First total synthesis of the alkaloid polycitrin B

Article abstract of DOI:10.1016/S0040-4020(00)00168-X

Starting from 3,5-dibromo-4-methoxy-phenylacetic acid methyl ester 2, a first total synthesis of the marine alkaloid polycitrin B is reported, based on the Pd catalyzed coupling reaction of the triflate 4 with the (4- methoxymethoxy-phenyl)tributylstannan

Full text of DOI:10.1016/S0040-4020(00)00168-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2699±2702
First Total Synthesis of the Alkaloid Polycitrin B
*
Egle M. Beccalli, Francesca Clerici and Alessandro Marchesini
Á Á
Istituto di Chimica Organica, Facolta di Farmacia, Universita degli Studi di Milano, Via Venezian 21, 20133 Milan, Italy
Received 8 October 1999; revised 1 February 2000; accepted 17 February 2000
AbstractÐStarting from 3,5-dibromo-4-methoxy-phenylacetic acid methyl ester 2, a ®rst total synthesis of the marine alkaloid polycitrin B
is reported, based on the Pd catalyzed coupling reaction of the tri¯ate 4 with the (4-methoxymethoxy-phenyl)tributylstannane. q 2000
Elsevier Science Ltd. All rights reserved.
Polycitrin A (la) and B (lb) are alkaloids that contain a
maleimide unit with two aromatic residues at positions 3
and 4, and the nitrogen atom substituted with a (4-hydroxy-
phenyl)ethyl residue. Their isolation from the marine
Ascidian Polycitor sp. and structure elucidation were
reported in 1994 by Kashman and coworkers.1 In 1995,
Steglich and coworkers2 reported the biomimetic synthesis
of Polycitrin A. We now report a total synthesis of polycitrin
B based on a Pd catalyzed cross coupling reaction, and
starting from 4-methoxyphenylacetic acid methyl ester.
6. Basic hydrolysis of the ester groups then provided
anhydride 7, which was brominated with bromine in glacial
acetic acid to give 8.
Polycitrin B was obtained by heating a mixture of
compound 8 with tyramine, Hunig's base and phenol at
1408C.2 Using these conditions, polycitrin B and polycitrin
A were both obtained in a 3:2 ratio. This result was
rationalized in terms of an SNAr reaction path9 with water
as the nucleophile, addition being assisted by the presence
of strongly electron withdrawing groups on the aromatic
ring. Better results were obtained working in the presence
of activated molecular sieves. In this case a considerable
improvement was observed in favour of the polycitrin B
and the yield of polycitrin A was diminished.
The dibromo ester 2 was prepared by bromination of
4-methoxyphenylacetic acid methyl ester following the
method reported for the bromination of the corresponding
acid.4,5 Condensation of the ester 2 with dimethyl oxalate
gave compound 3 as a 1:1 mixture of keto- and enol forms
1
(the H NMR spectra recorded in DMSO, showed the enol
The spectral data for the polycitrin B is in agreement with
those reported in literature.1 Only 2 mg of the compound
were isolated from the natural source as a yellowish
¯uorescent oil. By the synthetic path, the compound was
obtained in a good yield and crystallized from CH2Cl2-
pentane as yellow crystals.
form only). The tri¯ate 4 was obtained from 3 by reaction
with tri¯uoromethanesulfonic anhydride and in the presence
of Hunig's base.3
The coupling reaction between tri¯ate 4 and tributyl-(4-
methoxymethoxy-phenyl)-stannane6 was unsatisfactory
when carried out according to the classical Stille conditions
[Pd(PPh3)4, THF at re¯ux]7, the coupling product 5 being
obtained in a very low yield. A dramatic improvement was
achieved when the reaction was carried out in DMF at 70±
758C with Pd2dba3 [tris(dibenzylideneacetone)dipalladium]
as the catalyst and in the presence of triphenylphosphine.
Using these conditions, 5 was obtained in 81% yield
(Scheme 1).
Experimental
Melting points were determined on a BuÈchi 510 apparatus
and are uncorrected. IR spectra were recorded on a JASCO
IR Report 100 instrument, in Nujol mull for solids and as
1
liquid ®lms for oils. H NMR and 13C NMR spectra were
recorded on a Varian Gemini 200 or a Bruker AVANCE
DRX 300 spectrometer. Chemical shifts are expressed in
ppm (d) relative to TMS. UV spectra were recorded on a
UVICON 943 Kontron instrument. Mass spectra were
obtained by electron impact ionization at 70 eV from a
MD 800 Finnigan instrument using the direct exposure
probe (DEP). Column chromatography was performed on
Kieselgel Merck 60, 0.063±0.2 mm. Organic extracts were
Removal of the methoxymethyl ether in 5 was achieved
with trimethyl silyl chloride-sodium iodide8 giving phenol
Keywords: alkaloids; coupling reactions; palladium and compounds; tin and
compounds.
* Corresponding author. Tel.: 1270-601774; fax: 1270-638473; e-mail:
egle.beccalli@unimi.it
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00168-X

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E. M. Beccalli et al. / Tetrahedron 56 (2000) 2699±2702
Scheme 1.
dried with Na2SO4. Evaporation of the solvent was carried
out under vacuum on a rotary evaporator.
chromatography (pentane±CH2CI2 1:1) to give the
compound 2 (12.5 g, 80%) as white crystals, mp 39±408C
(hexane), (lit.5 mp 368C from MeOH).
3,5-Dibromo-4-methoxy-phenyl acetic acid methyl ester
2. To a solution of 4-methoxy-phenyl acetic acid methyl
ester (9.18, 50 mmol) in anhydrous chloroform (90 mL),
FeBr2 was added (1.72 g, 7.9 mmol). A solution of bromine
(7.8 mL, 150 mmol) in chloroform (15 mL) was added
dropwise to the reaction vessel. After the mixture was stir-
red for 48 h at room temperature, additional bromine (4 mL,
77 mmol) and FeBr2, (400 mg, 1.85 mmol) were added. The
solution was stirred for 48 h, then poured carefully into an
excess of 5% aqueous NaHSO3, and extracted with Et2O
(2£50 mL). The combined ethereal extracts were washed
with H2O and then dried. Removal of the solvent afforded
the crude product which was puri®ed by silica gel column
2-(3,5-Dibromo-4-methoxy-phenyl)-3-hydroxy-but-2-
enedioic acid dimethyl ester 3. To a methanolic solution of
sodium methoxide, formed by adding Na (1.38 g, 60 mmol)
to anhydrous methanol (130 mL), compound 2 (10 g,
30 mmol) and dimethyloxalate (5.3 g, 45 mmol) were
added. The mixture was heated under re¯ux for 5 h, then
the solvent was evaporated and the residue diluted with 4%
HCl (70 mL) and extracted with CH2CI2 (2£50 mL). The
organic layer was dried, ®ltered and evaporated. The crude
product was puri®ed by silica gel column chromatography
(pentane±CH2C12 2:1) to give compound 3 as an oil in
quantitative yield; C13H12Br2O6 requires C, 36.82; H, 2.85.

E. M. Beccalli et al. / Tetrahedron 56 (2000) 2699±2702
2701
Found: C, 36.70; H, 2.80. nmax 3450, 1725, 1642 cm21; dH
(300 MHz DMSO-d6) 3.60 (3H, s, OMe), 3.78 (3H, s,
OMe), 3.81 (3H, s, OMe), 7.54 (2H, s, aryl-H), 12.40 (1H,
s, exchange with D2O, OH).
MeOH, 20 mL). The reaction mixture immediately turned
red. Water (1.2 mL) was then added and the mixture was
heated under re¯ux for 2 h. After solvent evaporation, the
residue was diluted with 4% HCl and extracted with
CH2C12 (2£40 mL). The combined organic layers were
dried, ®ltered and evaporated and the crude product puri®ed
by silica gel column chromatography (CH2C12±Et2O 20:1)
to give 7 (1.16 g, 77%) as yellow solid, mp 181±1838C
(hexane±CH2C12); C17H10Br2O5 requires C, 44.97; H,
2.22. Found: C, 45.02; H, 2.19; nmax 3420, 1820, 1750,
1739 cm21; dH (200 MHz CDCl3) 3.95 (3H, s, OMe), 5.25
(1H, bs, exchange with D2O, OH), 6.90 (2H, d, Jˆ9.0 Hz,
aryl-H), 7.53 (2H, d, Jˆ9.0 Hz, aryl-H), 7.71 (2H, s, aryl-
H).
2-(3,5-Dibromo-4-methoxy-phenyl)-3-(tri¯uoromethane-
sulfonyloxy)-but-2-enedioic acid dimethyl ester 4.
Compound 3 (5.6 g, 13.2 mmol) was dissolved in dry
dichloromethane (70 mL) and N,N-diisopropylethylamine
(3.4 mL, 19.8 mmol) was added. The reaction mixture was
cooled at 08C and a solution of tri¯uoromethanesulfonic
anhydride (2.82 mL, 17 mmol) in CH2Cl2 (10 mL) was
added dropwise with stirring. The mixture was kept at 08C
for 15 min, then warmed to room temperature and washed
with water (2£40 mL). The organic layer was dried, ®ltered
and evaporated and the residue puri®ed by silica gel column
chromatography (hexane±CH2Cl2 1:1) to give 4 (6.9 g,
84%) as white solid, mp 107±1088C (pentane±Et2O);
C14H11Br2F3O8S requires C, 30.24; H, 1.99. Found: C,
3-(3,5-Dibromo-4-methoxy-phenyl)-4-(3,5 dibromo-4-
hydroxy-phenyl)-furan-2,5-dione 8. To a stirred solution
of 7 (883 mg, 1.94 mmol) in glacial acetic acid (30 mL) a
solution of bromine (0.6 mL, 11.64 mmol) in acetic acid
(10 mL) was added dropwise at room temperature in
10 min. After stirring for 1 h, the solution was poured into
Na2SO3±H2O solution to give a yellow precipitate. The
solid was ®ltered off, washed with cool water and dried in
vacuo. Recrystallization from pentane±Et2O yielded 8
(1.09 g, 89%) as yellow crystals; mp 191±1938C;
C17H8Br4O5 requires C, 33.37; H, 1.32. Found: C, 33.42;
H, 1.26; nmax 3400, 1820, 1740 cm21; dH (300 MHz
CDCl3) 3.97 (3H, s, OMe), 6.30 (1H, bs, exchange with
D2O, OH), 7.75 (4H, s, aryl-H).
30.41; H, 1.96; nmax 1722, 1717, 1620 cm21
; dH
(200 MHz CDCl3) 3.92 (3H, s, OMe), 3.93 (3H, s, OMe),
3.95 (3H, s, OMe), 7.68 (2H, s, aryl-H).
2-(3,5-Dibromo-4-methoxy-phenyl)-3-(4-methoxymethoxy-
phenyl)-but-2-enedioic acid dimethyl ester 5. Compound
4
(1.7 g, 34 mmol) and tributyl-(4-methoxymethoxy-
phenyl)-stannane6 (2.18 g, 51 mmol) were dissolved in
DMF (10 mL). Pd2dba3 (155 mg, 0.17 mmol) and Ph3P
(96 mg, 0.36 mmol) were added to this solution and the
mixture was heated at 70±758C for 1 h. After this time,
the solution was poured into a saturated NaCl±H2O solution
(150 mL) and extracted with Et2O (2£50 mL). The organic
layer was dried, ®ltered and evaporated and the residue
puri®ed by crystallization giving 5 (1.52 g, 81%) as white
crystals, mp 133±1348C (Et2O); C21H20Br2O7 requires C,
46.35; H, 3.70. Found: C, 46.21; H, 3.66; nmax 1721,
1699, 1583 cm21; dH (200 MHz CDCl3) 3.44 (3H, s,
OMe), 3.82 (3H, s, OMe), 3.85 (3H, s, OMe), 3.86 (3H, s,
OMe), 5.15 (2H, s, CH2O), 6.90 (2H, d, Jˆ9.0 Hz, aryl-H),
7.01 (2H, d, Jˆ9.0 Hz, aryl-H), 7.24 (2H, s, aryl-H).
Polycitrin B 1b. A mixture of 8 (300 mg, 0.49 mmol),
phenol (1.2 g), N,N-diisopropylethylamine (0.7 mL),
tyramine (140 mg, 1 mmol) and activated molecular sieves,
Ê
4 A, powder (1 g) (Aldrich) was heated with vigorous stir-
ring under argon for 2 h at 1408C. The brown melt was
cooled, dissolved in CH2Cl2 (30 mL), ®ltered and the
®ltered washed with 4% HCl (40 mL). The organic layer
was dried, ®ltered and evaporated. The crude mixture was
chromatographed on silica gel (eluent pentane±CH2Cl2 2:1
to CH2Cl2 to CH2C12-Et2O 20:1), giving polycitrin B
(320 mg, 89%); mp 140±1428C (CH2C12±pentane) (lit.1
oil); C25H17Br4NO5 requires C, 41.08; H, 2.34; N, 1.92.
Found: C, 41.22; H, 2.58; N, 2.05; UV (CH3OH): lmax
(e)ˆ208 (61028), 273 (19861), 490 (10278); nmax 3350 br,
1842, 1678 cm21; dH (300 MHz acetone-d6) 2.88 (2H, t,
Jˆ7.6 Hz, CH2), 3.77 (2H, bs, exchange with D2O, OH),
3.79 (2H, t, Jˆ7.6 Hz, CH2), 3.94 (3H, s, OMe), 6.79 (2H,
d, Jˆ8.4 Hz, aryl-H), 7.11 (2H, d, Jˆ8.4 Hz, aryl-H), 7.73
(2H, s, aryl-H), 7.78 (2H, s, aryl-H); dC (300 MHz acetone±
d6) 33.70, 40.29, 60.74, 110.95, 115.73, 118.26, 122.97,
127.94, 129.35, 130.15, 133.00, 134.22, 134.47, 134.66,
152.74, 155.61, 156.48, 169.78, 169.86; m/z (EI) 733 (2),
731 [M1] (3), 729 (2), 613 (4), 611 (6), 609 (4), 527 (4), 525
(6), 523 (4), 339 (3), 337 (6), 335 (3), 279 (3), 277 (6), 275
(3), 177 (3), 163 (4), 161 (4), 148 (7), 120 (100); and poly-
citrin A (51 mg, 14%); mp 170±1728C (CH2C12±pentane)
(lit.2 mp 180±1818C from CHC13±MeOH).
2-(3,5-Dibromo-4-methoxy-phenyl)-3-(4-hydroxy-phenyl)-
but-2-enedioic acid dimethylester 6. To a solution of
compound 5 (1.8 g, 3.3 mmol) in dry acetonitrile (40 mL)
at 2208C, NaI (600 mg, 4 mmol) and trimethylsilyl chloride
(0.85 mL, 6.6 mmol) were added. After stirring at this
temperature for 20 min., the mixture was allowed to warm
to room temperature. The acetonitrile was then removed in
vacuo and the residue extracted with Et2O (2£30 mL). The
organic phase was dried, ®ltered and evaporated and the
crude product puri®ed by silica gel column chromatography
(CH2Cl2±Et2O 20:1) to give 6 (1.52 g, 92%) as white crys-
tals, mp 1678C (pentane±Et2O); C19H16Br2O6 requires C,
45.63; H, 3.22. Found: C, 45.48; H 3.19; nmax 3220br,
1699, 1583 cm21; dH (200 MHz CDCl3) 3.82 (3H, s,
OMe), 3.85 (3H, s, OMe), 3.86 (3H, s, OMe), 5.07 (1H, s,
exchange with D2O, OH), 6.70 (2H d, Jˆ8.7 Hz, aryl-H),
6.96 (2H, d, Jˆ8.7 Hz, aryl-H), 7.24 (2H, s, aryl-H).
3-(3,5-Dibromo-4-methoxy-phenyl)-4-(4-hydroxy-phenyl)-
furan-2,5-dione 7. To a solution of compound 6 (1.66 g,
3.3 mmol) in MeOH (60 mL) was added a solution of
sodium methoxide (from Na 536 mg, 23.3 mmol in
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