New regiocontrolled syntheses of pyrrolopyrazinones and its application to the synthesis of peramine

Article abstract of DOI:10.1016/j.tet.2017.05.004

Two novel regiocontrolled syntheses of pyrrolopyrazinones were developed. N-Methylpyrrole amide and 1-bromo-1-alkyne were annulated in the presence of a copper catalyst to give 3-substituted pyrrolopyrazinone in a regioselective manner. In contrast, heating N-methylpyrrole amide with the same haloalkyne in the presence of K₃PO₄ provided the haloaminal, which was transformed regioselectively into 4-substituted pyrrolopyrazinone. The former procedure was successfully applied to the synthesis of peramine, a natural product isolated from an endophytic fungus.

Full text of DOI:10.1016/j.tet.2017.05.004

Accepted Manuscript
New regiocontrolled syntheses of pyrrolopyrazinones and its application to the
synthesis of peramine
Yuta Yamamoto, Atsuo Nakazaki, Toshio Nishikawa
PII:
S0040-4020(17)30470-2
10.1016/j.tet.2017.05.004
TET 28670
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 March 2017
Revised Date: 28 April 2017
Accepted Date: 1 May 2017
Please cite this article as: Yamamoto Y, Nakazaki A, Nishikawa T, New regiocontrolled syntheses of
pyrrolopyrazinones and its application to the synthesis of peramine, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.05.004.
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ACCEPTED MANUSCRIPT
New regiocontrolled syntheses of pyrrolopyrazinones
and its application to the synthesis of peramine
Yuta Yamamoto, Atsuo Nakazaki, and Toshio Nishikawa*
Graduate School of Bioagricultural Sciences, Nagoya University
Furo-cho, Chikusa, Nagoya 464-8601, Japan
Abstract: Two novel regiocontrolled syntheses of pyrrolopyrazinones were developed.
N-Methylpyrrole amide and 1-bromo-1-alkyne were annulated in the presence of a copper catalyst
to give 3-substituted pyrrolopyrazinone in a regioselective manner. In contrast, heating
N-methylpyrrole amide with the same haloalkyne in the presence of K3PO4 provided the haloaminal,
which was transformed regioselectively into 4-substituted pyrrolopyrazinone. The former
procedure was successfully applied to the synthesis of peramine, a natural product isolated from an
endophytic fungus.
------------------------------------------------------------------------
Peramine (1) was isolated from fungal-endophyte-infected perennial ryegrass (Lolium perennue
L.) by Rowan and co-workers (Figure 1).1 This natural product is one of a well-known family of
alkaloids that are produced by endophytes associated with grass,2 and deters insect feeding without
acute toxicity to animals.3 Therefore, peramine has been expected to be a lead compound of
selective agrochemical against insects. However, the molecular mechanism of action has not been
fully elucidated.4 In the course of our studies on guanidine-containing natural products, such as
tetrodotoxin and saxitoxin,5 we became interested in peramine because of its unique structure,
which comprises both guanidine and pyrrolopyrazinone. Pyrrolopyrazinone is a rare structural
motif in natural products, which has only been found in peramine and nannozinone B (2),6 a natural
product isolated from myxobacteria.
On the other hand, the dihydro structure of
pyrrolopyrazinone is found in an important class of biologically active marine pyrrole-alkaloids,
such as hanishin/longamide B (3a,b), 7 dibromophakellstatin (4), dibromophakellin (5), and
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palau’amine (7).8 Among these natural products, dibromophakellstatin (4) and dibromophakellin
(5) have been synthesized from pyrrolopyrazinone-containing intermediates 6a and 6b,
respectively.9 Therefore, construction of pyrrolopyrazinone and its dihydro derivatives has
received considerable attention from the synthetic community, and many synthetic approaches have
been reported.10 So far, the pyrrolopyrazinone structure of peramine has been synthesized from
pyrrole-2-carboxylic acid or its derivatives in a stepwise manner (in three or four steps).11 Herein,
we disclose strategically new syntheses of the pyrrolopyrazinone ring, which are more direct and
concise, directed toward the synthesis of peramine.
Figure 1. Structures of tetrodotoxin, saxitoxin, peramine (1) and related compounds
Syntheses of pyrrolopyrazinones
We envisaged that the 3-substituted pyrrolopyrazinone ring A of peramine could be constructed
from N-methylpyrrole amide 812 and 1-halo-1-alkyne in two steps (Scheme 1): (i) the pyrrole NH
could be coupled with 1-halo-1-alkyne using a copper catalyst to give N-alkynylated pyrrole B,13
(ii) which would undergo 6-endo cyclization to 3-substituted pyrrolopyrazinone A in the presence
of a metal catalyst. Although pyrrole amide 8 possesses two NH groups for N-alkynylation, we
expected that the pyrrole nitrogen would be more reactive than the amide nitrogen, as benzylation
of compound 8 with benzyl bromide in the presence of K3PO4 gave N-benzylamide 9 exclusively
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(Scheme 2).14 Single-step synthesis of pyrrolopyrazinone A from N-methylpyrrole amide 8 and
1-halo-1-alkyne might be possible, if we could find a catalyst that promotes both steps. With these
considerations in mind, we first investigated N-alkynylation of pyrrole amide 8 with
1-bromo-1-octyne (10) as a model substrate in the presence of a copper catalyst.
O
O
N
N
H
N
HN
H
Me
X
Me
3
R
A
8
R
O
N
HN
(ii) 6-endo
cyclization
Me
(i) N-alkynylation
B
R
Scheme 1. Synthetic plan for regioselective construction of 3-substituted pyrrolopyrazinone A
Scheme 2. Reactivity of N-methylpyrrole amide 8
Representative results for the N-alkynylation of pyrrole amide 8 are summarized in Table 1. In
accordance with the report by Hsung and co-workers,15 a mixture of 8, 10, and K3PO4 in toluene
was heated at 80 °C in the presence of catalytic amounts of CuSO4·5H2O and 1,10-phenanthroline
(I) for two days. Bromoalkyne 10 was consumed, but desired product B (R = C6H13) was not
obtained and a significant amount of pyrrole amide 8 was recovered (entry 1). Fortunately, trace
amount of pyrrolopyrazinone 11 was detected, which implied that the catalyst might promote not
only N-alkynylation of the pyrrole NH, but also the desired cyclization of the resulting
N-alkynylpyrrole B. Bromoaminal 13, an unexpected product, was also detected, the structure of
which was later determined by X-ray crystallographic analysis (Figure 2). 16 As the low
conversion might be due to the poor solubility of amide 8 in toluene, DMF was next used as a
solvent to increase the solubility (entry 2). Under these conditions, the yields of 11 and 13 were
improved to 23% and 24%, respectively, and 4-bromopyrrolopyrazinone 12 was also obtained in
12% yield. We next examined other copper salts, such as CuI and Cu(acac)2, and found that
Cu(acac)2 gave moderate yields of 11 and 12, while suppressing production of bromoaminal 13
(entries
3
and 4).
Subsequently, various ligands were examined, including
(II), trans-1,2-cyclohexanediamine (III), and
N,N,N′,N′-tetramethylethylenediamine
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3,4,7,8-tetramethyl-1,10-phenanthroline (IV) (entries 5, 6, and 7). We found that the highest
yields of 11 and 12 were obtained with 1,10-phenanthroline (I) as the ligand (entry 4). When
3,4,7,8-tetramethyl-1,10-phenanthroline (IV) was used as the ligand, the rate of the reaction
dramatically increased without production of bromoaminal 13, although the yields of 11 and 12
were not improved (entry 7). Under these conditions, iminoethers 14 and 15 were also obtained.17
The reaction temperature under the conditions using Cu(acac)2 and ligand (IV) did not significantly
influence the yields of the products (entries 7–9). As bromide 12 was easily transformed into 11
under hydrogenolysis conditions (H2/Pd-C in MeOH) in good yield, the catalytic conditions realized
a concise route to the 3-substituted pyrrolopyrazinone from N-methylpyrrole amide and
1-bromo-1-alkyne. The regioselectivity of this annulation can be attributed to preferential
formation of N-alkynylpyrrole. This expected result is supported by the experiment shown in
Scheme 3, where N,N-dimethylpyrrole amide 16 reacted with 1-bromo-1-octyne (10) under the
conditions of entry 8 (Table 1) gives a mixture of N-alkynylpyrrole 17 and 18. The latter product
might be formed by hydrolysis of a cyclic iminoether as 14.
Table 1. Reactions of pyrrole amide 8 with 1-bromo-1-octyne (10) in the presence of a copper
catalyst
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O
N
N
Br
Figure 2. ORTEP drawing of compound 13
The regioselectivity of this annulation can be attributed to preferential formation of
N-alkynylpyrrole. This expected result is supported by the experiment shown in Scheme 3, where
N,N-dimethylpyrrole amide 16 reacted with 1-bromo-1-octyne (10) under the conditions of entry 8
(Table 1) gives a mixture of N-alkynylpyrrole 17 and 18. The latter product might be formed by
hydrolysis of a cyclic iminoether as 14.18
Scheme 3. Reaction of N,N-dimethylpyrrole amide 16 and 1-bromo-1-octyne (10):
(RSM: Recovered starting material)
Although bromoaminal 13 was an unexpected by-product, we explored the conditions for its
preferential production because of the unique structure and the possibility that aminal 13 might be
transformed to pyrrolopyrazinone 11 by ring expansion. After several experiments, we found that
bromoaminal 13 was obtained in the absence of catalyst. A DMF solution of N-methylpyrrole
amide 8 and 1-bromo-1-octyne (10) heated at 120 °C with K3PO4 gave aminal 13 in 45% yield
along with small amounts of pyrrolopyrazinones 11 and 19, and dibromoaminal 24 (entry 1, Table
2).19 The reaction with 1-chloro-1-octyne (20) under identical conditions gave a better yield of
corresponding chloroaminal 22 (60% yield) (entry 2), and a lower temperature (80 °C) improved
the yield of aminal 22 to 68% (entry 3). On the other hand, the reaction with 1-iodo-1-octyne (21)
gave a complex mixture of unidentified products (entry 4).
Table 2. Reactions of pyrrole amide 8 with 1-halo-1-octynes
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During investigation of the formation of this haloaminal, we noticed that related reactions had
been reported by Urabe and co-workers 20 for nucleophilic addition of sulfonamides to
1-bromo-1-alkynes. On the basis of their proposed mechanism, we proposed reaction mechanisms
for the formation of haloaminals 13 and 22, as well as minor products 11 and 19 (Scheme 4). As
the pyrrole nitrogen of 8 is more nucleophilic than the amide nitrogen, the pyrrole nitrogen
preferentially attacks the 1-halo-1-alkyne to give vinyl halide C. However, under these conditions,
C may be protonated to iminium intermediate D, which cyclizes to aminals 13 and 22 or
pyrrolopyrazinone 19 by attacking the iminium or the halide carbon with the amide nitrogen,
respectively. Formation of dibromide product 24 could be explained by bromination of C
followed by cyclization. Small amounts of pyrrolopyrazinones 11 and 19 might be obtained by
ring expansion of aminals 13 and 22, respectively.
Scheme 4. Proposed mechanism for the formation of haloaminals 13 and 22, and
pyrrolopyrazinones 11 and 19
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We therefore investigated the synthesis of 11 by ring expansion of aminals 13 and 22 with a
silver salt, which has been employed as an activator in ring-expansion of alkyl halides.21
Bromoaminal 13 was heated with AgOTf in toluene at 100 °C to give 4-substituted
pyrrolopyrazinone 19 in high yield without formation of 11 (Scheme 5). The reason for preferential
migration of the pyrrole nitrogen is not clear. Chloroaminal 22 was also transformed into 19
exclusively under similar conditions. Thus, we established a two-step and regiocontrolled
synthesis of 4-substituted pyrrolopyrazinone 19 from 8 and 1-halo-1-alkyne.
Scheme 5. Ring expansion of haloaminals 13 and 22 to pyrrolopyrazinone 19
Synthesis of peramine
With these new concise procedures for constructing pyrrolopyrazinones, we next investigated
their application to the synthesis of peramine (1). As peramine could be synthesized by
guanidinylation of compound E under Mitsunobu conditions (Scheme 6),22,23 we attempted to
prepare E from N-methylpyrrole amide 8 and a derivative of 5-bromopent-4-yn-1-ol (26) by the
annulation developed in this study. Our preliminary experiments indicated that an intramolecular
reaction of 26 occurred under the annulation conditions. To avoid an intramolecular reaction of
1-bromoalkyne 26, the corresponding TBS ether 27 was used for the annulation. Bromoacetylene
27 was easily prepared from pent-4-yn-1-ol (25) in two steps, including silylation and bromination
under conventional conditions.
Scheme 6. Synthetic plan for peramine (1)
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Annulation between 8 and 27 was carried out under the conditions of entry 4 (Table 1) to afford
pyrrolopyrazinone 28 and its bromide 29 in 13% and 12% yields, respectively. The yields of 28
and 29 were improved to 22% and 19% when the conditions of entry 8 using ligand IV were
employed (Scheme 7). In this specific case, compound 30 was also obtained in 14% yield.24
These yields are lower than those obtained for the model system, probably because the oxygen
functionality of 27 may interact with the alkyne moiety under these conditions.
Scheme 7. Annulation of N-methylpyrrole amide 8 and bromoacetylene 27
Products 28 and 29 were then converted into peramine (1), as shown in Scheme 8. The TBS
group of 28 was deprotected with TBAF to give 31, whereas hydrogenolysis of 29 resulted in
debromination concomitant with deprotection of the TBS group to give 31. Guanidinylation of 31
with bis-Boc-guanidine under Mitsunobu conditions using DMEAD (di-2-methoxyethyl
azodicarboxylate)25 and Ph3P gave 32 in 82% yield. The NMR spectra of these products were in
good agreement with the literature data.11d Deprotection of the Boc groups with TFA furnished
peramine (1) in good yield. NMR spectra of the corresponding diacetate 33 were identical to those
in the literature.26
Scheme 8. Synthesis of peramine (1)
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In summary, we have developed two methods using the same starting materials for
regiocontrolled construction of 3- and 4-substituted pyrrolopyrazinones from N-methylpyrrole
amide and 1-halo-1-alkyne. The copper-catalyzed annulation method realized the short-step
synthesis of peramine compared to the previous routes.11 This new route should provide an easily
accessible route to a variety of analogues of the natural product.
Experimental27
1-Benzyl-N-methyl-1H-pyrrole-2-carboxamide (9): A screw-cap test tube equipped with a
magnetic stir bar, was charged with pyrrole amide 8 (62 mg, 0.51 mmol) and DMF (1.0 mL). After
the pyrrole amide was completely dissolved in DMF, K3PO4 (0.16 g, 0.75 mmol) and benzyl
bromide (60 ꢀL, 0.48 mmol) were added. The mixture was stirred at 80 °C for 2 hours, and then
diluted with water (1 mL) after cooling to room temperature. The mixture was extracted with
AcOEt (x3). The combined organic extracts were washed with H2O (x1) and brine (x1), dried over
anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography (silica
gel, 3.3 g, hexane:Et2O = 1:2) to afford compound 9 (71 mg, 65%) as a white solid. Mp 90-92 °C.
IR (KBr) νmax 3364, 1631 cm-1. 1H NMR (400 MHz, DMSO-d6) δ 2.66 (3H, d, J = 4.5 Hz, N-CH3),
5.59 (2H, s, Ph-CH2-), 6.07 (1H, dd, J = 4.0, 2.5 Hz, pyrrole), 6.76 (1H, dd, J = 4.0, 2.0 Hz, pyrrole),
7.02 (1H, dd, J = 2.5, 2.0 Hz, pyrrole), 7.08 (2H, d, J = 7.5 Hz, Ph), 7.21 (1H, m, Ph), 7.24-7.32
(2H, m, Ph), 7.95 (1H, m, NH). 13C NMR (100 MHz, DMSO-d6) δ 25.5, 50.5, 107.3, 112.4, 125.2,
126.7, 126.9, 127.0, 128.3, 139.7, 161.8. HRMS (ESI, positive): calcd for C13H14N2ONa (M+Na),
237.0998; found, 237.1027.
General procedure of annulation of Table 1 exemplified by entry 8: A screw-cap test tube
equipped with a magnetic stir bar, was charged with pyrrole amide 8 (62 mg, 0.50 mmol), Cu(acac)2
(11 mg, 0.050 mmol), ligand IV (23 mg, 0.099 mmol) and dry DMF (1 ml). The reaction vessel was
flushed with argon and capped. The mixture was stirred at 80 °C for 30 minutes, and the mixture
was cooled to room temperature. Then bromoacetylene 10 (114 mg, 0.764 mmol) and K3PO4 (214
mg, 1.01 mmol) were added. The reaction vessel was flushed with argon and capped, and then
stirred at 60 °C for 4 hours when 1-bromo-1-octyne was consumed by TLC analysis. The reaction
mixture was cooled to room temperature, and diluted with H2O (2 mL). The mixture was filtered
through a pad of celite, and the filtrate was extracted with CH2Cl2 (x3). The combined organic
extracts were washed with H2O (x1) and brine (x1), dried over anhydrous Na2SO4, and concentrated.
The residue contained compounds 11, 12, 13, 14, and 15, whose yields were calculated by the
relative integration values of 1H NMR spectra (in CDCl3) of the products and
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1,1,2,2-tetrachloroethane as an internal standard. The starting material 8 was contained in the
aqueous layer, which was extracted with EtOAc (x4) after saturation of the aqueous layer with NaCl.
The combined extract was dried over Na2SO4 and then concentrated. The yield of 8 was calculated
1
by the relative integration values of H NMR spectra (in DMSO-d6) of the product and
1,1,2,2-tetrachloroethane as an internal standard.
Purification of compounds 11, 12, 14, and 15: The residue containing these compounds was
purified by column chromatography (flash silica gel, 7 g, hexane:AcOEt = 4:1 to 3:1) to afford a
mixture of compounds 12 and 15 (51 mg, 12:15 = 1:1) and a mixture of compounds 11 and 14 (28
mg, 11:14 = 6:1). The former mixture was further purified by column chromatography (flash
silica gel, 5 g, hexane:AcOEt = 6:1 to 4:1) to afford compounds 12 (24 mg, 15%) and 15 (28 mg
16%), respectively. The latter mixture was further purified by preparative TLC (benzene:MeCN =
4:1) to afford compounds 11 (23 mg, 20%) and 14 (4 mg, 3%).
1
Compound 11: light yellow solid. Mp 91-95 °C. IR (KBr) νmax 1623 cm-1. H NMR (400 MHz,
CDCl3) δ 0.90 (3H, t, J = 7.0 Hz , -CH2-CH3), 1.26-1.46 (6H, m, -(CH2)3-), 1.59 (2H, m, -CH2-),
2.47 (2H, t, J = 8.0 Hz, -CH=C-CH2), 3.44 (3H, s, N-CH3), 6.50 (1H, dd, J = 4.0, 2.5 Hz, pyrrole),
6.78 (1H, s, -CH=C-CH2), 7.00 (1H, dd, J = 2.5, 1.5 Hz, pyrrole), 7.03 (1H, brd, J = 4.0 Hz,
pyrrole). 13C NMR (100 MHz, CDCl3) δ 14.0, 22.5, 28.3, 28.8, 28.9, 30.7, 31.5, 105.7, 109.4, 112.0,
117.2, 123.1, 128.7, 157.2. HRMS (ESI, positive): calcd for C14H20N2ONa (M+Na), 255.1468;
found, 255.1485.
Compound 12: Colorless oil. IR (KBr) νmax 1659 cm-1. 1H NMR (400 MHz, CDCl3) δ 0.91 (3H, t, J
= 7.0 Hz, -CH2-CH3), 1.28-1.40 (4H, m, -(CH2)2-), 1.40-1.50 (2H, m, -CH2-), 1.53-1.64 (2H, m,
-CH2-), 2.74-2.83 (2H, m, -CBr=C-CH2), 3.56 (3H, s, N-CH3), 6.57 (1H, dd, J = 4.0, 2.5 Hz,
13
pyrrole), 7.21 (1H, dd, J = 4.0, 1.5 Hz, pyrrole), 7.38 (1H, dd, J = 2.5, 1.5 Hz, pyrrole). C NMR
(100 MHz, CDCl3) δ 14.0, 22.5, 28.1, 29.0, 30.4, 31.4, 31.5, 97.6, 111.9, 112.0, 119.4, 123.8, 127.6,
156.2. HRMS (ESI, positive): calcd for C14H19N2ONaBr (M+Na), 333.0573; found, 333.0589.
1
Compound 13: Colorless crystal. Mp 117-121 °C. IR (KBr) νmax 1676 cm-1. H NMR (400 MHz,
CDCl3) δ 0.61 (1H, m, -CHaHb-(CH2)3-), 0.82 (3H, t, J = 7.0 Hz, -CH2-CH3), 1.00 (1H, m,
-CHaHb-(CH2)3-), 1.09-1.26 (6H, m, -(CH2)3-CH3), 1.96-2.09 (2H, m, C(aminal)-CH2-), 2.96 (3H, s,
N-CH3), 3.69 (1H, d, J = 11.5 Hz, -CHaHb-Br), 3.73 (1H, d, J = 11.5 Hz, -CHaHb-Br), 6.45 (1H, dd,
J = 4.0, 2.5 Hz, pyrrole), 6.59 (1H, dd, J = 4.0, 1.0 Hz, pyrrole), 6.89 (1H, dd, J = 2.5, 1.0 Hz,
13
pyrrole). C NMR (100 MHz, CDCl3) δ 13.9, 22.2, 22.4, 24.5, 28.5, 31.4, 35.1, 37.2, 78.8, 104.7,
114.8, 115.3, 128.1, 160.5. HRMS (ESI, positive): calcd for C14H21N2ONaBr (M+Na), 335.0730;
found, 335.0748.
Compound 14: Yellow oil. IR (KBr) νmax 1669 cm-1. 1H NMR (400 MHz, CDCl3) δ 0.90 (3H, t, J =
7.0 Hz, -CH2-CH3), 1.23-1.43 (6H, m, -(CH2)3-), 1.62 (2H, quint, J = 7.0 Hz -CH2-), 2.34 (2H, t, J =
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7.0 Hz, -CH=C-CH2), 3.16 (3H, s, C=N-CH3), 6.33 (1H, dd, J = 4.0, 3.0 Hz, pyrrole), 6.49 (1H, s,
-CH=C-CH2), 6.76 (1H, dd, J = 3.0, 1.5 Hz, pyrrole), 6.84 (1H, brd, J = 4.0 Hz, pyrrole). 13C NMR
(100 MHz, CDCl3) δ 14.0, 22.5, 26.5, 28.6, 30.7, 31.5, 32.8, 103.4, 109.1, 111.1, 118.0, 119.6,
143.0, 146.1. HRMS (ESI, positive): calcd for C14H21N2O (M+H), 233.1648; found, 233.1644.
1
Compound 15: Yellow oil. IR (NaCl) νmax 1687, 1469 cm-1. H NMR (400 MHz, CDCl3) δ 0.90
(3H, t, J = 7.0 H, -CH3), 0.91 (3H, t, J = 7.0 H, -CH3), 1.20-1.54 (12H, m, -CH2-), 1.58-1.73 (4H, m,
-CH2-), 2.49 (2H, t, J = 7.0 Hz, -CH2-), 2.60 (2H, t, J = 7.0 Hz, -CH2-), 3.16 (3H, s, C=N-CH3),
6.35 (1H, dd, J = 4.0, 2.5 Hz, pyrrole), 6.86 (1H, dd, J = 4.0, 1.5 Hz, pyrrole), 7.12 (1H, dd, J = 2.5,
13
1.5 Hz, pyrrole). C NMR (100 MHz, CDCl3) δ 13.99, 14.03, 19.6, 22.5, 26.9, 28.55, 28.57, 28.6,
30.4, 31.3, 31.5, 32.9, 69.5, 99.8, 102.2, 109.9, 110.9, 118.0, 119.0, 145.0, 147.3. HRMS (ESI,
positive): calcd for C22H33N2O (M+H), 341.2587; found, 341.2569.
Transformation of 12 to 11: A round-bottomed flask (5 mL) equipped with a magnetic stir bar,
was charged with compound 12 (32.6 mg, 0.105 mmol), 5% Pd/C (28 mg) and MeOH (0.50 mL).
The reaction vessel was evacuated and filled with hydrogen. This procedure was repeated three
times. The mixture was stirred vigorously under a slightly positive pressure of hydrogen (with a
Tedlar Bag). After 1 hour, the mixture was treated with NEt3 (0.75 mL) and filtered through a pad of
celite. The filtrate was concentrated. The residue was purified by column chromatography (flash
neutral silica gel, 1 g, hexane:Et2O = 1:2) to afford compound 11 (19.8 mg, 81%) as a white solid.
Reaction of 16 with 1-bromo-1-octyne (10) (Scheme 3): A flame-dried screw-cap test tube
equipped with a magnetic stir bar, was charged with N,N-dimethyl pyrrole amide 16 (67.0 mg,
0.485 mmol), Cu(acac)2 (13 mg, 0.055 mmol), ligand IV (26.3 mg, 0.111 mmol) and dry DMF (1.0
mL). The reaction vessel was flushed with argon and capped. After stirring at 80 °C for 30 minutes,
the mixture was cooled to room temperature. Then 1-bromo-1-octyne (10) (130 mg, 0.77 mmol)
and K3PO4 (211 mg, 1.00 mmol) were added. The reaction vessel was flushed with argon and
capped. The mixture was stirred at 60 °C for 4.5 hours, and then diluted with H2O (1 mL) after
cooling to rt. The mixture was filtered through a pad of celite and the filtrate was extracted with
AcOEt-hexane (3:1) (x3). The combined organic extracts were washed with H2O (x1) and brine
(x1), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column
chromatography (flash silica gel, 3.8 g, hexane:Et2O = 1:2) to afford a mixture of compounds 17
and 18 (79.4 mg, 17:18 = 3:1), which was further purified by preparative TLC (hexane:acetone =
10:1) to give compound 17 (56.1 mg, 47%) as a colorless oil and compound 18 (14.1 mg, 11%) as a
red oil.
Compound 17: IR (KBr) νmax 1638, 2359 cm-1. 1H NMR (400 MHz, CDCl3) δ 0.89 (3H, t, J = 7.0
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Hz, -CH2-CH3), 1.22-1.46 (6H, m, -(CH2)3-), 1.50-1.61 (2H, m, -CH2-), 2.34 (2H, t, J = 7.0 Hz ,
-C≡C-CH2-), 3.08 (6H, s, N(CH3)2), 6.11 (1H, dd, J = 4.0, 3.0 Hz, pyrrole), 6.35 (1H, dd, J = 4.0,
1.5 Hz, pyrrole), 6.87 (1H, dd, J = 3.0, 1.5 Hz, pyrrole). 13C NMR (100 MHz, CDCl3) δ 14.0, 18.3,
22.5, 28.56, 28.64, 31.3, 68.9, 72.4, 109.0, 112.3, 127.3, 129.5, 162.8. HRMS (ESI, positive): calcd
for C15H22N2ONa (M+Na), 269.1624; found, 269.1615.
1
Compound 18: IR (KBr) νmax 1730, 1618 cm-1. H NMR (400 MHz, CDCl3) δ 0.87 (3H, t, J = 7.0
Hz, -CH2-CH3), 1.19-1.35 (6H, m, -(CH2)3-), 1.50-1.70 (2H, m, -CH2-), 2.41 (2H, t, J = 7.5 Hz ,
-C=O-CH2-), 2.88-3.41 (6H, brs, N(CH3)2), 4.96 (2H, s, N(pyrrole)-CH2-C=O), 6.17 (1H, dd, J =
4.0, 2.5 Hz, pyrrole), 6.46 (1H, dd, J = 4.0, 2.0 Hz, pyrrole), 6.64 (1H, dd, J = 2.5, 2.0 Hz, pyrrole).
13C NMR (100 MHz, CDCl3) δ 14.0, 22.5, 23.3, 28.8, 31.5, 39.4, 57.5, 107.4, 113.7, 125.1, 126.0,
164.0, 205.5. HRMS (ESI, positive): calcd for C15H24N2O2Na (M+Na), 287.1730; found, 287.1723.
A General procedure of Table 2 exemplified by entry 1 A flame-dried screw-cap tube equipped
with a magnetic stir bar, was charged with pyrrole amide 8 (75 mg, 0.60 mmol) and DMF (1.0 mL).
After the pyrrole amide was completely dissolved in DMF, K3PO4 (384 mg, 1.80 mmol) and
1-bromo-1-octyne 10 (227 mg, 1.20 mmol) were added. The mixture was heated at 120 °C for 4
hours. The reaction was cooled to room temperature and diluted with H2O (1 mL). The mixture was
treated with saturated Na2SO3 solution, and the crude mixture was extracted with AcOEt (x3). The
combined organic extracts were washed with H2O (x1) and brine (x1), dried over anhydrous
Na2SO4, and concentrated. The residue contained compounds 13, 11, 19 and 24, whose yields were
1
calculated by relative integration values of H NMR spectra (in DMSO-d6) of the products to
1,1,2,2-tetrachloroethane as an internal standard.
Purification of compounds 13, 11, and 24: The residue was purified by column chromatography
(neutral flash silica gel, 10 g hexane:AcOEt = 5:7 to 3:1 to 1:1 ) to give a mixture of compounds 13,
11, and 24 (13:11:24 = 39:4:7, 114 mg), which was further purified by column chromatography
(neutral flash silica gel, 6 g, benzene:AcOEt = 15:1 to 11.5:1 to 8:1) to afford compounds 13 (68
mg, 36%), 11 (3 mg, 2%) and 24 (20 mg, 9%).
In entry 2 and 3, product 22 could not be completely separated from compound 11 by column
chromatography, however, pure 22 was obtained from the crude mixture by the followings:
Column chromatography (flash silica gel, 7 g, hexane:AcOEt = 2:1 to 1:1) gave a mixture of
compounds 22 and 11 (22:11 = 6:1, 98 mg), which was further purified by column chromatography
(flash silica gel, 5 g, hexane:THF = 3:1 to 2:1) to afford compound 22 (28 mg, 21%) and a mixture
of 11 and 22 (22:11 = 63:1, 49 mg).
Compound 22: Light yellow solid. Mp 102-105 °C. IR (KBr) νmax 1676 cm-1. 1H NMR (400 MHz,
CDCl3) δ 0.61 (1H, m, -CHaHb-(CH2)3-), 0.82 (3H, t, J = 7.0 Hz, -CH2-CH3), 1.00 (1H, m,
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-CHaHb-(CH2)3-), 1.09-1.28 (6H, m, -(CH2)3-CH3), 1.93-2.08 (2H, m, C(aminal)-CH2-), 2.97 (3H, s,
N-CH3), 3.77 (1H, d, J = 12.0 Hz, -CHaHb-Cl), 3.82 (1H, d, J = 12.0 Hz, -CHaHb-Cl), 6.45 (1H, dd,
J = 4.0, 2.5 Hz, pyrrole), 6.59 (1H, dd, J = 4.0, 1.0 Hz, pyrrole), 6.90 (1H, dd, J = 2.5, 1.0 Hz,
13
pyrrole). C NMR (100 MHz, CDCl3) δ 13.9, 21.6, 22.4, 24.7, 28.5, 31.4, 34.4, 48.6, 79.5, 104.8,
114.8, 115.6, 128.0, 160.6. HRMS (ESI, positive): calcd for C14H21N2OClNa (M+Na), 291.1235;
found, 291.1238.
Compound 19: Colorless oil. IR (KBr) νmax 1636 cm-1. 1H NMR (400 MHz, CDCl3) δ 0.90 (3H, t, J
= 7.0 Hz, -CH2-CH3), 1.27-1.48 (6H, m, -(CH2)3-), 1.68 (2H, quint, J = 7.0 Hz, -CH2-), 2.61 (2H, t,
J = 8.0 Hz, -CH=C-CH2), 3.44 (3H, s, N-CH3), 6.14 (1H, s, -CH=C-CH2), 6.59 (1H, dd, J = 4.0, 2.5
13
Hz, pyrrole), 7.11 (1H, dd, J = 2.5, 1.5 Hz, pyrrole), 7.15 (1H, dd, J = 4.0, 1.5 Hz, pyrrole). C
NMR (100 MHz, CDCl3) δ 14.0, 22.5, 26.3, 28.7, 29.0, 31.5, 34.7, 110.2, 112.4, 115.0, 115.5, 119.5,
124.5, 156.0. HRMS (ESI, positive): calcd for C14H20N2ONa (M+Na), 255.1468; found, 255.1486.
1
Compound 24: Yellow oil. IR (KBr) νmax 1699 cm-1. H NMR (400 MHz, CDCl3) δ 0.59 (1H, m,
-CHaHb-(CH2)3-), 0.82 (3H, t, J = 7.0 Hz, -CH2-CH3), 0.99 (1H, m, -CHaHb-(CH2)3-), 1.09-1.29 (6H,
m, -(CH2)3-CH3), 2.05 (1H, ddd, J = 15.0, 12.0, 4.5 Hz, C(aminal)-CHaHb-), 2.46 (1H, ddd, J = 15.0,
12.0, 4.5 Hz, C(aminal)-CHaHb-), 2.97 (3H, s, N-CH3), 5.91 (1H, s, -CHBr2), 6.47 (1H, dd, J = 4.0,
2.5 Hz, pyrrole), 6.66 (1H, dd, J = 4.0, 1.0 Hz, pyrrole), 7.18 (1H, dd, J = 2.5, 1.0 Hz, pyrrole). 13C
NMR (100 MHz, CDCl3) δ 13.9, 22.4, 22.9, 25.1, 28.5, 31.4, 33.9, 49.5, 81.6, 105.4, 114.7, 117.4,
128.4, 160.5. HRMS (ESI, positive): calcd for C14H20N2ONaBr2 (M+Na), 412.9835; found,
412.9828.
Ring expansion of 13. A Young tube equipped with a magnetic stir bar and covered with aluminum
foil, was charged with aminal 13 (18 mg, 0.62 mmol), AgOTf (104 mg, 0.380 mmol) and toluene
(0.37 mL). The mixture was stirred at 100 °C for 5 hours, then cooled to room temperature. The
mixture was filtered through a pad of celite, saturated NaHCO3 solution was added. The filtrate was
extracted with AcOEt (x3). The combined organic extracts were washed with H2O (x1) and brine
(x1), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column
chromatography (flash neutral silica gel, 0.5 g, hexane:Et2O = 1:8) to afford compound 19 (12.2 mg,
93%) as a yellow oil.
Annulation of 8 and 27 (Scheme 7): A flame-dried round-bottomed flask (10 mL) equipped with a
magnetic stir bar, was charged with pyrrole amide 8 (310 mg, 2.50 mmol), Cu(acac)2 (55 mg, 0.25
mmol), ligand IV(116 mg, 0.496 mmol) and dry DMF (5 ml). The reaction vessel was flushed with
argon and connected with an inlet adapter with 3-way stop-cock. The mixture was stirred at 80 °C
for 30 minutes under argon flow, and the mixture was cooled to room temperature. Then
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bromoacetylene 27 (1.04 g, 3.75 mmol) and K3PO4 (1.06 g, 4.98 mmol) were added. The mixture
was degassed by four freeze-thaw and covered with argon, and then stirred at 60 °C for 3 hours
when 27 was consumed by TLC analysis. The reaction mixture was cooled to room temperature,
and diluted with H2O (2 mL). The mixture was filtered through a pad of celite, and the filtrate was
extracted with CH2Cl2 (x3). The combined organic extracts were washed with H2O (x1) and brine
(x1), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column
chromatography (flash neutral silica gel, 57 g, hexane:AcOEt = 6:1 to 3:1) to afford compound 28
(179 mg, 22%), compound 29 (190 mg, 19%) and compound 30 (184 mg, 14%).
1
Compound 28: White solid. Mp 123-127 °C. IR (KBr) νmax 1627 cm-1. H NMR (400 MHz,
CDCl3) δ 0.07 (6H, s, (CH3)3C-Si-(CH3)2-), 0.91 (9H, s, (CH3)3C-Si-(CH3)2-), 1.74-1.86 (2H, m,
-CH2-), 2.61 (2H, brt, J = 8.5 Hz, -CH=C-CH2), 3.47 (3H, s, N-CH3), 3.70 (2H, t, J = 5.5 Hz,
-OCH2-), 6.51 (1H, dd, J = 4.0, 2.5 Hz, pyrrole), 6.81 (1H, brs, -CH=C-CH2), 7.00 (1H, dd, J = 2.5,
1.5 Hz, pyrrole), 7.05 (1H, brd, J = 4.0 Hz, pyrrole). 13C NMR (100 MHz, CDCl3) δ -5.4, 18.2, 25.9,
27.0, 29.0, 31.5, 61.5, 105.9, 109.5, 112.1, 117.2, 123.1, 128.3, 157.2. HRMS (ESI, positive): calcd
for C17H28N2O2NaSi (M+Na), 343.1812; found, 343.1789.
Compound 29: Light yellow oil. IR (KBr) νmax 1661 cm-1. 1H NMR (400 MHz, CDCl3) δ 0.08 (6H,
s, (CH3)3C-Si-(CH3)2-), 0.91 (9H, s, (CH3)3C-Si-(CH3)2-), 1.74-1.86 (2H, m, -CH2-), 2.87-2.96 (2H,
m, -CBr=C-CH2), 3.58 (3H, s, N-CH3), 3.70-3.73 (2H, t, J = 5.5 Hz, -OCH2), 6.57 (1H, dd, J = 4.0,
3.0 Hz, pyrrole), 7.21 (1H, dd, J = 4.0, 1.5 Hz, pyrrole), 7.37 (1H, dd, J = 3.0, 1.5 Hz, pyrrole). 13C
NMR (100 MHz, CDCl3) δ -5.4, 18.2, 25.9, 28.3, 30.4, 31.1, 61.9, 97.6, 111.9, 112.1, 119.4, 123.8,
127.4, 156.2. HRMS (ESI, positive): calcd for C17H28N2O2SiBr (M+H), 399.1098; found, 399.1125.
1
Compound 30: Light yellow oil. IR (NaCl) νmax 1687, 1470 cm-1. H NMR (400 MHz, CDCl3) δ
0.06 (6H, s, (CH3)3C-Si-(CH3)2-), 0.07 (6H, s, (CH3)3C-Si-(CH3)2-), 0.90 (9H, s,
(CH3)3C-Si-(CH3)2-), 0.91 (9H, s, (CH3)3C-Si-(CH3)2-), 1.78-1.95 (4H, m, -CH2-), 2.58 (2H, t, J =
7.0 Hz, -CH2-), 2.69 (2H, t, J = 7.5 Hz, -CH2-), 3.17 (3H, s, C=N-CH3), 3.70 (2H, t, J = 6.0 Hz,
-OCH2-), 3.74 (2H, t, J = 6.0 Hz, -OCH2-), 6.36 (1H, dd, J = 4.0, 2.5 Hz, pyrrole), 6.91 (1H, brs,
13
pyrrole), 7.13 (1H, dd, J = 2.5, 1.5 Hz, pyrrole). C NMR (100 MHz, CDCl3) δ -5.4, 16.1, 18.2,
18.3, 25.8, 25.9, 27.3, 30.1, 31.6, 32.7, 61.4, 62.2, 69.3, 99.7, 102.2, 110.3, 111.1, 118.2, 118.6,
145.2, 146.9. HRMS (ESI, positive): calcd for C28H49N2O3Si2 (M+H), 517.3276; found,
517.3297.
Compound 31 from 28. To a solution of compound 28 (0.154 g, 0.429 mmol) in dry THF (2.0 mL)
at 0 °C was added TBAF (1.0 M in THF, 0.6 mL, 0.58 mmol). The mixture was stirred until
compound 28 was consumed by TLC analysis. The reaction was quenched with saturated NH4Cl
solution (1 mL), and the crude mixture was extracted with AcOEt (x6). The combined organic layer
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was washed with brine (x1), dried over anhydrous Na2SO4, and concentrated. The residue was
purified by column chromatography (silica gel, 11 g, CH2Cl2:acetone = 2:1) to afford compound 31
1
(89.7 mg, 91%) as a white solid. Mp 127-131 °C. IR (KBr) νmax 3470, 1633 cm-1. H NMR (400
MHz, acetone-d6) δ 1.77-1.88 (2H, m, -CH2-), 2.69 (2H, td, J = 7.0, 0.5 Hz, -CH=C-CH2-), 3.43
(3H, s, N-CH3), 3.63-3.73 (3H, m, -CH2-OH), 6.47 (1H, dd, J = 4.0, 2.5 Hz, pyrrole), 6.84 (1H, brd,
J = 4.0 Hz, pyrrole), 7.14 (1H, brs, -CH=C-CH2-), 7.22 (1H, dd, J = 2.5, 1.5 Hz, pyrrole). 13C NMR
(100 MHz, acetone-d6) δ 27.5, 28.9, 32.3, 61.3, 106.3, 109.4, 112.3, 118.6, 124.1, 129.9, 157.2.
HRMS (ESI, positive): calcd for C11H14N2O2Na (M+Na), 229.0948; found, 229.0921.
Compound 31 from 29. A round-bottomed flask (5 mL) equipped with an inlet adaptor and
magnetic stir bar, was charged with compound 29 (32.6 mg, 105 ꢀmol), 5% Pd/C (28 mg) and
MeOH (0.5 mL). The reaction vessel was evacuated and then filled with hydrogen. This
procedure was repeated three times. The mixture was stirred vigorously under a slightly positive
pressure of hydrogen (with a Tedlar Bag) until compound 29 was consumed by TLC analysis. The
mixture was treated with NEt3 (0.75 mL), then filtered through a pad of celite. The filtrate was
concentrated. The residue was purified by column chromatography (flash neutral silica gel, 0.85 g,
acetone:CH2Cl2:MeOH = 40:10:1) to afford compound 31 (13.4 mg, 82%) as a white solid.
Compound 32. A flame-dried round-bottomed flask (5 mL) equipped with a magnetic stir bar, was
charged with the compound 31 (38 mg, 0.18 ꢀmol), N,N’-bis(tert-butyloxycarbonyl)guanidine (75
mg, 0.29 mmol), DMEAD (68 mg, 0.29 mmol) and triphenylphosphine (76 mg, 0.29 mmol). Dry
THF (1.9 mL) was added and the solution was stirred at 40 °C until compound 31 was consumed by
TLC analysis. The resulting suspension was dissolved in CH2Cl2 and concentrated. The residue was
re-dissolved in CH2Cl2 and water, then extracted with CH2Cl2 (x3). The combined organic layer
was washed H2O (x1) and brine (x1), dried over anhydrous Na2SO4, and concentrated. The residue
was purified by column chromatography (neutral open silica gel, 5 g, hexane:AcOEt = 1:1) to
afford compound 32 (67.0 mg, 82%) as a white solid. Mp 195-197 °C (lit.11d 197-199 °C). IR
(KBr) νmax 3386, 1722, 1640, 1609 cm-1. 1H NMR (400 MHz, CDCl3) δ 1.50 (9H, s, Boc), 1.51 (9H,
s, Boc), 1.92 (2H, quant, J = 7.5 Hz, -CH2-), 2.57 (2H, t, J = 7.5 Hz, -CH=C-CH2-), 3.48 (3H, s,
N-CH3), 3.99 (2H, m, -CH2-N-), 6.51 (1H, dd, J = 4.0, 2.5 Hz, pyrrole), 6.96 (1H, s, -CH=C-CH2-),
7.00-7.08 (2H, m, pyrrole), 9.19 (1H, brs, NH), 9.38 (1H, brs, NH). 13C NMR (100 MHz, CDCl3) δ
27.2, 27.9, 28.0, 28.3, 28.9, 43.9, 79.0, 84.1, 105.9, 109.6, 112.1, 117.5, 123.0, 127.7, 154.7, 157.1,
160.5, 163.8. HRMS (ESI, positive): calcd for C22H34N5O5 (M+H), 448.2555; found, 488.2552.
Peramine (1): To a solution of compound 32 (19.6 mg, 0.067 ꢀmol) in CH2Cl2 (1.0 mL) was added
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TFA (1.0 mL) at 0 °C. After stirring for 30 minutes at room temperature, the mixture was
concentrated in vacuo. The residue was purified by column chromatography (Cosmosil 75C18-OPN,
2 g, H2O to 8% MeOH containing 0.001% TFA) to afford peramine (1) (13 mg, 83%) as a light
orange oil. 1H NMR (400 MHz, 4% CD3CO2D/D2O) δ 1.56-1.72 (2H, m, -CH2-), 2.31 (2H, t, J =
7.5 Hz, -CH=C-CH2-), 3.09 (2H, t, J = 7.0 Hz, -CH2-N-), 3.13 (3H, s, N-CH3), 6.46 (1H, dd, J = 4.0,
2.5 Hz, pyrrole), 6.79 (1H, brd J = 4.0 Hz, pyrrole), 6.87 (1H, s, -CH=C-CH2), 7.04 (2H, dd, J = 3.0,
13
1.5 Hz, pyrrole). C NMR (100 MHz, 4% CD3CO2D/D2O) δ 26.5, 27.2, 29.6, 40.5, 108.0, 109.3,
113.0, 113.1 119.5, 121.9, 127.5, 128.2, 157.0, 158.5. HRMS (ESI, positive): calcd for C12H18N5O
(M+H), 248.1506; found, 248.1506.
Peramine diacetate 33: A round-bottomed flask (10 mL) equipped with magnetic stir bar, was
charged with peramine (1) (7.9 mg, 22 ꢀmol), NEt3 (400 ꢀL), Ac2O (250 ꢀL) and pyridine (250 ꢀL),
and then capped with a rubber septum. After stirring at room temperature for 1 hour, NEt3 (100 ꢀL),
Ac2O (60 ꢀL) and pyridine (60 ꢀL) were added. After further stirring for 1 hour, the resulting
solution was diluted with toluene (3 mL) and then concentrated in vacuo. The residue was dissolved
in toluene (3 mL) and evaporated in vacuo. This procedure was repeated three times. Purification
by preparative TLC (CH2Cl2:acetone = 3:1) afforded compound 33 (4.8 mg, 66%) as a light yellow
1
solid. Mp 130-132 °C (lit.11a; 150-152 °C). IR (KBr) νmax 3286, 1698, 1677, 1623 cm-1. H NMR
(400 MHz, CDCl3) δ 1.87-2.01 (2H, m, -CH2-), 2.13 (3H, s, Ac), 2.18 (3H, s, Ac), 2.59 (2H, t, J =
7.0 Hz, -CH=C-CH2-), 3.47 (3H, s, N-CH3), 3.55 (2H, q, J = 6.5 Hz -CH2-N-), 6.53 (1H, dd, J = 4.0,
2.5 Hz, pyrrole), 6.87 (1H, s, -CH=C-CH2-), 7.02 (1H, dd, J = 2.5, 1.5 Hz, pyrrole), 7.06 (1H, brd, J
= 4.0 Hz, pyrrole), 9.15 (1H, brs, NH). 13C NMR (100 MHz, CDCl3) δ 25.1, 27.6, 28.0, 28.7, 29.0,
39.8, 106.1, 109.8, 112.3, 117.5, 123.1, 127.3, 155.7, 157.1, 172.8, 186.1. HRMS (ESI, positive):
calcd for C16H21N5O3Na (M+Na), 354.1537; found, 354.1564.
Acknowledgment: This work was supported by a Grant-in-Aid for Scientific Research (B) (No.
16H04915), a Grant-in-Aid for Scientific Research on Innovative Areas “Chemical Biology of
Natural Products” (No. 23102015) from MEXT. Y.Y. thanks to the Program for Leading Graduate
Schools: IGER Program in Green Natural Sciences from MEXT.
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17. The structures of 11, 14, and 15 were determined by analysis of 2D-NMR spectra. For the
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Tetrahedron Lett. 2003, 44, 4203-4206.
22. Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994, 35, 977-980.
23. During preparation of this manuscript, a similar route (from E to 1) was reported. See ref.
11d.
24. The structure of 30 was determined by analogous manner to compound 15.
25. Sugiura, T.; Hagiya, K. Chem. Lett. 2007, 36, 566-567.
26. NMR spectra of peramine (1) were not identical to those reported in ref. 1b, 11a, and 11d,
probably because of the different counterions of the guanidinium group. When NMR spectra
of our synthesized peramine were collected under the same conditions, different chemical shifts
were observed. We therefore confirmed the structure of the corresponding diacetate 33,
whose NMR spectra were identical to those in the literature.
27. General experimental is included in the supporting information.
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