Organocatalytic enantioselective formal synthesis of bromopyrrole alkaloids via aza-Michael addition

Article abstract of DOI:10.1039/c1ob06078c

An unprecedented organocatalytic enantioselective formal synthesis of bromopyrrole alkaloid natural products is reported. An organocatalytic aza-Michael addition using pyrroles as the N-centered nucleophile is utilized as the enantioselective step to construct the nitrogen-substituted stereogenic carbon center in bromopyrrole alkaloids in good yield and excellent enantioselectivity. The aza-Michael product is converted via lactamization using a Staudinger-type reductive cyclization to the key intermediate, which was previously used in the total synthesis of bromopyrrole alkaloid natural products.

Full text of DOI:10.1039/c1ob06078c

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PAPER
Organocatalytic enantioselective formal synthesis of bromopyrrole alkaloids
via aza-Michael addition†
Su-Jeong Lee, Seok-Ho Youn and Chang-Woo Cho*
Received 4th July 2011, Accepted 22nd August 2011
DOI: 10.1039/c1ob06078c
An unprecedented organocatalytic enantioselective formal synthesis of bromopyrrole alkaloid natural
products is reported. An organocatalytic aza-Michael addition using pyrroles as the N-centered
nucleophile is utilized as the enantioselective step to construct the nitrogen-substituted stereogenic
carbon center in bromopyrrole alkaloids in good yield and excellent enantioselectivity. The aza-Michael
product is converted via lactamization using a Staudinger-type reductive cyclization to the key
intermediate, which was previously used in the total synthesis of bromopyrrole alkaloid natural
products.
a (+)-enantiomer from Agelas ceylonica, shows cytotoxic activity
Introduction
against P-388 lymphocytic leukemia cells.4 (-)-Cyclooroidin5 and
the agesamides as an epimeric mixture6 were isolated from the
Mediterranean sponge Agelas oroides and the Okinawan sponge
Agelas sp., respectively, but only limited biological investigations
were reported.
Bromopyrrole alkaloids, an important class of natural products
isolated from marine sponges, possess a variety of interesting
biological activities.1 The pyrrolopiperazinone moiety is one of the
key skeletons found in a great number of bromopyrrole alkaloids.
Examples of bromopyrrole alkaloids with the pyrrolopiperazinone
skeleton include hanishin, longamide B, longamide B methyl ester,
cyclooroidin and the agesamides (Fig. 1). Hanishin, isolated with
low enantiomeric purity from extracts of the highly polymorphic
sponge Acanthella carteri, displays cytotoxic activity against
NSCLC-N6 human non-small-cell-lung carcinoma.2 Longamide
B, isolated as a racemate from the Caribbean sponge Agelas dispar,
exhibits antibiotic activity against the Gram-positive bacteria
Bacillus subtilis and Staphilococcus aureus.3 Longamide B methyl
ester, isolated as a racemate from Homaxinella sp. and then as
Although their biological activities and chemical structures
possessing the relatively rare nitrogen-substituted stereogenic
carbon center are interesting, few asymmetric total syntheses
of the above bromopyrrole alkaloids have been reported.7 The
known asymmetric syntheses of the bromopyrrole alkaloids have
utilized Pd-catalyzed enantioselective annulation7c,e and chiral
pool strategies7a,b,d to construct the chiral pyrrolopiperazinone
skeleton. However, it is surprising that the use of organocat-
alytic synthetic routes remains unexplored in the asymmetric
synthesis of the bromopyrrole alkaloids. Recently, we reported
the enantio- and diastereoselective organocatalytic cascade aza-
Michael addition–aldol reactions of 2-trihaloacetylpyrroles as
the N-centered heteroaromatic nucleophiles to a,b-unsaturated
aldehydes to afford the highly functionalized chiral pyrrolizines
(Scheme 1).8 We deemed the aza-Michael addition process9,10 in
Fig. 1 Bromopyrrole alkaloids with the pyrrolopiperazinone skeleton.
Department of Chemistry, Kyungpook National University, Daegu, 702-
701, Republic of Korea. E-mail: cwcho@knu.ac.kr; Fax: +82-53-950-6330;
Tel: +82-53-950-5334
† Electronic supplementary information (ESI) available: Copies of 1H
NMR and 13C NMR spectra of compounds 3, 5–22. Chiral HPLC analysis
data for compounds 3, 5–15. See DOI: 10.1039/c1ob06078c
Scheme 1 Organocatalytic asymmetric cascade aza-Michael addition–al-
dol reactions of 2-trihaloacetylpyrroles to a,b-unsaturated aldehydes.
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Table 1 Optimization of enantioselective organocatalytic aza-Michael
additions of pyrroles 1 with protected (E)-4-hydroxybut-2-enals 2a
this cascade reaction applicable to the asymmetric synthesis of the
key intermediate of the bromopyrrole alkaloids.
Therefore, we report an organocatalytic asymmetric formal
synthesis of the bromopyrrole alkaloids via the enantioselective
aza-Michael additions of bromopyrroles as the N-centered het-
eroaromatic nucleophiles to a,b-unsaturated aldehydes bearing
protected hydroxymethyl substituents, followed by lactamization
using a Staudinger-type reductive cyclization to synthesize the
key intermediate previously used in the total synthesis of the
bromopyrrole alkaloids (Scheme 2).
Entry R1
R2
T/◦C
Product Yieldb (%) eec (%)
1
2
3
4
5
6
CN
CO2CH3 Bz
CN
CN
CN
CN
Bz
-20
-20
-20
3
4
5
6
6
6
70
76
n.r.d
78
TBS
80
87
91
93
TBDPS -20
TBDPS -30
TBDPS -40
77
76
76
Scheme 2 The synthetic strategy for the formal synthesis of the bromopy-
rrole alkaloids.
a Procedure: To a mixture of pyrrole 1 (100 mol%), catalyst (20 mol%)
and PhCO2H (40 mol%) in toluene (0.1 M) was added a,b-unsaturated
aldehyde 2 (200 mol%) in one portion. The reaction mixture was allowed
to stir at -20, -30 or -40 ◦C for 18 h, at which point the aldehyde was
directly reduced to the alcohol with NaBH4 (110 mol%) in EtOH (0.1 M).
b Isolated yield for two steps. c Determined by HPLC analysis on chiral
stationary phase (Chiralpak AD-H). d No reaction.
Results and discussion
Our synthetic plan to prepare the common key intermediate in the
total syntheses of the bromopyrrole alkaloids focused on efficiently
preparing enantiomerically pure aza-Michael product with the
defined absolute configuration via an organocatalytic enantios-
elective aza-Michael addition of pyrroles 1 to a,b-unsaturated
aldehydes 2, and constructing the pyrrolopiperazinone skeleton
via a lactamization of the aza-Michael product. We had previously
defined the favorable conditions for the aza-Michael addition step
during the stepwise optimization of the cascade reaction of 2,4-
dicyanopyrrole withcrotonaldehyde.8 Therefore, we undertookthe
further optimization of the organocatalytic enantioselective aza-
Michael additions of pyrroles 1 with a,b-unsaturated aldehydes 2
(Table 1).
The aza-Michael addition of 4,5-dibromo-1H-pyrrole-2-
carbonitrile (1a) to Bz-protected (E)-4-hydroxybut-2-enal 2a
using PhCO2H (40 mol%) as the acid additive in toluene
at -20 ◦C was performed in the presence of (S)-a,a-bis[3,5-
bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl
ether11 as the organocatalyst, providing the corresponding aza-
Michael product 3 in 70% yield and 76% enantiomeric excess (ee)
(Table 1, entry 1). All of the products in the addition reactions
were obtained after in situ reduction of the aza-Michael aldehyde
products into the alcohols using NaBH4 in ethanol. However,
in the case of methyl 4,5-dibromo-1H-pyrrole-2-carboxylate (1b),
the aza-Michael addition did not provide the desired product
4 under the same conditions (Table 1, entry 2). We speculated
that the benzoate anion from the acid additive PhCO2H was not
sufficiently basic to deprotonate pyrrole 1b based on the proposed
mechanism of the cascade reaction presented earlier by our group.8
Through variation of the protecting groups of (E)-4-hydroxybut-
2-enal in the aza-Michael additions with 1a, the TBDPS group
was identified as the ideal protecting group, affording a 77% yield
of 6 in 87% ee (Table 1, entries 3–4). Gratifyingly, by lowering the
reaction temperature to -40 ◦C, the ee of 6 increased to 93%, while
sustaining the yield at 76% (Table 1, entries 5–6).
Next, we examined the scope of pyrroles as nucleophiles in
the enantioselective organocatalytic aza-Michael additions of
TBDPS-protected (E)-4-hydroxybut-2-enal 2c under the opti-
mized conditions to explore the feasibility of making a variety
of biologically active pyrrolopiperazinone alkaloid derivatives. A
series of 2-cyanopyrroles bearing various substituents, such as 4-
cyano, 4-nitro and 4,5-dihalo, were examined (Figs 2 and 3). In
all cases, chiral aza-Michael products 7–15 were obtained in good
yields and excellent enantioselectivities. In particular, chemose-
lective reductions were developed using the corresponding aza-
Michael aldehyde products from 4-halo-5-iodo-1H-pyrrole-2-
carbonitriles as nucleophiles, depending on the reducing agents
(Fig. 3). NaBH4–reduction of the aza-Michael aldehyde products
from the pyrroles provided the alcohol products along with the
reduction of iodo group on the pyrrole moiety (Fig. 3, 10–
12). In contrast, BH3·SMe2–reduction of the same aza-Michael
aldehyde products afforded the alcohol products without any
reduction of the iodo group (Fig. 3, 13–15). The halo groups
on the pyrrole moiety in aza-Michael products 7, 10–15 can be
used for carbon–carbon coupling reactions to synthesize various
pyrrolopiperazinone alkaloid derivatives.12
Elaboration of the aza-Michael product 6 to the key intermedi-
ate 22 was achieved in seven steps (Scheme 3).
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Fig. 2 Enantioselective organocatalytic aza-Michael additions of TB-
DPS-protected (E)-4-hydroxybut-2-enal 2c with various 2-cyanopyrroles
1. See the experimental section for detailed procedures. Cited yields are
of isolated material for two steps. Enantiomeric excess was determined by
HPLC analysis on chiral stationary phase (Chiralpak AD-H).
Methylation of 6 with iodomethane in the presence of silver
oxide in acetonitrile at reflux provided the ether 16 in 98%
yield.13 The TBDPS group of 16 was removed by hydrogen
chloride in methanol to afford the alcohol 17 in 90% yield.
Subsequent tosylation of 17 with p-toluenesulfonyl chloride in
pyridine gave the tosylate 18 in 97% yield. The introduction of
an azide group into 18 using sodium azide in dimethyl sulfoxide
provided the azide 19 in 82% yield.14 The amide formation of 19
was carried out using sodium hydroxide and hydrogen peroxide
in methanol–dichloromethane to give the azide–amide 20 in
95% yield.15
To complete the formal synthesis of the bromopyrrole alkaloids,
a Staudinger reaction of 20 was performed with triphenylphos-
phine and water in tetrahydrofuran at reflux to provide the
corresponding amine product.16 However, surprisingly, rather than
providing the amine product, the reaction gave the pyrrolop-
iperazinone 21 as the direct conversion product in 84% yield
via a Staudinger-type reductive cyclization.17 To the best of our
knowledge, there has been no report on the direct lactamization
via the Staudinger-type reductive cyclization of azides and amides,
although the Staudinger ligation of azides and activated carboxy
acids, including esters, is well-known.18 Therefore, it was sup-
posed that the lactamization to construct the pyrrolopiperazinone
skeleton would be performed by a nucleophilic attack of the
iminophosphorane, generated by the reaction between the azide
group and triphenylphosphine, to the amide group followed by
hydrolysis, and/or a nucleophilic attack of the amine group
generated by the Staudinger reaction to the amide group.19 Finally,
demethylation of 21 using boron tribromide in dichloromethane
provided the key intermediate 22 (85% yield)7a that had been
previously used in the synthesis of the bromopyrrole alkaloids.
The spectroscopic and analytical data for 22 were in full agreement
Fig. 3 Enantioselective organocatalytic aza-Michael additions followed
by chemoselective reductions of TBDPS-protected (E)-4-hydroxybut-2-
enal 2c with 4-halo-5-iodo-1H-pyrrole-2-carbonitriles 1. See the experi-
mental section for detailed procedures. Cited yields are of isolated material
for two steps. Enantiomeric excess was determined by HPLC analysis on
chiral stationary phase (Chiralpak AD-H).
with reported values.7a,c,e The absolute stereochemistry at C(4)
in 22 was assigned by comparing the specific optical rotation
of 22 with that reported in the literature.7a,c,e The absolute
stereochemical assignment of all aza-Michael products is based
on the absolute stereochemistry of 6, which was determined to
be the S configuration on the basis of the absolute configuration
of 22. Thus our organocatalytic enantioselective formal synthesis
of the bromopyrrole alkaloids was accomplished from 1a in
eight linear steps (36% overall yield, 93% ee).20 The bromopy-
rrole alkaloids, such as hanishin, longamide B, longamide B
methyl ester, cyclooroidin and the agesamides, can be synthesized
from the intermediate 22 in a few steps according to known
procedures.7
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development of new aza-Michael additions and their application
to the synthesis of biologically active natural products.
Experimental
General
All reactions were run under an atmosphere of argon, unless
otherwise indicated. Toluene was distilled from calcium hydride.
Chemical reagents were purchased and used without further purifi-
cation, unless otherwise noted. Pyrroles 112a,21 and a,b-unsaturated
aldehydes 222 were prepared according to the previously reported
procedures. TLC analysis was carried out using silica gel plates
(Merck 60 F254). Flash column chromatography was carried out
on silica gel (230–400 mesh). Melting points were determined on
a Barnstead melting point apparatus in open capillaries and are
uncorrected. Infrared spectra were recorded on a Perkin-Elmer
spectrometer. 1H NMR spectra were recorded with a Bruker
(400 MHz) spectrometer. Chemical shifts are reported in d units.
Coupling constants are reported in Hz. 13C NMR spectra were
recorded with a Bruker (100 MHz) spectrometer. Chemical shifts
are reported in d units. 13C NMR spectra were routinely run with
broadband decoupling. Mass spectral data were obtained from
the Korea Basic Science Institute (Daegu) on a Jeol JMS 700 high
resolution mass spectrometer. HPLC analysis was performed on
an Agilent 1200 Series with UV detector using a chiral separation
column (Chiralpak AD-H).
Representative procedure for the organocatalytic enantioselective
aza-Michael additions
To a mixture of pyrrole 1 (100 mol%), organocatalyst (20 mol%)
and PhCO2H (40 mol%) in toluene (0.1 M) was added a,b-
unsaturated aldehyde 2 (200 mol%) in one portion. The reaction
mixture was allowed to stir at -20, -30 or -40 ◦C for 18 h, at
which point the aldehyde was directly reduced with either NaBH4
(110 mol%) in EtOH (0.1 M) or BH3·SMe2 (110 mol%) in THF
(0.1 M) to alcohol. After 30 min, the reaction was quenched
by saturated aqueous NaHCO3. The mixture was poured into
ethyl acetate and the layers were separated. The organic layer was
washed with saturated aqueous NaHCO3 and brine and dried over
MgSO4. The organic layer was filtered and evaporated. The crude
residue was purified by silica gel column chromatography.
Scheme 3 The formal synthesis of the key intermediate 22 from the
aza-Michael addition product 6.
Conclusion
We achieved the concise asymmetric formal synthesis of bro-
mopyrrole alkaloids via the organocatalytic enantioselective
aza-Michael addition followed by lactamization, from 4,5-
dibromo-1H-pyrrole-2-carbonitrile (1a) to the key intermedi-
ate 22 in eight steps. The aza-Michael addition of vari-
ously substituted 2-cyanopyrroles, including 1a, to TBDPS-
protected (E)-4-hydroxybut-2-enal 2c using (S)-a,a-bis[3,5-
bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl
ether as the organocatalyst and benzoic acid as the acid additive,
followed by chemoselective reduction provided the corresponding
aza-Michael products 6–15 in good yields and excellent enan-
tioselectivities. In addition, the lactamization of the amide group
and the azide group was directly carried out to construct the
pyrrolopiperazinone skeleton in good yield via a Staudinger-type
reductive cyclization. Furthermore, this is the first example of
the organocatalytic route for the asymmetric synthesis of the
bromopyrrole alkaloids. Future studies will be devoted to the
(2¢S)-4,5-dibromo-1-(1¢-benzoyloxy-4¢-hydroxybutan-2¢-yl)-1H-
pyrrole-2-carbonitrile (3)
Colorless oil (93 mg, 70%); [a]2D2 +4.0 (c 1, CH3OH) in the case of
76% ee (Table 1, entry 1); 1H NMR (400 MHz, CDCl3) d 7.92 (d,
J = 7.6 Hz, 2H), 7.58–7.55 (m, 1H), 7.44–7.40 (m, 2H), 6.99 (s, 1H),
5.33–5.22 (m, 1H), 4.81–4.67 (m, 2H), 3.83–3.77 (m, 1H), 3.50 (dt,
J = 10.8, 3.6 Hz, 1H), 2.57–2.45 (m, 1H), 2.34–2.23 (m, 1H), 1.73
(s, 1H); 13C NMR (100 MHz, CDCl3) d 165.8, 133.3, 129.5, 128.9,
128.4, 124.3, 113.7, 112.7, 102.6, 99.5, 65.2, 57.9, 57.2, 32.6; FTIR
(neat) 3487, 3125, 2956, 2221, 1722, 1415, 1314, 1270, 1118, 711
cm-1; HRMS (EI) calcd for [M]+ C16H14Br2N2O3 439.9371, found
439.9373; HPLC (Chiralpak AD-H, Hexane/IPA = 90/10, 0.9
mL min-1, l = 254 nm) 24.9 min (minor isomer), 27.2 min (major
isomer).
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(2¢S)-4,5-dibromo-1-[1¢-(tert-butyldimethylsilyloxy)-4¢-
hydroxybutan-2¢-yl]-1H-pyrrole-2-carbonitrile (5)
[M]+ C26H29N3O2Si 443.2029, found 443.2032; HPLC (Chiralpak
AD-H, Hexane/IPA = 90/10, 1.0 mL min-1, l = 254 nm) 6.0 min
(minor isomer), 9.6 min (major isomer).
White solid (106 mg, 78%); mp 70–72 ◦C; [a]D22 -12.0 (c 1, CH3OH)
1
in the case of 80% ee (Table 1, entry 3); H NMR (400 MHz,
(2¢S)-1-[1¢-(tert-butyldiphenylsilyloxy)-4¢-
CDCl3) d 6.95 (s, 1H), 4.99–4.88 (m, 1H), 4.09–4.05 (m, 1H),
3.90 (dd, J = 10.8, 5.2 Hz, 1H), 3.75–3.71 (m, 1H), 3.53–3.43
(m, 1H), 2.43–2.32 (m, 1H), 2.18–2.08 (m, 1H), 1.48 (s, 1H),
0.79 (s, 9H), 0.01 (s, 3H), -0.05 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 123.7, 114.1, 113.0, 102.3, 98.9, 64.4, 60.5, 58.4, 32.4,
25.4, 17.8, -5.6, -5.8; FTIR (neat) 3438, 2928, 2855, 2221, 1413,
1319, 1249, 1109, 835, 777 cm-1; HRMS (FAB) calcd for [M+H]+
C15H25O2N2Br2Si 451.0052, found 451.0049; HPLC (Chiralpak
AD-H, Hexane/IPA = 90/10, 0.9 mL min-1, l = 254 nm) 5.6
min (minor isomer), 6.6 min (major isomer).
hydroxybutan-2¢-yl]-4-nitro-1H-pyrrole-2-carbonitrile (9)
◦
Light yellow solid (93 mg, 67%); mp 88–90 C; [a]2D1 +16.1 (c 1,
1
CH3OH); H NMR (400 MHz, CDCl3) d 7.71 (d, J = 1.6 Hz,
1H), 7.52–7.34 (m, 11H), 4.70–4.66 (m, 1H), 3.94 (dd, J = 11.2,
3.2 Hz, 1H), 3.86 (dd, J = 11.2, 6.8 Hz, 1H), 3.69–3.64 (m, 1H),
3.48–3.42 (m, 1H), 2.11–2.05 (m, 2H), 1.72 (s, 1H), 1.01 (s, 9H); 13
C
NMR (100 MHz, CDCl3) d 136.4, 135.4, 135.3, 132.0, 131.9, 130.1,
130.1, 127.8, 123.9, 114.6, 111.2, 105.7, 65.5, 59.3, 57.9, 33.1, 26.6,
18.9; FTIR (neat) 3419, 3127, 2928, 2857, 2230, 1512, 1389, 1308,
1113, 702 cm-1; HRMS (EI) calcd for [M]+ C25H29N3O4Si 463.1927,
found 463.1932; HPLC (Chiralpak AD-H, Hexane/IPA = 90/10,
1.0 mL min-1, l = 254 nm) 11.2 min (minor isomer), 17.8 min
(major isomer).
(2¢S)-4,5-dibromo-1-[1¢-(tert-butyldiphenylsilyloxy)-4¢-
hydroxybutan-2¢-yl]-1H-pyrrole-2-carbonitrile (6)
◦
White solid (131 mg, 76%); mp 99–101 C; [a]2D0 +18.2 (c 1,
1
CH3OH) in the case of 93% ee (Table 1, entry 6); H NMR (400
(2¢S)-1-[1¢-(tert-butyldiphenylsilyloxy)-4¢-
MHz, CDCl3) d 7.61–7.56 (m, 2H), 7.51–7.34 (m, 8H), 6.91 (s,
1H), 5.07–4.96 (m, 1H), 4.11 (t, J = 10.0 Hz, 1H), 3.93–3.87 (m,
1H), 3.70–3.63 (m, 1H), 3.47–3.38 (m, 1H), 2.36–2.25 (m, 1H),
2.11–2.00 (m, 1H), 1.42 (s, 1H), 0.96 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 135.4, 132.6, 132.3, 129.9, 129.8, 127.7, 123.8, 114.2,
112.8, 102.4, 99.0, 65.0, 60.3, 58.2, 32.3, 26.4, 18.9; FTIR (neat)
3391, 2929, 2858, 2223, 2102, 1416, 1311, 1113, 700 cm-1; HRMS
(EI) calcd for [M]+ C25H28Br2N2O2Si 574.0287, found 574.0286;
HPLC (Chiralpak AD-H, Hexane/IPA = 95/5, 1.0 mL min-1, l =
254 nm) 7.8 min (minor isomer), 8.7 min (major isomer).
hydroxybutan-2¢-yl]-4-chloro-1H-pyrrole-2-carbonitrile (10)
Colorless oil (98 mg, 72%); [a]2D4 -8.2 (c 1, CH3OH); 1H NMR (400
MHz, CDCl3) d 7.54–7.35 (m, 10H), 6.87 (d, J = 1.6 Hz, 1H), 6.70
(d, J = 1.6 Hz, 1H), 4.61–4.55 (m, 1H), 3.85 (dd, J = 10.8, 3.6 Hz,
1H), 3.76 (dd, J = 10.8, 6.8 Hz, 1H), 3.65–3.59 (m, 1H), 3.46–3.40
(m, 1H), 2.04–1.98 (m, 2H), 1.58 (s, 1H), 1.00 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 135.5, 135.4, 132.3, 132.2, 129.9, 129.9, 127.8,
127.8, 121.8, 118.2, 112.9, 112.6, 104.3, 66.1, 58.3, 58.3, 33.5, 26.5,
19.0; FTIR (neat) 3394, 3114, 2930, 2858, 2223, 1427, 1128, 1113,
700 cm-1; HRMS (EI) calcd for [M]+ C25H29ClN2O2Si 452.1687,
found 452.1684; HPLC (Chiralpak AD-H, Hexane/IPA = 90/10,
1.0 mL min-1, l = 254 nm) 7.8 min (minor isomer), 10.1 min (major
isomer).
(2¢S)-5-bromo-1-[1¢-(tert-butyldiphenylsilyloxy)-4¢-
hydroxybutan-2¢-yl]-4-chloro-1H-pyrrole-2-carbonitrile (7)
1
Yellow oil (118 mg, 74%); [a]2D1 +26.8 (c 1, CH3OH); H NMR
(2¢S)-4-bromo-1-[1¢-(tert-butyldiphenylsilyloxy)-4¢-
hydroxybutan-2¢-yl]-1H-pyrrole-2-carbonitrile (11)
(400 MHz, CDCl3) d 7.63–7.55 (m, 2H), 7.51–7.33 (m, 8H), 6.85
(s, 1H), 5.03–4.93 (m, 1H), 4.12 (t, J = 9.6 Hz, 1H), 3.93–3.86 (m,
1H), 3.68–3.63 (m, 1H), 3.42 (dt, J = 10.0, 3.6 Hz, 1H), 2.36–2.25
(m, 1H), 2.10–1.99 (m, 1H), 1.49 (s, 1H), 0.96 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 135.4, 132.6, 132.2, 129.9, 129.8, 127.7, 121.1,
113.4, 112.9, 111.7, 101.4, 64.9, 59.8, 58.2, 32.3, 26.4, 18.9; FTIR
(neat) 3368, 3114, 2929, 2858, 2224, 1426, 1329, 1113, 825, 701,
508 cm-1; HRMS (EI) calcd for [M]+ C25H28BrClN2O2Si 530.0792,
found 530.0791; HPLC (Chiralpak AD-H, Hexane/IPA = 95/5,
1.0 mL min-1, l = 254 nm) 7.4 min (minor isomer), 8.5 min (major
isomer).
1
Yellow oil (107 mg, 72%); [a]2D5 -9.3 (c 1, CH3OH); H NMR
(400 MHz, CDCl3) d 7.54–7.36 (m, 10H), 6.92 (d, J = 1.6 Hz,
1H), 6.78 (d, J = 1.6 Hz, 1H), 4.64–4.58 (m, 1H), 3.85 (dd, J =
10.8, 3.6 Hz, 1H), 3.76 (dd, J = 10.8, 6.8 Hz, 1H), 3.67–3.61 (m,
1H), 3.49–3.41 (m, 1H), 2.06–2.00 (m, 2H), 1.47 (s, 1H), 1.00 (s,
9H); 13C NMR (100 MHz, CDCl3) d 135.4, 135.4, 132.3, 132.2,
129.9, 129.9, 127.8, 124.3, 120.6, 112.5, 105.2, 96.4, 66.1, 58.3,
58.3, 33.5, 26.5, 19.0; FTIR (neat) 3446, 3071, 2931, 2858, 2221,
1427, 1318, 1113, 758, 702, 504 cm-1; HRMS (EI) calcd for [M]+
C25H29BrN2O2Si 496.1182, found 496.1185; HPLC (Chiralpak
AD-H, Hexane/IPA = 95/5, 0.95 mL min-1, l = 254 nm) 9.0
min (minor isomer), 11.7 min (major isomer).
(2¢S)-1-[1¢-(tert-butyldiphenylsilyloxy)-4¢-
hydroxybutan-2¢-yl]-1H-pyrrole-2,4-dicarbonitrile (8)
◦
Light yellow solid (83 mg, 62%); mp 93–95 C; [a]2D2 -9.0 (c 1,
(2¢S)-1-[1¢-(tert-butyldiphenylsilyloxy)-4¢-hydroxybutan-2¢-yl]-4-
iodo-1H-pyrrole-2-carbonitrile (12)
1
CH3OH); H NMR (400 MHz, CDCl3) d 7.52–7.37 (m, 10H),
7.32 (d, J = 1.2 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 4.71–4.65 (m,
1H), 3.91 (dd, J = 11.2, 3.6 Hz, 1H), 3.83 (dd, J = 11.2, 7.2 Hz,
1H), 3.67–3.62 (m, 1H), 3.44–3.38 (m, 1H), 2.10–1.99 (m, 2H),
1.57 (s, 1H), 1.00 (s, 9H); 13C NMR (100 MHz, CDCl3) d 135.4,
135.3, 132.0, 131.9, 130.2, 130.1, 130.0, 127.8, 121.9, 114.2, 111.5,
106.3, 94.5, 65.5, 59.0, 57.8, 33.1, 26.5, 18.9; FTIR (neat) 3447,
3128, 2931, 2858, 2231, 1428, 1114, 702 cm-1; HRMS (EI) calcd for
Light yellow oil (124 mg, 76%); [a]2D1 -19.0 (c 1, CH3OH); 1H NMR
(400 MHz, CDCl3) d 7.53–7.35 (m, 10H), 6.98 (d, J = 2.0 Hz, 1H),
6.86 (d, J = 1.6 Hz, 1H), 4.64–4.58 (m, 1H), 3.84 (dd, J = 10.8,
3.6 Hz, 1H), 3.77 (dd, J = 10.8, 6.8 Hz, 1H), 3.65–3.60 (m, 1H),
3.47–3.41 (m, 1H), 2.06–2.01 (m, 2H), 1.53 (s, 1H), 1.00 (s, 9H);
13C NMR (100 MHz, CDCl3) d 135.5, 135.4, 132.4, 132.3, 129.9,
7738 | Org. Biomol. Chem., 2011, 9, 7734–7741
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129.9, 129.2, 127.8, 127.8, 125.6, 112.3, 106.4, 66.2, 59.9, 58.3,
58.2, 33.6, 26.6, 19.0; FTIR (neat) 3447, 3071, 2930, 2857, 2222,
1589, 1460, 1427, 1310, 1114, 758, 702, 504 cm-1; HRMS (EI)
calcd for [M]+ C25H28N2O2SiI 543.0965, found 543.0968; HPLC
(Chiralpak AD-H, Hexane/IPA = 95/5, 1.0 mL min-1, l = 254
nm) 9.4 min (major isomer), 10.9 min (minor isomer).
1.24 mmol) in acetonitrile (6.2 mL, 0.2 M) at rt. The mixture was
allowed to stir at reflux for 12 h. The solids were removed by
filtration and the solvents removed. The residue was purified by
flash chromatography (SiO2: 10% EtOAc in hexanes) to provide
the ether 16 in 98% yield (717 mg, 1.22 mmol) as a colorless oil.
1
[a]2D0 +30.9 (c 1, CH3OH); H NMR (400 MHz, CDCl3) d 7.58–
7.56 (m, 2H), 7.49–7.34 (m, 8H), 6.92 (s, 1H), 5.01–4.96 (m, 1H),
4.11 (t, J = 10.0 Hz, 1H), 3.87 (dd, J = 10.8, 4.4 Hz, 1H), 3.40–3.35
(m, 1H), 3.25 (s, 3H), 3.04 (dt, J = 9.6, 4.0 Hz, 1H), 2.31–2.25
(m, 1H), 2.08–2.02 (m, 1H), 0.95 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 135.4, 132.7, 132.4, 129.8, 129.8, 127.7, 123.7, 114.3,
112.8, 102.4, 98.9, 67.8, 64.9, 60.6, 58.6, 30.1, 26.5, 18.9; FTIR
(neat) 3071, 2930, 2857, 2221, 1415, 1313, 1114, 798, 702, 504
cm-1; HRMS (EI) calcd for [M]+ C26H30Br2N2O2Si 588.0443, found
588.0442.
(2¢S)-1-[1¢-(tert-butyldiphenylsilyloxy)-4¢-hydroxybutan-2¢-yl]-4-
chloro-5-iodo-1H-pyrrole-2-carbonitrile (13)
Colorless oil (132 mg, 76%); [a]2D1 -22.5 (c 1, CH3OH); 1H NMR
(400 MHz, CDCl3) d 7.59–7.57 (m, 2H), 7.49–7.34 (m, 8H), 6.99
(s, 1H), 4.99–4.92 (m, 1H), 4.14 (dd, J = 10.8, 9.6 Hz, 1H), 3.89
(dd, J = 11.2, 4.8 Hz, 1H), 3.70–3.63 (m, 1H), 3.44–3.36 (m,
1H), 2.36–2.27 (m, 1H), 2.09–2.00 (m, 1H), 1.42 (s, 1H), 0.96
(s, 9H); 13C NMR (100 MHz, CDCl3) d 135.4, 132.6, 132.2,
129.9, 129.8, 127.7, 124.3, 112.6, 106.2, 104.4, 89.4, 65.1, 63.4,
58.2, 32.5, 26.5, 18.9; FTIR (neat) 3448, 3071, 2930, 2857, 2219,
1427, 1306, 1113, 741, 702, 504 cm-1; HRMS (EI) calcd for [M]+
C25H28ClN2O2SiI 578.0653, found 578.0648; HPLC (Chiralpak
AD-H, Hexane/IPA = 95/5, 0.9 mL min-1, l = 254 nm) 8.0 min
(minor isomer), 10.2 min (major isomer).
(2¢S)-4,5-dibromo-1-(1¢-hydroxy-4¢-methoxybutan-2¢-yl)-1H-
pyrrole-2-carbonitrile (17)
1.25 M HCl solution in methanol (6.4 mL, 8.0 mmol) was added
to 16 (236 mg, 0.4 mmol). The mixture was stirred at rt for 12 h, at
which point 1.25 M HCl solution in methanol (6.4 mL, 8.0 mmol)
was added once more and the mixture was stirred at rt for 48 h.
The mixture was evaporated to remove methanol and quenched
by saturated NaHCO3. The mixture was extracted with ethyl
acetate and the organic layer was dried over MgSO4. Filtration,
concentration and purification by flash chromatography (SiO2:
30% EtOAc in hexanes) provided the alcohol 1◦7 in 90% yield (126
mg, 0.358 mmol) as a white solid. mp 63–65 C; [a]2D1 -5.2 (c 1,
CH3OH); 1H NMR (400 MHz, CDCl3) d 6.95 (s, 1H), 4.90–4.84
(m, 1H), 4.19–4.13 (m, 1H), 3.99–3.93 (m, 1H), 3.47–3.42 (m,
1H), 3.29 (s, 3H), 3.10 (dt, J = 9.6, 4.0 Hz, 1H), 2.34–2.26 (m,
1H), 2.24–2.15 (m, 1H), 2.05 (t, J = 5.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) d 123.7, 113.9, 112.7, 102.3, 99.5, 67.9, 63.5, 61.0,
58.6, 30.4; FTIR (neat) 3449, 3124, 2890, 2226, 1411, 1379, 1313,
1121, 1085, 828 cm-1; HRMS (EI) calcd for [M]+ C10H12Br2N2O2
349.9265, found 349.9263.
(2¢S)-4-bromo-1-[1¢-(tert-butyldiphenylsilyloxy)-4¢-hydroxybutan-
2¢-yl]-5-iodo-1H-pyrrole-2-carbonitrile (14)
Yellow oil (133 mg, 71%); [a]2D1 -44.8 (c 1, CH3OH); 1H NMR (400
MHz, CDCl3) d 7.59–7.57 (m, 2H), 7.49–7.34 (m, 8H), 6.99 (s, 1H),
4.98–4.92 (m, 1H), 4.14 (dd, J = 10.8, 9.6 Hz, 1H), 3.89 (dd, J =
11.2, 4.8 Hz, 1H), 3.68–3.63 (m, 1H), 3.40 (dt, J = 9.6, 4.0 Hz, 1H),
2.35–2.27 (m, 1H), 2.08–2.00 (m, 1H), 1.47 (s, 1H), 0.96 (s, 9H); 13
C
NMR (100 MHz, CDCl3) d 135.5, 132.6, 132.3, 129.9, 129.8, 127.8,
124.4, 112.6, 106.3, 104.5, 89.3, 65.2, 63.4, 58.3, 32.6, 26.5, 19.0;
FTIR (neat) 3456, 3071, 2930, 2219, 1427, 1311, 1114, 758, 702,
504 cm-1; HRMS (EI) calcd for [M]+ C25H28BrN2O2SiI 622.0148,
found 622.0153; HPLC (Chiralpak AD-H, Hexane/IPA = 95/5,
1.0 mL min-1, l = 254 nm) 7.8 min (minor isomer), 10.1 min (major
isomer).
(2¢S)-4,5-dibromo-1-[4¢-methoxy-1¢-(p-toluenesulfonyloxy)butan-
2¢-yl]-1H-pyrrole-2-carbonitrile (18)
(2¢S)-1-[1¢-(tert-butyldiphenylsilyloxy)-4¢-hydroxybutan-2¢-yl]-4,5-
diiodo-1H-pyrrole-2-carbonitrile (15)
1
Light yellow oil (149 mg, 74%); [a]2D1 -36.0 (c 1, CH3OH); H
p-Toluenesulfonyl chloride (136 mg, 0.713 mmol) was added to
a solution of 17 (114 mg, 0.324 mmol) in pyridine (0.32 mL,
1.0 M). The mixture was allowed to stir at rt for 16 h. The
mixture was quenched by water and extracted with ethyl acetate.
The organic layer was washed with saturated NH4Cl and brine,
dried over Na2SO4. Filtration, concentration and purification by
flash chromatography (SiO2: 25% EtOAc in hexanes) provided the
tosylate 18 in 97% yield (159 mg, 0.314 mmol) as a colorless oil.
[a]2D0 -12.0 (c 1, CH3OH); 1H NMR (400 MHz, CDCl3) d 7.64 (d,
J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.74 (s, 1H), 5.11–5.01
(m, 1H), 4.53 (t, J = 10.2 Hz, 1H), 4.32 (dd, J = 10.2, 4.0 Hz, 1H),
3.41–3.36 (m, 1H), 3.23 (s, 3H), 2.96 (dt, J = 9.6, 3.6 Hz, 1H),
2.45 (s, 3H), 2.29–2.20 (m, 1H), 2.16–2.07 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 145.2, 132.0, 129.9, 127.6, 124.0, 113.9,
112.3, 102.1, 99.5, 69.4, 67.2, 58.6, 57.4, 30.3, 21.6; FTIR (neat)
3125, 2927, 2877, 2221, 1598, 1367, 1177, 1122, 981, 813, 666, 554
cm-1; HRMS (EI) calcd for [M]+ C17H18Br2N2O4S 503.9354, found
503.9358.
NMR (400 MHz, CDCl3) d 7.58–7.56 (m, 2H), 7.48–7.34 (m, 8H),
7.06 (s, 1H), 5.03–4.96 (m, 1H), 4.12 (dd, J = 10.8, 9.6 Hz, 1H),
3.88 (dd, J = 10.8, 4.8 Hz, 1H), 3.70–3.62 (m, 1H), 3.45–3.37 (m,
1H), 2.35–2.27 (m, 1H), 2.08–1.99 (m, 1H), 1.40 (s, 1H), 0.96 (s,
9H); 13C NMR (100 MHz, CDCl3) d 135.4, 132.6, 132.3, 129.9,
129.8, 129.7, 127.8, 127.7, 112.3, 105.5, 95.5, 77.2, 75.5, 65.2, 64.3,
58.2, 32.7, 26.5, 19.0; FTIR (neat) 3452, 3071, 2930, 2218, 1427,
1362, 1298, 1113, 757, 702, 504 cm-1; HRMS (EI) calcd for [M]+
C25H28N2O2SiI2 670.0010, found 670.0005; HPLC (Chiralpak AD-
H, Hexane/IPA = 95/5, 0.9 mL min-1, l = 254 nm) 16.6 min (major
isomer), 17.7 min (minor isomer).
(2¢S)-4,5-dibromo-1-[1¢-(tert-butyldiphenylsilyloxy)-4¢-
methoxybutan-2¢-yl]-1H-pyrrole-2-carbonitrile (16)
Iodomethane (6.2 mL, 0.2 M) and silver oxide (431 mg, 1.86 mmol)
was added to a solution of the conjugate product 6 (715 mg,
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(2¢S)-1-(1¢-azido-4¢-methoxybutan-2¢-yl)-4,5-dibromo-1H-pyrrole-
2-carbonitrile (19)
1H); 13C NMR (100 MHz, CDCl3) d 159.8, 124.7, 115.6, 106.7,
100.5, 68.7, 58.7, 52.0, 42.9, 31.7; FTIR (neat) 3215, 3083, 2923,
1651, 1547, 1466, 1427, 1332, 1120, 963, 760 cm-1; HRMS (EI)
calcd for [M]+ C10H12Br2N2O2 349.9265, found 349.9266.
Sodium azide (122 mg, 1.884 mmol) was added to a solution of
18 (159 mg, 0.314 mmol) in dimethyl sulfoxide (3.14 mL, 0.1 M)
at rt. The mixture was allowed to stir at 65 ◦C for 24 h. The
mixture was quenched by water and extracted with ethyl acetate.
The organic layers was washed with water and brine, then dried
over Na2SO4. Filtration, concentration and purification by flash
chromatography (SiO2: 20% EtOAc in hexanes) provided the azide
19 in 82% yield (97 mg, 0.257 mmol) as a white solid. mp 45–
(4S)-6,7-dibromo-4-(2¢-hydroxyethyl)-3,4-dihydropyrrolo[1,2-
a]pyrazin-1(2H)-one (22)
Boron tribromide (1 M solution in dichloromethane, 1.2 mL,
1.2 mmol) was slowly added to a solution of 21 (84 mg, 0.24 mmol)
in dichloromethane (2.8 mL, 0.085 M) at -20 ◦C. The mixture was
stirred at rt for 6 h and quenched by water. The aqueous layer was
extracted twice with ethyl acetate. The combined organic layers
were dried over MgSO4. Filtration, concentration and purification
by flash chromatography (SiO2: 5% MeOH in dichloromethane)
provided the key intermediate 2◦2 in 85% yield (69 mg, 0.204 mmol)
◦
1
47 C; [a]2D1 +4.0 (c 1, CH3OH); H NMR (400 MHz, CDCl3)
d 6.99 (s, 1H), 4.97–4.87 (m, 1H), 4.02–3.92 (m, 1H), 3.67 (dd,
J = 13.2, 5.2 Hz, 1H), 3.46–3.41 (m, 1H), 3.28 (s, 3H), 3.03 (dt,
J = 10.0, 3.6 Hz, 1H), 2.42–2.32 (m, 1H), 2.20–2.12 (m, 1H); 13
C
NMR (100 MHz, CDCl3) d 124.4, 114.0, 112.7, 102.3, 99.7, 67.4,
58.7, 58.2, 53.6, 31.6; FTIR (neat) 3101, 2936, 2217, 2101, 1413,
1312, 1275, 1121, 1086, 965, 914 cm-1; HRMS (EI) calcd for [M]+
C10H11Br2N5O 374.9330, found 374.9328.
1
as a white solid. mp 139–141 C; [a]1D9 -28.9 (c 1, CH3OH); H
NMR (400 MHz, CD3OD) d 6.91 (s, 1H), 4.60–4.56 (m, 1H), 3.81
(dd, J = 13.6, 4.0 Hz, 1H), 3.68–3.63 (m, 3H), 2.03–1.94 (m, 1H),
1.87–1.79 (m, 1H); 13C NMR (100 MHz, CD3OD) d 161.1, 126.1,
116.3, 108.0, 101.2, 59.2, 53.3, 43.3, 35.5; FTIR (neat) 3431, 3243,
2921, 1647, 1617, 1545, 1426, 1335, 1053, 960, 750 cm-1; HRMS
(EI) calcd for [M]+ C9H10Br2N2O2 335.9109, found 335.9109.
(2¢S)-1-(1¢-azido-4¢-methoxybutan-2¢-yl)-4,5-dibromo-1H-pyrrole-
2-carboxamide (20)
1 N aqueous sodium hydroxide (0.48 mL, 0.48 mmol) and
hydrogen peroxide (30 wt.% in H2O, 0.48 mL, 0.144 mmol) were
added to a solution of 19 (91 mg, 0.241 mmol) in methanol–
dichloromethane (10 : 1 v/v, 4.82 mL, 0.05 M). The mixture
was allowed to stir at rt for 12 h. The mixture was quenched
by saturated Na2S2O3 and saturated NH4Cl. The mixture was
extracted with dichloromethane and water. The organic layer was
dried over MgSO4. Filtration, concentration and purification by
flash chromatography (SiO2: 40% EtOAc in hexanes) provided the
azide–amide 20 in 95% yield (91 mg, 0.229 mmol) as a colorless oil.
Acknowledgements
This research was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(2009-0070538).
Notes and references
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1
[a]1D9 -36.0 (c 1, CH3OH); H NMR (400 MHz, CDCl3, mixture
of two conformers, major : minor = 57 : 43) d 6.82 (s, 0.57H) and
6.73 (s, 0.43H), 6.01–5.73 (m, 2.43H) and 4.99–4.89 (m, 0.57H),
4.36 (t, J = 11.2 Hz, 0.57H) and 4.10 (t, J = 11.2 Hz, 0.43H), 3.62
(dd, J = 12.8, 5.2 Hz, 1H), 3.39–3.32 (m, 1H), 3.25 (s, 3H), 3.24–
3.17 (m, 0.43H) and 3.06–2.98 (m, 0.57H), 2.50–2.42 (m, 1H),
2.19–2.06 (m, 1H); 13C NMR (100 MHz, CDCl3, mixture of two
conformers) major: d 161.9, 126.6, 117.8, 114.7, 98.9, 68.5, 59.0,
58.5, 54.1, 31.9, minor: d 161.9, 129.5, 115.8, 107.2, 101.6, 68.8,
58.5, 55.5, 53.1, 31.1; FTIR (neat) 3345, 3188, 2928, 2874, 2102,
1662, 1606, 1420, 1278, 1118, 953, 758 cm-1; HRMS (EI) calcd for
[M]+ C10H13Br2N5O2 392.9436, found 392.9439.
(4S)-6,7-dibromo-4-(2¢-methoxyethyl)-3,4-dihydropyrrolo[1,2-
a]pyrazin-1(2H)-one (21)
8 J.-Y. Bae, H.-J. Lee, S.-H. Youn, S.-H. Kwon and C.-W. Cho, Org. Lett.,
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Triphenylphosphine (195 mg, 0.75 mmol) was added to a solution
of 20 (135 mg, 0.34 mmol) in tetrahydrofuran (3.4 mL, 0.1 M).
The mixture was stirred at rt for 1 h, at which point water
(0.037 mL, 2.04 mmol) was added and the mixture was refluxed
for 20 h. The solvent removed and the residue was purified by
flash chromatography (SiO2: 85% EtOAc in hexanes) to give the
pyrrolopiperazinone 21 in 84% yield (100 mg, 0.285 mmol) as a
white solid. mp 113–115 ◦C; [a]D21 -27.1 (c 1, CH3OH); 1H NMR
(400 MHz, CDCl3) d 7.26 (br s, 1H), 6.98 (s, 1H), 4.52–4.47 (m,
1H), 3.85 (dd, J = 13.2, 4.0 Hz, 1H), 3.65 (dd, J = 13.2, 4.8 Hz, 1H),
3.47–3.44 (m, 2H), 3.35 (s, 3H), 2.13–2.04 (m, 1H), 1.96–1.88 (m,
9 For a review on organocatalytic asymmetric aza-Michael reactions, see:
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Catal., 2010, 352, 2291; (i) L. Deiana, G.-L. Zhao, S. Lin, P. Dziedzic,
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Org. Biomol. Chem., 2011, 9, 7734–7741 | 7741
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