One-pot synthesis of trisubstituted monomethylated benzene-1,3-diols via a Michael addition-Dieckmann cyclization sequence from methyl (E)3-methoxy-4- methoxycarbonylbut-2-enoate anion and methyl alkynoates and its application to the total synthesis of nidulol

Article abstract of DOI:10.1055/s-2005-872082

The reaction of methyl (E)3-methoxy-4-methoxycarbonylbut-2-enoate (1) with a number of methyl alkynoates under appropriate conditions gave the monomethylated trisubstituted resorcinol derivatives 3 in a regiocontrolled manner, via a Michael addition-Dieckmann cyclization sequence in one pot. The resorcinol 3d, prepared in this manner, was used as the starting material for a three step, highly efficient (54% from 3d) synthesis of the bioactive fungal metabolite nidulol (4). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872082

PAPER
2293
One-Pot Synthesis of Trisubstituted Monomethylated Benzene-1,3-diols via
a Michael Addition–Dieckmann Cyclization Sequence from Methyl (E)-3-
Methoxy-4-methoxycarbonylbut-2-enoate Anion and Methyl Alkynoates and
Its Application to the Total Synthesis of Nidulol
S
ynthesis of Trisub
d
stituted Mon
r
omethy
i
lated B
á
enzene-1,3
n
-diols Covarrubias-Zúñiga,*a Laura San Germán-Sánchez,a Luis A. Maldonado,a Moisés Romero-Ortega,b
José G. Ávila-Zárragac
a
Instituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, México D.F., México
E-mail: adriancz@servidor.unam.mx
b
Departamento de Química Orgánica, Facultad de Química, Universidad Autónoma del Estado de México, Paso Tollocan, Toluca, Estado
de México, México
c
Facultad de Química, Universidad Nacional Autónoma de México, Coyoacán 04510, D. F., México
Received 16 August 2004; revised 26 January 2005
Abstract: The reaction of methyl (E)-3-methoxy-4-methoxycarbo-
nylbut-2-enoate (1) with a number of methyl alkynoates under ap-
propriate conditions gave the monomethylated trisubstituted
resorcinol derivatives 3 in a regiocontrolled manner, via a Michael
addition–Dieckmann cyclization sequence in one pot. The resorci-
nol 3d, prepared in this manner, was used as the starting material for
a three step, highly efficient (54% from 3d) synthesis of the bioac-
tive fungal metabolite nidulol (4).
Scheme 1
Keywords: resorcinol, alkynoates, Michael addition, Dieckmann
cyclization, tandem reactions
Table 1 Preparation of Monomethylated Resorcinols 3
Alkynoate R
Product Temp
(°C)
Time
(h)
Yield
(%)
The resorcinol system is present in a large number of nat-
urally occurring and biologically active compounds.1 The
formation of resorcinols from aliphatic precursors has
been investigated extensively,2 however, the preparation
of monomethyl ethers of resorcinol derivatives from ali-
phatic compounds in one pot has not been reported in the
literature. In previous papers, we have used dimethyl 1,3-
acetonedicarboxylate as one component in the synthesis
of aromatic compounds3,4 via tandem reactions (Michael
addition5 and intramolecular Dieckmann6 and aldol7 cy-
clization). We describe herein a new regiocontrolled route
to selectively monomethylated resorcinols and the appli-
cation of this methodology to a total synthesis of nidulol.8
2a
2b
2c
2d
2e
2f
Bn
3a
3b
3c
3d
3e
3f
25
25
25
25
25
60
25
25
2
2
58
50
71
68
52
55
63
65
Et
CH2OCH3
CH2OTHP
Pr
2
2
2
Ph
18
18
18
2g
2h
n-C5H11
3g
(CH2)3OCH3 3h
We chose to commence these studies with methyl (E)-4- The data in Table 1 show that the acetylenic substituent
carbomethoxy-3-methoxybut-2-enoate (1),9 on the expec- has an important effect on the reaction rate, since the phe-
tation that the condensation of this entity with methyl nyl compound 2f required heating to effect the reaction
alkynoates would generate monomethylated resorcinols, (entry 6). It is worth noting that by the methodology here
perhaps as a mixture of regioisomers, but in each compo- reported, the obtained resorcinols already have the methyl
nent the site of the methoxy group would be predeter- group at the OH function less prone to be methylated,
mined. Indeed, the sodium salt of the above mentioned which is a synthetic advantage for the nidulol total synthe-
enol ether 1, generated with sodium hydride in DMF solu- sis. Thus we decided to carry out a total synthesis of nid-
tion, reacted with various methyl alkynoates to afford a ulol (4). We conceived one approach starting from the
single monomethylated resorcinol derivative 3, in every resorcinol 3d, which already has all the carbon skeleton of
case (Scheme 1, Table 1).
nidulol (4). An attempted synthesis based upon this anal-
ysis would therefore have to accomplish the subsequent
generation of the lactone ring and the selective reduction
of the methyl ester to methyl group over the lactone.
Scheme 2 shows our synthetic approach.
SYNTHESIS 2005, No. 14, pp 2293–2296
Advanced online publication: 20.07.2005
x
x.
x
x
.
2
0
0
5
DOI: 10.1055/s-2005-872082; Art ID: M06404SS
© Georg Thieme Verlag Stuttgart · New York

2294
A. Covarrubias-Zúñiga et al.
PAPER
OMe
OMe
O
O
OMe
O
c
a
MeO2C
3d
b
HO2C
HO
Me
HO
O
O
O
HO
4
5
6
Scheme 2 Reagents and conditions: (a) AcOH–H2O (1:1), reflux, 2 h; (b) KOH, EtOH–H2O (1:1), reflux, 2 h; (c) 1. Et3N, ClCO2Et, 2. NaBH4,
THF, H2O, 0 °C to r.t.
Thus, 3d was converted into the phthalide 5 under mildly drawing methoxycarbonyl groups. Additionally the for-
acidic conditions, and this material was saponified with mation of 3 should be more sterically favored than 10.
potassium hydroxide in 50% aqueous ethanol at reflux
temperature. The carboxylic acid 6 so obtained (85% from
3d), was converted into nidulol (4, 63%) by reduction of
In summary, this research provides a short and efficient
method for the synthesis of pentasubstituted mono-O-
methylated resorcinols with regiocontrol from aliphatic
precursors and the utility of this methodology is con-
the mixed ethyl carbonic-carboxylic anhydride with sodi-
um borohydride,10 a reaction which must proceed via an
firmed with the quite convenient synthesis of the natural
intermediate o-quinone methide.
product nidulol (4).
There are two possible isomeric products 3 and 10 which
could be formed in the tandem reactions investigated
Melting points are uncorrected. TLC was performed on silica gel 60
herein, but only 3 was obtained in every case. This conclu-
sion is supported by NOESY experiments and by the total
synthesis without isomeric compounds of nidulol (4).
This observation can be rationalized in the following man-
ner (Scheme 3). Allene 7 is formed by means of a Michael
addition of the sodium salt of enol ether 1 and the methyl
alkynoate. The conjugated triene 8, which isomerizes to
the thermodynamically more favored enolate 9, can be
proposed to be formed by a double bond isomerization in-
volving a prototropic rearrangement of the H conjugated
to the allenic system.11 The carbanion 9 is stabilized by
conjugation with the carbon–carbon and carbon–oxygen
double bonds, by the inductive effect of the b-methoxy
group, and by chelation of the metal cation of the enolate
with the b-methoxy group. Furthermore the electrophilic-
ity of the involved carbonyl esters are quite different, the
b-methoxy ester being less electrophilic than the ester
arising from the methyl alkynoate, as a result of the reso-
nance stabilization called the push-pull effect12 between
the electron-donating methoxy and the electron-with-
F254 and visualized by UV irradiation; column chromatography pu-
rifications were carried out using silica gel (70–230 mesh). 1H NMR
spectra were recorded at either 300 MHz (Varian Unity 300); while
13C NMR spectra were run at 75 MHz (Varian Unity 300). Mass
spectra were measured at 70 eV (EI) (JEOL JMS-AX505HA). The
required substrates 2a,132b,142c,152d,162e,17 and 2h17 were synthe-
sized by deprotonation of the acetylenic substrates with n-BuLi fol-
lowed by carboalkylation with methyl choroformate17 from
acetylenic substrates. Compounds 2f,g were purchased from Ald-
rich Inc., and used without further purification.
5-Substituted 3-Methoxy-2,4-dimethoxycarbonylphenol Deriv-
atives 3a–h; General Procedure
The diester 1 (0.5 g, 2.65 mmol) was added to a suspension of NaH
(60%, 0.15 g, 3.72 mmol) in anhyd DMF (6 mL) with magnetic stir-
ring under argon. After 15 min, the mixture was maintained at r.t. or
heated according to the alkyl alkynoate used and this was finally
added (2.92 mmol); the reaction mixture was then stirred for the
stated period. H2O (30 mL) was added and the resulting solution
was acidified to pH 7 with dil. HCl, and the aqueous phase was ex-
tracted with EtOAc (3 × 10 mL). The combined organic extracts
were washed with H2O (10 mL), dried (Na2SO4), filtered and con-
centrated. The residue was purified by column chromatography on
Scheme 3
Synthesis 2005, No. 14, 2293–2296 © Thieme Stuttgart · New York

PAPER
Synthesis of Trisubstituted Monomethylated Benzene-1,3-diols
2295
silica gel (22.5 g), the phenol being eluted with EtOAc–hexanes
(2:98).
1H NMR (CDCl3): d = 0.94 (t, 3 H, J = 7.5 Hz), 1.55–1.67 (m, 2 H),
2.50 (t, 2 H, J = 7.6 Hz), 3.79 (s, 3 H), 3.89 (s, 3 H), 3.99 (s, 3 H),
6.65 (s, 1 H), 11.36 (s, 1 H).
5-Benzyl-3-methoxy-2,4-dimethoxycarbonylphenol (3a)
Yield: 0.509 g (58%); yellow oil.
IR (neat): 3443, 2952, 1732, 1666, 1237 cm–1.
1H NMR (CDCl3): d = 3.71 (s, 2 H), 3.78 (s, 3 H), 3.79 (s, 3 H), 3.98
13C NMR (CDCl3): d = 13.8, 23.4, 35.7, 52.1, 52.6, 63.7, 104.8,
114.0, 121.8, 148.4, 159.0, 163.6, 167.9, 170.2.
MS (EI): m/z (%) = 282 (M+, 62), 250 (100), 222 (73), 220 (32), 207
(33).
(s, 3 H), 6.56 (s, 1 H), 7.13 (m, 5 H), 11.36 (s, 1 H).
13C NMR (CDCl3): d = 39.3, 52.1, 52.7, 63.9, 105.1, 115.0, 121.7,
Anal. Calcd for C14H18O2: C, 59.57; H, 6.38. Found: C, 57.62; H,
6.41.
126.6, 128.5, 129.1, 138.3, 146.9, 159.2, 163.6, 167.7, 170.2.
3-Methoxy-2,4-dimethoxycarbonyl-5-phenylphenol (3f)
Yield: 0.462 g (55%); yellow solid; mp 98–100 °C.
IR (KBr): 3400, 2947, 1732, 1668, 1254 cm–1.
MS (EI): m/z (%) = 330 (M+, 75), 298 (100), 266 (87), 223 (72), 213
(57).
Anal. Calcd for C18H18O6: C, 65.51; H, 5.45. Found: C, 65.46, H,
5.47.
H NMR (CDCl3): d = 3.60 (s, 3 H), 3.87 (s, 3 H), 4.02 (s, 3 H), 6.83
(s, 1 H), 7.38 (s, 5 H), 11.46 (s, 1 H).
5-Ethyl-3-methoxy-2,4-dimethoxycarbonylphenol (3b)
Yield: 0.356 g (50%); yellow oil.
IR (neat): 3426, 2953, 1732, 1667, 1253 cm–1.
1H NMR (CDCl3): d = 1.20 (t, 3 H, J = 7.6 Hz), 2.57 (q, 2 H, J = 7.6
Hz), 3.79 (s, 3 H), 3.89 (s, 3 H), 3.98 (s, 3 H), 6.57 (s, 1 H), 11.36
(s, 1 H).
13C NMR (CDCl3): d = 52.1, 52.8, 64.1, 105.9, 114.7, 121.5, 127.8,
128.4, 138.9, 147.3, 159.3, 163.5, 167.6, 170.2.
MS (EI): m/z (%) = 316 (M+, 55), 284 (100), 253 (27), 241 (17), 283
(16).
Anal. Calcd for C14H18O6: C, 53.16; H, 5.69. Found: C, 53.24; H,
5.74.
13C NMR (CDCl3): d = 14.3, 26.7, 52.2, 52.7, 63.8, 104.7, 113.3,
121.5, 149.9, 158.9, 163.8, 167.9, 170.2.
3-Methoxy-2,4-dimethoxycarbonyl-5-pentylphenol (3g)
Yield: 0.519 g (63%); yellow oil.
IR (neat): 3400, 2955, 1732, 1666, 1264 cm–1.
MS (EI): m/z (%) = 268 (M+, 35), 236 (100), 205 (38), 148 (26), 91
(23).
Anal. Calcd for C13H16O6: C, 58.20; H, 5.97. Found: C, 58.28; H,
6.02.
1H NMR (CDCl3): d = 0.88 (t, 3 H, J = 9.9 Hz), 1.26–1.37 (m, 6 H),
2.52 (t, 2 H, J = 11.7 Hz), 3.79 (s, 3 H), 3.89 (s, 3 H), 3.98 (s, 3 H),
6.65 (s, 1 H), 11.35 (s, 1 H).
3-Methoxy-2,4-dimethoxycarbonyl-5-methoxymethylphenol
(3c)
Yield: 0.536 g (71%); yellow oil.
IR (neat): 3550, 2995, 1731, 1667, 1236 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.36 (s, 3 H), 3.81 (s, 3 H), 3.88
(s, 3 H), 4.00 (s, 3 H), 4.43 (s, 2 H), 6.85 (s, 1 H), 11.41 (s, 1 H).
13C NMR (CDCl3): d = 52.2, 52.8, 58.6, 63.9, 71.9, 106.1, 112.6,
13C NMR (CDCl3): d = 22.4, 29.9, 31.55, 32.4, 33.7, 52.2, 52.7,
63.8, 104.7, 114.0, 121.7, 148.8, 158.9, 163.6, 168.0, 170.3.
MS (EI): m/z (%) = 310 (M+, 32), 22 (100), 278 (36), 254 (18), 207
(30).
Anal. Calcd for C16H22O6: C, 61.93; H, 7.09. Found: C, 61.87; H,
7.19.
119.5, 144.7, 159.6, 164.0, 167.2, 170.2.
3-Methoxy-2,4-dimethoxycarbonyl-5-methoxypropylphenol
(3h)
MS (EI): m/z (%) = 284 (M+, 36), 252 (100), 205 (69), 221 (24), 237
Yield: 0.539 g (65%); yellow oil.
IR (neat): 3408, 2952, 2873, 1731, 1667, 1237, 1118 cm–1.
1H NMR (CDCl3): d = 1.76–1.89 (m, 2 H), 2.61 (t, 2 H, J = 7.8 Hz),
3.36 (t, 2 H, J = 7.4 Hz), 3.29 (s, 3 H), 3.79 (s, 3 H), 3.89 (s, 3 H),
3.99 (s, 3 H), 6.67 (s, 1 H), 11.35 (s, 1 H).
13C NMR (CDCl3): d = 30.1, 30.3, 52.2, 52.7, 58.5, 63.8, 71.6,
105.0, 114.2, 121.8, 148.0, 159.2, 163.6, 167.8, 170.2.
MS (EI): m/z (%) = 312 (M+, 21), 222 (100), 254 (71), 207 (32), 235
(13), 281 (12).
(18).
Anal. Calcd for C13H16O7: C, 54.92; H, 5.63. Found: C, 54.98; H,
5.69.
3-Methoxy-2,4-dimethoxycarbonyl-5-(tetrahydropyranyl-
oxymethyl)phenol (3d)
Yield: 0.64g (68%); pale yellow oil.
IR (neat): 3390, 2950, 1732, 1668, 1236 cm–1.
1H NMR (CDCl3): d = 1.50–1.76 (m, 6 H), 3.49–3.56 (m, 1 H),
3.83–3.86 (m, 1 H), 3.81 (s, 3 H), 3.88 (s, 3 H), 4.00 (s, 3 H), 4.75–
4.49 (AB system, 2 H, J = 14.7 Hz), 4.65 (t, 1 H, J = 3.3 Hz), 6.92
(s, 1 H), 11.44 (s, 1 H).
Anal. Calcd for C15H20O7: C, 57.69; H, 6.41. Found: C 57.65; H,
6.45.
13C NMR (CDCl3): d = 19.0, 25.3, 30.25, 52.2, 52.8, 62.0, 63.9,
5-Hydroxy-7-methoxy-6-methoxycarbonylphthalide (5)
66.1, 98.1, 105.9, 112.7, 119.5, 114.9, 159.5, 164.0, 167.1, 170.2.
MS (EI): m/z (%) = 354 (M+, 1), 222 (100), 221 (95), 254 (65), 85
(25), 207 (22).
Phenol 3d (1.31 g, 3.7 mmol) was dissolved in AcOH (5 mL) and
H2O (5 mL) was added. The mixture was stirred at reflux for 2 h.
After cooling to r.t., the mixture was poured into H2O (35 mL) and
extracted with EtOAc (3 × 15 mL). The combined organic extracts
were washed with H2O (2 × 10 mL), dried (Na2SO4), filtered, and
concentrated. The residue was purified by column chromatography
on silica gel (30 g) with EtOAc–hexanes (1.5:8.5) as eluent to give
0.845 g (96%) of phthalide 5; white solid; mp 165–168 °C.
Anal. Calcd for C17H22O8: C,57.62; H, 6.21. Found: C, 57.67; H,
6.25.
3-Methoxy-2,4-dimethoxycarbonyl-5-propylphenol (3e)
Yield: 0.39 g (52%); orange oil.
IR (neat): 3384, 2957, 2874, 1731, 1667 cm–1.
IR (KBr): 3450, 3083, 2960, 1747, 1665, 1217 cm–1.
Synthesis 2005, No. 14, 2293–2296 © Thieme Stuttgart · New York

2296
A. Covarrubias-Zúñiga et al.
PAPER
1H NMR (CDCl3): d = 4.02 (s, 3 H), 4.13 (s, 3 H), 5.18 (s, 2 H), 6.75
(s, 1 H), 11.88 (s, 1 H).
13C NMR (CDCl3): d = 53.1, 63.5, 68.3, 106.0, 107.9, 109.4, 154.1,
Professor J. Muchowski and Dr. N. Zúñiga for helpful discussions.
We thank Messrs. B. Quiroz, R. Patiño, L. Velasco and F.J. Pérez
for running the spectra.
162.5, 167.6, 167.8, 170.8.
MS: m/z (%) = 238 (M+, 62), 206 (100), 177 (50), 150 (38), 149
(22).
References
(1) Ingham, J. L. Progress in the Chemistry of Organic Natural
Products, Vol. 43; Herz, W.; Grisebach, H.; Kirby, G. W.,
Eds.; Springer-Verlag: Vienna, 1983.
Anal. Calcd for C11H10O6: C, 55.46; H, 4.20. Found: C, 55.52; H,
4.27.
(2) (a) Review: Bamfield, P.; Gordon, P. F. Chem. Soc. Rev.
1984, 13, 441. (b) Ghera, E.; Ben-David, Y. J. Org. Chem.
1988, 53, 2972. (c) Itoh, Y.; Brossi, A.; Hamel, E.; Lin, C.
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(3) Covarrubias-Zúñiga, A.; Maldonado, L. A.; Ríos-Barrios,
E.; Gonzalez-Lucas, A. Synth. Commun. 1998, 28, 3461.
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Commun. 1998, 28, 1525.
6-Carboxy-5-hydroxy-7-methoxyphthalide (6)
To a solution of 5 (0.5 g, 2.1 mmol) in EtOH (5 mL) was added a
solution of KOH (1.17 g, 17.8 mmol, 85%) in H2O (5 mL). The re-
sulting mixture was boiled under argon with stirring for 2 h. The
mixture was poured into ice-water (20 mL) and extracted with Et2O.
The aqueous layer was acidified with 20% HCl to pH 3, extracted
with Et2O (4 × 20 mL), and dried (Na2SO4). Concentration of the
Et2O layer gave a residue which was purified by column chromatog-
raphy on silica gel (12.5 g) with EtOAc–hexanes–HCO2H (1:9:0.1)
as eluent to give 0.42 g (89%) of the carboxylic acid 6; white solid;
mp 201–205 °C.
IR (KBr): 3490, 3092, 1756, 1701, 1422, 773 cm–1.
1H NMR (CDCl3–DMSO-d6): d = 4.07 (s, 3 H), 5.20 (s, 2 H), 6.78
(s, 1 H), 7.80 (s, 2 H).
13C NMR (CDCl3–DMSO-d6): d = 61.9, 67.3, 104.3, 107.2, 110.5,
(5) Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1959,
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(6) Schaefer, J. P.; Bloomfield, J. J. Org. React. 1967, 15, 1.
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151.9, 159.1, 164.7, 166.6, 169.0.
MS: m/z (%) = 224 (M+, 43), 206 (100), 177 (44), 150 (26), 148
(19).
Anal. Calcd for C10H8O6: C, 53.57; H, 3.57. Found: C, 53.63; H,
3.56.
5-Hydroxy-7-methoxy-6-methylphthalide (Nidulol, 4)
To a stirred solution of the carboxylic acid 6 (194 mg, 1 mmol) in
anhyd THF (4 mL) and Et3N (0.35 mL, 2.2 mmol), cooled in an ice
bath, was added ClCO2Et (0.1 mL, 1 mmol). After 15 min, the cool-
ing bath was removed and the stirring was continued for 45 min at
r.t. The suspension was filtered and washed with anhyd THF (10
mL). The combined THF solution was added dropwise over a peri-
od of 30 min to a stirred solution of NaBH4 (94 mg, 2.5 mmol) in
H2O (1 mL) at r.t. After 3.5 h, the mixture was acidified with 5%
HCl to pH 3, and extracted with Et2O. The Et2O extract was washed
with brine, dried (Na2SO4), and evaporated. The residue was puri-
fied by column chromatography on silica gel (3.6 g) using EtOAc–
hexanes (1:9) as eluent to give pure nidulol 4 (0.106 g, 63%), with
spectral data comparable to the literature values for the natural
product;18 mp 230–234 °C (Lit.8 mp 234 °C).
(16) Earl, R. A.; Towsend, L. B. Org. Synth. 1981, 60, 81.
(17) Brandsma, L. Preparative Acetylenic Chemistry; Elsevier:
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Nagai, M. Chem. Pharm. Bull. 1984, 32, 2622.
(b) Achenbach, H.; Mühlenfeld, A.; Brillinger, G. U. Liebigs
Ann. Chem. 1985, 1596.
1H NMR (CDCl3, 200 MHz): d = 2.14 (s, 3 H), 4.01 (s, 3 H), 5.10
(s, 2 H), 6.66 (s, 1 H), 9.70 (br s, 1 H).
Acknowledgment
This research was supported by a Grant-in-aid for Scientific rese-
arch No.27610-E from CONACYT, México. The authors thank
Synthesis 2005, No. 14, 2293–2296 © Thieme Stuttgart · New York