Total synthesis of mycophenolic acid

Article abstract of DOI:10.1016/S0040-4020(03)00102-9

A convergent total synthesis of the natural compound mycophenolic acid 1 is described. The synthetic strategy for the construction of the hexasubstituted aromatic nucleus was based on a ring annulation sequence, involving a Michael addition reaction and intramolecular Dieckmann condensation reaction in situ as the key step. Subsequent transformations of the substituents afforded the target mycophenolic acid 1.

Full text of DOI:10.1016/S0040-4020(03)00102-9

Tetrahedron 59 (2003) 1989–1994
Total synthesis of mycophenolic acid
*
Adrian Covarrubias-Zuniga, Armando Gonzalez-Lucas and Mireya M. Domınguez
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Instituto de Quımica, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Ciudad Universitaria, Coyoacan 04510, Mexico
Received 5 November 2002; revised 13 January 2003; accepted 16 January 2003
Abstract—A convergent total synthesis of the natural compound mycophenolic acid 1 is described. The synthetic strategy for the
construction of the hexasubstituted aromatic nucleus was based on a ring annulation sequence, involving a Michael addition reaction and
intramolecular Dieckmann condensation reaction in situ as the key step. Subsequent transformations of the substituents afforded the target
mycophenolic acid 1. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
all the carbon atoms for the target molecule skeleton. A
preliminary coomunication of this work has appeared
elsewhere.9f We now provide further details of our total
synthesis of mycophenolic acid 1 from 2-geranyl-dimethyl-
1,3-acetonedicarboxylate anion with 4-pivaloyloxy-2-buty-
nal.12 The key step of our synthetic approach involves
tandem reactions (Michael-addition13 and intramolecular
regioselective Dieckmann-cyclization14).
Mycophenolic acid 1, one of the highly substituted
phthalides, is a natural product, present in a number of
Penicillium spp,1,2 notably brevi-compactum, was first
isolated 106 years ago;3 it possesses many in vitro and in
vivo biological activities, including antifungal,4 anti-
bacterial,5 antiviral,6 and immunosuppressive7 properties.
Mycophenolic acid 1 was originally synthesized by Birch
and Wright8 and has been the subject of several total9 and
formal syntheses which focus on the preparation of the
intermediates 210 or 311 (Fig. 1).
As shown in the retro-synthetic evaluation depicted in
Scheme 1, mycophenolic acid 1 would be obtained from
phthalide 10 by selective ozonolysis of the terminal double
bond followed by Jones oxidation,9b esterification of the
resulting acid, selective demethylation with BCl3 of the
methyl ethers and finally hydrolysis of the methyl ester.
Phthalide 10 can in turn be prepared from resorcinol 6 by
methylation of the hydroxyl groups, followed by reduction
of aldehyde to alcohol, mesylation of this alcohol,
subsequent reduction of the mesylate and formation of
phthalide 10 with catalytic esterification using K2CO3 in
MeOH. Resorcinol 6 could be formed by the reaction of the
anion of 4 with the alkynal 5 by means of the Michael-
addition and Dieckmann-cyclization; this is considered the
crucial step in the present synthesis since the positions of
substituents with appropriate functional groups from the two
The preparation of highly substituted benzenes is one of the
classic problems in organic synthesis, and mycophenolic
acid has been a goal for synthetic methods because the
chemical structure of mycophenolic acid has a hexa-
substituted aromatic ring, and the regiocontrolled synthesis
of such highly substituted aromatic systems presents a
synthetic challenge. The most common syntheses of
mycophenolic acid use benzene ring constructions which
simultaneously introduce five of the six required sub-
stituents. The synthetic approach reported herein has the
particularity that the aromatic ring of the Mycophenolic acid
with its six substitutents is constructed in one step and has
Figure 1.
Keywords: mycophenolic acid; Michael addition; Dieckmann condensation.
*
Corresponding author. Tel.: þ52-56-22-44-50; fax: þ52-56-16-22-03; e-mail: adriancz@servidor.unam.mx
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00102-9

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A. Covarrubias-Zun˜iga et al. / Tetrahedron 59 (2003) 1989–1994
1990
Scheme 1.
precursor compounds would induce the formation of the
aromatic ring with the six substituents properly positioned.
The preparation of 5 has been reported elsewhere,12 and 4
would be easily formed by alkylation of sodium dimethyl-
1,3-acetonedicarboxylate anion with geranyl chloride.
ketoalcohols 13a and 13b. A decrease in yield was observed
when the reaction was carried out at lower temperatures.
A plausible mechanism for this event is shown in Scheme 2.
The vinyl carbanion 14, initially formed by Michael
addition of the 2-geranyl dimethyl 1,3-acetonedicarboxylate
4 enolate to the alkynal 5, is rapidly protonated by the more
acidic methine proton to give carbanion 15, precursor of the
desired resorcinol 6. In spite of its apparent stability, the
highly crowded nature of this intermediate allows its
isomerization to enolate 16, precursor of the ketoalcohols
13a and 13b in 62% yield. We suggest that the delocalized
anion 15 is kinetically formed from 14 and isomerizes to the
thermodynamic (less crowded) enolate 16, it is noteworthy
that when the dimethyl 1,3-acetonedicarboxylate, (Scheme
3) is made to react with 5, the phenol 17 is obtained with
88% yield;12 the resorcinol 18, which is supposed to stem
from the kinetic enolate, is not detected. This behaviour can
2. Results and discussion
The route to 1 described herein is based on the experience
we acquired in the synthesis of phenols,12,15 and resorci-
nols16 using tandem reactions of dimethyl 1,3-acetone-
dicarboxylate anion with alkynals, alkynones and alkyl
alkynoates, respectively. The resorcinol 6 was assembled in
a single step, with all substituents already in place with high
regiocontrol in 33% yield. In this reaction two more
compounds were also obtained with 62% yield in a nearly
1:1 ratio, these were identified as the diastereomeric
Scheme 2.

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1991
Scheme 3.
Scheme 4. (a) NaH, DMF, MeI, 88%. (b) NaBH4, MeOH, 89%. (c) Et3N, MeSO2Cl, CH2Cl2. (d) NaBH4, DMF, 77%.
Scheme 5. (a) O3, CH2Cl2, pyridine, Me2S, 2788C, 52%. (b) CrO3, Hþ, acetone, 2308C. (c) CH2N2, AcOEt, 54% from (11). (d) BCl3, CH2Cl2, 86%. (e) LiOH,
H2O, Hþ, 93%.
be attributed to the greater acidic character of the a proton
of the keto carbonyl in the kinetic enolate mentioned above.
CH2Cl2 (69% yield). This epoxide was transformed with
HIO4 in aqueous THF into the oily aldehyde 11 in 80%
yield, (Scheme 5). 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 assembly of complex polysubstituted aromatic
compounds. The application of this methodology to another
natural product synthesis is in progress and will be
reported in due course (Scheme 6).
In the case of the enolate 15 (Scheme 2) we propose that a
charge delocalization over the neighboring groups is less
effective, due to steric reasons, than in enolate 16, favoring
the formation of 13a,b. All our efforts to transform the
ketoalcohols to 6 by a retroaldol reaction were unsuccessful.
The resorcinol 6 gave dimethyl ether 7 in 88% yield with
NaH and MeI in dry DMF. With 6 and 7 we could not
prepare the corresponding phthalide. Reduction of the
formyl group with NaBH4 in dry MeOH gave the alcohol
8 in 89% yield, mesylation of 8 with MsCl and Et3N in dry
CH2Cl2 and subsequent reduction of the crude mesylate
with NaBH4 in dry DMF produced the compound 9 in 77%
yield from 8, (Scheme 4).
Scheme 6.
The preparation of phthalide 10 was effected in quantitative
yield on treatment of 9 with K2CO3 in dry MeOH. Selective
ozonolysis of compound 10 afforded the aldehyde 11 in 52%
yield. Jones oxidation of compound 11 at 2308C9b followed
by esterification with CH2N2 gave the methyl O-methyl
ester of mycophenolic acid 12 in 54% yield from 11. The
selective demethylation with BCl3 in CH2Cl2 was
achieved in 86% yield. Hydrolysis of the methyl ester
with LiOH in H2O furnished mycophenolic acid 1 in 93%
yield as colorless crystals, mp 139–1418C (lit.9a mp 139–
1418C) with identical properties to the natural compound.
3. Experimental
3.1. General
Melting points are uncorrected, thin-layer chromatography
was performed on silica gel 60 F254 plates and visualized by
UV irradation; column chromatography purifications were
carried out using silica gel (70–230 mesh). 1H NMR spectra
were recorded at either 200 or 300 MHz, while 13C NMR
were run at 75 MHz. Mass spectra were measured at 70 (EI)
or 200 eV (CI). Elemental analyses were performed by
Galbraith Laboratories.
Finally, because of the problem of reproducibility of the
yield in the ozonolysis reaction, compound 10 was
epoxidized to compound 19 with m-CPBA at 2708C in

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3.1.1. Dimethyl 1-geranyl-1,3-acetonedicarboxylate (4)
25.50 (CH3), 26.37 (CH2), 27.02 (CH3), 29.72 (CH2), 33.38
(CH2), 38.80 (CH3), 39.81 (CH2), 52.34 (CH3), 52.67
(CH3), 62.55 (C), 63.61 (CH2), 68.76 (CH2), 117.58 (CH2),
123.93 (CH2), 131.35 (C), 131.44 (C), 139.89 (C), 153.87
(C), 165.10 (C), 172.06 (C), 177.67 (C), 190.86 (C); MS
(CI) 479 (Mþþ1, 100), 447 (8), 377 (9), 209 (9). Anal. calcd
for C26H38O8: C, 65.27; H, 7.94. Found: C, 65.41; H, 7.85.
Dimethyl 1,3-acetonedicarboxylate (40 g, 96%, 0.22 mol)
was added dropwise to a mixture of NaH (60%, 9.68 g,
24.2 mmol) and dry THF (320 mL) with magnetic stirring.
To the resulting solution, geranyl chloride (95%, 46 g,
253 mmol) 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, dried over anhyd.
Na2SO4 and concentrated. The residue was subjected to
column chromatography (800 g of silica gel) and the
ketoester 4 (56 g, 82% yield) was eluted using 5% ethyl
13b Less polar. IR 3500, 2971, 1736, 1144 cm21; 1H NMR
d ppm 1.20 (s, 9H), 1.55–1.70 (br s overlapping with two s,
1H, OH), 1.58 (s, 3H), 1.62 (s, 3H), 1.66 (s, 3H), 1.90–
2.15 m (4H), 2.56 (dd, 1H, J¼4.7 Hz, Jgem¼19.6 Hz), 2.56–
2.80 (m, 2H), 2.92 (dd, 1H, Jgem¼19.6 Hz, J¼4.1 Hz), 3.70
acetate in hexane. IR (neat) 2925, 1747, 1721, 1238 cm21
;
1H NMR d ppm 1.58 (s, 3H), 1.62 (s, 3H), 1.62 (s, 3H), 1.67
(s, 3H), 1.93–2.16 (m, 4H), 2.58 (t, 1H, J¼7.35 Hz), 3.58
(ABsys, 2H, J¼15.9 Hz), 3.64 (t, 1H, J¼7.3 Hz), 5.0–5.5.1
(m, 2H); 13C NMR d ppm 16.01 (CH3), 17.63 (CH3), 25.62
(CH3), 26.46 (CH2), 26.83 (CH2), 39.51 (CH2), 48.22
(CH2), 52.38 (CH3), 52.48 (CH3), 58.68 (CH), 119.15 (CH),
123.92 (CH), 131.56 (C), 138.89 (C), 166.99 (C), 169.35
(C), 197.36 (C); MS (EI) m/z (relative intensity) 310 (Mþ,
5), 209 (86), 136 (58), 136 (58), 69 (100). Anal. calcd for
C17H26O5: C, 65.80; H, 8.38. Found: C, 65.89; H, 8.42.
(s, 3H), 3.82 (s, 3H), 4.61 (t, 1H, J¼4.4 Hz), 4.78 (ABsys
,
2H, J¼16 Hz), 5.03 (br t, 1H, J¼6.8 Hz), 5.25 (t, 1H,
J¼7.5 Hz); 13C NMR d ppm 16.03 (CH3), 17.71 (CH3),
25.67 (CH3), 26.42 (CH2), 27.12 (CH3), 28.46 (CH2), 33.33
(CH2), 38.90 (C), 39.92 (CH2), 52.54 (CH3), 52.68 (CH3),
62.13 (C), 63.76 (CH2), 69.33 (CH), 118.19 (CH), 123.93
(CH), 131.24 (C), 131.81 (C), 139.68 (C), 153.12 (C),
165.25 (C), 169.86 (C), 177.82 (C), 191.11 (C); MS (CI) m/z
(relative intensity) 479 (Mþþ1, 100), 447 (7), 360 (16), 103
(16). Anal. calcd for C26H38O8: C, 65.27; H, 7.94. Found: C,
65.43; H, 7.82.
3.1.2. 2-Geranyl-6-formyl-4-methoxycarbonyl-5-
pivaloyloxymethyl resorcinol (6)
3.1.4. 2-Geranyl-6-formyl-4-methoxycarbonyl-5-
pivaloyloxymethyl resorcinol dimethyl ether (7)
(3.1 g, 10 mmol) of (4) was added dropwise to a suspension
of NaH (60%, 13.5 mmol, 0.54 g) in dry THF (31 mL) with
magnetic stirring. To the resulting solution, 4-(pivaloyl-
oxy)-2-butynal12 5 (15 mmol, 2.55 g) was added and after
2 h, the mixture was poured into dilute HCl (30 mL). The
organic phase was separated and the aqueous layer was
extracted with ethyl acetate. The combined organic phase
was washed with brine, dried over anhyd. Na2SO4, and
concentrated. The residue was subjected to column
chromatography, the resorcinol 6 (1.47 g, 33% yield)
being eluted with 5% ethyl acetate in hexane (100 g of
silica gel), and the diasteromeric ketols 13a,b in 62% yield.
6 Mp 62–638C, IR (KBr) 3347, 2976, 1739, 1676,
6 (0.5 g, 1.12 mmol) was dissolved in dry DMF (10 mL) and
NaH (0.1 g, 60%, 2.5 mmol) was added portionwise with
stirring. MeI (99%, 0.4 g, 2.8 mmol) was added dropwise
and stirring continued for 3 h. The reaction mixture was
poured into water (20 mL) and extracted with ethyl ether.
The organic layer was separated, washed with H2O, dried
(Na2SO4), filtered, and concentrated. The residue was
purified by column chromatography (eluant ethyl acetate–
hexane, 0.3:9.7, 15 g of silica gel) affording 7 (467 mg, 88%
yield). IR (neat) 3508, 2976, 1739, 1135 cm21; 1H NMR d
ppm 1.17 (s, 9H), 1.57 (s, 3H), 1.64 (s, 3H), 1.78 (s, 3H),
1.95–2.12 (m, 4H), 3.42 (d, 2H), J¼6.6 Hz), 3.78 (s, 3H),
3.88 (s, 3H), 3.94 (s, 3H), 4.80 (s, 2H), 5.05 (t, 1H,
J¼6.6 Hz), 5.15 (t, 1H, J¼6.6 Hz), 5.29 (s, 2H); 13C NMR d
ppm 16.21 (CH3), 17.62 (CH3), 23.66 (CH2), 25.59 (CH3),
26.53 (CH2), 27.01 (CH3), 38.84 (C), 39.60 (CH2), 52.36
(CH3), 56.34 (CH2), 60.94 (CH2), 62.56 (CH3), 62.95
(CH3), 122.55 (CH), 124.16 (CH), 125.65 (C), 129.89 (C),
130.44 (C), 131.39 (C), 132.29 (C), 135.70 (C), 156.99 (C),
159.67 (C), 178.62 (C); MS (EI) m/z (relative intensity) 476
(Mþ, 2), 305 (58), 273 (40), 123 (68), 57 (100). Anal. calcd
for C27H40O7: C, 68.06; H, 8.40. Found: C, 68.09; H, 8.37.
1
1135 cm21; H NMR d ppm 1.16 (s, 9H), 1.54 (s, 3H),
1.60 (s, 3H), 1.75 (s, 3H), 1.90–2.10 (m, 4H), 3.37 (d, 2H,
J¼6.3 Hz), 3.92 (s, 3H), 5.01 (t, 1H, J¼6.3 Hz), 5.18 (t, 1H,
J¼7.2 Hz), 5.57 (s, 2H), 10.11 (s, 1H), 11.66 (s, 1H), 12.84
(s, 1H); 13C NMR d ppm 16.12 (CH3), 17.56 (CH3), 21.51
(CH2), 25.53 (CH2), 26.64 (CH2), 27.03 (CH3), 38.69 (C),
39.72 (CH2), 52.86 (CH3), 58.54 (CH2), 107.31 (C), 113.58
(C), 117.67 (C), 120.57 (CH), 124.34 (CH), 131.12 (C),
136.24 (C), 141.32 (C), 165.10 (C), 165.18 (C), 170.65 (C),
177.61 (C), 193.94 (CH); MS (EI) m/z (relative intensity)
446 (Mþ, 3), 344 (55), 275 (76), 243 (100), 123 (73), 57
(53). Anal. calcd for C25H34O7: C, 67.26; H, 7.62. Found: C,
67.28; H, 7.59.
3.1.5. 2-Geranyl-6-hydroxymethyl-4-methoxycarbonyl-
5-pivaloyloxymethyl resorcinol dimethyl ether (8)
3.1.3. Diasteromeric ketols 13a,b
7 (1 g, 2.1 mmol) was dissolved in dry MeOH (15 mL) and
NaBH4 (79.5 mg, 2.1 mmol) was added with stirring. After
0.5 h the reaction mixture was poured into water (30 mL),
extracted with ethyl ether, the organic layer was separated,
dried (Na2SO4), filtered and concentrated. The residue was
purified by column chromatography (eluant 6% ethyl
acetate in hexane) affording 8 (894 mg, 89% yield). IR
(neat) 3508, 2976, 1739, 1135 cm21; 1H NMR d ppm 1.17
(s, 9H), 1.57 (s, 3H), 1.64 (s, 3H), 1.78 (s, 3H), 1.95–2.12
13a More polar. IR (neat) 3508, 2970, 1736, 1687,
1
1143 cm21; H NMR d ppm 1.21 (s, 9H), 1.57 (s, 3H),
1.65 (s, 3H), 1.66 (s, 3H), 1.92–2.10 (m, 4H), 2.57 (dd, 1H,
Jgem¼19.3 Hz, J¼7.4 Hz), 2.72–2.85 (m, 3H), 3.6–3.8 (bs
overlapping with two s, 1H, OH), 3.77 (s, 3H), 3.83 (s, 3H),
4.18 (br s, 1H), 4.79 (Absys, 2H, J¼16 Hz), 4.95–5.05 (two
overlapping br t, 2H); 13C d ppm 16.13 (CH3), 17.55 (CH3),

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1993
(m, 4H), 3.42 (d, 2H, J¼6.6 Hz), 3.78 (s, 3H), 3.88 (s, 3H),
3.94 (s, 3H), 4.80 (s, 2H), 5.05 (t, 1H, J¼6.6 Hz), 5.15 (t,
1H, J¼6.6 Hz), 5.29 (s, 2H); 13C NMR d ppm 16.21 (CH3),
17.62 (CH3), 23.66 (CH2), 25.59 (CH3), 26.53 (CH2), 27.01
(CH3), 38.84 (C), 39.60 (CH2), 52.369 (CH3), 56.34 (CH2),
60.94 (CH2), 62.56 (CH3), 62.95 (CH3), 122.55 (CH),
124.16 (CH), 125.65 (CH), 129.89 (CH), 130.44 (CH),
131.39 (C), 132.29 (C), 135.70 (C), 156.99 (C), 159.67 (C),
167.79 (C), 178.62 (C); MS (EI) m/z (relative intensity) 476
(Mþ, 2), 305 (58), 273 (40), 273 (40), 123 (68), 57 (100).
Anal. calcd for C27H40O7: C, 68.06; H, 8.40. Found: C,
68.09; H, 8.37.
(84), 123 (100). Anal. calcd for C21H28O4: C, 73.25; H,
8.13. Found: C, 73.29; H, 8.11.
3.1.8. (E)-1,3-Dihydro-4,6-dimethoxy-7-methyl-3-oxo-
5(3-methyl-2-hexenal)isobenzofuranone (11)
Ozonized oxygen was bubbled through a solution of 10
(0.6 g) in methanol (5 mL) at 2788C until the disappearance
of 10, checked by thin-layer chromatography. Dimethyl
sulfide (0.6 mL) was added to the reaction mixture and it
was stirred at 2108C for 1 h, at 08C for 1 h and then at room
temperature for 1 h to perform the reductive cleavage of the
resulting ozonide. Evaporation of methanol gave the
aldehyde 11, 288 mg, 52% yield crude. A fraction of this
compound was purified by thin layer chromatography using
30% ethyl acetate in hexane as eluant to obtain an analytical
sample. IR (neat) 2923, 1758, 1724, 1128 cm21; 1H NMR d
ppm 1.81 (s, 3H), 2.18 (s, 3H), 2.31 (t, 2H, Ja¼7.4 Hz), 2.50
(td, 1H, Ja¼7.4 Hz, Jb¼1.9 Hz), 3.40 (d, 2H, J¼6.6 Hz),
3.76 (s, 3H), 4.05 (s, 3H), 5.13 (s, 2H), 5.14–5.22 (m, 1H),
9.72 (t, 1H, Jb¼1.9 Hz); 13C NMR d ppm 11.52 (CH3),
16.30 (CH3), 23.40 (CH2), 31.74 (CH2), 42.01 (CH2), 60.19
(CH3), 62.65 (CH3), 68.34 (CH2), 112.57 (C), 120.01 (C),
123.74 (CH), 128.79 (C), 133.53 (C), 146.76 (C), 156.74
(C), 162.74 (C), 168.93 (C), 202.34 (CH); MS (EI) m/z
(relative intensity) 348 (Mþ, 93), 243 (43), 221 (100), 44
(54). Anal. calcd for C19H24O6: C, 67.92; H, 6.91. Found: C,
68.11, H, 6.79.
3.1.6. 2-Geranyl-4-methoxycarbonyl-6-methyl-5-
pivaloyloxymethyl resorcinol dimethyl ether (9)
The alcohol 8 (0.5 g, 1.05 mmol) was dissolved in dry
CH2Cl2 (5 mL), the solution was cooled in an ice bath and
with stirring were added dry Et3N (0.32 mL, 2.1 mmol) and
MsCl (0.125 mL, 1.58 mmol). The solution was stirred at
258C for 2.5 h and then poured into water (10 mL) and
extracted with ether. The ether extract was dried (Na2SO4),
filtered and concentrated to give a residue which was
dissolved under an Ar atmosphere in dry DMF (5 mL), and
NaBH4 (20 mg, 0.53 mmol) was added. The reaction
mixture was stirred for 2.5 h at 258C, poured into ice-
water (10 mL), and extracted with ether. Drying, filtration,
and concentration of the organic layer gave an oily residue
which was purified by column chromatography using ethyl
acetate–hexane (0.5:9.5) as eluent. 9 (372 mg) was obtained
3.1.9. (E)Methyl-1,3-dihydro-4,6-dimethoxy-7-methyl-3-
oxo-5-(methyl-2-hexenoate) isobenzofuranone (12)
1
in 77% yield. IR (neat) 2971, 1731, 1204, 1148 cm21; H
NMR d ppm 1.16 (s, 9H), 1.54 (s, 3H), 1.61 (s, 3H), 1.75 (s,
3H), 1.9–2.1 (m, 4H), 2.25 (s, 3H), 3.36 (d, 2H, J¼6.6 Hz),
3.68 (s, 3H), 3.74 (s, 3H), 3.87 (s, 3H), 5.02 (bs, 3H), 5.17 (t,
1H, J¼6.6 Hz); 13C NMR d ppm 11.91 (CH3), 16.22 (CH3),
17.63 (CH3), 23.69 (CH2), 25.62 (CH3), 26.55 (CH2), 27.13
(CH3), 38.87 (C), 39.63 (CH2), 52.35 (CH3), 60.74 (CH3),
61.44 (CH2), 62.62 (CH3), 122.91 (CH), 124.21 (CH),
125.91 (C), 127.76 (C), 129.74 (C), 131.08 (C), 131.38 (C),
135.43 (C), 154.49 (C), 158.94 (C), 168.19 (C), 178.22 (C);
MS (EI) m/z (relative intensity) 460 (Mþ, 7), 289 (100), 123
(47), 57 (32). Anal. calcd for C27H40O6: C, 70.43; H, 8.69.
Found: C, 70.45; H, 8.68.
A solution of the aldehyde 11 (0.32 g, 1 mmol) in 60 mL of
acetone was cooled to 2308C with a dry ice–bromobenzene
bath. Jones reagent17 (0.7 mL, 1.4 equiv.) was added
dropwise by syringe over 3 min, and the resulting brown
mixture was stirred at 2308C for 4 h. Isopropyl alcohol
(197 mg, 3.22 mmol) was added, and the resulting mixture
was filtered through a pad of Celite with the aid of two 5 mL
portions of acetone and then concentrated to afford a brown
oil. The oil was dissolved in ethyl acetate and methylated
with diazomethane and purified by column chromatography
on silica gel (6 g) eluting with 2% ethyl acetate in hexane to
give 12 as a colorless oil, yield 189 mg (54% yield). IR
(neat) 2927, 1740, 1443, 1377 cm21; 1H NMR d ppm 1.74
(s, 3H), 2.12 (s, 3H), 2.20 (m, 4H), 3.34 (d, 2H, J¼6.6 Hz),
3.55 (s, 3H), 3.71 (s, 3H), 3.97 (s, 3H), 5.08 (s, 2H), 5.11 (t,
1H, J¼6.9 Hz); 13C NMR d 11.38 (CH3), 16.00 (CH3),
23.27 (CH2), 32.70 (CH2), 34.44 (CH2), 51.33 (CH3), 60.87
(CH3), 62.49 (CH3), 68.24 (CH2), 112.38 (C), 119.93 (C),
123.51 (CH), 128.83 (C), 133.69 (C), 146.63 (C), 156.59
(C), 162.67 (C), 168.86 (C), 173.62 (C); MS (EI) (relative
intensity) 348 (Mþ, 93), 243 (43), 221 (100), 44 (54). Anal.
calcd for C19H24O6: C, 65.51; H, 6.89. Found: C, 65.62; H,
6.77.
3.1.7. 2-Geranyl-5,7-dimethoxy-4-methylphthalide (10)
9 (0.3 g, 0.65 mmol) was dissolved in dry MeOH (3 mL)
and anhyd. K2CO3 (12.5 mg, 0.09 mmol) was added with
stirring. After 6 h, the reaction mixture was poured into H2O
(10 mL) and extracted with ether. Drying, filtration, and
concentration of the organic layer gave a residue which was
purified by column chromatography (4.5 g of silica gel) with
5% ethyl acetate in hexane as eluant, giving 223.6 mg of 10
(quantitative yield). IR (neat) 2923, 1762, 1473, 1129 cm21
;
1H NMR d ppm 1.57 (s, 3H), 1.63 (s, 3H), 1.79 (s, 3H),
1.90–2.15 (m, 4H), 2.18 (s, 3H), 3.41 (d, 2H, J¼6.9 Hz),
3.70 (s, 3H), 4.05 (s, 3H), 5.05 (t, 1H, J¼6.6 Hz), 5.13 (bs,
3H); 13C 11.51 (CH3), 16.17 (CH3), 17.63 (CH3), 23.39
(CH2), 25.63 (CH3), 26.52 (CH2), 39.66 (CH2), 60.95
(CH3), 62.61 (CH3), 68.32 (CH2), 112.55 (C), 119.98 (C),
122.72 (CH), 124.14 (CH), 129.43 (C), 131.37 (C), 135.52
(C), 146.52 (C), 156.76 (C), 162.74 (C), 168.97 (C); MS
(EI) m/z (relative intensity) 344 (Mþ, 18), 275 (73), 221
3.1.10. (E)-6-[1,3-Dihydro-4-hydroxy-6-methoxy-7-
methyl-3-oxo-5-isobenzofuranyl]-4-methyl-4-hexenoic
acid (1)
12 (125 mg) was dissolved in dry CH2Cl2 (5 mL) and
cooled to 2788C and 5 mL of BCl3 (1 M in CH2Cl2) was
added with stirring. After 12 h at room temperature. H2O

´
A. Covarrubias-Zun˜iga et al. / Tetrahedron 59 (2003) 1989–1994
1994
(25 mL) was added to decompose the complex and destroy
the excess of reagent and the organic layer was washed with
H2O and dried (Na2SO4). Evaporation to dryness afforded a
residue (103 mg) which was dissolved in MeOH (2 mL) and
treated with a solution of LiOH/H2O (14 mg, 0.33 mmol) in
0.5 mL of water. The reaction mixture was stirred at room
temperature for 6 h and then diluted with water and washed
with ether. The aqueous layer was cooled on ice, acidified to
pH 3 with HCl (10%) and extracted with ether, drying over
Na2SO4 and evaporation gave mycophenolic acid 1 (92 mg,
80% from 12: mp 139–1418C (lit9a 139–1418C) with
identical properties to the natural compound.
We thank Messrs. R. Patin˜o, R. Gavin˜o, L. Velasco, and F. J.
´
Perez for running the spectra.
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´
´ ´ ´
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This research was supported by a Grant-in aid for scientific
´
research No. 40361-5-3352E from CONACYT, Mexico.
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