A new synthesis of the phytotoxin porritoxin

Article abstract of DOI:10.1016/j.tet.2006.03.076

A convenient synthesis of the phytotoxin porritoxin is described. Central to the approach employed is the formation of the isoindolinone template obtained via a directed lithiation/Parham cyclization process enabling the concomitant connection of an aceta

Full text of DOI:10.1016/j.tet.2006.03.076

Tetrahedron 62 (2006) 5787–5790
A new synthesis of the phytotoxin porritoxin
*
Anne Moreau, Axel Couture, Eric Deniau and Pierre Grandclaudon
´
ˆ
Laboratoire de Chimie Organique Physique, UMR 8009 ‘Chimie Organique et Macromoleculaire’, Batiment C3(2),
´
Universite des Sciences et Technologie de Lille, F-59655 Villeneuve d’Ascq Cedex, France
´
Received 10 February 2006; revised 6 March 2006; accepted 22 March 2006
Available online 27 April 2006
Abstract—A convenient synthesis of the phytotoxin porritoxin is described. Central to the approach employed is the formation of the iso-
indolinone template obtained via a directed lithiation/Parham cyclization process enabling the concomitant connection of an acetal append-
age. Further conversion into the requisite hydroxyalkyl chain, selective deprotection, and O-prenylation complete the synthesis of the title
compound.
Ó 2006 Elsevier Ltd. All rights reserved.
H
N
O
1. Introduction
O
Porritoxin, as well as some other isoindolinone centered
alkaloids, e.g., fumaridine,1 fumaramidine,2 nuevamine,3 and
piperolactam B,4 belongs to this unique class of compounds
whose structural assignments have been a subject of discus-
sion and controversy. Initially this phytotoxin produced by
the fungus Alternaria porri (Ellis) Ciferri, the causal fungus
of black spot disease in stone-leek and onion was ascribed
structure 1 characterized by a benzoxazocine skeleton.5
However, probably shaken by the suggestion of Ayer and
Miao who isolated stachybotramide 2 having an isoindole
moiety6 and then pointed out that the structure of porritoxin
might be incorrect, the isolating group decided to launch a
detailed structural reinvestigation. Finally persuasive data
based upon detailed 2D NMR analysis 1H–13C and 1H–15N
HMBC experiments convinced the authors to reassign their
structure from 1 to 3 (Fig. 1).7 Recently this revised structure
was unambiguously confirmed by Kelly and Cornella8 who
reported the first total synthesis of the natural product. The
marked advantages of their elegant synthesis lie mainly in
the small number of steps and efficiency of the process. In
this synthetic approach the key reaction is the formylation
of the aromatic ring system by making use of iron penta-
carbonyl then allowing the formation of the lactam unit by
reductive amination and subsequent trans-amidification.
O
Me
O
HO
OH
MeO
N
1
HO
O
2
O
O
OH
N
Me
MeO
3
Figure 1.
2. Results and discussion
In this paper we wish to delineate an alternative synthesis of
the title compound that relies upon our long standing expe-
rience in the field of isoindolinone chemistry.9 Our synthetic
tactic outlined in the retrosynthetic analysis shown in
Scheme 1 hinges upon the Parham cyclization reaction of
the aromatic carbamate 4 equipped with diverse and dense
functionalities liable to secure the assembling of the rather
congested isoindolinone template. Compound 4 could be
in turn obtained by acylation of the secondary amine 6.
We also conjectured that the annulation process likely to
give rise to 5 would allow the concomitant connection of
an acetal appendage, which may serve as a handle for further
conversion into the hydroxyalkyl chain present in the target
Keywords: Alkaloids; Parham procedure; Isoindolinones.
* Corresponding author. Tel.: +33 3 20 43 44 32; fax: +33 3 20 33 63 09;
e-mail: axel.couture@univ-lille1.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.076

5788
A. Moreau et al. / Tetrahedron 62 (2006) 5787–5790
natural product. De-isopropylation followed by ultimate
prenylation then should complete the total synthesis of the
target compound.
obtained with a very satisfactory yield (63%) upon immedi-
ate aqueous workup. Subsequent manipulation of the acetal
residue by a two-step sequence provided the hydroxyalkyl-
ated isoindolinone 8 in fairly good yield. Regeneration of
the 6-hydroxyphenolic function delivered the phenolic iso-
indolinone 9, which can be regarded as an immediate precur-
sor of the target alkaloid.8 Indeed prenylation of 9 afforded 3
whose spectral data are in excellent agreement with those
reported for natural porritoxin.7
O
O
OMe
OMe
iPr-O
O
OH
N
N
Me
Me
MeO
MeO
MeO
3
5
iPr-O
iPr-O
Br
Br
NH
O
OMe
OMe
3. Conclusion
OMe
OMe
Me
N
Me
In conclusion we have defined a new synthetic route to natu-
ral product porritoxin. The key step of this approach made
use of a directed lithiation/Parham cyclization process,
which enabled the rapid construction of a highly functional-
ized isoindolinone. The concomitant incorporation of an
acetal residue was used as a way to connect the requisite
hydroxyethyl appendage. With this versatile synthetic route
in hand, further studies will concentrate on exploring the
potential of this approach for the elaboration of structurally
modified biogenetic congeners.
MeO
OMe
4
6
Scheme 1.
The first facet of the synthesis was then the elaboration of the
benzylamine derivative 6. This compound was readily
obtained as depicted in Scheme 2 by a reductive amination
process involving the readily accessible benzaldehyde deriv-
ative 7 with aminoacetaldehyde dimethyl acetal. Acylation
with methyl chloroformate proceeded uneventfully to de-
liver the carbamate 4, a possible candidate for the planned
Parham cyclization process. The Parham protocol hinges
upon the trapping of an aromatic organometallic species
with a suitable internal electrophile thereby providing the
potential for direct access to an annulated compound.10 Op-
timal conditions to ensure the requisite generation of the aryl
metalled species derived from 4 by bromine–metal intercon-
version were then explored. For this purpose variations of the
base, solvent, temperature profile, and incorporation of carb-
anion modifiers were all screened based upon literature pre-
cedents.10 After various experimentation we found that upon
adding a solution of carbamate 4 in THF to a solution of
n-BuLi (3 equiv) and TMEDA (3 equiv) in THF at ꢀ78 ꢁC
for 30 min, the consumption of the parent compound was es-
sentially complete and thedesired annulated compound 5was
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 dis-
tilled from CaH2. Dry glassware was obtained by oven-dry-
ing and assembly under dry Ar. The glassware was equipped
with rubber septa and reagent transfer was performed by sy-
ringe techniques. For flash chromatography, Merck silica gel
60 (40–63 mm, 230–400 mesh ASTM) was used. The melt-
ing points were obtained on a Reichert–Thermopan appara-
tus and are not corrected. NMR spectra: Bruker AM 300
OMe
1.
H2N
OMe
ClCOOMe
Et3N, CH2Cl2
iPr-O
Me
iPr-O
Me
iPr-O
Me
Br
Br
NH
Br
toluene , ∆
O
N
OMe
OMe
OMe
OMe
2. NaBH4 , MeOH
CHO
MeO
MeO
MeO
OMe
4
(70%)
7
6 (70%)
1. FeCl3, 6H2O
acetone-CH2Cl2
r.t. , 2 h
1. n-BuLi , TMEDA
(3 equiv)
O
O
OMe
OMe
BCl3, CH2Cl2
iPr-O
iPr-O
Me
OH
THF , -78 °C
0 °C
N
N
2. then 4 , THF
2. NaBH4 , MeOH
Me
MeO
5
3. H3O+
MeO
OH
(63%)
Br
8
(62%)
O
O
HO
Me
O
OH
N
N
K2CO3, acetone, ∆
Me
MeO
MeO
9
(60%)
3
(65%)
Scheme 2.

A. Moreau et al. / Tetrahedron 62 (2006) 5787–5790
5789
(300 and 75 MHz, for 1H and 13C), CDCl3 as solvent, TMS
as internal standard. Microanalyses were performed by the
CNRS microanalysis center.
(63%); 1H NMR (dH) 1.30 (d, J¼5.9 Hz, 6H, 2ꢂCH3), 2.12
(s, 3H, CH3), 3.37 (s, 6H, 2ꢂOCH3), 3.66 (d, J¼5.1 Hz,
2H, NCH2), 3.81 (s, 3H, OCH3), 4.47 (s, 2H, ArCH2N),
4.50–4.60 [m, 2H, CHMe2+CH(OMe2)], 7.03 (s, 1H, aro-
matic H) ppm; 13C NMR (dC) 9.6, 22.1, 44.4, 49.7, 54.4,
59.6, 70.6, 102.5, 102.9, 123.7, 123.8, 131.4, 153.5, 157.5,
168.8 ppm. Anal. Calcd for C17H25NO5 (323.4): C, 63.14;
H, 7.79; N, 4.33%. Found: C, 62.99; H, 7.98; N, 4.39%.
4.1.1. N-(6-Bromo-4-isopropoxy-2-methoxy-3-methyl-
benzyl)-N-(2,2-dimethoxyethyl)amine (6). A solution of
benzaldehyde derivative 79e (2.10 g, 7.3 mmol) and 2,2-di-
methoxyethylamine (0.77 g, 7.3 mmol) in toluene (50 mL)
was refluxed for 3 h in a Dean–Stark apparatus. After evapo-
ration of the solvent the crude oily imine (2.60 g) was dis-
solved in MeOH (50 mL) and NaBH4 (0.53 g, 13.9 mmol)
was added portionwise and the mixture was stirred for 2 h
at room temperature. After addition of solid NH4Cl and stir-
ring for 30 min, the solution was concentrated under vacuum.
The residue was dissolved in CH2Cl2 (50 mL), washed with
water and brine, and dried (Na2SO4). Evaporation of the sol-
vent left the amine 6 as a yellow oil, which was purified by
column chromatography using ethyl acetate–NEt3 (90:10)
as eluent. Yield 1.91 g (70%); 1H NMR (dH) 1.30 (d,
J¼6.1 Hz, 6H, 2ꢂCH3), 2.05 (s, 3H, CH3), 2.71 (d,
J¼5.6 Hz, 2H, NCH2), 3.31 (s, 6H, 2ꢂOCH3), 3.72 (s, 3H,
OCH3), 3.86 (s, 2H, ArCH2N), 4.41–4.50 [m, 2H, CHMe2+
CH(OMe2)], 6.81 (s, 1H, aromatic H) ppm; 13C NMR (dC)
9.5, 22.1, 47.7, 50.1, 53.6, 61.3, 70.8, 103.7, 113.4, 120.7,
121.7, 125.0, 156.6, 158.6 ppm. Anal. Calcd for
C16H26BrNO4 (376.3): C, 51.07; H, 6.96; N, 3.72%. Found:
C, 50.98; H, 7.09; N, 3.93%.
4.1.4. 2-(2-Hydroxyethyl)-6-isopropoxy-4-methoxy-5-
methyl-2,3-dihydro-1H-isoindol-1-one (8). A solution of
5 (0.39 g, 1.2 mmol) and iron(III) chloride hexahydrate
(0.92 g, 3.4 mmol) in a mixture of acetone–dichloromethane
(1:4, 10 mL) was vigorously stirred over a period of 2 h at
room temperature. The crude mixture was poured onto
a aqueous satd NH4Cl solution (5 mL), filtered on Celite,
and extracted with CH2Cl2 (3ꢂ10 mL). The organic extracts
were washed successively with water, brine, and dried over
Na2SO4. The solvents were removed in vacuo then the crude
solid residue was dissolved in MeOH (15 mL) and treated
under stirring by portionwise addition of NaBH4 (95 mg,
2.5 mmol). Stirring was maintained at room temperature
for an additional 1 h. After concentration under vacuum,
the residue was dissolved in CH2Cl2 (10 mL) and washed
with aqueous satd NH4Cl solution (10 mL). After drying
(Na2SO4) the solvent was evaporated under vacuum to
afford a solid residue, which was purified by flash column
chromatography on silica using acetone–hexanes (80:20)
as eluent. White crystals, yield 207 mg (62%); mp 113–
4.1.2. Methyl N-(6-bromo-4-isopropoxy-2-methoxy-3-
methylbenzyl)-N-(2,2-dimethoxyethyl)carbamate (4).
Methyl chloroformate (0.45 g, 4.8 mmol) was added drop-
wise to a stirred solution of amine 6 (1.40 g, 3.7 mmol) and
NEt3 (0.76 g, 7.5 mmol) in CH2Cl2 (50 mL) at 0 ꢁC. Stirring
was maintained for 3 h at room temperature. The mixturewas
washed with water and brine, and dried (Na2SO4). After
evaporation of the solvent the oily residue was purified
by column chromatography using ethyl acetate–hexanes
(50:50) as eluent to furnish 4 as a colorless oil. Yield 1.13 g
(70%); 1H NMR (dH) 1.32 (d, J¼6.1 Hz, 6H, 2ꢂCH3), 2.06
(s, 3H, CH3), 3.12–3.23 (m, 2H, NCH2), 3.32 (s, 6H,
2ꢂOCH3), 3.66 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 4.43–
4.56 [m, 2H, CHMe2+CH(OMe2)], 4.67–4.72 (br s, 2H,
ArCH2N), 6.83 (s, 1H, aromatic H) ppm; 13C NMR (dC)
9.6, 22.1, 45.9, 47.0, 52.7, 54.3, 61.0, 70.7, 102.4, 113.4,
120.8, 121.4, 122.2, 157.1, 159.6 ppm. Anal. Calcd for
C18H28BrNO6 (434.3): C, 49.78; H, 6.50; N, 3.22%. Found:
C, 49.85; H, 6.38; N, 3.01%.
1
114 ꢁC; H NMR (300 MHz, CDCl3) d 1.33 (d, J¼6.0 Hz,
6H), 2.15 (s, 3H), 3.10–3.52 (br s, 1H), 3.73 (t, J¼5.0 Hz,
2H), 3.84 (s, 3H), 3.90 (t, J¼5.0 Hz, 2H), 4.52 (s, 2H),
4.58 (heptuplet, J¼6.0 Hz, 1H), 7.04 (s, 1H) ppm; 13C
NMR (75 MHz, CDCl3) d 10.0, 22.4, 46.6, 50.3, 60.0,
62.0, 71.0, 102.7, 123.8, 124.3, 131.8, 153.8, 157.9,
170.1 ppm. Anal. Calcd for C15H21NO4 (279.3): C,
64.50; H, 7.58; N, 5.01%. Found: C, 64.59; H, 7.76; N,
4.83%.
4.1.5. 6-Hydroxy-2-(2-hydroxyethyl)-4-methoxy-5-methyl-
2,3-dihydro-1H-isoindol-1-one (9). A solution of BCl3
(1 M in CH2Cl2, 0.8 mL, 0.8 mmol) was added dropwise
by syringe to a degassed solution of isoindolinone 8
(112 mg, 0.4 mmol) in CH2Cl2 (10 mL) at 0 ꢁC under Ar. Af-
ter stirring for 2 h at 0 ꢁC, the reaction mixture was quenched
with a few pieces of crushed ice. The aqueous phase was ex-
tracted with CH2Cl2 (3ꢂ10 mL) and Et2O (3ꢂ10 mL). The
organic solvents were combined and dried (Na2SO4). The
solvents were removed invacuum and the crude solid residue
was finally recrystallized from toluene–ethanol to afford 7.
4.1.3. 2-(2,2-Dimethoxyethyl)-6-isopropoxy-4-methoxy-
5-methyl-2,3-dihydro-1H-isoindol-1-one (5). A solution
of n-BuLi (2 M in pentane, 3 mL, 6.0 mmol) and TMEDA
(0.7 g, 6.0 mmol) in dry THF (5 mL) was carefully degassed
by three freeze–thaw cycles and stirred at ꢀ78 ꢁC under dry
deoxygenated Ar. A solution of methyl carbamate derivative
4 (0.87 g, 2.0 mmol) in degassed THF (25 mL) was then
added dropwise through a canula. The mixture was stirred
for 30 min at ꢀ78 ꢁC. After addition of aqueous satd
NH4Cl solution (5 mL) and Et2O (25 mL), the aqueous layer
was separated and extracted with Et2O (25 mL). The organic
layers were cumulated, dried (Na2SO4), and concentrated un-
der vacuum. The crude oily residue was purified by column
chromatography using ethyl acetate–hexanes–CH2Cl2
(40:40:20) as eluent to give 5 as a yellow oil. Yield 0.41 g
1
White crystals, yield 57 mg (60%); mp 176–178 ꢁC; H
NMR (300 MHz, DMSO-d6) d 2.1 (s, 3H), 3.53–3.67 (m,
4H), 4.61 (s, 2H), 6.87 (s, 1H), 9.81 (br s, 1H) ppm; 13C
NMR (75 MHz, DMSO-d6) d 10.3, 45.6, 49.8, 59.1, 60.2,
61.8, 104.2, 120.0, 122.1, 132.8, 154.3, 157.5, 168.3 ppm.
Anal. Calcd for C12H15NO4 (237.3): C, 60.75; H, 6.37; N,
5.90. Found: C, 60.54; H, 6.19; N, 6.09.
4.1.6. Porritoxin (3). By prenylation of 9 (40 mg) following
a reported procedure.8 White crystals from hexane–toluene,
yield 34 mg (65%); mp 115–116 ꢁC (lit.7 115–116 ꢁC).
Analytical and spectral data matched those reported for the
natural product.7,8

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A. Moreau et al. / Tetrahedron 62 (2006) 5787–5790
7. Horiuchi, M.; Maoka, T.; Iwase, N.; Ohnishi, K. J. Nat. Prod.
2002, 65, 1204–1205.
Acknowledgements
8. Cornella, I.; Kelly, T. R. J. Org. Chem. 2004, 69, 2191–
2193.
This research was supported by the Centre National de la Re-
cherche Scientifique and MENESR (grant to A.M.). Techni-
9. (a) Hoarau, C.; Couture, A.; Cornet, H.; Deniau, E.; Grandclau-
don, P. J. Org. Chem. 2001, 66, 8064–8069; (b) Couture, A.;
Deniau, E.; Grandclaudon, P.; Hoarau, C.; Rys, V. Tetrahedron
Lett. 2002, 43, 2207–2210; (c) Deniau, E.; Enders, D.; Couture,
A.; Grandclaudon, P. Tetrahedron: Asymmetry 2003, 14, 2253–
2258; (d) Rys, V.; Couture, A.; Deniau, E.; Grandclaudon, P.
Tetrahedron 2003, 59, 6615–6619; (e) Moreau, A.; Couture,
A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Org. Biomol.
Chem. 2005, 3, 2305–2309; (f) Moreau, A.; Couture, A.;
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(g) Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.
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´
cal assistance from Melanie Dubois is also acknowledged.
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