Synthesis of Porritoxin

Article abstract of DOI:10.1021/jo0356210

A total synthesis following the sequence in Scheme 1 confirms that porritoxin possesses revised structure 3, not the originally assigned 1. A key reaction was the use of iron pentacarbonyl to formylate an aryllithium when DMF and methyl formate proved ins

Full text of DOI:10.1021/jo0356210

from 1 to 3. The data supporting the structure reassign-
Syn th esis of P or r itoxin
Ivan Cornella and T. Ross Kelly*
Department of Chemistry, Eugene F. Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467
ross.kelly@bc.edu
Received November 4, 2003
Abstr a ct: A total synthesis following the sequence in
Scheme 1 confirms that porritoxin possesses revised struc-
ture 3, not the originally assigned 1. A key reaction was the
use of iron pentacarbonyl to formylate an aryllithium when
DMF and methyl formate proved insufficiently reactive.
ment of 1 to 3 are persuasive, but an independent
corroboration is desirable and neither 1 nor 3 has
previously been prepared by total synthesis. We now
report the total synthesis of 3 and the identity of
synthetic 3 with natural porritoxin, thereby confirming
3 as the structure of the natural product.
The isolation of the phytoxin porritoxin was recorded
in 1992.1 Porritoxin was assigned structure 1, based
largely on spectroscopicsespecially NMRsmeasurements.
A reinvestigation2 of the structure of porritoxin was
stimulated by the similarity of its spectra with corre-
sponding parts of spectra subsequently recorded3 for
stachybotramide (2). The reinvestigation (reported in
2002), which relied primarily on detailed 2D NMR
analysis, led to the revision of the structure of porritoxin
The synthesis of 3 was accomplished according to
Scheme 1. Thus, commercially available acid 4 was
converted to diisopropylamide 5 by acid chloride forma-
tion (SOCl2) followed by reaction with diisopropylamine.
Ortho-lithiation/formylation of 5 to give 7 was anticipated
to be routine, given the known, high-yielding ortho-
lithiation/formylation conversions of 12 to 144 and 13 to
SCHEME 1. Syn th esis of P or r itoxin
10.1021/jo0356210 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/14/2004
J . Org. Chem. 2004, 69, 2191-2193
2191

155 (eq 1).
thatsunlike many of the formylating agents listed by
LarocksFe(CO)5 is commercially available.
In the event, ortho-lithiation of 5 to 6 followed by
reaction with Fe(CO)5 and treatment with acetic acid
(presumably7 for protonolysis of the carbonyl/iron bond)
gave 7 in excellent yield.
The remainder of the synthesis proceeded uneventfully.
Condensation of 7 with ethanolamine gave imine 8, which
was ordinarily not isolated but reduced in situ to 9 with
NaBH3CN. Heating of 9 neat at 180 °C resulted in
cyclization, affording 10. We have previously described
the utility of MeSLi in hot hexamethylphosphoramide
(HMPA) for the nucleophilic cleavage of aryl methyl
ethers.8 Use of the commercially available sodium ana-
logue MeSNa9 in HMPA at 160 °C led to selective
monodeprotection of the less hindered ether in 10 to give
phenol 11. Finally, the prenylation of 11 afforded 3. The
melting point and spectra of synthetic 3 are in excellent
agreement with those reported1 for natural porritoxin.
In conclusion, we have accomplished the first total
synthesis of porritoxin and confirmed that the revised
structure 3 is that of the natural product.
To our surprise, ortho-lithiation of 5 with s-BuLi
followed by attempted formylation with dimethylforma-
mide or methyl formate led either to formation of only
traces of 7 and recovery of 5 or, under forcing conditions
(e.g., reaction of 6 with DMF or methyl formate at 60
°C), nonproductive consumption of 5. Inclusion of addi-
tives (HMPA or tetramethylethylenediamine) or use of
solvents other than THF failed to circumvent the im-
passe. D2O-quench studies gave 16 (assayed by integra-
tion of the resonance for the aromatic proton(s) in 5/16),
establishing that formation of 6 was occurring cleanly.
Given the positive precedents (eq 1), we attribute the
failure of 6 to react with HCONMe2/HCOOMe to a
buttressing effect in which the C-4 methyl in 6 forces the
C-3 methoxy into a conformation that inhibits reaction
with HCONMe2/HCOOMe. Use of the less sterically
encumbered diethylamide analogue 17 did not improve
the outcome. Since 6 does react with D2O (to give 16), 6
is clearly capable of reaction. Thus, a formylating agent
more reactive than HCONMe2/HCOOMe but compatible
with the aprotic environment necessitated by an orga-
nolithio species was required. Examination of Larock’s6
three-page list of anion-compatible formylating agents did
not lead to an obvious sure cure, but the list included
iron pentacarbonyl. The relative reactivity of Fe(CO)5 vis-
a`-vis HCOOMe was not clear, but Fe(CO)5 was listed as
a reagent that formylates Grignard reagents.7 A particu-
larly compelling argument in favor of trying Fe(CO)5 is
Exp er im en ta l Section 10
N,N-Diisop r op yl-3,5-d im eth oxy-4-m eth ylben za m id e (5).
A suspension of 3,5-dimethoxy-4-methylbenzoic acid (4) (10.2 g,
51.0 mmol) in SOCl2 (15.0 mL, 206 mmol) was stirred under N2
at 80 °C until gas evolution ceased (ca. 0.5 h). Excess SOCl2 was
then removed by repeated azeotropic distillation with dry toluene
(3 × 100 mL) in vacuo (rotary evaporator at 40 °C, ca. 6 Torr),
and the resulting brownish solid was dissolved in dry CH2Cl2
(20 mL). i-Pr2NH (15.0 mL, 107 mmol) was then added via
syringe dropwise over 15 min; the reaction was exothermic, and
a precipitate formed. The resulting mixture was stirred over-
night (14 h) at room temperature to ensure complete reaction
and then diluted with more CH2Cl2 (80 mL) and washed with 1
N NaOH (200 mL). The aqueous wash was extracted with more
CH2Cl2 (100 mL), and the combined organic phases were
successively washed with water and brine and dried over
magnesium sulfate. The solvent was evaporated in vacuo to give
a crystalline brownish solid which was purified by flash column
chromatography on silica gel (8 × 7 cm) with 2% then 5% (v/v)
MeOH in CH2Cl2 as eluent to yield a slightly yellow crystalline
solid (12.9 g, 90%): mp 117-118 °C; 1H NMR (400 MHz, CDCl3)
δ 6.47 (s, 2 H), 3.81 (s, 6 H), 3.69 (bs, 2 H), 2.08 (s, 3 H), 1.46
(bs, 6 H), 1.24 (bs, 6 H); 13C NMR (100 MHz, CDCl3) δ 170.9,
157.9, 136.9, 114.9, 101.0, 55.8, 20.9, 8.3 (due to coincidence or
broadening into the baseline, one peak appears missing); IR
(film) ν 2967, 2935, 1630, 1606 cm-1; HRMS (ESI) calcd for
* Corresponding author.
C
16H25NO3Na [M + Na] 302.1732, found 302.1725. Anal. Calcd
(1) Suemitsu, R.; Ohnishi, K.; Horiuchi, M.; Kitaguchi, A.; Odamura,
K. Phytochemistry 1992, 31, 2325-2326.
(2) Horiuchi, M.; Maoka, T.; Iwase, N.; Ohnishi, K. J . Nat. Prod.
2002, 65, 1204-1205.
for C16H25NO3: C, 68.79; H, 9.02; N, 5.01. Found: C, 68.84; H,
9.10; N, 5.01.
2-F or m yl-N,N-d iisop r op yl-3,5-d im eth oxy-4-m eth ylben -
za m id e (7). A 1.40 M solution of s-butyllithium in hexanes (0.80
mL, 1.1 mmol) was added dropwise to a solution of N,N-
diisopropyl-3,5-dimethoxy-4-methylbenzamide (5) (313 mg, 1.12
mmol) in dry THF (10 mL) stirred under Ar at -78 °C in a dry
ice/acetone bath. After 1 h at the same temperature, D2O-quench
of a 0.1 mL aliquot showed correct deuterium incorporation by
1H NMR. Iron pentacarbonyl (0.16 mL, 1.2 mmol; CAUTION:
p yr op h or ic a n d h igh ly toxic) was added dropwise over 1 min,
and the reaction mixture was allowed to warm to room temper-
ature overnight (ca. 11 h). Glacial acetic acid (0.10 mL, 1.7 mmol)
was added in one portion to the dark green solution, and the
resulting deep red mixture was stirred for 15 min. Dilution with
(3) Ayer, W. A.; Miao, S. Can. J . Chem. 1993, 71, 487-493.
(4) Chen, C.-W.; Beak, P. J . Org. Chem. 1986, 51, 3325-3334. The
conversion of 12 to 14 had already been reproduced in good yield in
our laboratories (Scopton, A.; Kelly, T. R., unpublished results).
(5) (a) Hauser, F. M.; Hewawasam, P.; Baghdanov, V. M. J . Org.
Chem. 1988, 53, 223-224. (b) Evans, J . C.; Klix, R. C.; Bach, R. D. J .
Org. Chem. 1988, 53, 5519-5527. (c) Parker, K. A.; Spero, D. M.;
Koziski, K. A. J . Org. Chem. 1987, 52, 183-188.
(6) Larock, R. C. Comprehensive Organic Transformations, 2nd ed.;
Wiley-VCH: New York, 1999; pp 1381-1383.
(7) Yamashita, M.; Miyoshi, K.; Nakazono, Y.; Suemitsu, R. Bull.
Chem. Soc. J pn. 1982, 55, 1663-1664.
(8) Kelly, T. R.; Dali, H. M.; Tsang, W.-G. Tetrahedron Lett. 1977,
3859-3860.
(9) For an early use of CH3SNa, see: Kornblum, N.; Scott, A. J . Am.
Chem. Soc. 1974, 96, 590-591. For an overview of aryl methyl ether
cleavage with thiolates, see: Merriman, G. In Encyclopedia of Reagents
for Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995;
Vol. 5, pp 3161-3163.
(10) For general experimental procedures see the Supporting In-
formation in: Kelly, T. R.; Silva, R. A.; De Silva, H.; J asmin, S.; Zhao,
Y. J . Am. Chem. Soc. 2000, 122, 6935-6949.
2192 J . Org. Chem., Vol. 69, No. 6, 2004

diethyl ether (100 mL) was followed by washing the organic layer
with aqueous 1 N HCl (50 mL), 0.1 N NaOH (50 mL), a saturated
solution of NaHCO3 (40 mL), water, and brine. The organic
phase was dried over magnesium sulfate, and the solvent was
evaporated in vacuo to give a yellow solid which was purified
by flash column chromatography on silica gel (2 × 15 cm) with
2% then 5% (v/v) MeOH in CH2Cl2 as eluent to yield a slightly
yellow solid (311 mg, 92%): mp 119-121 °C; 1H NMR (400 MHz,
CDCl3) δ 10.22 (s, 1 H), 6.44 (s, 1 H), 3.87 (s, 3 H), 3.83 (s, 3 H),
3.48 (m, 2 H), 2.13 (s, 3 H), 1.63 (bs, 3 H), 1.55 (bs, 3 H), 1.05 (s,
6 H); 13C NMR (100 MHz, CDCl3) δ 188.0, 168.8, 163.1, 162.5,
139.7, 119.9, 118.7, 104.1, 63.0, 56.0, 51.0, 45.7, 21.0, 20.8, 20.0,
19.7, 8.6; IR (film) ν 2971, 2936, 1684, 1636 cm-1; HRMS (ESI)
calcd for C17H25NO4Na [M + Na] 330.1681, found 330.1685.
Anal. Calcd for C17H25NO4: C, 66.42; H, 8.20; N, 4.56. Found:
C, 66.45; H, 8.28; N, 4.59.
2,3-Dih yd r o-2-(2-h yd r oxyeth yl)-4,6-d im eth oxy-5-m eth yl-
1H-isoin d ol-1-on e (10). A mixture of 2-formyl-N,N-diisopropyl-
3,5-dimethoxy-4-methylbenzamide (7) (1.00 g, 3.25 mmol), eth-
anolamine (0.39 mL, 6.5 mmol), and NaBH3CN (0.41 g, 6.5
mmol) in dry methanol (10 mL) was stirred under Ar in the
presence of activated 3 Å molecular sieves (ca. 1 g) for 1 h.
Bromocresol green (ca. 5 mg) was then added;11 a change in color
from yellow to blue was observed. Then, concentrated HCl was
added until (ca. 0.5 mL) the blue coloration changed to yellow
(pH ∼4). The reaction mixture was stirred at room temperature
(ca. 2 h) until formation of 9 was complete as indicated by TLC
(5:95 MeOH/CH2Cl2). A saturated aqueous solution of NaHCO3
was added until (ca. 20 mL) the pH was ∼9; the reaction mixture
was extracted with diethyl ether (3 × 20 mL). The combined
organic extracts were washed with water and brine and dried
over magnesium sulfate. The solvent was evaporated in vacuo
to give an off-white solid (975 mg); 200 mg of that crude material
was heated at 180 °C until (ca. 3 h) gas evolution (presumably
diisopropylamine) ceased. Once at room temperature, the result-
ing pale yellow solid was purified by preparative TLC (5:95
MeOH/CH2Cl2) to yield 10 as an off-white solid (105 mg, 61%
from 7): mp 125-127 °C; 1H NMR (400 MHz, CDCl3) δ 7.01 (s,
1 H), 4.52 (s, 2 H), 3.90 (t, J ) 4.8 Hz, 2 H), 3.85 (s, 3 H), 3.85
(s, 3 H), 3.74 (t, J ) 4.8 Hz, 2 H), 3.45 (bs, 1 H), 2.16 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 169.5, 159.1, 153.1, 131.5, 123.9,
122.7, 99.9, 61.7, 59.7, 56.0, 50.0, 46.4, 9.5; IR (film) ν 3378, 2936,
1668, 1621 cm-1; HRMS (ESI) calcd for C13H17NO4Na [M + Na]
274.1055, found 274.1054. Anal. Calcd for C13H17NO4: C, 62.14;
H, 6.82; N, 5.57. Found: C, 62.28; H, 6.90; N, 5.68.
2,3-Dih yd r o-2-(2-h yd r oxyet h yl)-4-m et h oxy-5-m et h yl-6-
[(3-m eth yl-2-bu ten yl)oxy]-1H-isoin d ol-1-on e (P or r itoxin ,
3). A suspension of 2,3-dihydro-2-(2-hydroxyethyl)-4,6-dimethoxy-
5-methyl-1H-isoindol-1-one (10) (29 mg, 0.11 mmol), sodium
thiomethoxide (29 mg, 0.41 mmol), and dry HMPA (0.20 mL)
was stirred at 160 °C. After 2 h at the same temperature, TLC
(1:9 MeOH/CH2Cl2) of an aliquot partitioned between water and
dichloromethane showed disappearance of starting material (Rf
∼0.4) and a new spot at Rf ∼ 0.2. Once at room temperature,
water (10 mL) was added to the mixture and the HMPA was
washed out of the aqueous phase by extracting with CH2Cl2 (6
× 10 mL). The water was evaporated in vacuo, and the crude,
water-soluble phenol 10 (or the corresponding phenoxide) was
dissolved in dry acetone (3 mL). K2CO3 (18 mg, 0.13 mmol) was
added, and the mixture was stirred under Ar. Dimethylallyl
bromide (25 µL, 0.21 mmol) was added via syringe, and the
resulting suspension was refluxed overnight (ca. 11 h). TLC (1:9
MeOH/CH2Cl2) showed consumption of starting material and a
new spot at Rf ∼0.3. Filtration and evaporation of the filtrate
afforded a pale yellow oil which was purified by preparative TLC
(1:9 MeOH/CH2Cl2) to yield 3 as an off-white solid (28 mg, 83%
from 10): mp 114-116 °C (lit.1 mp 115-116 °C); 1H NMR (400
MHz, DMSO-d6) δ 6.95 (s, 1 H), 5.47 (t, J ) 6.8 Hz, 1 H), 4.84
(bs, 1 H), 4.57 (s, 2 H), 4.51 (d, J ) 6.8 Hz, 2 H), 3.84 (s, 3 H),
3.60 (m, 2 H), 3.55 (t, J ) 5.2 Hz, 2 H), 2.10 (s, 3 H), 1.74 (s, 3
H), 1.65 (s, 3 H); 13C NMR (100 MHz, DMSO-d6) δ 167.5, 158.7,
152.4, 138.0, 132.2, 125.1, 121.8, 120.5, 99.7, 68.7, 59.7, 56.4,
49.2, 45.1, 26.0, 18.5, 10.2; IR (film) ν 3344, 2960, 1667 (broad)
cm-1; HRMS (ESI) calcd for C17H23NO4Na [M + Na] 328.1511,
found 328.1525.
Ack n ow led gm en t. We thank Dr. M. Horiuchi1 for
providing a copy of the 1H NMR spectrum of natural
porritoxin and Mr. Alex Scopton for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR spectra of synthetic 3. This material is available free
of charge via the Internet at http://pubs.acs.org.
(11) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J . Am. Chem. Soc.
1971, 93, 2897-2904.
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