Synthesis of some monocyclic analogues of mycophenolic acid via the Johnson ortho ester Claisen rearrangement

Article abstract of DOI:10.1016/j.bmc.2005.07.013

The synthesis of some monocyclic analogues of mycophenolic acid in which the lactone ring has been eliminated, leaving the aromatic ring intact and the same oxygenated substituents flanking the hexenoic acid side chain with an (E)-geometry at the double b

Full text of DOI:10.1016/j.bmc.2005.07.013

Bioorganic & Medicinal Chemistry 13 (2005) 6521–6528
Synthesis of some monocyclic analogues of mycophenolic acid
via the Johnson ortho ester Claisen rearrangement
a
Ma Elena Meza-Avin˜a, Mario Ordon˜ez, Mario Fernandez-Zertuche,
a
a,
*
´
Lourdes Rodrıguez-Fragoso, Jorge Reyes-Esparza
b
b
´
and Abril A. Martınez de los Rıos-Corsino
b
´
´
a
´
´
Centro de Investigaciones Quımicas, Universidad Autonoma del Estado de Morelos, Ave. Universidad 1001,
Col. Chamilpa, 62210, Cuernavaca, Morelos, Mexico
b
´
Facultad de Farmacia, Universidad Autonoma del Estado de Morelos, Ave. Universidad 1001,
Col. Chamilpa, 62210 Cuernavaca, Morelos, Mexico
Received 6 June 2005; revised 4 July 2005; accepted 5 July 2005
Available online 24 August 2005
Abstract—The synthesis of some monocyclic analogues of mycophenolic acid in which the lactone ring has been eliminated, leaving
the aromatic ring intact and the same oxygenated substituents flanking the hexenoic acid side chain with an (E)-geometry at the
double bond, has been accomplished via the Johnson ortho ester Claisen rearrangement. The synthetic methodology reported here
allows the preparation of mycophenolic acid analogues bearing alkyl substituents at the a- and b-positions on the side chain.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
difficult to achieve the drug levels needed for anticancer
activity.9 The MPA structure has been extensively mod-
ifieds,10 and, except for those kinds of derivatives that
can be transformed to MPA in vivo, the reported com-
pounds are inactive or have a diminished activity. In
1996, Anderson et al.11 obtained the first monocyclic
analogues, 2, of MPA with anticancer activity although
with 2 orders of magnitude less potency than MPA.
Three novel indole analogues were also reported by
Lai and Anderson12 in which the carboxamide deriva-
tive 3 was selected for advanced studies against prostate
cancer.
In the more than 100 years since its discovery,1 myco-
phenolic acid (MPA) 1a has been the subject of intensive
in vivo and in vitro biological evaluations including
antifungal,2 antibacterial,3 and immunosuppressive
properties.4 MPA is an inhibitor of inosine-50-mono-
phosphate dehydrogenase5 (IMPDH), a key enzyme in
the de novo biosynthesis of guanine nucleotides causing
a suppression of lymphocyte activity in humans;6 this
inhibition is believed to mediate its immunosuppresive
activity. Mycophenolate mofetil 1b (MMF), the mor-
pholinoethyl ester prodrug of MPA has been found to
be clinically effective for the reversal and prevention of
kidney and heart transplant rejection; 1b was approved
in the United States in 1995 for use in renal transplant
patients7 and in 1998 for heart transplant procedures.8
O
OH
CH3
OH
CH3
O
R
CO2H
CO2R
O
OCH3
OCH3
Cl
CH3
1a R = H
1b R = ethylmorpholine
2a R = CH3
2b R = CH3O
MPA itself has been tested clinically against various
tumors without success. The major drawback with
MPA as an anticancer drug in humans is its conjugation
with glucoronic acid, a process that makes it extremely
H
CH3
N
OH
CH3 R1
H2N
CO2H
CO2H
O
R2
OCH3
4a R1 = R2 = H
3
Keywords: Mycophenolic acid; Ortho esters; Claisen–Johnson
rearrangement.
4b
4c
R
R
1 = CH3, R2 = H
1 = C2H5, R2 = H
*
4d R1 = H, R2 = CH3
4e R1 = CH3, R2 = CH3
Corresponding author. Tel.: +52 777 329 7997; fax: +52 777 329
7997; e-mail: mfz@ciq.uaem.mx
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.07.013

6522
M. E. Meza-Avin˜a et al. / Bioorg. Med. Chem. 13 (2005) 6521–6528
2. Results and discussion
double bond with KMnO4 and H5IO6 in a mixture of
isopropanol/water afforded aldehyde 8 in 68% yield.18
In this paper, we report the synthesis of the monocyclic
analogues 4 of MPA, these compounds have been de-
signed as potential anticancer drugs, maintaining some
structural features essential for biological activity in
MPA. Although the lactone ring has been eliminated,
the hexenoic acid side chain with an (E)-geometry at
the double bond remains unchanged. Furthermore, the
phenolic and methoxy functionalities in the aromatic
ring surrounding the side chain also remain unchanged,
particularly the free phenolic function, which is an
absolute requirement for MPA activity.13
Aldehyde 8 was treated with the Grignard reagents de-
rived from 2-bromopropene or trans-2-bromobutane
providing the required allyl alcohols 9a and 9b for the
Claisen–Johnson protocol in 65% and 66% yield, respec-
tively (Scheme 2).
When alcohols 9 were subjected to the Claisen–Johnson
conditions with a variety of ortho esters 10 in xylenes at
145 ꢁC and in the presence of catalytic amount of propi-
onic acid, the c,d-unsaturated esters 12 were obtained in
very good yields (Table 1). In our first experiment (entry
1), alcohol 9a (R2 = H) and ortho ester 10 (R1 = H)
afforded 12a in 95% yield.
A prominent structural feature of analogues 4 is the
presence of an (E)-trisubstituted double bond, which
along with its c,d relationship to the carboxylic carbonyl
group satisfy the structural prerequisite for the Johnson
ortho ester Claisen rearrangement,14 the most powerful
method for the synthesis of c,d-unsaturated carbonyl
compounds.15
Analysis of Table 1 reveals that the synthesis of the a-es-
ters 12b–d was accomplished by introduction of the
appropriate R1 substituent in the ortho ester 10 used
(Table 1, entries 2–4). Therefore, when the reaction
was carried out with alcohol 9a (R2 = H) and the corre-
sponding substituted ortho esters 10 (R1 = CH3, C2H5,
Cl), the side chain of 12b–d already containing the
a-substituent was assembled in a direct manner and in
very good yields. Reports on the use of heteroatom
substituted ortho esters in the Johnson protocol are rare
in the literature. Daub et al.19 has shown that trimethyl
methoxy orthoacetate participates in the Claisen reac-
tion producing a-methoxy-c,d-unsaturated esters in rea-
sonable yields. In this regard, it is noteworthy to
mention that the use of trimethyl chloro ortho ester 10
(R = Cl, entry 4) represents another example of a het-
eroatom substituted ortho ester as a partner in the Cla-
isen–Johnson procedure that allows the introduction of
a chlorine group at the a-position of ester 12d.
The allyl alcohols 9a and 9b needed for the Claisen pro-
cess were prepared from aldehyde 8, which, in turn, was
obtained from the protected phenol 5 (Scheme 1). The
THP protected 3-methoxyphenol 5 was functionalized
with an allyl substituent at C-2 following BuchiÕs proce-
dure.16 Thus, compound 5 was treated with of n-BuLi
(1.5 equiv) at ꢀ10 ꢁC followed by subsequent additions
of anhydrous CuI and allyl bromide, which upon acidic
workup (aqueous oxalic acid) provided 6 in 96% yield.
The phenolic function of 6 was protected again with
the t-butyldimethylsilyl group (TBS) following standard
literature procedures,17 affording compounds 7 in 83%
yield. Finally, the oxidative cleavage of the terminal
OH
OTHP
The synthesis of the b-methylated ester 12e (Table 1, entry
5) was performed using alcohol 9b (R2 = CH3) and ortho
ester 10 (R1 = H) in the same manner. When these com-
pounds were heated in xylenes at 145 ꢁC in the presence
of a catalytic amount of propionic acid as before, afforded
12e in 69% yield. Finally, the a,b-dimethylated ester 12f
(entry 6) was prepared using aldehyde 9b (R2 = CH3)
and ortho ester 10e (R1 = CH3) under exactly the same
conditions affording ester 12f in 85% yield. According to
literature precedents,20 the (Z)-geometry of the double
bond in the allyl alcohol 9b used, provides 12f with an anti
arrangement of the methyl groups at the a- and b-posi-
tions. The relative stereochemistry of these centers was
confirmed on the basis of an X-ray crystal structure of
acid 4e, obtained by removal of the phenolic protecting
1) n-BuLi,THF
2) CuI, 0 oC
3) BrCH2CH=CH2
4) oxalic acid
(96%)
OMe
OMe
6
5
TBSCl, DMF
imidazole
(83%)
OTBS
OTBS
KMnO4, H5IO6
i-PrOH/H2O
(68%)
CHO
OMe
OMe
8
7
Scheme 1.
CH3
OTBS
CH3
CH3
OTBS
CH3
OTBS
BrMg
BrMg
CHO
OCH3
CH3
THF, -20˚C
(66%)
OH CH3
OH
O
O
THF, -20˚C
(65%)
CH3
9b
9a
CH3
8
Scheme 2.

M. E. Meza-Avin˜a et al. / Bioorg. Med. Chem. 13 (2005) 6521–6528
Table 1. Claisen–Johnson reaction of allyl alcohols 9 with orthoacetates 10
6523
Entry
Ester R3
Allyl alcohol R2
Ortho ester R1
Yield (%)
1
2
3
4
5
6
C2H5
C2H5
CH3
H
H
12a (95)
12b (89)
12c (69)
12d (98)
12e (69)
12f (85)
H
CH3
C2H5
Cl
H
CH3
C2H5
C2H5
H
CH3
CH3
H
CH3
Figure 1. X-ray structure of compound 4e.
group and base hydrolysis of the ester function (Fig. 1) in
which the anti arrangement of the methyl groups
can be seen.21 The (E)-geometry of the double bond on
compound 12f is the result of a cyclic transition state
in a chair conformation derived from 11 where the [3,3]
sigmatropic event takes place,22 we assume the same
geometry for all compounds 12. We have also utilized
the Claisen–Johnson rearrangement protocol in the
synthesis of b-alkylated analogues of MPA possessing
exactly the same side chain where the (E)-geometry has
also been corroborated by X-ray diffraction studies.23
In the last steps of our sequence (Scheme 3), removal of
the phenolic TBS protecting group on compounds 12
was carried out with tetra n-butylammonium fluoride
(TBAF) in THF to obtain esters 13, followed by hydro-
lysis of the ester functionality under the usual saponifi-
cation conditions (LiOH in water–methanol mixtures),
OH
CH3 R1
OH
CH3 R1
LiOH, CH3OH
H2O
CO2H
CO2R3
TBAF
THF
12
R2
R2
OCH3
OCH3
4
13
4a R1 = R2 = H (78%)
13a R1 = R2 = H, R3 = Et (95%)
4b R1 = CH3, R2 = H (76%)
4c R1 = C2H5, R2 = H (66%)
4d R1 = H, R2 = CH3 (68%)
4e R1 = CH3, R2 = CH3 (80%)
13b R1 = CH3, R2 = H, R3 = Et (99%)
13c R1 = C2H5, R2 = H, R3 = Me (85%)
13d R1= Cl, R2 = H, R3 = Me (72%)
13e R1 = H, R2 = CH3, R3= Et (85%)
13f R1 = CH3, R2 = CH3, R3 = Et (75%)
Scheme 3.

6524
M. E. Meza-Avin˜a et al. / Bioorg. Med. Chem. 13 (2005) 6521–6528
affording acids 4 in yields ranging from 60% to 80%, ex-
cept in the case of the chlorinated derivative 13d, where
a complex mixture of products was observed.
hexanes was added. The reaction mixture was stirred
at room temperature for 10 h and after this period of
time, 22.65 g (118.95 mmol) of anhydrous CuI was add-
ed. After stirring at room temperature for 1 h, the reac-
tion mixture was again cooled between ꢀ10 and 0 ꢁC
and 45.45 g (375.68 mmol) of allyl bromide was added.
The solution was stirred at room temperature for 1 h,
heated at reflux for 2 h, cooled to ambient temperature
and poured into a flask containing 300 mL of water.
The resulting mixture was filtered through a bed of Cel-
ite and extracted with ethyl acetate (3· 300 mL). The
combined organic extracts were washed with 300 mL
of saturated aqueous NH4Cl, dried over anhydrous
Na2SO4 and the solvent removed in vacuo. The product
was redissolved in 1.0 L of a 90% aqueous methanolic
solution and treated with 5.25 g (58.31 mmol) of oxalic
acid. At the end of this procedure, the solvent was re-
moved in vacuo, and the crude product dissolved in
300 mL of ethyl acetate. The organic solution was
washed with 300 mL of water and the aqueous phase
extracted with ethyl acetate (3· 300 mL), the organic
phases were combined, washed with 300 mL of water,
dried over Na2SO4 and the solvent in vacuo to give
the crude product. Flash chromatography (hexane/ethyl
acetate, 9:1) gave 39.53 g (96%) of the product as a red
oil.
We investigated the cytotoxic effect of the 11 monocyclic
analogues (13a–f and 4a–e) of MPA on the growth of
259Q and BMK/16-myc24 cells using MTT (1-(4,5-di-
methylthiazol-2yl)-3,5-diphenylformazan) assay, (1 nM,
10 nM, 100 nM, 1 lM, 10 lM, 100 lM, 1 mM). Unfor-
tunately, none of the analogues tested showed cytotoxic-
ity against these cells lines. We believe that the absence
of any cytotoxic effect in these analogues may be due
mainly to the lack of the lactone ring and to a lesser
extent to the absence of the methyl group at C-4 in
the aromatic ring. Although in previous reports10 it
was observed that modification of these structural fea-
tures lead to a diminished or even loss in the biological
activity of mycophenolic acid analogues, on the other
hand, Anderson et al.11 and particularly Lai and Ander-
son12 report some promising anticancer activity in one
of his monocyclic carboxamide analogues lacking these
groups.
3. Conclusions
In conclusion, the synthetic scope of the Claisen–John-
son protocol has been extended since a-, b-, and a,b-di-
substituted derivatives can be prepared from a single
aldehyde precursor by appropriate choice of the R1
group in the ortho ester used in the Claisen protocol,
the appropriate R2 group in the Grignard reagent used
to prepare allylic alcohols 9 and combinations of both.
However, none of the 11 analogues prepared with this
methodology showed significant anticancer activity in
the cell lines used.
1H NMR (200 MHz) d 7.07 (t, J = 8.2 Hz, 1H), 6.49 (d,
J = 8.2 Hz, 2H), 5.98 (m, J = 10.0, 6.0, 1.8 Hz, 1H), 5.32
(s, 1H), 5.11 (dq, J = 10.0, 1.8 Hz, 1H), (5.04, q,
J = 1.8 Hz, 1H), 3.80 (s, 3H), 3.46 (dt, J = 6.0, 1.8 Hz,
2H). IR (thin film) 3443, 2942, 2839, 1599, 1469 cmꢀ1
.
MS (EI) m/z 164 (M+).
4.2. 2-Allyl-1-O-tert-butyldimethylsilyloxy-3-methoxy-
benzene (7)
4. Experimental
2-Allyl-3-methoxyphenol, 6 (4.15 g, 23.04 mmol) was
dissolved in 45 mL of N,N-dimethylformamide, under
a nitrogen atmosphere at room temperature, then,
2.32 g (34.13 mmol) of imidazole was added. The mix-
ture was stirred at room temperature for 10 min and
5.30 g (35.14 mmol) of tert-butyldimethyl silyl chloride
was added and the stirring was continued for 8 h. The
mixture was then poured into 50 mL of water, extracted
with ethyl acetate (3· 50 mL). The combined organic ex-
tracts were washed with water (4· 100 mL), dried over
Na2SO4 and the solvent removed in vacuo to give the
crude material. Flash column chromatography (hex-
ane/ethyl acetate, 9:1) gave 5.84 g (83%) of the product
as a colorless oil. 1H NMR (200 MHz) d 7.04 (t,
J = 8.0 Hz, 1H), 6.49 (t, J = 8.0, 2.0 Hz, 2H), 5.94 (m,
J = 11.0, 6.0, 1.8 Hz, 1H), 4.96 (dq, J = 7.4, 1.8 Hz,
1H), 4.90 (t, J = 1.8 Hz, 1H), 3.78 (s, 3H), 3.40 (dt,
J = 6.0, 1.8 Hz, 2H), 1.00 (s, 9H), 0.22 (s, 6H). IR (thin
film) 2930, 2896, 2858, 1593, 1469 cmꢀ1. MS (EI) m/z
278 (M+).
IR spectra were obtained using a Brucker vector 22 FT-
IR spectrometer; NMR spectra were recorded on a Mer-
cury-2000 and Inova Varian spectrometer at 200 and
1
400 MHz for H and 50 and 100 MHz for 13C. Unless
otherwise specified, CDCl3 was used as a solvent. Gas
chromatography–mass spectra analyses were performed
on an Agilent 6890 series equipped with an electronic
impact mass detector Agilent 5973N at 70 eV; HRMS
data were obtained on a JEOL MStation JMS-700.
Melting points were determined on a Fisher–Johns melt-
ing point apparatus. THF was distilled from Na-benzo-
phenone immediately before use, and other solvents
were purified using standard procedures. Flash column
chromatography was carried out on silica gel (230–499
mesh) and thin layer chromatography was performed
with silica gel 60 F254 plates.
4.1. 2-Allyl-3-methoxyphenol (6)
In a round bottomed flask equipped with a magnetic
stirrer and under a nitrogen atmosphere, 52.16 g
(250.43 mmol) of 2-(3-methoxyphenoxy)tetrahydro-2H-
pyrane,25 was dissolved in 530 mL of anhydrous THF,
at a temperature between ꢀ10 and 0 ꢁC. Then, 250 mL
(375.68 mmol) of a 1.5 M solution of n-butyllithium in
4.3. (2-O-tert-Butyldimethylsilyloxy-6-methoxyphenyl)-
acetaldehyde (8)
To a solution of 61 g (219 mmol) of 2-allyl-1-O-tert-
butyldimethylsilyloxy-3-methoxybenzene (7) dissolved

M. E. Meza-Avin˜a et al. / Bioorg. Med. Chem. 13 (2005) 6521–6528
6525
in 840 mL of isopropanol 96.9 g (613.4 mmol) of
KMnO4 previously dissolved in 350 mL of water was
added slowly. The reaction course was followed by thin
layer chromatography (hexane/ethyl acetate, 9:1) until
disappeareance of the starting material. At this point,
109.8 g (481.9 mmol) of H5IO6, dissolved in 100 mL of
water was added. When the reaction was over (TLC),
the mixture was poured into 500 mL of water, extracted
with ethyl acetate (3· 500 mL) and the combined ex-
tracts washed with NaHCO3 (4· 500 mL) until pH 7.
The organic phase was dried (Na2SO4) and the solvent
removed. Flash column chromatography (hexane/ethyl
acetate, 9:1) gave 42.02 g (68%) of the product as a yellow
oil. 1H NMR (400 MHz) d 9.37 (t, J = 2.0 Hz, 1H), 6.91
(t, J = 8.4 Hz, 1H), 6.32 (ddd, J = 8.4, 1.2 Hz, 2H), 3.57
(s, 3H), 3.44 (d, J = 2.0 Hz, 2H), 0.76 (s, 9H), 0.1 (s, 6H).
IR (thin film) 2957, 2935, 2895, 2860, 1728, 1594,
1471 cmꢀ1. MS (EI) m/z 280 (M+).
9H), 0.25 (d, J = 5.4 Hz, 9H). IR (thin film) 34689,
2934, 2860, 1591, 1469 cmꢀ1. MS (EI) m/z 337 (M+).
4.5. General procedure for the Claisen–Johnson reactions
In a round bottomed flask equipped with stirrer, a vig-
reux column and a thermometer, 1.0 equiv of the allyl
alcohols (9a and 9b), 10.0 equiv of the ortho esters
(10) and 0.4 equiv of propionic acid were dissolved in
15 mL of xylenes. The reaction mixture was heated in
an oil bath at 145 ꢁC, until the reaction was complete
(TLC). The solvent was evaporated and the crude prod-
ucts then obtained were purified by flash column chro-
matography (hexane/ethyl acetate, 9:1).
4.5.1. Ethyl-(4E)-6-(2-O-tert-butyldimethylsilyloxy-6-meth-
oxyphenyl)-4-methylhex-4-enoate (12a). Yield: 3.28 g
1
(90%) as a yellow oil. H NMR (400 MHz) d 7.00 (t,
J = 8.0 Hz, 1H), 6.45 (ddd, J = 8.0, 0.8 Hz, 2H), 5.20
(td, J = 6.8, 1.4 Hz, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.77
(s, 3H), 3.33 (d, J = 6.8 Hz, 2H), 2.36 (m, J = 6.8, 4.4,
1.4 Hz, 2H), 2.27 (m, J = 6.8, 4.4 Hz, 3H), 1.75 (s, 3H),
1.19 (t, J = 7.2 Hz, 3H), 1.00 (s, 9H), 0.23 (s, 6H). IR (thin
film) 2957, 2934, 2860, 1737, 1592, 1469 cmꢀ1. MS (EI)
m/z 392 (M+).
4.4. General procedure for the preparation of allyl alcohols
(9a) and (9b)
In a round bottomed flask equipped with a magnetic
stirrer, a condenser and under a nitrogen atmosphere,
1.5 equiv of metalic magnesium (previously dried),
90 mL of anhydrous THF, 1.0 equiv of the correspond-
ing vinyl halide (2-bromopropene or trans-2-bromobu-
tene) and a catalytic amount of iodine were added and
the resulting mixture heated at reflux until the magne-
sium was consumed (5 h). In a separate flask, 1.0 equiv
4.5.2. Ethyl-(4E)-6-(2-O-tert-butyldimethylsilyloxy-6-meth-
oxyphenyl)-2,4-dimethylhex-4-enoate (12b). Yield: 4.71 g
1
(89%) as a yellow oil. H NMR (400 MHz) d 7.00 (t,
J = 8.0 Hz, 1H), 6.47 (ddd, J = 8.0, 0.8 Hz, 2H), 5.20
(td, J = 6.8, 1.2 Hz, 1H), 4.02 (c, J = 7.2 Hz, 2H), 3.78
(s, 3H), 3.32 (d, J = 6.8 Hz, 2H), 2.57 (m, J = 8.0,
7.0 Hz, 2H), 2.34 (ddd, J = 13.2, 7.0, 0.8 Hz, 1H), 1.99
(dd, J = 13.2, 8.0 Hz, 1H), 1.73 (d, J = 0.8 Hz, 3H), 1.18
(t, J = 7.2 Hz, 3H), 1.04 (d, J = 7.2 Hz, 3H) 1.00 (s, 9H),
0.26 (s, 6H). 13C NMR (100 MHz) 177.0, 158.9, 154.3,
131.6, 126.5, 126.1, 120.8, 111.8, 103.9, 60.2, 55.8, 44.2,
38.2, 26.0, 23.0, 18.5, 16.6, 16.0, 14.4, ꢀ3.9. IR (thin film)
2956, 2934, 2859, 1734, 1591, 1468 cmꢀ1. MS (EI) m/z
349; 303. (M+).
of
(2-O-tert-butyldimethylsilyloxy-6-methoxyphe-
nyl)acetaldehyde (8) was dissolved in 65 mL of anhy-
drous THF. The solution was cooled to ꢀ10 ꢁC and
the Grignard reagent previously prepared was added
dropwise. The mixture was stirred at this temperature
until the presence of the product was detected (TLC,
hexane/ethyl acetate, 9:1). The reaction mixture was
quenched with 30 mL of a saturated aqueous solution
of NH4Cl and 70 mL of ethyl acetate. The aqueous
phase was extracted with ethyl acetate (3· 100 mL)
and the combined extracts were washed with 100 mL
of brine, dried over Na2SO4 and the solvent removed.
The resulting allyl alcohols were purified by flash col-
umn chromatography (hexane/ethyl acetate, 9:1).
4.5.3. Methyl-(4E)-6-(2-O-tert-butyldimethylsilyloxy-6-
methoxyphenyl)-2-ethyl-4-methylhex-4-enoate (12c). Yield:
1
0.85 g (69%) as a yellow oil. H NMR (200 MHz) d 6.97
(t, J = 8.0 Hz, 1H), 6.45 (dd, J = 8.0, 0.8 Hz, 2H), 5.17
(td, J = 7.0, 1.2 Hz, 1H), 3.76 (s, 3H), 3.50 (s, 3H), 3.30
(d, J = 7.0 Hz, 2H), 2.44 (m, J = 8.0, 7.0, 3.0, 1.6 Hz,
1H), 2.24 (dd, J = 13.2, 8.0 Hz, 1H), 2.06 (dd, J = 13.2,
7.0 Hz, 1H), 1.73 (d, J = 1.2 Hz, 3H), 1.50 (m, J = 7.2,
6.0, 3.0, 1.6 Hz, 2H), 1.00 (s, 9H), 0.84 (t, J = 7.2 Hz,
3H), 0.24 (s, 6H). 13C NMR (50 MHz, CDCll) d
1776.3, 158.6, 154.0, 131.5, 126.2, 125.7, 120.6, 111.6,
103.8, 55.8, 51.3, 46.2, 42.9, 26.2, 23.2, 18.7, 16.3, 12.0,
ꢀ3.6. IR (thin film) 2958, 2933, 2859, 1738, 1592,
1469 cmꢀ1. HRMS (EI) calcd for C23H38O4Si: 406.2539.
Found: 406.2522.
4.4.1. 1-(2-O-tert-Butyldimethylsilyloxy-6-methoxyphenyl)-
3-methylbut-3-en-2-ol (9a). Yield: 3.0 g (65%) as a yellow
oil. 1H NMR (400 MHz) d 7.06 (t, J = 8.0 Hz, 1H),
6.5(ddd, J = 38.0, 0.4 Hz, 2H), 5.00 (t, J = 1.4 Hz, 1H),
4.82 (t, J = 1.4 Hz, 1H), 4.22 (td, J = 9.6, 4.0, 1.0 Hz,
1H), 3.82 (s, 3H), 2.99 (dd, J = 13.6, 3.2 Hz, 2H), 2.87
(dd, J = 13.6, 9.6 Hz, 2H), 2.75 (d, J = 4.0 Hz, 1H), 1.84
(s, 3H), 1.01 (s, 9H), 0.26 (d, J = 6.0 Hz, 6H). IR (thin
film) 3563, 3078, 2934, 2893, 2860, 1592, 1469 cmꢀ1. MS
(EI) m/z 322 (M+).
4.4.2. 1-(2-O-tert-Butyldimethylsilyloxy-6-methoxyphenyl)-
3-methylpent-3-en-2-ol (9b). Yield: 3.60 g (66%) as a yel-
low oil. H NMR (200 MHz) d 7.03 (t, J = 8.0 Hz, 1H),
6.49 (dd, J = 8.0, 4.8 Hz, 2H), 5.25 (qquint, J = 7.0,
1.0 Hz, 1H), 4.77 (dd, J = 9.2, 4.0 Hz, 1H), 3.79(s, 3H),
2.91 (m, J = 13.2, 9.2, 4.0 Hz, 2H), 1.79 (quint,
J = 1.0 Hz, 3H), 1.53 (dq, J = 7.0, 1.0 Hz, 3H), 1.02 (s,
4.5.4. Methyl-(4E)-6-(2-O-tert-butyldimethylsilyloxy-6-
1
methoxyphenyl)-2-chloro-4-methylhex-4-enoate
(12d).
Yield: 2.52 g (98%) as a reddish oil. 1H NMR
(200 MHz) d 6.98 (t, J = 8.0 Hz, 1H), 6.45 (dd, J = 8.0,
0.8 Hz, 2H), 5.29 (td, J = 7.0, 1.2 Hz, 1H), 4.33 (t,
J = 7.6 Hz, 1H), 3.77 (s, 3H), 3.60 (s, 3H), 3.32 (d,

6526
M. E. Meza-Avin˜a et al. / Bioorg. Med. Chem. 13 (2005) 6521–6528
J = 7.0 Hz, 2H), 2.69 (dd, J = 14.0, 7.6 Hz, 1H), 2.49
(dd, J = 14.0, 7.6 Hz, 1H), 1.77 (s, 3H), 1.00 (s, 9H),
0.23 (s, 6H). IR (thin film) 2955, 2932, 2858, 1750,
1592, 1469 cmꢀ1. MS (EI) m/z 413 (M+).
(t, J = 8.4 Hz, 1H), 6.47 (dd, J = 8.4, 1.2 Hz, 2H), 5.25
(td, J = 7.2, 0.8 Hz, 1H), 5.15 (s, 1H), 4.05 (q,
J = 6.8 Hz, 2H), 3.79 (s, 3H), 3.39 (d, J = 7.2 Hz, 2H),
2.62 (m, J = 14, 7.6, 6.8 Hz, 1H), 2.37 (dd, J = 14.0,
7.6 Hz, 1H), 2.06 (dd, J = 14.0, 7.6 Hz, 1H), 1.79 (d,
J = 0.8 Hz, 3H), 1.19 (t, J = 6.8 Hz, 3H), 1.09 (d,
J = 6.8 Hz, 3H). 13C NMR (100 MHz) d 176.6, 158.1,
155.3, 134.4, 127.2, 124.7, 115.4, 109.0, 103.3, 60.5,
56.0, 44.2, 38.3, 22.4, 17.0, 16.2, 14.5. IR (thin film)
3425, 2976, 2936, 1707, 1599, 1468 cmꢀ1. MS (EI) m/z
292 (M+). HRMS (EI) calcd for C17H24O4: 292.1675.
Found: 292.162.
4.5.5. Ethyl-(4E)-6-(2-O-tert-butyldimethylsilyloxy-6-meth-
oxyphenyl)-3,4-dimethylhex-4-enoate (12e). Yield: 5.01 g
1
(69%) as a yellowish oil. H NMR (400 MHz) d 7.00 (t,
J = 8.4 Hz, 1H), 6.47 (ddd, J = 8.4, 0.8 Hz, 2H), 5.20
(td, J = 6.8, 1.2 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 3.78
(s, 3H), 3.31 (d, J = 6.8 Hz, 2H), 2.58 (m, J = 14.0, 8.0,
6.8 Hz, 1H) , 2.37 (dd, J = 14.0, 6.8 Hz, 1H), 2.18 (dd,
J = 14.0, 8.0 Hz, 1H), 1.70 (d, J = 1.2 Hz, 3H), 1.17 (t,
J = 7.2 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H). IR (thin film)
2958, 2931, 2858, 1735, 1592, 1470 cmꢀ1. MS (EI) m/z
406 (M+).
4.6.3. Methyl-(4E)-6-(2-hydroxy-6-methoxyphenyl)-2-
ethyl-4-methylhex-4-enoate (13c). Yield: 0.52 g (85%) as
1
a beige solid, mp 46–47 ꢁC. H NMR (200 MHz) d 7.04
(t, J = 8.2 Hz, 1H), 6.44 (dd, J = 8.2 Hz, 2H), 5.22 (tq,
J = 7.0, 1.2 Hz, 1H), 3.78 (s, 3H), 3.54 (s, 3H), 3.37 (d,
J = 7.0 Hz, 2H), 2.49 (m, J = 8.8, 6.0, 3.0 Hz, 1H), 2.20
(m, J = 13.6, 8.8, 6.0 Hz, 1H), 1.78 (d, J = 1.2 Hz, 3H),
1.56 (m, J = 7.5, 3.0 Hz, 2H), 0.87 (t, J = 7.5 Hz, 3H).
13C NMR (50 MHz) d 176.3, 158.0, 155.1, 134.1, 127.0,
124.5, 115.5, 108.9, 103.2, 56.0, 51.6, 46.3, 42.9, 25.6,
22.6, 16.4, 12.3. IR (thin film) 3296, 2957, 2936, 2872,
1700, 1599, 1470 cmꢀ1. HRMS (EI) calcd for C17H24O4:
292.1675. Found: 292.162.
4.5.6. Ethyl-(4E)-6-(2-O-tert-butyldimethylsilyloxy-6-meth-
oxyphenyl)-2,3,4-trimethylhex-4-enoate (12f). Yield: 5.29 g
(85%) as a yellow oil . H NMR (400 MHz) d 7.02 (t,
1
J = 8.4 Hz, 1H), 6.49 (dd, J = 8.4 Hz, 2H), 5.25 (td,
J = 6.8, 1.2 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.79 (s,
3H), 3.35 (d, J = 6.8 Hz, 2H), 2.29 (m, J = 6.8, 3.6 Hz,
2H), 1.63 (d, J = 1.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H),
1.02 (s, 9H), 0.97 (dd, J =6.6 Hz, 6H), 0.24 (s, 6H). 13C
NMR (100 MHz) d 177.2, 159.1, 154.3, 135.4, 126.5,
126.0, 121.0, 111.8, 104.0, 60.2, 55.8, 46.7, 44.0, 26.0,
22.7, 18.5, 18.2, 16.5, 14.5, 12.0, ꢀ3.9. IR (thin film)
2961, 2935, 2861, 1733, 1592, 1469 cmꢀ1. MS (EI) = m/z
420 (M+). HRMS (EI) calcd for C24H40O4Si: 420.2696.
Found: 420.2485.
4.6.4. Methyl-(4E)-6-(2-hydroxy-6-methoxyphenyl)-2-chloro-
4-methylhex-4-enoato (13d). Yield: 1.53 g (72%) as a yel-
1
low oil. H NMR (200 MHz) d 6.98 (t, J = 8.2 Hz, 1H),
6.42 (dd, J = 8.2, 3.2 Hz, 2H), 5.53 (s, 1H), 5.34 (tq,
J = 7.4, 0.8 Hz, 1H), 3.77 (s, 3H), 3.61 (s, 3H), 3.37 (d,
J = 7.4 Hz, 2H), 2.70 (dd, J = 13.6, 7.6 Hz, 1H), 2.53
(dd, J = 13.6, 7.6 Hz, 1H), 1.80 (d, J = 0.8 Hz, 3H).
13C NMR (50 MHz) d 170.1, 158.1, 154.7, 130.0,
127.8, 127.0, 115.2, 108.7, 103.2, 55.9, 55.6, 53.0, 45.4,
22.6, 16.2. IR (thin film) 3452, 2953, 2839, 1739, 1598,
1469 cmꢀ1. MS (EI) m/z 298 (M+). HRMS (EI) calcd
for C15H19O4Cl: 298.0972. Found: 298.0968.
4.6. General procedure for the deprotection of the phenolic
functions
To 1.0 equiv of compounds (12a to 12f) dissolved in
30 mL of anhydrous THF at 0ꢁC, 19.1 mmol of a 1 M
solution of n-tetrabutyl ammoniun fluoride was added.
The reaction was monitored by thin layer chromatogra-
phy (hexane/ethyl acetate, 9:1), until the starting materi-
als has disappeared, then 10 mL of an aqueous saturated
NH4Cl was added. The mixture was extracted with ethyl
acetate (3· 40 mL), washed with 40 mL of brine, dried
over Na2SO4 and the solvent evaporated. The products
obtained were purified using flash column chromatogra-
phy (hexane/ethyl acetate, 9:1).
4.6.5. Ethyl-(4E)-6-(2-hydroxy-6-methoxyphenyl)-3,4-di-
methylhex-4-enoato (13e). Yield: 2.9 g (85%) as a yellow
1
oil. H NMR (200 MHz) d 7.02 (t, J = 8.4 Hz, 1H), 6.46
(dd, J = 8.4, 2.2 Hz, 2H), 5.28 (t, J = 6.8 Hz, 1H), 4.03
(q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 3.39 (d, J = 6.8 Hz,
2H), 2.64 (m, J = 14.4, 6.8 Hz, 1H), 2.39 (dd, J = 14.4,
7.6 Hz, 1H), 2.28 (m, J = 14.4, 7.6 Hz, 1H), 1.76 (d,
J = 0.8 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H), 1.04 (d,
J = 6.8 Hz, 3H). IR (thin film) 3418, 2965, 2840, 171,
1600, 1469 cmꢀ1. MS (EI) 292 m/z (M+). HRMS (EI)
calcd for C17H24O4: 292.1675. Found: 292.1646.
4.6.1. Ethyl-(4E-)6-(2-hydroxy-6-methoxyphenyl)-4-methy-
hex-4-enoate (13a). Yield: 1.69 g (95%) as a yellow oil. 1H
NMR (400 MHz) d 7.05 (t, J = 8.0 Hz, 1H), 6.47 (dd,
J = 8.0, 2.8 Hz, 2H), 5.26 (td, J = 7.2, 1.2 Hz, 1H), 5.11
(s, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 3.40 (d,
J = 7.2 Hz, 2H), 2.42 (m, J = 6.9, 2.0, 1.2 Hz, 2H), 2.33
(m, J = 8.4, 6.8 Hz, 2H), 1.81 (d, J = 1.2 Hz, 3H), 1.21
(t, J = 7.2 Hz, 3H). 13C NMR (100 mHz) d 173.6, 158.2,
155.4, 135.8, 127.3, 123.1, 115.4, 109.1, 103.3, 60.6, 56.0,
34.9, 33.2, 22.3, 16.3, 14.4. IR (thin film) 3423, 2984,
2936,1709,1600,1468 cmꢀ1.MS(EI)m/z278(M+). HRMS
(EI) calcd for C16H22O4: 278.1518. Found: 278.1536.
4.6.6. Ethyl-(4E)-6-(2-hydroxy-6-methoxyphenyl)-2,3,4-
trimethylhex-4-enoate (13f). Yield: 1.92 g (75%) as a yel-
low oil. 1H NMR (400 MHz) d 7.03 (t, J = 8.2 Hz, 1H),
6.45 (dd, J = 8.2 Hz, 2H), 5.30 (tq, J = 7.0, 1.4 Hz, 1H),
4.12 (q, J = 7.4 Hz, 2H), 3.79 (s, 3H), 3.40 (d,
J = 7.0 Hz, 2H), 2.34 (m, J = 10.2, 6.4 Hz, 2H), 1.68
(d, J = 1.4 Hz, 3H), 1.24 (t J = 7.4 Hz, 3H), 0.99 (dd,
J = 6.4 Hz, 6H). 13C NMR (100 MHz) d 176.8, 158.2,
155.3, 138.4, 127.2, 124.5, 115.3, 108.9, 103.3, 60.4,
55.9, 46.7, 43.9, 22.2, 18.2, 16.6, 14.5, 12.3. IR (thin film)
4.6.2. Ethyl-(4E)-6-(2-hydroxy-6-methoxyphenyl)-2,4-di-
methylhex-4-enoate (13b). Yield: 3.28 g (99%) as a slightly
1
yellow solid, mp 55–56 ꢁC. H NMR (400 MHz) d 7.04

M. E. Meza-Avin˜a et al. / Bioorg. Med. Chem. 13 (2005) 6521–6528
6527
3426, 2972, 2935, 1705, 1600, 1468 cmꢀ1. MS (EI) 306
m/z (M+). HRMS (EI) calcd for C18H26O4: 306.1831.
Found: 306.1843.
1599, 1468 cmꢀ1. MS (EI) = m/z 264 (M+). HRMS
(EI) calcd for: C15H20O4 264.1362. Found: 264.1341.
4.7.5. (4E)-6-(2-Hydroxy-6-methoxyphenyl)-2,3,4-trimethyl-
hex-4-enoic acid (4e). Yield: 0.45 g (80%) as a redish
solid, mp 110–111 ꢁC. H NMR (200 MHz) d 7.03 (t,
4.7. General procedure for the basic hydrolysis
1
To 1.0 equiv of esters (13a to 13f) dissolved in 36 mL of
a 4:1 mixture of THF:ethanol, were added 4.0 eq of
LiOH previously dissolved on 5 mL of water. When
the reaction was completed (TLC), the solvent was evap-
orated and the residue was dissolved in 30 mL of water,
acidified to pH 1 with 10% aqueous HCl and extracted
with ethyl acetate (3· 40 mL). The organic phases were
dried (Na2SO4) and the solvent was evaporated. The
products were purified using flash column chromatogra-
phy (hexane/ethyl acetate, 8:2).
J = 8.4 Hz, 1H), 6.45 (dd, J = 8.4, 28 Hz, 2H), 5.31
(tq, J = 7.0, 1.2 Hz, 1H), 3.79 (s, 3H), 3.41 (d,
J = 7.0 Hz, 2H), 2.36 (m, J = 10.3, 6.6 Hz, 2H), 1.69 (s,
3H), 1.05 (d, J = 6.6 Hz, 6H). 13C NMR (50 MHz) d
182.0, 158.4, 155.3, 138.1, 127.4, 124.9, 115.4, 109.0,
103.4, 56.0, 46.4, 43.6, 22.2, 18.1, 16.4, 12.3. IR (thin
film) 3436, 2983, 2936, 1681, 1600, 1467 cmꢀ1. HRMS
(EI) calcd for C16H22O4: 278.1518. Found: 278.1530.
4.8. In vitro assays
4.7.1. (4E)-6-(2-Hydroxy-6-methoxyphenyl)-4-methyhex-
4-enoic acid (4a). Yield: 1.27 g (78%) as yellow solid, mp
62–63 ꢁC. 1H NMR (400 MHz) d 7.03 (t, J = 8.0 Hz,
1H), 6.45 (dd, J = 8.0, 3.6 Hz, 2H), 5.27 (td,
J = 6.8 Hz, 1H), 4.47 (s, 1H), 3.80 (s, 3H), 3.40 (d,
J = 6.8 Hz, 2H), 2.42 (m, J = 6.9, 2.0, 1.2 Hz, 2H),
2.33 (m, J = 8.4, 6.8 Hz, 2H), 1.81 (d, J = 1.2 Hz, 3H),
1.21 (t J = 7.2 Hz, 3H). IR (thin film) 3409, 2924,
1711, 1601, 1467 cmꢀ1. MS (EI) 250 m/z (M+). HRMS
(EI) calcd for: C17H24O4 250.1205. Found: 250.1245.
259Q and BMK cells were maintained in DMEM and
DMEM F-12, respectively, and were grown at 37 ꢁC in
a 5% CO2 atmosphere, 5 · 103 cells/well were inoculated
in 95-well plates. Various doses of analogues were added
to each well and inoculated for 24 h. Fifty microliters of
MTT (5 mg/mL) was added and the plate was incubated
for 4 h. The absorbance of MTT-formazan was mea-
sured using a 550 nm filter-equipped microplate reader
(BIORAD Ultramark).
4.7.2. (4E)-6-(2-Hydroxy-6-methoxyphenyl)-2,4-di-
methyhex-4-enoic acid (4b). Yield: 1.72 g (76%) as a yel-
low solid, mp 81–82 ꢁC. H NMR (200 MHz) d 6.70 (t,
Acknowledgments
1
´
The authors wish to thank CONACyT of Mexico for
J = 8.0 Hz, 1H), 6.43 (dd, J = 8.0, 3.0 Hz, 2H), 5.28 (t,
J = 7.0 Hz, 1H), 3.78 (s, 3H), 3.38 (d, J = 7.0 Hz, 2H),
2.64 (m, J = 14.0, 7.0 Hz, 1H), 2.40 (dd, J = 14.0,
7.0 Hz, 1H), 2.06 (dd, J = 14.0, 7.0 Hz, 1H), 1.78 (s,
3H), 1.10 (d, J =7.0 Hz, 3H). 13C NMR (50 MHz) d
182.1, 158.0, 155.0, 133.6, 127.1, 125.1, 115.5, 108.9,
103.3, 56.0, 44.0, 38.1, 22.6, 16.8, 16.2. IR (thin film)
financial support for this work (3112P-E9607). One of
us, MEMA, also wishes to thank CONACyT for a
Graduate Scholarship (96633). We are also indebted
´
to Dr. Miguel A. Mun˜oz Hernandez for his valuable
help for the obtention of the X-ray structure of
compound 4e.
3406, 2977, 2935, 1706, 1598, 1468 cmꢀ1
.
MS
(EI) = 264 m/z (M+). HRMS (EI) calcd for C15H20O4:
264.1362. Found: 264.1358.
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