Synthesis of 6-allyl-7-hydroxy-5-methoxy-4-methylphthalide, a key intermediate in the synthesis of mycophenolic acid

Article abstract of DOI:10.1081/SCC-100104047

A convergent aromatic annulation strategy based on the Michael addition of the dimethyl 1-allyl-1,3-acetonedicarboxylate anion 8 to 4-pivaloyloxy-2-butynal 9, followed by a regiocontrolled Dieckmann-type cyclization over the adequate methyl ester group, h

Full text of DOI:10.1081/SCC-100104047

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SYNTHESIS OF 6-ALLYL-7-
HYDROXY-5-METHOXY-4-
METHYLPHTHALIDE, A
KEY INTERMEDIATE IN THE
SYNTHESIS OF MYCOPHENOLIC
ACID
Adrián Covarrubias-Zúnniga a , José Diaz-
Dominguez a & José S. Olguín-Uribe b
a Instituto de Quimica, Universidad Nacional
Autónoma de México, Circuito Exterior, Ciudad
Universitaria, Coyoacán, 04510, Mèxico
b Universidad Autónoma Metropolitana,
Ixtapalapa, Mèxico
Published online: 09 Nov 2006.
To cite this article: Adrián Covarrubias-Zúnniga , José Diaz-Dominguez &
José S. Olguín-Uribe (2001) SYNTHESIS OF 6-ALLYL-7-HYDROXY-5-METHOXY-4-
METHYLPHTHALIDE, A KEY INTERMEDIATE IN THE SYNTHESIS OF MYCOPHENOLIC
ACID, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 31:9, 1373-1381, DOI: 10.1081/SCC-100104047
To link to this article: http://dx.doi.org/10.1081/SCC-100104047
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SYNTHETIC COMMUNICATIONS, 31(9), 1373–1381 (2001)
SYNTHESIS OF 6-ALLYL-7-HYDROXY-5-
METHOXY-4-METHYLPHTHALIDE,
A KEY INTERMEDIATE IN THE
SYNTHESIS OF MYCOPHENOLIC ACID
Adrian Covarrubias-Zuniga,1, Jose Diaz-Dominguez,1
*
and Jose S. Olguın-Uribe2
1Instituto de Quimica, Universidad Nacional Autonoma de
Mexico, Circuito Exterior, Ciudad Universitaria,
Coyoacan 04510, Mexico
2Universidad Autonoma Metropolitana
Ixtapalapa, Mexico
ABSTRACT
A convergent aromatic annulation strategy based on the
Michael addition of the dimethyl 1-allyl-1,3-acetonedicarbox-
ylate anion 8 to 4-pivaloyloxy-2-butynal 9, followed by
a
regiocontrolled Dieckmann-type cyclization over the
adequate methyl ester group, has been applied to an efficient
formal synthesis of the antitumor antibiotic, mycophenolic
acid 1. This tandem annulation reaction generates the fully
substituted aromatic intermediate 12, which was transformed
by a simple six-step sequence to 2, and even to 1 by the
methodology of Birch et al.15
* Corresponding author.
1373
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1374
COVARRUBIAS-ZUNIGA ET AL.
Mycophenolic acid (1) is produced as a metabolite of a number of
Pencillium spp., notably brevi-compactum.1–3 Its structure was proposed by
Raistrick.4 The synthesis of a degradation product with the phthalidic ske-
leton was realized by Logan and Newbold,5 which confirmed the structure
except for the configuration of the double bond. The biosynthesis of 1 has
been reported.6 It has diverse in vitro and in vivo biological activities,
including antifungal,7,8 antibacterial,9–10 antiviral,11 and immunosuppres-
sive12 properties. It has been tested clinically against various tumors without
success13 and has been found to be effective as an antipsoriatic.14
As far as we are aware, there are seven total syntheses15–21 and six
formal syntheses22–27 of 1 reported in the literature. The subject of this
article is a new formal synthesis of 1 through the phthalide 2 (Scheme 1),
which has been reported as an intermediate in Birch’s15 and in Patterson’s
total syntheses of 1.19
Scheme 1.
The route to 2 described herein is based on the experience we acquired
in the synthesis of phenols28 3 and resorcinols29 4 using tandem
reactions of dimethyl 1,3-acetonedicarboxylate anion 5 with alkynals 6
and alkyl alkynoates 7, respectivelty, (Scheme 2) and from a total synthesis
of mycophenolic acid.30
RESULTS AND DISCUSSION
We now report the extension of these annulation strategies to a formal
synthesis of 1 that assembles the requisite aromatic unit present therein in a
single step, with all substituents already in place with high regiocontrol. The
key step in this approach is the construction of the hexasubstituted resorci-
nol derivative 12 (Scheme 3) via Michael addition of the carbanion 8 to the
alkynal 9, followed by a regioselective Dieckmann-type cyclization of the
resulting enolate 10, followed by a spontaneous aromatization of 11 to give
12 in 32% yield.

MYCOPHENOLIC ACID INTERMEDIATE
1375
Scheme 2.
Scheme 3.
With compound 12 on hand, the completion of the synthesis was
accomplished by employing the six-step sequence shown in Scheme 4.
Dimethylation of resorcinol 12 with NaH and Me2SO4 in dry DMF gave
compound 13 in 86% yield, and subsequent reduction of the formyl group
with NaBH4 in dry MeOH gave alcohol 14 in 86% yield. Alcohol 14 was

1376
COVARRUBIAS-ZUNIGA ET AL.
mesylated with MsCl and Et3N in CH2Cl2, and the crude mesylate was
reduced with NaBH4 to compound 15, in 80% overall yield from 12. The
formation of phthalide 16 was effected in quantitative yield on treatment of
15 with K2CO3 in anhydrous MeOH. Finally, selective cleavage of 16 to 2
was achieved with BCl3 in CH2Cl2 as described by Birch et al.15
Scheme 4.
In conclusion, the synthesis reported in this article serves to highlight
the utility of our aromatic regiocontrolled annulation method as an efficient
method for the rapid assembly of complex polysubstituted aromatic com-
pounds. This highly convergent route, which delivers phthalide 2 in seven
steps from 8 and 9 (16% overall yield), can be effected at an multigram scale;
it is noteworthy that the framework of the key aromatic intermediate 2 is
formed in one regiocontrolled step from two aliphatic easily obtained com-
pounds. This makes the synthesis of many analogues by the Patterson’s total
synthesis19 easily feasible.
Melting points are uncorrected. Thin-layer chromatography was per-
1
formed on silica gel 60 F254 plates and visualized by UV irradiation. H
NMR spectra was recorded earlier at 200 or 300 MHz, while 13C NMR
spectra were run at 75MHz in CDCl 3 solution. Low and high-resolution
mass spectra were measured at 70 eV (EI). Elemental analyses were
performed by Galbraith Laboratories, Inc.; column chromatography
purifications were carried out using silica gel (70–230 mesh).

MYCOPHENOLIC ACID INTERMEDIATE
Dimethyl 1-Allyl-1.3-acetonedicarboxylate (8)
1377
Dimethyl 1,3-acetonedicarboxylate (18 g, 0.1 mol) was added dropwise
to a mixture of NaH (60%, 4.4 g, 0.11 mol) and dry THF (180 mL) with
magnetic stirring. To the resulting solution, allyl bromide (97%, 8 mL, 0.09
mol) was added. After 14 h, the mixture was poured into dilute HCl (100
mL), extracted with ethyl ether, and the organic phase was washed with
water (50 mL), dried over anhyd Na2SO4 and concentrated. The residue
was subjected to column chromatography (360 g of silica gel) and the ketoe-
ster 8 (10.2 g, 53% yield) was eluted using 5% ethyl acetate in hexane. IR
1
(neat) 1745, 1718, 1240 cm–1; H NMR ꢀ ppm 2.63 (tt, 2H, J ¼7, 1), 3.61
(d, 2H, J ¼4.7), 3.70 (m, 1H), 3.73 (s, 6H), 5.00–5.20 (m, 2H), 5.60–5.82
(m, 1H); 13C NMR ꢀ ppm 31.9, 48.1, 52.5, 58.1, 117.8, 133.7, 166.9, 169.0,
196.7; MS m/z (relative intensity) 190 (Mþ -24. 100), 172 (40), 144 (27), 115
(26). Anal. calc. for C10H14O5: C, 56.07; H, 6.54. Found: C, 56.01; H, 6.49.
4-Pivaloyloxy-2-butynal (9)
2-Butyn-1,4-diol (99%, 86.9 g, 1 mol) was dissolved in a mixture of dry
pyridine (160 mL) and dry CH2Cl2 (3 L). To the magnetically stirred sol-
ution was added dropwise over a period of 6–8 h pivaloyl chloride (99%,
99.6 mL, 0.8 mol). The mixture was stirred overnight at room temperature,
then washed with H2O (2ꢀ1 L), dried with Na2SO4. The CH2Cl2 was dis-
tilled and the pyridine removed by azeotropic distillation with toluene, to
give a syrup that was purified by column chromatography (869 g silica gel
and 2% ethyl acetate in hexane as eluent), yielding 70.7 g of 4-pivaloyloxy-2-
1
butynol as an oil (56% yield). H NMR ꢀ ppm 1.22 (s, 9H), 4.18 (t, 1H, J
¼1.88), 4.30 (td, 2H, J ¼1.88, 6.08), 4.70 (t, 2H, J ¼1.88). Anal. calc. for
C9H14O3: C, 63.52; H, 8.23. Found: C, 63.58; H, 8.23. Found: C, 63.58; H,
8.29. This alcohol was oxidized to 9 according to the procedure of Veliev
and Guseinov31 in 38–42% yield. 1H NMR ꢀ ppm 1.24 (s, 9H), 4.86 (s, 2H),
9.24 (s, 1H). Anal. calc. for C9H12O3: C, 64.28; H, 7.14. Found: C, 64.33;
H, 7.16.
2-Allyl-6-formyl-4-methoxycarobonyl-5-pivaloyloxymethyl
Resorcinol (12)
(1.2 g, 5.60 mmol) was added dropwise to a suspension of NaH (60%,
0.28 g, 7.0 mmol) in dry THF (12 mL) with magnetic stirring. To the result-
ing solution, 4-(Pivaloyloxy)-2-butynal (0.989 g, 5.88 mmol) was added and,

1378
COVARRUBIAS-ZUNIGA ET AL.
after 2 h, the mixture was poured into dilute HCl (15mL). The organic
phase was separated and the aqueous phase was extracted with ethyl acetate.
The combined organic phase was washed with bring (50 mL), dried over
anhyd. Na2SO4, and concentrated. The residue was subjected to column
chromatography, the resorcinol 12 (0.63 g, 32%) being eluted with 5%
ethyl acetate in hexane (50 g of silica gel): 12: IR (neat) 3381, 1733, 1668,
1
1638 cm–1; H NMR ꢀ ppm 1.10 (s, 9H), 3.45(d, 2H, J ¼ 6), 3.96 (s, 3H),
4.90–5.12 (m, 2H), 5.62 (s, 2H), 5.85–6.04 (m, 1H), 10.18 (s, 1H), 11.79 (s,
3H), 11.90 (s, 1H); 13C NMR ꢀ ppm 26.5, 27.0, 38.8, 53.0, 58.5, 107.2, 113.5,
115.3, 115.9, 134.7, 141.8, 165.2, 135.3, 170.6, 177.7, 194.0; MS m/z (relative
intensity) 350 (Mþ, 8), 22(265), 248 (100), 57 (57), Anal. calc. For C18H22O7:
C, 61.71; H, 6.28. Found: C, 61.82; H, 6.33.
2-Allyl-6-formyl-4-methyoxycarbonyl-5-pivaloyloxymethyl Resorcinol
Dimethyl Ether (13)
12 (0.6 g, 1.71 mmol) was dissolved in dry DMF (12 mL) and NaH
(0.158 g, 3.9 mmol) was added portionwise with stirring. Me2SO4 (0.5g,
4.0 mmol) was added dropswise and stirring continued for 6 h. The reaction
mixture was poured into water (30 mL) and extracted with ether (3ꢀ50 mL).
The organic layer was separated, washed with water (20 mL) and brine
(20 mL), dried (Na2SO4) filtered, and concentrated. The residue was purified
by column chromatography (eluant ethyl acetate:hexane, 0.3: 9.7, 24 g of
silica gel) affording 13 (564 mg, 87%): IR (neat) 1732, 1694, 1208, 1153 cm–1;
1H NMR ꢀ ppm 1.15(s, 9H), 3.47 (d, 2H, J ¼ 4.8), 3.84 (s, 3H), 3.91 (s, 1H),
4.95–5.20 (m, 2H), 5.33 (s, 2H), 5.90–6.05 (m, 1H); 10.40 (s, 1H); 13C NMR
ꢀ ppm 26.8, 27.1, 38.7, 52.7, 59.9, 62.7, 64.6, 116.0, 125.2, 126.9, 128.7,
135.2, 160.7, 164.4, 166.9, 177.9, 190.6; MS m/z (relative intensity) 347
(Mþ-MeOH), 2), 276 (100), 261 (87), 57 (48),. Anal. calc. for C20H26O7:
C, 63.49; H, 6.87. Found: C, 63.57; H, 6.91.
2-Allyl-6-hydroxymethyl-4-methoxycarbonyl-5-pivalyoxymethyl
Resorcinol Dimethyl Ether (14)
13 (0.5g, 1.3 mmol) was dissolved in dry MeOH (5mL) and NaBH
4
(49.2 mg, 1.3 mmol) was added with stirring. After 0.5h the reaction mixture
was poured into water (15mL), extracted with ether (4 ꢀ 20 mL), the organic
layer was separated, dried (Na2SO4), filtered and concentrated. The residue
was purified by column chromatography (eluant ethyl acetate:hexane,
0.6:9.4) affording 14 (434 mg, 86%). IR (neat) 3485, 1731, 1202, 1150 cm–1;

MYCOPHENOLIC ACID INTERMEDIATE
1379
1H NMR ꢀ ppm 1.14 (s, 9H), 3.40–3.47 (broad d, 2H), 3.70–3.85broad s,
exchange with D2O, 3.76 (s, 3H), 3.90 (s, 3H), 4.76 (s, 2H), 4.95–5.05 (m,
1H), 5.03 (t, 1H, J ¼ 1.8); 5.27 (s, 2H), 5.90–6.05 (m, 1H); 13C NMR ꢀ ppm
27.0, 28.9, 38.9, 52.4, 56.3, 60.9, 62.7, 63.2, 115.5, 125.7, 128.4, 19.9, 132.9,
136.4, 157.0, 159.7, 167.7, 178.6; MS m/z (relative intensity) 363 (Mþ-OH,
8), 278 (52), 247 (100), 57 (83). Anal calc. for C20H28O7: C, 63.15; H, 7.36.
Found: C, 63.32; H, 7.49.
2-Allyl-4-methoxycarbonyl-6-methyl-5-pivaloyloxymethyl Resorcinol
Dimethyl Ether (15)
The alcohol 14 (0.45g, 1.18 mmol) was dissolved in dry CH 2Cl2
(5mL), the solution was cooled in an ice bath and with stirring were
added dry Et3N (0.35mL, 2.36 mmol) and MsCl (0.14 mL, 1.77 mmol).
The solution was stirred at 25ꢁC for 1.5h, then purified into 10 ml of
water and extracted with ether. The ether extract was dried (Na2SO4), fil-
tered, and concentrated to give a residue that was dissolved under a N2 atm
into dry DMF (5mL), and NaBH 4 (22 mg, 0.59 mmol)) was added. The
reaction mixture was stirred for 1.5h at 25 ꢁC, then poured into ice water
(20 mL) and extracted with ether. Drying, filtration, and concentration of
the organic layer gave an oily residue that was purified by column chroma-
tography using ethyl acetate:hexane (0.5:9.5) as eluant. 15 (344 mg) was
1
obtained in 80% yield. IR (neat) 1733, 1204, 1150 cm–1; H NMR ꢀ ppm
1.56 (s, 9H), 2.65(s. 3H), 3.80–3.95(broad d, 2H), 4.15(s, 3H), 4.27 (s, 3H),
5.37–4.00 (m, 1H), 5.44 (s, 2H), 6.35–6.45 (m, 1H), 13C NMR ꢀ ppm 27.1,
28.9, 38.9, 52.3, 60.9, 61.4, 62.8, 115.4, 115.3, 126.0, 127.7, 127.8, 131.8,
131.7, 136.7, 154.6, 159.0, 168.1, 178.1; MS m/z (relative intensity) 364
(Mþ, 14), 263 (61), 247 (93), 232 (100), 57 (28). Anal. calc. for C20H28O6:
C. 65.93; H, 7.69. Found: C, 66.11, H, 7.86.
6-Allyl-5,7-dimethyoxy-4-methylphthalimide (16)
15 (0.25g, 0.68 mmol) was dissolved in dry MeOH (2.5mL) and
anhyd.K2CO3 (12.5mg. 0.09 mmol) was added with stirring. After 1.5h,
the reaction mixture was poured into H2O (10 mL) and extracted with
ether (4 ꢀ 15mL). Drying, filtration, and concentration of the organic
layer gave 170 mg (quantitative yield) of 16. IR (neat) 1759, 1601, 1131,
1
772 cm–1; H NMR ꢀ ppm 2.19 (s, 3H), 3.40–3.50 (m, 2H), 3.79 (s, 3H),
4.06 (s, 3H), 4.90–5.08 (m, 2H), 5.15 (s, 2H), 5.87–6.11 (m, 1H); 13C NMR ꢀ
ppm 11.5, 28.5, 29.6, 61.2, 62.8, 68.3, 115.2, 119.9, 127.3, 136.9, 147.0, 156.8,

1380
COVARRUBIAS-ZUNIGA ET AL.
162.8, 168.8; MS m/z (relative intensity) 248 (Mþ, 100), 233 (48), 217
(90), 207 (50); Anal. calc. for C14H16O4: C, 67.74; H, 6.45. Found:
C, 67.83; H, 6.62.
6-Allyl-7-hydroxy-5-methoxy-4-methylphthalide (2)
To 25mg of 16 was added 12 mL of BCl3 (1M in Ch2Cl2) with stirring.
After 10 days at 25ꢁC. H2O (25mL) was added, the organic layer was
separated and washed with H2O. Drying over Na2SO4 and evaporation to
dryness afforded 20 mg of 17 (85%) : m.p. 91–92ꢁC (EtOH/H2O) (lit.15,18
91–92ꢁC).
ACKNOWLEDGMENTS
This research was supported by a Grant-in-aid for Scientific research
No. 27610-\E from CONACYT, Mexico.
The authors thank Professor Joseph Muchowski and Dr. Noe Zuniga
for helpful discussions. We thank Messrs. C. Conteras, R. Patino, R.
Gavino, L. Velasco, and F.J. Perez. for running the spectra.
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Received in the USA July 24, 2000