Table 2
To clarify the mechanism of this reaction, several acidic con-
ditions were next examined using hydrazone 4a (Table 2). We
conjectured that anhydrous hydrogen chloride generated from
Ph
Ph
thionyl chloride and alcohol would work as a proton source to
promote the reaction. At this stage, the reaction mechanism
can be represented as depicted in Figure 4. Two molecules of
hydrazone 4a were condensed with the loss of hydrazine salt
to yield symmetric azine 12a. Azine 12a was isomerized with
the aid of acid, and 3,3-sigmatropic rearrangement led to cycli-
zation immediately under heating with the loss of ammonium
salt. When the cyclization was accomplished in THF with thionyl
chloride, no pyrrole was obtained at all because no hydrogen
chloride was produced. Furthermore, the combination of
acetyl chloride and ethanol also gave pyrrole 7a in good yield.
Although hydrogen chloride seemed to be an essential factor,
aqueous hydrochloric acid hardly promoted the reaction (entries
7 and 8). Also, sulfuric acid and phosphoric acid were not suit-
able (entries 9 and 10). Acetic acid promoted only the isomeriza-
tion of the hydrazone 4a to give 4a0 in 19% yield, and 67% of the
starting material was recovered. Hydrobromide in acetic acid
produced a small amount of pyrrole 7a. Thus, the combination
of thionyl chloride and alcohol is the best condition. Although
the yield scarcely decreased when the amount of thionyl chlo-
ride was reduced to 5 mol equiv (91%), use of 2.5 mol equiv of
thionyl chloride severely lowered the yield (63%). Further studies
aimed at developing a novel method for the synthesis of pyrroles
CO2Et
conditions
N
EtO2C
CO2Et
N
H
7a
H2N
4a
Entry
Conditions
Yield (%)
1
2
3
4
5
6
7
8
9
SOCl2 (ꢀ10), EtOH
SOCl2 (ꢀ5), EtOH
SOCl2 (ꢀ2.5), EtOH
SOCl2, THF
AcCl, EtOH
AcOH
0.5 M aq HCl, EtOH
36% aq HCl, EtOH
98% H2SO4, EtOH
85% H3PO4, EtOH
46% HBr, EtOH
TFA, CH2Cl2
94
91
63
0
84
0a
3
8
12
0b
8c
26
10
11
12
a
(Z)-Hydrazone was isolated in 19% yield. Starting material was recovered in 67%
yield.
b
c
Starting material was recovered in 31% yield.
Starting material was recovered in 5% yield.
tyrosine was esterified with methanol and subjected to diazotiza-
tion. The resulting diazo ester was reduced to hydrazone 4c, and
4c was heated in a sealed tube under acidic conditions to give pyr-
role 7c in good yield. Hydrolysis of 7c gave corresponding carbox-
ylic acid 13c,14 the synthetic intermediate of 8 and 9.7c The same
conversions were applied to 3,4,5-trimethoxy tyrosine obtained
by known procedures15 to yield pyrrole 7d,16 the intermediate of
11.6
from other
esters are in progress.
In conclusion, we have developed a novel method for the syn-
thesis of 3,4-diarylpyrrole-2,5-dicarboxylates via -diazo esters
a-diazo esters derived from a variety of a-amino acid
a
that are easily obtained from phenylalanine derivatives. Our meth-
od is milder than the Piloty–Robinson pyrrole synthesis, and pyr-
roles are obtained in good yields.
4a
CO2Et
Ph
Ph
Ph
H2N
CO2Et
CO2Et
Ph
Ph
Ph
CO2Et
NH
Ph
EtO2C
Ph
CO2Et
Ph
CO2Et
NH
N
N
N
H2N
H
EtO2C
N
H
EtO2C
NH
N
N
H
7a
H3N NH3
Ph
CO2Et
12a
4a
Figure 4.

E. Yasui et al. / Tetrahedron Letters 50 (2009) 4762–4765
4765
10. (a) Iwao, M.; Takeuchi, T.; Fujikawa, N.; Fukuda, T.; Ishibashi, F. Tetrahedron
Lett. 2003, 44, 4443–4446; (b) Fukuda, T.; Hayashida, Y.; Iwao, M. Heterocycles
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Acknowledgments
This work was financially supported by MEXT. HAITEKU (2008)
and the Uehara Memorial Foundation (2008).
12. Typical experimental procedure for the synthesis of pyrrole 7a: Hydrazone 4a
(176.1 mg, 0.85 mmol) was dissolved in ethanol (2 mL) in a sealed tube. To this
solution, thionyl chloride (0.62 mL, 8.50 mmol) diluted in ethanol (3 mL) was
slowly added at 0 °C, and the mixture was stirred for 45 min at 90 °C. After
cooling to room temperature, the reaction mixture was slowly poured into
saturated NaHCO3 (30 mL) and extracted with ethyl acetate (10 mL) thrice. The
organic phase was dried over Na2SO4 and concentrated under reduced pressure.
Theresultingresiduewas purifiedbysilicagel column chromatography(hexane/
ethyl acetate = 3:1) to give 7a as colorless crystals (145.5 mg, 94%).
Recrystallization from ethyl acetate and hexane afforded colorless needles, mp
(151–151.8 °C). Data for 7a: 1H NMR (400 MHz, CDCl3) d 9.86 (br s, 1H), 7.21–
7.16 (m, 6H), 7.15–7.19 (m, 4H), 4.22 (q, 4H, J = 8.0 Hz), 1.17 (t, 6H, J = 8.0 Hz); 13C
NMR (100 MHz, CDCl3) d 160.55, 133.14, 131.46, 130.93, 127.34, 127.00, 121.64,
60.97, 14.09; IR (KBr) 3325, 1703, 1302, 1242 cmꢁ1; HRMS (EI) calcd for
C22H21NO4 (M+) 363.1471, found 363.1477.
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reported by Gupton et al.9b Data for 13c: mp 199–200.5 °C (DMSO) (lit.9b 200–
202 °C); 1H NMR (400 MHz, DMSO-d6) d 11.58 (br s, 1H), 6.92 (d, J = 8.0 Hz, 4H),
6.69 (d, J = 8.0 Hz, 4H), 3.68 (s, 6H); 13C NMR (100 MHz, DMSO-d6) d 162.01,
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128.19, 121.10, 108.50, 60.98, 56.15, 52.04; IR (KBr) 3276, 2942, 1702, 1239,
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