A brief total synthesis of fumaramidine

Article abstract of DOI:10.1016/j.tet.2006.01.008

The first total synthesis of the alkaloid fumaramidine is reported. The synthetic tactics involve the sequential construction of the isoindolinone template by a Parham cyclization process followed by benzylic lactam deprotonation, interception with the su

Full text of DOI:10.1016/j.tet.2006.01.008

Tetrahedron 62 (2006) 2917–2921
A brief total synthesis of fumaramidine
*
Marc Lamblin, Axel Couture, Eric Deniau and Pierre Grandclaudon
´ ˆ
UMR 8009 ‘Chimie Organique et Macromoleculaire’, Laboratoire de Chimie Organique Physique, Batiment C3(2),
´
´
Universite des Sciences et Technologie de Lille, F-59655 Villeneuve d’Ascq Cedex, France
Received 23 November 2005; revised 16 December 2005; accepted 4 January 2006
Available online 26 January 2006
Abstract—The first total synthesis of the alkaloid fumaramidine is reported. The synthetic tactics involve the sequential construction of
the isoindolinone template by a Parham cyclization process followed by benzylic lactam deprotonation, interception with the suitable
carboxaldehyde and ultimate E1cb elimination. Final N-lactam deprotection completes the synthesis of the Z configured title compound.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
involving N-methylation of the phthalideisoquinolines 5
to their quaternary analogs 6 followed by unspecified
rearrangements including Hoffmann elimination (Scheme 1,
path a).4
The creeper Fumaria parviflora Lam (Fumariaceae) is
widespread in Pakistan where it is commonly known as Pit
Papra and where its extracts are used in folk medicine as a
blood purifier and as an anthelmintic, as well as in the
treatment of skin diseases and diarrhea.1 The crude
alkaloidal extracts have initially indicated the presence of
17 isoquinoline bases2 and additionally four enelactams,
that is, fumaramidine 1, fumaramine 2, fumaridine 3 and
narceine imide 4 (Fig. 1) were isolated from the strongly
basic ethanolic extracts of dried plant material.3
But it has also been conjectured that the transformation of 6
to 1–4 might be performed with ammonium hydroxide
usually used in the course of their isolation since it has been
shown that enol lactones 7 react with ammonia to form
hydroxylactams 8 liable to undergo facile dehydration to the
enelactams 1–4 (Scheme 1, path b).5 Until and unless the
presence of hydroxyl and enelactams 8 and 1–4, respect-
ively is conclusively demonstrated in the plant extracts prior
to strongly base treatments it can be concluded that these
enelactams are artifacts and not true alkaloids. This problem
Figure 1.
However, their presence in the natural source is not
guaranteed and is still a subject for discussion. They can
indeed be formed by a logical biogenetic sequence
Keywords: Alkaloids; Parham procedure; Ene lactams; Isoindolinones.
*
Corresponding author. Tel.: C33 3 20 43 44 32; fax: C33 3 20 33 63 09;
e-mail: axel.couture@univ-lille1.fr
Scheme 1.
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.008

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M. Lamblin et al. / Tetrahedron 62 (2006) 2917–2921
prompted us to launch a project related to the total synthesis
of these highly conjugated models and we delineate in this
paper a tactically new synthesis of the exemplary
representative fumaramidine 1 that relies upon our long-
standing experience in the field of N-acylenamine and
isoindoline chemistry.6,7
appendage on the lactam ring has been shown to be
particularly efficient owing to the highly conjugated
character of the resulting enelactams.10 And finally,
application of the Parham cyclization process for the
elaboration of five-membered lactams are scarce but a
number of structurally related systems have been success-
fully prepared under the agency of this process.11
The first facet of the synthesis was then the elaboration of
the polyfunctionalized aldehyde 10. This compound was
readily obtained by regioselective bromination of the
dimethoxylated phenethylamine derivative 12 and the
subsequent installation of the formyl functionality was
achieved by bromine/lithium interconversion from 13 and
subsequent trapping with DMF as the formylating agent
(Scheme 3).
2. Results and discussion
A swift skimming over the structural composition of this
enelactam reveals that this alkaloid can be regarded as
having a Z configured stilbenoid system fused with a lactam
ring. But besides it turns out that a number of synthetic
issues has also to be addressed such as (i) the connection of
diverse and dense functionalities on the environmentally
different aromatic units and in particular the assemblage of
an unsymmetrically disubstituted isoindolinone and (ii) the
presence of an unsubstituted nitrogen lactam, which may
require a problematic deprotection step for such models
with a high degree of conjugation.8 As far as we are aware
no total synthesis of 1 has appeared in print. For the
elaboration of compound 1 we opted for the synthetic route
depicted in the retrosynthetic Scheme 2.
Scheme 3.
The elaboration of the second partner of the synthesis, that
is, isoindolinone 9, required the preliminary preparation of
the bromoarylcarbamate 11. This compound was readily
obtained by the two-step sequence portrayed in Scheme 4.
Reductive amination involving the easily available bromo-
piperonal 14 and para-methoxybenzylamine delivered the
secondary amine 15 incorporating the nitrogen protecting
group para-methoxybenzyl (PMB). Treatment of 15 with
methyl chloroformate provided the carbamate 11 candidate
for the planned Parham cyclization process. This annulation
technique hinges upon aromatic lithiation and subsequent
trapping with an internal electrophile. Carbamate 11 was
then exposed to n-BuLi at K100 8C to ensure halogen/
lithium interconversion and the intramolecular ring closure
was instantaneous since the annulated compound 9 was
solely obtained in an excellent yield upon immediate
aqueous work up (scheme 4).
Scheme 2.
We assumed that fumaramidine 1 would be conceivably
assembled by sequential basic treatment of the protected
isoindolinone 9, quenching with the poly and differentially
substituted benzaldehyde 10 followed by dehydration of the
primary adduct and ultimate deprotection. We envisaged
building up the parent isoindolinone 9 by reliance on the
Parham cyclization process involving the tetrasubstituted
aromatic carbamate 11. Literature precedents gave support
to the feasibility of this synthetic approach. Isoindolinones
have been successfully metalated at the benzylic position of
the heteroring system thus allowing the connection of a
range of electrophiles.9 E1cb elimination from erythro and
threo isoindolinones equipped with an O-alkoxybenzyl
The final installation of the pendant arylmethylene unit on
the isoindolinone framework required four phases, which
could be fortunately performed as a single one-pot
reaction. For this purpose compound 9 was smoothly
deprotonated with KHMDS in THF at K78 8C and
subsequently allowed to react with the appropriate
aldehyde 10 (Scheme 4). To trigger off the E1cb
elimination process the transient oxanion 16 was O-silyl-
ated in situ with TMSCl and subsequently treated in the
sequel with KHMDS at K78 8C. Warming to 0 8C was
followed by acidic aqueous work up and gratifyingly

M. Lamblin et al. / Tetrahedron 62 (2006) 2917–2921
2919
Scheme 4.
conducting this reaction according to this procedure
afforded straightforwardly and solely the protected
arylmethylideneisoindolinone 17 with an excellent yield.
Compound 17 was obtained exclusively with the undesired
E geometry and configurational assignments were deter-
mined by NOE experiments. However, at this stage
stereochemical considerations about the central double
bond were not crucial for the ultimate formation of the Z
configured target product. Indeed removal of the selected
benzyl protection of the nitrogen lactam of 17 is usually
achieved by treatment in boiling TFA in the presence
of anisole as cation scavenger.12 These conditions are
appropriate to favor the formation of the thermodynami-
cally more stable stereoisomer with the mandatory Z
configuration and the target product 1 was obtained
exclusively and in an excellent yield by this technique.
The constitution and stereochemistry of this synthetic
enelactam 1 agree with those reported for the alkaloid
extracted from natural sources.4
4. Experimental
4.1. General
Tetrahydrofuran (THF) was pre-dried with anhydrous
Na2SO4 and distilled over sodium benzophenone ketyl
under Ar before use. DMF, CH2Cl2, NEt3, and toluene were
distilled from CaH2. Dry glassware was obtained by oven
drying and assembly under dry Ar. The glassware was
equipped with rubber septa and reagent transfer was
performed by syringe techniques. For flash chromato-
graphy, Merck silica gel 60 (40–63 mm; 230–400 mesh
ASTM) was used. The melting points were obtained on a
Reichert-Thermopan apparatus and are not corrected. NMR
spectra: Bruker AM 300 (300 and 75 MHz, for 1H, and 13C),
CDCl3 as solvent, TMS as internal standard. Microanalyses
were performed by the CNRS microanalysis center.
N,N-Dimethyl-3,4-dimethoxy-b-phenethylamine 1213 and
2-bromopiperonal 1414 were synthesized according to
literature methods.
4.2. Synthesis of the benzaldehyde derivative 14
3. Conclusion
In conclusion, a simple and efficient first total synthesis of
the enelactam fumaramidine from fumariceae species has
been disclosed. The advantages of this synthesis, which lie
mainly in the small number of steps, their procedural
simplicity and high efficiency provide a strong incentive for
the elaboration of similar structurally modified alkaloids as
well as their biogenetically related congeners.
4.2.1. N,N-Dimethyl-3,4-dimethoxy-5-bromo-b-phene-
thylamine (13). Bromine (7.6 mmol, 0.4 mL) was added
dropwise under stirring to a solution of N,N-dimethyl-3,
4-dimethoxy-b-phenethylamine 12 (800 mg, 3.8 mmol) and
potassium acetate (560 mg, 3.8 mmol). Stirring was
maintained for 16 h at room temperature, the solution was
concentrated under vacuum and the residue was dissolved in

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M. Lamblin et al. / Tetrahedron 62 (2006) 2917–2921
CH2Cl2 (60 mL). The solution was washed successively
with saturated aqueous Na2CO3 (20 mL), aqueous sodium
thiosulfate (10%, 20 mL), and brine. The organic layer was
dried (Na2SO4) and the solvent was evaporated under
vacuum. The crude oily residue was purified by column
chromatography using AcOEt–hexanes–NEt3 (80/10/10) as
eluent to deliver the amine 13 as a yellow oil. Yield 921 mg
(82%); 1H NMR (dH) 2.30 (s, 6H, 2!NCH3), 2.44–2.49 (m,
2H, CH2), 2.79–2.84 (m, 2H, CH2), 3.81 (s, 3H, OCH3),
3.83 (s, 3H, OCH3), 6.72 (s, 1H aromatic H), 6.96 (s, 1H,
aromatic H) ppm; 13C NMR (dC) 34.1, 45.3, 56.0, 56.1,
59.7, 113.1, 114.1, 115.6, 131.5, 147.9, 148.4 ppm. Anal.
Calcd for C12H18BrNO2 (288.2): C, 50.01; H, 6.30; N
4.86%. Found: C, 50.25; H, 4.63; N 4.67%.
(2!30 mL), brine and dried (Na2SO4). After evaporation of
the solvent, the crude oily residue was purified by column
chromatography using AcOEt–NEt3 (90/10) as eluent to
deliver the amine 15 as a light yellow oil. Yield 6.45 mg
1
(92%); H NMR (dH) 1.71 (br s, 1H, NH), 3.70 (s, 2H,
NCH2), 3.78 (s, 5H, NCH2COCH3), 6.02 (s, 2H, OCH2O),
6.71 (d, JZ7.8 Hz, 1H, aromatic H), 6.82–6.87 (m, 3H,
aromatic H), 7.25 (d, JZ8.3 Hz, 2H, aromatic H) ppm; 13C
NMR (dC) 52.1, 52.2, 55.3, 101.4, 102.7, 107.0, 113.7,
123.0, 129.4, 132.3, 132.6, 146.3, 146.7, 158.6 ppm. Anal.
Calcd for C16H16BrNO3 (350.2): C, 54.87; H, 4.61; N
4.00%. Found: C, 54.65; H, 4.92; N 4.11%.
4.3.2. Methyl N-(4-bromobenzo[1,3]dioxol-5-ylmethyl)-
N-(4-methoxbenzyl)carbamate (11). Methyl chlorofor-
mate (1.04 g, 11 mmol) was added slowly under stirring to
a cooled (0 8C) solution of amine 15 (3.51 g, 10 mmol) in
Et2O (50 mL) followed by a solution of NaOH (440 mg,
11 mmol) in water (5 mL). The mixture was stirred at 0 8C
for 30 min and the ethereal layer was separated, washed
with aqueous HCl (4 M; 3!30 mL), water (30 mL) and
dried (Na2SO4). After evaporation of the solvent, the crude
oily residue was purified by column chromatography using
AcOEt–hexanes (40/60) as eluent to deliver the carbamate
11 as a colorless oil. Yield 2.98 g (73%); 1H NMR (dH) 3.78
(s, 6H, 2!OCH3), 4.37–4.46 (m, 4H, 2!NCH2), 6.02 (s,
2H, OCH2O), 6.62–6.73 (m, 3H, aromatic H), 6.83 (d, JZ
8.5 Hz, 2H, aromatic H), 7.13 (d, JZ11.5 Hz, 2H, aromatic
H) ppm; 13C NMR (dC) 48.5, 49.2, 53.0, 55.3, 101.5, 107.3,
113.9, 120.8, 122.2, 128.8, 129.3, 129.5, 146.3, 146.9,
157.3, 159.0 ppm. Anal. Calcd for C18H18BrNO5 (408.2):
C, 52.96; H, 4.44; N 3.43%. Found: C, 53.09; H, 4.33;
N 3.27%.
4.2.2. 2-(2-Dimethylaminoethyl)-4,5-dimethoxybenz-
aldehyde (10). A solution of n-BuLi (1.64 mL, 1.6 M in
hexane, 2.6 mmol) was added dropwise by syringe at
K78 8C under Ar to a solution of amine 13 (550 mg,
2.0 mmol) in dry THF (50 mL). The reaction mixture was
stirred at K78 8C for 15 min and DMF (140 mg, 0.2 mL,
2.6 mmol) was added. The solution was stirred at K78 8C
for 1 h, then at room temperature for an additional 1 h and
treated with saturated aqueous NH4Cl (5 mL). The
mixture was diluted with water (10 mL), extracted with
Et2O (3!50 mL) and the combined organic extracts were
dried (MgSO4). Evaporation of solvents in vacuo left an
oily residue, which was purified by flash column
chromatography with AcOEt–hexanes–NEt3 (80/10/10)
as eluent to furnish 10 as a yellow solid. Yield 331 mg
(70%); mp 54–55 8C (from hexane–toluene); 1H NMR
(dH) 2.25 (s, 6H, 2!NCH3), 2.43–2.48 (m, 2H, CH2),
3.03–3.08 (m, 2H, CH2), 3.85 (s, 3H, OCH3), 3.87 (s, 3H,
OCH3), 6.68 (s, 1H, aromatic H), 7.24 (s, 1H, aromatic
H), 10.12 (s, 1H, CH]O) ppm; 13C NMR (dC) 30.1, 45.3,
55.9, 56.0, 62.0, 111.1, 113.0, 126.8, 138.3, 147.6, 153.6,
189.5 (CHO) ppm. Anal. Calcd for C13H19NO3 (237.3): C,
65.80; H, 8.07; N 5.90%. Found: C, 66.01; H, 8.03; N
6.05%.
4.3.3. 7-(4-Methoxybenzyl)-6,7-dihydro[1,3]dioxolo[4,5-e]-
isoindol-8-one (9). A solution of n-BuLi (3.6 mL, 1.6 M in
hexane, 5.76 mmol) was added dropwise by syringe at
K90 8C under Ar to a solution of carbamate 11 (1.96 g,
4.8 mmol) in dry THF (50 mL). The reaction mixture was
stirred at K90 8C for 20 min then allowed to warm to
K40 8C over a period of 30 min followed by addition of
saturated aqueous NH4Cl (5 mL). The mixture was diluted
with water (20 mL), extracted with Et2O (3!25 mL) and
the combined organic layers were dried (MgSO4). Evapora-
tion of the solvent in vacuo left an oily residue, which was
purified by flash column chromatography with AcOEt–
hexanes (60/40) as eluent to furnish the isoindolinone 9 as a
yellow oil. Yield 898 mg (63%); 1H NMR (dH) 3.74 (s, 3H,
OCH3), 4.14 (s, 2H, NCH2), 4.62 (s, 2H, NCH2), 6.07 (s, 2H,
OCH2O), 6.72 (d, JZ7.8 Hz, 1H, aromatic H), 6.80 (d, JZ
8.5 Hz, 2H, aromatic H), 6.86 (d, JZ7.8 Hz, 1H, aromatic
H) 7.19 (d, JZ8.5 Hz, 2H, aromatic H) ppm; 13C NMR (dC)
45.7, 49.4, 55.3, 102.6, 111.0, 114.1, 115.2, 129.0, 129.5,
130.2, 134.3, 143.4, 148.3, 159.1, 165.8 (CO) ppm. Anal.
Calcd for C17H15BrNO4 (297.3): C, 68.68; H, 5.09; N
4.71%. Found: C, 68.46; H, 5.39; N 4.82%.
4.3. Synthesis of the isoindolinone 9
4.3.1. N-(4-Bromobenzo[1,3]dioxol-5-ylmethyl)-N-(4-
methoxybenzyl)amine (15). A solution of 2-bromopi-
peronal (4.85 g, 20 mmol) and 4-methoxybenzylamine
(2.74 g, 20 mmol) in toluene (70 mL) was refluxed in the
Dean–Stark apparatus for 3 h. Evaporation of the solvent
under vacuum left quantitatively the [1-(4-bromobenzo-
[1,3]dioxol-5-ylmethyl)methylidene]-(4-methoxybenzyl)-
amine as a yellow oil, which was treated in the next step
without further purification. (6.98 g); 1H NMR (dH) 3.79 (s,
3H, CH3), 4.75 (s, 2H, NCH2), 6.07 (s, 2H, OCH2O), 6.77
(d, JZ8.3 Hz, 1H, aromatic H), 6.88 (d, JZ8.3 Hz, 2H,
aromatic H), 7.24 (d, JZ8.3 Hz, 2H, aromatic H), 7.65 (d,
JZ8.3 Hz, 1H, aromatic H), 8.60 (s, 1H, CH]N) ppm; 13C
NMR (dC) 55.3, 64.5, 103.8, 104.0, 107.8, 113.9, 122.9,
128.4, 129.1, 131.3, 146.1, 149.4, 158.7, 159.1
(CH]N) ppm. Sodium borohydride (832 mg, 22 mmol)
was added portionwise to a solution of the crude imine
(6.98 g, 20 mmol) in MeOH (100 mL). The reaction mixture
was then stirred at room temperature for 30 min and then
concentrated under vacuum. The oily residue was dissolved
in CH2Cl2 (100 mL). The solution was washed with water
4.4. Synthesis of fumaramidine (1)
4.4.1. 6-{1-[2-(2-Dimethylaminoethyl)-4,5-dimethoxy-
phenyl]meth-(E)-ylidene}-7-(4-methoxybenzyl)-6,7-
dihydro[1,3]dioxolo[4,5-e]isoindo-8-one (17). A solution
of KHMDS (2.2 mL, 0.5 M in toluene, 1.1 mmol) was

M. Lamblin et al. / Tetrahedron 62 (2006) 2917–2921
2921
added dropwise at K78 8C under Ar to a stirred solution of
Acknowledgements
isoindolinone 9 (297 mg, 1 mmol) in THF (50 mL). After
stirring at K78 8C for 10 min a solution of benzaldehyde
derivative 10 (260 mg, 1.1 mmol) in THF (10 mL) was
added dropwise. The resulting solution was allowed to
warm to room temperature over 15 min then recooled to
K78 8C. Chlorotrimethylsilane (119 mg, 1.1 mmol) was
added and the mixture was allowed to warm slowly to room
temperature and recooled to K78 8C. KHMDS (2.2 mL,
0.5 M in toluene, 1.1 mmol) was then added and warming to
room temperature over 30 min allowed the completion of
E1cb elimination reaction. Saturated aqueous NH4Cl
(5 mL) was added and the mixture was diluted with water
(20 mL), extracted with Et2O (3!20 mL). After drying of
the combined organic layers (Na2SO4), evaporation of
solvent in vacuo left an oily residue, which was purified by
flash column chromatography with AcOEt–NEt3 (90/10) as
eluent to furnish the arylmethyleneisoindolinone 17 as a
yellow oil. Yield 418 mg (81%); 1H NMR (dH) 1.90 (s, 6H,
2!NCH3), 2.11 (t, JZ7.5 Hz, 2H, CH2), 2.41 (t, JZ7.5 Hz,
2H, CH2), 3.63 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 3.80 (s,
3H, OCH3), 4.95 (s, 2H, NCH2), 6.13 (s, 2H, OCH2O), 6.36
(s, 1H, CH]), 6.69–6.74 (m, 3H, aromatic H), 6.82 (s, 1H,
aromatic H), 7.14–7.21 (m, 3H, aromatic H), 7.25 (m, 1H,
aromatic H) ppm; 13C NMR (dC) 31.7 (CH2Ar), 45.1 (2!
NCH3), 42.6 (CH2, PMB), 55.0 (OCH3, PMB), 55.8
(OCH3), 55.9 (OCH3), 60.3 (NCH2), 100.6 (OCH2O),
110.1 (CH]), 112.6 (CH), 113.3 (CH), 113.4 (CH), 114.1
(2!CH, PMB), 123.2 (CH), 125.7 (C), 127.3 (2!CH,
PMB), 129.1 (C), 130.1 (C), 132.1 (C), 135.1 (C), 136.0 (C),
144.3 (C), 147.1 (C), 148.8 (C), 149.3 (C), 158.8 (C), 166.6
(CO) ppm. Anal. Calcd for C30H32N2O6 (516.6): C, 69.75;
H, 6.24; N 5.42%. Found: C, 69.58; H, 6.11; N 5.17%.
This research was supported by the Centre National de la
Recherche Scientifique and MENESR (grant to M.L.).
Technical assistance from M. Dubois is also acknowledged.
References and notes
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4.4.2. Fumaramidine (1). A solution of the arylmethylene
isoindolinone 17 (260 mg, 0.5 mmol) and anisole (540 mg,
5.0 mmol) in trifluoroacetic acid (10 mL) was refluxed
under Ar for 24 h. The reaction mixture was concentrated
under vacuum, the residue was dissolved in CH2Cl2 (20 mL)
and NEt3 (0.5 mL) was added with stirring. Water (3!
50 mL) was then added, and the organic layer was washed
with brine, dried (MgSO4) and concentrated to yield an oily
residue. Purification by flash column chromatography using
AcOEt–NEt3 (95/5) as eluent and recrystallization from
EtOH gave a yellow solid: mp 266–267 8C (dec). The
spectral data of synthetic 1 (180 mg, 91%) matched those
reported for the natural product.3,4 1H NMR (dH) 2.24 (s,
6H, 2!NCH3), 2.46 (t, JZ7.9 Hz, 2H, CH2), 2.77 (t, JZ
7.9 Hz, 2H, CH2), 3.86 (s, 3H, OCH3), 3.87 (s, 3H, OCH3),
6.14 (s, 2H, OCH2O), 6.43 (s, 1H, CH]), 6.74 (s, 1H,
aromatic H), 6.82 (s, 1H, aromatic H), 7.02 (d, JZ8.0 Hz,
aromatic H), 7.25 (d, JZ8.0 Hz, aromatic H), 8.34 (br s, 1H,
NH) ppm; 13C NMR (dC) 31.8 (CH2Ar), 45.5 (2!NCH3),
55.9 (OCH3), 56.2 (OCH3), 60.7 (NCH2), 103.0 (CH]),
103.1 (OCH2O), 111.7 (CH), 112.0 (CH) 113.1 (CH), 113.2
(CH), 125.6 (C), 131.8 (C), 132.0 (C), 133.3 (C), 143.4 (C),
147.7 (C), 148.7 (C), 149.3 (C), 166.1 (CO) ppm.
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