A new total synthesis of porritoxin

Article abstract of DOI:10.1021/jo052592f

A concise and efficient total synthesis of the phytotoxin porritoxin is described. The key step of the synthesis is based upon a Parham cyclization methodology which enables the creation of the lactam unit embedded in the title compound framework with the

Full text of DOI:10.1021/jo052592f

A New Total Synthesis of Porritoxin
Anne Moreau, Magali Lorion, Axel Couture,*
Eric Deniau, and Pierre Grandclaudon
Laboratoire de Chimie Organique Physique, UMR 8009
“Chimie Organique et Macromole´culaire”, UniVersite´ des
Sciences et technologies de Lille, Baˆtiment C3(2),
F-59655 VilleneuVe d’Ascq Cedex, France
axel.couture@uniV-lille1.fr
ReceiVed December 16, 2005
of the 6-hydroxyphenolic function, thereby providing 7, the
immediate precursor of the target alkaloid 4.
Herein, we wish to delineate a tactically and conceptually
new synthetic approach to alkaloid porritoxin 4 that relies upon
our long-standing experience in the field of isoindolinone
chemistry.4 Our strategy is based upon the exploitation of the
Parham cyclization process for the creation of the five-
membered lactam embedded in the isoindolinone framework
of the targeted porritoxin. The protocol developed by Parham
which hinges upon aromatic lithiation and subsequent reaction
with an internal electrophile occupies a place of choice in the
arsenal of synthetic tactics for the assembling of carbo- and
heterocyclic systems.5 However, applications of this concept
to the elaboration of five-membered lactams are scarce,6 and
as far as we are aware, utilization of carbamates as internal
electrophiles has been confined thus far to acyclic systems.6a,7
We then reasoned that porritoxin 4 would be obtained by
A concise and efficient total synthesis of the phytotoxin
porritoxin is described. The key step of the synthesis is based
upon a Parham cyclization methodology which enables the
creation of the lactam unit embedded in the title compound
framework with the concomitant formation of the tethered
hydroxyakyl chain.
Porritoxin is a phytotoxin produced by the fungus Alternaria
porri (Ellis) Ciferi responsible for black spot disease of
commercially important plants such as stone-leek, lettuce, and
onion.1 This nonspecific toxin was isolated in 1992 from the
stationary liquid cultures of the above-mentioned fungi and was
initially assigned structure 1 possessing a unique benzoxazocine
skeleton. Later, comparison of the 1H and 13C NMR spectra of
the isolated product with zinniol (2) and also with the secondary
metabolite stachybotramide (3) having an isoindolinone moiety
led the isolating group to suspect an erroneous assignment.
Finally, persuasive data mainly based upon extensive reinves-
tigation of the structure by detailed 2D NMR analysis including
1H-13C and 1H-15N HMBC experiments led to the revision of
the structure of the natural product from 1 to 4.2
Recently, Kelly et al. reported the first total synthesis of the
revised structure 4 to confirm that porritoxin was not the
originally assigned 1.3 Their elegant and skillful synthetic
strategy hinges upon an ortho-lithiation/formylation with iron
pentacarbonyl process leading to 5 (retrosynthetic Scheme 1,
path a), a high-temperature annulation reaction giving rise to
isoindolinone 6 and ultimately the selective mono-deprotection
(4) (a) Hoarau, C.; Couture, A.; Cornet, H.; Deniau, E.; Grandclaudon,
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) Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun,
S. Tetrahedron 2004, 60, 6169-6176. (d) Moreau, A.; Couture, A.; Deniau,
E.; Grandclaudon, P. J. Org. Chem. 2004, 69, 4527-4530. (e) Rys, V.;
Couture, A.; Deniau, E.; Lebrun, S.; Grandclaudon, P. Synlett 2004, 2233-
2235. (f) Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P. Eur. J.
Org. Chem. 2005, 3437-3442. (g) Deniau, E.; Enders, D.; Couture, A.;
Grandclaudon, P. Tetrahedron: Asymmetry 2005, 16, 875-881.
(5) Reviews: (a) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982,
15, 300-305. (b) Wakefield, B. J. The Chemistry of Organolithium
Compounds, 2nd ed.; Pergamon: New York, 1990. (c) Gray, M.; Tinkl,
M.; Snieckus, V. In ComprehensiVe Organometallic Chemistry II; Abel,
E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Exeter, 1995; Vol.
11, pp 66-92. (d) Ardeo, A.; Collado, M. I.; Osante, I.; Ruiz, J.; Sotomayor,
N.; Lete, E. In Targets in Heterocyclic Systems; Atanassi O., Spinelli, D.,
Eds.; Italian Society of Chemistry: Rome, 2001; Vol. 5, pp 393-418. (e)
Clayden, J. Organolithiums: SelectiVity for Synthesis; Elsevier Science
Ltd.: Oxford, 2002. (f) Mealy, M. J.; Bailey, W. F. J. Organomet. Chem.
2002, 646, 59-67. (g) Sotomayor, N.; Lete, E. Curr. Org. Chem., 2003, 7,
275-300. (h) Na´jera, C.; Sansano, J. M.; Yus, M. Tetrahedron 2003, 59,
9255-9303.
* To whom correspondence should be addressed. Fax: +33 (0)3 20 33 63
09.
(1) Suemitsu, R.; Ohnishi, K.; Horiuchi, M.; Kitaguchi, A.; Odamura,
(6) (a) Carmen de la Fuente, M.; Dominguez, D. Tetrahedron 2004, 60,
10019-10028. (b) Giger, R. K. A. Swiss Pat. 1985, CH 648300; Chem.
Abstr. 1985, 103, 71188. (c) Rys, V.; Couture, A.; Deniau, E.; Grandclaudon,
P. Eur. J. Org. Chem. 2003, 1231-1237.
(7) Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S.
Org. Biomol. Chem. 2005, 3, 2305-2309.
K. Phytochemistry 1992, 31, 2325-2326.
(2) Horiuchi, M.; Maoka, T.; Iwase, N.; Ohnishi, K. J. Nat. Prod. 2002,
65, 1204-1205.
(3) Cornella, I.; Kelly, T. R. J. Org. Chem. 2004, 69, 2191-2193.
10.1021/jo052592f CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/04/2006
J. Org. Chem. 2006, 71, 3303-3305
3303

SCHEME 1
SCHEME 2
prenylation of 7, and we then conjectured that this fused alkaloid
would be conceivably assembled by a Parham-type cyclization
of the N-bromobenzyl-substituted oxazolidinone 8 (retrosyn-
thetic Scheme 1, path b) equipped with the diverse and dense
functionalities present in the targeted compound. We also
anticipated that interception of the aryllithiated species derived
from 8 by the oxazolidinone ring system, i.e., a cyclic carbamate,
would provide the potential for direct access to a protected
version of the target 7 and the concomitant connection of the
hydroxyalkyl chain.
Our investigation toward this synthetic approach started from
the benzaldehyde derivative 9 equipped at this point of the
synthesis with an isopropyl protecting group liable to survive
the planned synthetic manipulations. Conversion of this starting
material to one of the reaction partners required for the assembly
of 8, i.e., the rather congested benzyl chloride 11, was achieved
in two steps as shown in Scheme 2.
ensured by N-alkylation of 2-oxazolidinone with the benzyl
chloride derivative 11, and this simple operation delivered the
cyclic carbamate precursor 8 in an excellent yield (Scheme 2).
To ensure the optimal formation of the mandatory lithiated
species 12, variations of the solvent, base, temperature profile,
and the inclusion of anion modifiers were all screened on the
basis of precedents which have been shown to favor halogen/
metal interconversion while sparing sensitive functionalities.5
After considerable experimentations, we found that adding
parent compound 8 to n-butyllithium (3 equiv) and TMEDA (3
equiv) in THF at -78 °C for 30 min led to complete
consumption of the starting material and to isolation solely of
the hydroxyalkyl chain tethered isoindolinone 13 in a fairly good
yield. With this highly substituted isoindolinone 13 in hand,
we were only a deprotection and a prenylation away from the
target natural product. Thus, treatment of 13 with BCl3 in CH2-
Cl2 under mild conditions triggered off the cleavage of the
isopropyl protecting group. Finally O-prenylation in the sequel
of the phenolic 6-OH group of 7, the immediate precursor of
porritoxin,3 delivered the target final compound in an excellent
yield. The spectral data and melting point of 4 were in excellent
agreement with those published for porritoxin.2,3
Thus, manipulation of the carboxaldehyde residue in 9 by
reduction to the benzyl alcohol 10 was followed by complete
and smooth conversion into the halogenated derivative 11 upon
treatment with methanesulfonyl chloride (MsCl) in CH2Cl2.8
The subsequent installation of the oxazolidinone unit was
In conclusion, we have completed a concise second total
synthesis of the naturally occurring isoindolinone porritoxin.
The advantages of the synthesis lie mainly in the experimental
simplicity for the elaboration of the intermediates involved in
the assembly of this alkaloid, the high efficiency, and above
(8) (a) van Oijen, A. H.; Huck, N. P. M.; Kruijtzer, J. A. W.; Erkelens,
C.; van Boom, J. H.; Liskamp, R. M. J. J. Org. Chem. 1994, 59, 2399-
2408. (b) Vieira, E.; Bingelli, A.; Breu, V.; Bur, D.; Fischli, W.; Gu¨ller,
R.; Hirth, G.; Ma¨rki, H. P.; Mu¨ller, M.; Oefner, C.; Scalone, M.; Stadler,
H.; Wilhelm, M.; Wostl, W. Bioorg. Med. Chem. Lett. 1999, 9, 1397-
1402.
3304 J. Org. Chem., Vol. 71, No. 8, 2006

pentane, 2 mL, 4 mmol) and TMEDA (465 mg, 4 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
oxazolidinone 8 (0.47 g, 1.31 mmol) in degassed THF (15 mL)
was then added dropwise through a cannula. The mixture was stirred
for 30 min at -78 °C. Aqueous satd NH4Cl solution (5 mL) was
added, and after dilution with water (30 mL), the mixture was
extracted with CH2Cl2 (2 × 30 mL). The combined organic layers
were dried (Na2SO4), and the solvents were evaporated under
vacuum to left 13 as a solid residue which was purified by flash
column chromatography on silica using acetone/hexanes (80:20)
as eluent: white crystals from hexane/toluene, 0.23 g (69%); mp
113-114 °C; 1H NMR (300 MHz, CDCl3) δ 1.33 (d, J ) 6.0 Hz,
6H), 2.15 (s, 3H), 3.10-3.52 (br. s, 1H), 3.73 (t, J ) 5.0 Hz, 2H),
3.84 (s, 3H), 3.90 (t, J ) 5.0 Hz, 2H), 4.52 (s, 2H), 4.58 (hept, J
) 6.0 Hz, 1H), 7.04 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 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. Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N,
5.01. Found: C, 64.59; H, 7.76; N, 4.83.
6-Hydroxy-2-(2-hydroxyethyl)-4-methoxy-5-methyl-2,3-dihy-
dro-1H-isoindol-1-one (7). A solution of BCl3 (1 M in CH2Cl2,
3.75 mL, 3.75 mmol) was added dropwise by syringe to a degassed
solution of isoindolinone 13 (0.21 g, 0.75 mmol) in CH2Cl2 (15
mL) at 0 °C under Ar. After being stirred for 2 h at 0 °C, the
reaction mixture was poured onto a few pieces of crushed ice. The
aqueous phase was extracted with CH2Cl2 (3 × 10 mL) and Et2O
(3 × 10 mL). The organic solvents were combined and dried (Na2-
SO4). The solvents were removed under vacuum, and the crude
solid residue was finally recrystallized from toluene-ethanol to
afford 7: white crystals; 108 mg (61%); mp 176-178 °C; 1H NMR
(300 MHz, DMSO-d6) δ 2.1 (s, 3H), 3.53-3.67 (m, 4H), 4.61 (s,
2H), 6.87 (s, 1H), 9.81 (br. s, 1H); 13C NMR (75 MHz, DMSO-d6)
δ 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. Anal. Calcd for C12H15NO4: C, 60.75; H, 6.37;
N, 5.90. Found: C, 60.54; H, 6.19; N, 6.09.
all, the mildness of reaction conditions and the use of nonhaz-
ardous reagents. We also believe that this work provides a strong
incentive for the elaboration of similar structurally modified
naturally occurring alkaloids and their biogenetic congeners.
Experimental Section
(6-Bromo-4-isopropoxy-2-methoxy-3-methylphenyl)metha-
nol (10). NaBH4 (0.24 g, 6.3 mmol) was added portionwise to a
stirred solution of 9 (1.52 g, 5.3 mmol) in MeOH (25 mL). Stirring
was maintained at rt for an additional 1 h. After concentration under
vacuum, the residue was dissolved in CH2Cl2 (20 mL) and washed
with aqueous satd NH4Cl solution (20 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
ethyl acetate/hexanes (30:70) as eluent: white crystals from hexane/
toluene, 1.35 g (88%); mp 86-87 °C; 1H NMR (300 MHz, CDCl3)
δ 1.32 (d, J ) 6.1 Hz, 6H), 2.07 (s, 3H), 2.22 (br. s, 1H), 3.78 (s,
3H), 4.48 (hept, J ) 6.1 Hz, 1H), 4.75 (s, 2H), 6.85 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 9.3, 22.1, 60.1, 61.9, 70.8, 113.3, 120.9,
121.7, 125.6, 157.3, 158.8. Anal. Calcd for C12H17BrO3: C, 49.84;
H, 5.93. Found: C, 50.01; H, 5.87.
6-Bromo-4-isopropoxy-2-methoxy-3-methylbenzyl Chloride
(11). Methanesulfonyle chloride (MsCl, 0.80 g, 7.0 mmol) was
added by syringe to a solution of the benzyl alcohol derivative 10
(1.33 g, 4.6 mmol) and Et3N (0.71 g, 7.0 mmol) in CH2Cl2 (40
mL) at 0 °C. The solution was stirred overnight at rt, washed with
aqueous satd NaHCO3 solution and brine, and dried (MgSO4).
Evaporation of the solvent under vacuum afforded a yellow oil (1.02
g, 72%) which was used in the next step without further purifica-
tion: 1H NMR (300 MHz, CDCl3) δ 1.32 (d, J ) 6.1 Hz, 6H),
2.07 (s, 3H), 3.83 (s, 3H), 4.47 (hept, J ) 6.1 Hz, 1H), 4.78 (s,
2H), 6.87 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 9.5, 22.1, 41.8,
61.8, 70.8, 113.3, 120.8, 122.5, 122.8, 157.9, 158.7.
3-(6-Bromo-4-isopropoxy-2-methoxy-3-methylbenzyl)oxazo-
lidin-2-one (8). A solution of oxazolidin-2-one (0.37 g, 4.25 mmol)
in THF (10 mL) was added to a stirred suspension of NaH (0.12 g,
5.0 mmol) in THF (20 mL) under Ar. Once the addition was
complete (ca. 30 min), the mixture was stirred for 1 h at rt. A
solution of 11 (1.31 g, 4.25 mmol) in THF (10 mL) was then added
dropwise, and the mixture was refluxed overnight. After cooling,
water (20 mL) was added, and the mixture was extracted with Et2O
(3 × 25 mL). The combined organic layers were dried (Na2SO4),
and the solvent was evaporated under vacuum. The residue was
purified by flash column chromatography on silica using ethyl
acetate/hexanes (30:70) as eluent: white crystals from hexane/
toluene, 1.02 g (67%); mp 63-64 °C; 1H NMR (300 MHz, CDCl3)
δ 1.33 (d, J ) 6.1 Hz, 6H), 2.07 (s, 3H), 3.35 (dd, J ) 7.8 and 9.3
Hz, 2H), 3.71 (s, 3H), 4.22 (dd, J ) 7.8 and 9.3 Hz, 2H), 4.48
(hept, J ) 6.1 Hz, 1H), 4.58 (s, 2H), 6.85 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 9.9, 22.4, 43.1, 44.0, 61.5, 62.1, 71.1, 113.5, 120.1,
121.2, 122.6, 157.9, 158.3, 159.6. Anal. Calcd for C15H20BrNO4:
C, 50.29; H, 5.63; N, 3.91. Found: C, 50.50; H, 5.76; N, 4.03.
2-(2-Hydroxyethyl)-6-isopropoxy-4-methoxy-5-methyl-2,3-di-
hydro-1H-isoindol-1-one (13). A solution of n-BuLi (2 M in
Porritoxin (4). A stirred solution of 7 (90 mg, 0.38 mmol) and
1-bromo-3-methylbut-2-ene (69 mg, 0.46 mmol) in dry acetone (10
mL) was refluxed with K2CO3 (79 mg, 0.57 mmol) for 12 h. The
mixture was filtered on Celite and concentrated under vacuum, and
the solid residue was dissolved in Et2O (15 mL). The cooled solution
was washed with water, 10% NaOH solution (2 × 15 mL), and
brine and dried (Na2SO4). The organic layer was evaporated under
reduced pressure to afford the porritoxin 4: white crystals from
hexane/toluene, 111 mg (68%); mp 115-116 °C (lit.2 mp 115-
116 °C). Analytical and spectral data matched those reported for
the natural product.2,3
Acknowledgment. We thank MENSR for financial support
(grant to A. M. and M. L.) and Me´lanie Dubois for technical
assistance.
Supporting Information Available: General methods and
analytical data for compounds 7, 8, 13, and 4. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO052592F
J. Org. Chem, Vol. 71, No. 8, 2006 3305