Convenient preparation of 5-alkylidene-2,5-dihydropyrrol-2-ones by ring-transformations of γ-alkylidenebutenolides: Formal synthesis of pukeleimide A

Article abstract of DOI:10.1055/s-2005-862368

The reaction of γ-alkylidenebutenolides, readily available by cyclization of 1,3-bis-silyl enol ethers with oxalyl chloride, with amines in glacial acetic acid allows a convenient synthesis of 5-alkylidene-2,5- dihydropyrrol-2-ones. This method was applie

Full text of DOI:10.1055/s-2005-862368

LETTER
453
Convenient Preparation of 5-Alkylidene-2,5-dihydropyrrol-2-ones by
Ring-Transformations of g-Alkylidenebutenolides: Formal Synthesis of
Pukeleimide A
F
ormal Synthesis
h
of Pukeleim
r
ide
A
istian Haase, Peter Langer*
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18051 Rostock, Germany
E-mail: peter.langer@uni-greifswald.de
Received 29 November 2004
Me3SiO
OSiMe3
OMe
Abstract: The reaction of g-alkylidenebutenolides, readily avail-
able by cyclization of 1,3-bis-silyl enol ethers with oxalyl chloride,
with amines in glacial acetic acid allows a convenient synthesis of
5-alkylidene-2,5-dihydropyrrol-2-ones. This method was applied to
a formal total synthesis of the natural product pukeleimide A.
O
O
a
1
OMe
Cl
+
O
HO
O
O
Cl
3a (76%)
Key words: butenolides, cyclization, natural products, pyrrolones,
ring-transformation
2
b
O
H
OMe
N
O
5-Alkylidene-2,5-dihydropyrrol-2-ones are of consider-
able pharmacological relevance and occur in a number of
natural products.1 This structural class includes the ama-
ryllidacae alkaloids,2 the pukeleimides A-G,3 holomycin,4
isoampullicin, and linear oligopyrroles (for example bili-
rubine).5 In addition, 5-alkylidene-2,5-dihydropyrrol-2-
ones represent useful synthetic building blocks and have
been used during the synthesis of antibiotics.1,6 5-Alky-
lidene-2,5-dihydropyrrol-2-ones have been prepared, for
example, by Wittig reaction of maleimides with stabilized
ylides,7,8 1,3-dipolar cycloadditions of nitrones with alk-
enes and alkynes and hydrogenolysis of the isoxazolidines
formed,9 and by reaction of amines with dimethyl-b-oxo-
alkanedioates.10 Recently, we have developed a new ap-
proach to 5-alkylidene-3-amino-2,5-dihydropyrrol-2-
ones by cyclization of 1,3-dicarbonyl dianions with oxalic
acid-bis(imidoyl)chlorides.11 Unfortunately, this method
is limited by the fact that only N-aryl derivatives can be
prepared. A few years ago we reported12 an efficient
method for the synthesis of g-alkylidenebutenolides by
cyclization of 1,3-bis-silyl enol ethers13 with oxalyl chlo-
ride. Syntheses of 5-alkylidene-2,5-dihydropyrrol-2-ones
based on ring-transformations of g-alkylidenebutenolides
with amines have been only scarcely reported in the liter-
ature.14 These reactions have been carried out in two steps
under basic conditions and the yields are in some cases
relatively low. Abell and coworkers have reported an effi-
cient two-step synthesis of cyclic enamino esters from
enol lactones.15
O
O
BnO
Z-5a (55%)
c
OMe
H
N
BnO
O
O
+
OMe
4a (65%)
BnO
O
E-5a (22%)
d
Me
Me
N
N
O
O
e
OMe
OMe
HO
BnO
O
O
6a (78%)
5b (85%)
Scheme 1 Synthesis 5-alkylidene-2,5-dihydropyrrol-2-ones from
g-alkylidenebutenolides. Reagents and conditions: a) Me3SiOTf (0.3
equiv), CH2Cl2, –78 °C to 20 °C; b) BnBr, K2CO3, acetone, 24 h,
20 °C; c) NH4OAc, HOAc, 130 °C, 20 h; d) MeNH3Cl, HOAc,
130 °C, 20 h; e) i) BBr3, CH2Cl2, 30 min, 0 °C; ii) HCl (1 M).
context, we have also developed conditions for the
chemoselective deprotection of O-benzyl-substituted g-
alkylidenebutenolides. This methodology has been ap-
plied to a formal synthesis of the natural product pukele-
imide A.
The known a-hydroxy-g-alkylidenebutenolide 3a was
prepared by Me3SiOTf-catalyzed cyclization of 1,3-bis-
silyl enol ether 1a with oxalyl chloride (2).12b We have
previously demonstrated that the C-3 hydroxy group of
these compounds is of considerable synthetic utility and
can be functionalized by palladium-catalyzed cross-cou-
pling reactions or by other transformations.16 Our initial
attempts to convert 3a into the corresponding 5-alkyl-
idene-2,5-dihydropyrrol-2-one by treatment with amines
Herein, we wish to report an efficient and practical meth-
od for the synthesis of 5-alkylidene-2,5-dihydropyrrol-2-
ones based on ring-transformations of readily available
g-alkylidenebutenolides under acidic conditions. In this
SYNLETT 2005, No. 3, pp 0453–0456
1
6.
0
2.
2
0
0
5
Advanced online publication: 04.02.2005
DOI: 10.1055/s-2005-862368; Art ID: D35304ST
© Georg Thieme Verlag Stuttgart · New York

454
C. Haase, P. Langer
LETTER
proved unsuccessful. The reaction of 3a with aniline, 1-
aminohexane or ammonia resulted in the formation of in-
tractable mixtures. Ammonium acetate in boiling glacial
acetic acid has been previously employed for the synthesis
of maleimides from maleic anhydrides;8,17 this again af-
forded a complex mixture. Analysis of the products indi-
cated that the C-3 hydroxy-group had been transformed
into an amino group. Therefore, the hydroxy group was
protected by transformation of 3a into the benzyl ether 4a
(Scheme 1). The reaction of 4a with NH4OAc–HOAc af-
forded the desired 5-alkylidene-2,5-dihydropyrrol-2-one
5a as a separable mixture of E/Z-isomers (Z-5a: 55%, E-
5a: 22%). The best yields were obtained when the reaction
mixture was stirred under reflux for 20 hours (TLC
control).18 The employment of other solvents proved
unsuccessful.
O
R2
O
Me3SiO
R1
OSiMe3
R2
a
O
R1
HO
1b–d
3b–d
b
R2
O
R2
O
R3
N
O
c
O
O
R1
R1
BnO
BnO
4b–d
5c–i
d
The reaction of 4a with MeNH3Cl in HOAc afforded the
E-configured 5-alkylidene-2,5-dihydropyrrol-2-one 5b in
85% yield. The chemoselective removal of the benzyl-
group was mandatory for possible applications of our
methodology. We have found that the reaction of 5b with
BBr3 resulted in a clean cleavage of the benzyl ether to
give the desired product 6a. 5-Alkylidene-2,5-dihydro-
pyrrol-2-one 5b was isolated as the E-isomer, presumably
due to the steric interaction between the methyl and the
ester group. In the case of 5a, the Z-isomer is more stable
than the E-isomer, due to the formation of a NHO hydro-
gen bond. Isomerization of the isomerically pure minor
isomer E-5a was observed upon standing. The configura-
tion of the products was established by spectroscopic
methods (NOESY experiments). In addition, the chemical
shifts of the protons located on carbon C-4 and at the exo-
cyclic double bond are characteristic for the configuration
of the latter and were compared with reported values of
related molecules.8
O
R2
R3
N
O
R1
HO
6b–c
Scheme 2 Synthesis 5-alkylidene-2,5-dihydropyrrol-2-ones (for
R1, R2 and R3, see Table 1). Reagents and conditions: a) Me3SiOTf
(0.3 equiv), CH2Cl2, –78 °C to 20 °C; b) BnBr, K2CO3, acetone, 24 h,
20 °C; c) NH4OAc, MeNH3Cl or R3NH2, HOAc, 130 °C, 10–20 h; d)
i) BBr3, CH2Cl2, 30 min, 0 °C; ii) HCl (1 M).
idenebutenolide 3b,12b which was transformed into the
benzyl ether 4b (Scheme 2). The reaction of 4b with
NH4OAc–HOAc afforded the Z-configured 5-alkylidene-
2,5-dihydropyrrol-2-one 5c in 96% yield. Treatment of 5c
with BBr3 resulted in chemoselective cleavage of the ben-
zyl ether (in the presence of the methyl ether) to give 6b
in 91% yield. The chemoselectivity can be explained by
chelation of BBr3 to the lactam carbonyl group. Treatment
of 4b with MeNH3Cl–HOAc afforded the 5-alkylidene-
2,5-dihydropyrrol-2-one 5d as a separable mixture of
The preparative scope of our methodology was next
studied. The cyclization of 1,3-bis-silyl enol ether 1b with
oxalyl chloride afforded the known Z-configured g-alkyl-
Table 1 Products and Yields
4
5
c
d
e
f
6
R1
R2
R3
Yield of 4 (%)a Yield of 5 (%)a Yield of 6 (%)a E/Z ratio of 5b
b
b
OMe
OMe
OMe
OMe
Me
OMe
OMe
OMe
OMe
OMe
OMe
OEt
H
62
96
91
<2:98
7:3
c
Me
i-Bu
c-Hex
H
40 + 17d
40 + 25d
30 + 40d
76
–
c
–
3:2
c
–
2:3
c
g
h
i
c
64
83
86
<2:98
1:1
c
Me
Me
H
28 + 27d
91
–
c
d
OBn
–
<2:98
a Yields of isolated pure E- and Z-isomers.
b E/Z ratio refers to isolated pure isomers.
c Experiment was not carried out.
d Rearrangements were observed upon standing of pure isomers: Z-5d to E/Z = 1:3; Z-5e to E/Z = 2:3; E-5f to E/Z = 5:1; E-5h to E/Z = 1:1.
Synlett 2005, No. 3, 453–456 © Thieme Stuttgart · New York

LETTER
Formal Synthesis of Pukeleimide A
455
E/Z-isomers (E-5d: 40%, Z-5d: 17%). The reaction of 4b The application of our methodology to a formal synthesis
with i-BuNH2–HOAc afforded 5e as a separable mix- of the natural product pukeleimide A was studied. The tri-
ture of E/Z-isomers (E-5e: 40%, Z-5e: 25%). Treatment flate 11 was prepared from butenolide 3e. The Stille reac-
of 4b with c-HexNH2–HOAc afforded the 5-alkylidene- tion of 11 with SnMe4, employing our recently published
2,5-dihydropyrrol-2-one 5f as a separable mixture of E/Z- protocol,16b was unsuccessful. In contrast, the Suzuki re-
isomers (E-5f: 30%, Z-5f: 40%).
action of 11 with methylboronic acid afforded the buteno-
lide 12 in good yield. Treatment of 12 with MeNH3Cl–
HOAc afforded the E-configured 5-alkylidene-2,5-dihy-
dropyrrol-2-one 13 in 78% yield (Scheme 4). The latter
was obtained in 33% overall yield (4 steps from oxalyl
chloride). Compound 13 has been prepared earlier by Pat-
tenden et al. from methylmaleic anhydride (2 steps, 24%
yield)8 and represents a key-intermediate during the syn-
thesis of pukeleimide A.8
The reaction of NH4OAc–HOAc with 4c, prepared from
the known g-alkylidenebutenolide 3c,12b afforded the Z-
configured 5-alkylidene-2,5-dihydropyrrol-2-one 5g. The
reaction of 5g with BBr3 gave 6c. Treatment of 4c with
MeNH3Cl–HOAc gave 5h as a separable mixture of E/Z-
isomers. The reaction of NH4OAc–HOAc with 4d, avail-
able from the known butenolide 3d,12b afforded the Z-con-
figured 5-alkylidene-2,5-dihydropyrrol-2-one 5i. In case
of 5d–f and 5h, the formation of E/Z-isomeric mixtures
can be explained by the competing steric effect of the sub-
stituents R1 and R3. An isomerization of the isomerically
pure minor isomers was observed upon standing.
O
O
O
O
a
OEt
OEt
HO
TfO
O
O
3e
11 (92%)
O
O
O
O
a
b
OMe
OMe
HO
TfO
O
O
Me
7 (86%)
3a
O
O
N
O
c
OEt
OEt
Me
O
b
Me
O
12 (60%)
13 (78%)
Me
N
O
O
O
c
Me
N
OMe
OMe
OMe
O
Ph
O
Ph
O
N
8 (88%)
9 (85%)
O
O
OH
Pukeleimide A
d
Scheme 4 Formal total synthesis of pukeleimide A. Reagents and
conditions: a) Tf2O, pyridine, –78 °C to –10 °C; b) MeB(OH)2,
Pd(PPh3)4 (3 mol%), K3PO4 (1.5 equiv), 1,4-dioxane, reflux; c)
MeNH3Cl, HOAc, 140 h, 130 °C.
H
O
H
N
OMe
N
O
O
+
OMe
Ph
Ph
O
In conclusion, we have reported an efficient and practical
method for the synthesis of 5-alkylidene-2,5-dihydropyr-
rol-2-ones based on ring-transformations of g-alky-
lidenebutenolides readily available by cyclization of 1,3-
bis-silyl enol ethers with oxalyl chloride.
E-10 (20%)
Z-10 (70%)
Scheme 3 Synthesis of 5-alkylidene-2,5-dihydropyrrol-2-ones 9
and 10. Reagents and conditions: a) Tf2O, pyridine, –78 °C to –10 °C;
b) PhB(OH)2, Pd(PPh3)4 (3 mol%), K3PO4 (1.5 equiv), 1,4-dioxane,
reflux; c) MeNH3Cl, HOAc, 130 °C, 12 h; d) NH4OAc, HOAc,
130 °C, 12 h.
Acknowledgment
Financial support from the state of Mecklenburg-Vorpommern
(Landesforschungsschwerpunkt), from Revotar Biopharmaceuti-
cals AG and by grants of the Ministry of Economics, State of Bran-
denburg and the European Union and from the Deutsche
Forschungsgemeinschaft is gratefully acknowledged.
We have recently reported the synthesis of butenolide 8
by Suzuki reaction of triflate 7 with phenylboronic acid
(Scheme 3).16c The reaction of 8 with NH4OAc–HOAc af-
forded the 5-alkylidene-2,5-dihydropyrrol-2-one 10 in ex-
cellent yield (Scheme 3). The product was obtained as a
separable mixture of E/Z-isomers (Z-10: 70%, E-10: 20%.
Due to the formation of a NHO hydrogen bond, the Z-iso-
mer was the major product. Treatment of 8 with
MeNH3Cl–HOAc gave the E-configured product 9 in
85% yield.
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456
C. Haase, P. Langer
LETTER
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(385 mg, 5.0 mmol) in glacial acetic acid (5 mL) was
refluxed for 20 h. The mixture was cooled to 20 °C and
EtOAc was added. The organic layer was neutralized by
repeated washing with a sat. aq solution of NaHCO3. The
aqueous layer was extracted with EtOAc (3 ×) and the
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colorless solid (280 mg, 96%) without the need of further
purification; mp 103 °C, Rf = 0.25 (hexane–EtOAc = 4:1).
1H NMR (300 MHz, CDCl3): d = 3.75 (s, 3 H, OCH3), 3.89
(s, 3 H, OCH3), 5.30 (s, 2 H, CH2Ph), 5.44 (s, 1 H, CH), 7.37
(m, 5 H, Ph), 8.48 (br s, 1 H, NH). 13C NMR (75 MHz,
CDCl3): d = 51.63, 59.36 (OCH3), 74.17 (CH2Ph), 92.60
(CH), 127.35 (C), 128.56, 128.57, 128.73 (CH, Ph), 136.02,
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2953 (m), 2928 (w), 2859 (w), 1733 (s), 1702 (s), 1674 (s),
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Synlett 2005, No. 3, 453–456 © Thieme Stuttgart · New York