A total synthesis of the aromatic monoterpene espintanol

Article abstract of DOI:10.1055/s-2004-837305

A synthesis of the leishmanicidal and trypanocidal monoterpene espintanol from dimethyl 2-isopropyl-3-oxoglutarate and 2-butynal using a Michael addition-Dieckmann cyclization as the key step is described.

Full text of DOI:10.1055/s-2004-837305

SHORT PAPER
527
A Total Synthesis of the Aromatic Monoterpene Espintanol
T
otal
S
ynthesis of
d
the
A
romatic
r
M
onot
i
á
spintanoln Covarrubias Zúñiga,*a Moisés Romero-Ortega,b José G. Avila Zárragac
a
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán 04510, México
E-mail: adriancz@servidor.unam.mx
b
c
Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón-Paseo Tollocan, Toluca, Estado de México, México
Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, D. F., México
Received 10 August 2004; revised 17 October 2004
thesis of espintanol would have as a key step the conver-
gent synthesis of the resorcinol 4 with all the substituents
already in place via the reaction between the ketoester 2
and 2-butynal8 (3) under appropriate conditions
(Scheme 1). The formyl group in resorcinol 4, provides
the feasibility of converting the aromatic aldehyde to phe-
nol 6, after the convenient and necessary protection of the
hydroxyl groups, and finally the saponification of the
methyl ester 6 and subsequent decarboxylation of the re-
sulting carboxylic acid would provide espintanol (1).
Abstract: A synthesis of the leishmanicidal and trypanocidal
monoterpene espintanol from dimethyl 2-isopropyl-3-oxoglutarate
and 2-butynal using a Michael addition–Dieckmann cyclization as
the key step is described.
Key words: monoterpene, leishmanicidal, trypanocidal, cycliza-
tion, total synthesis
Espintanol (1), an aromatic monoterpene, was first isolat-
ed from the spruce tree Oxandra espintata.1 It presents an-
tiparasitic activity against a number of strains of
Trypanosoma cruzy and Leishmania.1 Four synthetic
routes to 1 have been reported in the literature: (a) Two
syntheses utilize as starting material the commercially
available carvacrol,1,2a which already possesses the car-
bon atoms for the molecule skeleton and only required the
selective substitution by two methoxy groups at the aro-
matic ring for affording the desired product. (b) Another
synthetic approach involves the dimethyl squarate,2b
which after conversion to a 4-alkenyl cyclobutenone ren-
ders the aromatic ring upon regiospecific thermal ring ex-
pansion. (c) The procedure starting from 3-ethoxy-but-2-
enoate2c comprises three steps to give, via one 2H-pyran-
2-one, a known aromatic ring,3 whose structure greatly re-
sembles that of 1. Herein we wish to report on a synthesis
using the readily available dimethyl 2-isopropyl-3-
oxoglutarate4 (2). In recent years we have developed a
total5a,b and a formal5c synthesis of mycophenolic acid by
means of tandem reactions based on Michael addition6
and intramolecular regioselective Dieckmann cycliza-
tion;7 the high regioselectivity of this procedure in the
preparation of resorcinols encouraged us to apply it to the
total synthesis of 1. Thus, we conceived that a total syn-
An attempted synthesis based upon this analysis would
therefore have to accomplish two major objectives if it
were to be successful: (a) construction of the carbon skel-
eton (i.e., preparation of resorcinol 4); (b) refunctionaliza-
tion over the aromatic ring in 4 with appropriately
protected oxygens (i.e., conversion of 4 to 6). Such an ac-
complishment is now described.
As outlined in Scheme 1, the key annulation reaction
commences with the Michael addition between the sodi-
um salt, generated from ketoester 2, and 2-butynal (3) fol-
lowed by a Dieckmann cyclization and spontaneous
aromatization to provide the hexasubstituted resorcinol 4
in 26% yield. The yields of the hexasubstituted aromatic
rings from acyclic precursors reported in the literature are
generally low,8 as in the present case. However, several
advantages can be mentioned in this aromatic ring synthe-
sis: the preparation of the highly substituted compound 4
in only one step; since, generally highly substituted ben-
zenes require long synthetic routes by conventional meth-
ods. The avoidance of ortho-meta-para mixtures common
in conventional aromatic synthesis, is another advantage;
the introduction of labels (13C, 14C) into aromatic com-
pounds, not an easy task by conventional synthesis,
Scheme 1
SYNTHESIS 2005, No. 4, pp 0527–0529
x
x
.
x
x
.2
0
0
5
Advanced online publication: 23.12.2004
DOI: 10.1055/s-2004-837305; Art ID: M06004SS
© Georg Thieme Verlag Stuttgart · New York

528
A. Covarrubias Zúñiga et al.
SHORT PAPER
Scheme 2 Reagents and conditions: (a) NaH, DMF, MeI, r.t., 12 h; (b) H2O2, MeOH, H2SO4, 10 h; (c) KOH, ethylene glycol–H2O (7:3),
130 °C; (d) CuO, quinoline, 200 °C, 15 min.
should be easier by one pot aromatic ring synthesis in
view of the greater availability of labeled acyclic com-
pounds, compared with the cyclic compounds. The re-
1H NMR spectra were recorded at either 200 MHz (Varian Gemini
Unity 300), while 13C NMR were run at 75 MHz (Varian Unity
300). Low-resolution (JOEL JMS-AX50) and high-resolution
mainder of our synthetic approach continued according to (JOEL JMS-SX102A) mass spectra were measured at 70 eV (EI).
the Scheme 2. Dimethylation of resorcinol 4 with NaH,
2-Isopropyl-6-formyl-4-methoxycarbonyl-5-methyl Resorcinol
MeI in anhydrous DMF gave the dimethyl ether 5 in 93%
(4)
yield. The phenolic hydroxy group could be generated
Ketoester 2 (3 g, 13.9 mmol) was added dropwise to a suspension
from aldehyde 5 by the Dakin reaction with H2O2, H2SO4
of NaH (0.72 g, 18 mmol, 60%) in anhyd THF (30 mL) with mag-
in anhydrous MeOH at room temperature9 for 10 hours,
affording the phenol 6 in 82% yield. With the obtention of
this compound the two principal objectives of the synthe-
sis were complete. Removal of the methyl ester was ac-
complished by saponification to the carboxylic acid 7 with
10 equivalents of KOH in ethylene glycol–H2O (7:3) at
130 °C under an atmosphere of Ar10 in 84% yield and fi-
nally decarboxylation of 7 using CuO in anhydrous quin-
oline at 200 °C under an atmosphere of Ar11 for 15
minutes afforded espintanol in 52% yield with spectral
data consistent with the literature values.1,2 Contrary to the
mycophenolic acid synthesis,5a,b developed in our group,
in which the ketoalcohols 8a,b were found as products, in
the present synthetic work (Figure 1) these isomeric a-hy-
droxyesters were not observed. We believe that this be-
havior could be due to steric reasons i.e., the isopropyl
group could be preventing the formation of 8c,d; on the
other hand, the Michael acceptor, 2-butynal, is prone to
anionic polymerization.
netic stirring. To the resulting solution, 2-butynal12 (1.13 g, 16.6
mmol) was added and after 1.5 h, the mixture was poured into dilute
HCl (25 mL). The organic phase was separated and the aqueous lay-
er was extracted with EtOAc (2 × 15 mL). The combined organic
phase was dried over anhyd Na2SO4, filtered and concentrated. The
residue was subjected to column chromatography, on silica gel (80
g) eluting with EtOAc–hexane (5:95) to afford the resorcinol 4
(0.91 g, 26% yield) as pale yellow crystals; mp 108–109 °C.
IR (KBr): 3624, 2962, 1660, 1628, 1294 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.31 (d, J = 7.1 Hz, 6 H), 2.73 (s,
3 H), 3.59 (septet, J = 7.1 Hz, 1 H), 3.97 (s, 3 H), 10.26 (s, 1 H),
12.14 (s, 1 H), 13.25 (s, 1 H).
13C NMR (CDCl3): d = 16.3, 19.8, 23.6, 52.4, 107.1, 113.6, 119.8,
146.4, 166.2, 166.6, 171.9, 194.1.
MS (EI): m/z (relative intensity) = 252 (42) [M+], 252 (42), 237
(34), 220 (18), 205 (100), 192 (54).
HRMS (FAB): m/z [M + 1]+ calcd for C13H16O5: 253.1076; found:
253.1074.
2-Isopropyl-6-formyl-4-methoxycarbonyl-5-methyl Resorcinol
Dimethyl Ether (5)
The resorcinol 4 (0.59 g, 2.34 mmol) was dissolved in anhyd DMF
(6 mL) and NaH (0.21 g, 5.25 mmol, 60%) was added portionwise
with stirring. MeI (0.96 g, 6.7 mmol, 99%) was added dropwise and
stirring continued for 5 h. The reaction mixture was poured into wa-
ter (20 mL) and extracted with Et2O (3 × 10 mL). The organic layer
was separated, washed with water (2 × 5 mL), dried over anhyd
Na2SO4, filtered and concentrated. The residue was purified by col-
umn chromatography on silica gel (18 g) eluting with EtOAc–hex-
ane (0.3:9.7) to afford 5 (0.62 g, 93% yield) as pale yellow crystals;
mp 82–84 °C.
Figure 1
IR (KBr) 2958, 1734, 1689, 1565, 1206 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33 (d, J = 7.1 Hz, 6 H), 2.44 (s,
In conclusion, the synthesis reported herein highlights the
utility of the present aromatic regiocontrolled annulation
method as an efficient approach in the synthesis of 3 H), 3.34 (septet, J = 7.1 Hz, 1 H), 3.72 (s, 3 H), 3.78 (s, 3 H), 3.93
(s, 3 H), 10.39 (s, 1 H).
polysubstituted aromatic compounds. This convergent
route delivers espintanol (1) in five steps from 5 (8.7%
overall yield).
13C NMR (CDCl3): d = 17.1, 21.7, 25.2, 52.5, 62.5, 65.4, 124.4,
126.9, 132.9, 137.7, 160.5, 165.5, 168.5, 191.6.
MS (EI): m/z (relative intensity) = 280 (100) [M+], 265 (16), 249
(28%), 233 (84%).
HRMS (FAB): m/z [M + 1]+ calcd for C15H20O5: 281.1389; found:
Melting points are uncorrected. TLC was performed on silica gel 60
F
254 plates and visualized by UV irradiation. Column chromatogra-
phy purifications were carried out using silica gel (70–230 mesh).
281.1385
Synthesis 2005, No. 4, 527–529 © Thieme Stuttgart · New York

SHORT PAPER
Total Synthesis of the Aromatic Monoterpene Espintanol
529
2-Isopropyl-4-methoxycarbonyl-5-methyl-6-hydroxy Resorci-
nol Dimethyl Ether (6)
layer was separated, dried (Na2SO4), filtered, and concentrated. The
residue was purified by column chromatography [eluent: EtOAc–
hexane (0.5:99.5); 2 g of silica gel] affording 1 (26 mg, 52% yield)
with spectral data comparable to the literature values;1 mp 42–43 °C
(lit.2a 43.3–44 °C).
1H NMR (200 MHz, CDCl3): d = 1.32 (d, J = 6.9 Hz, 6 H), 2.23 (s,
3 H), 3.33 (septet, J = 6.9 Hz, 1 H), 3.74 (s, 6 H), 6.14 (br s, 1 H),
6.45 (s, 1 H).
Aldehyde 5 (0.4 g, 1.43 mmol) was treated with aq H2O2 (227 mg,
1.87 mmol, 28%) and H2SO4 (24 mg) in MeOH (2 mL) with mag-
netic stirring at r.t. for 10 h. The reaction mixture was poured into
water (20 mL) and extracted with Et2O (3 × 10 mL). The organic
layer was separated, washed with water (5 mL), dried (Na2SO4), fil-
tered and concentrated. The residue was purified by column chro-
matography on silica gel (12 g) eluting with EtOAc–hexane (5:95)
to give the compound 6 (314 mg) as a yellow oil in 82% yield.
13C NMR (CDCl3): d = 15.7, 21.2, 25.7, 55.8, 61.8, 110.0, 121.4,
126.8, 141.1, 144.8, 152.0.
IR (neat): 3422, 2955, 1729, 1644, 1414 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.34 (d, J = 7.1 Hz, 6 H), 2.15 (s,
3 H), 3.34 (septet, J = 7.1 Hz, 1 H), 3.72 (s, 3 H), 3.78 (s, 3 H), 3.93
(s, 3 H), 5.4 (br s, 1 H).
13C NMR (CDCl3): d = 12.4, 22.1, 25.9, 52.3, 61.6, 63.0, 120.3,
125.5, 132.1, 143.9, 146.6, 149.0, 168.7.
Acknowledgment
This research was supported by a Grant-in-Aid for Scientific Re-
search No. 27610-E from Conacyt, México. The authors thank Dr.
Noé Zúñiga for helpful discussions. We thank Messrs. A. Peña, R.
Patiño, L. Velasco, and F. J. Pérez for running the spectra.
MS (EI): m/z (relative intensity) = 268 (100) [M+], 253 (16), 237
(26), 221 (84).
HRMS (FAB): m/z [M + 1]+ calcd for C14H20O5: 269.1392; found:
269.1390.
References
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2-Isopropyl-4-hydroxycarbonyl-5-methyl-6-hydroxy Resorci-
nol Dimethyl Ether (7)
The phenol 6 (0.2 g, 0.75 mmol) was dissolved in ethylene glycol
(2.1 mL), KOH (0.42 g) in water (0.9 mL) was added and Ar was
bubbled. The reaction mixture was heated to 130 °C for 2 h, cooled
at r.t., poured into water (20 mL), and extracted with Et2O (10 mL).
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(10%) and extracted with Et2O (4 × 10 mL). The organic layer were
separated, dried (Na2SO4), filtered, and concentrated. The residue
was purified by column chromatography [eluent: EtOAc–hexane
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crystals; mp 124–126 °C.
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IR (KBr) 3398, 2963, 1694, 1602, 1401 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.35 (d, J = 7.1 Hz, 6 H), 2.29 (s,
3 H), 3.36 (septet, J = 7.1 Hz, 1 H), 3.80 (s, 6 H), 4.03 (s, 1 H), 6.40
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132.2, 144.2, 147.4, 149.5, 171.7.
MS: m/z (relative intensity) = 254 (95) [M+], 239 (18), 221 (100).
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2-Isopropyl-4-hydroxy-5-methyl Resorcinol Dimethyl Ether (1)
The carboxylic acid 7 (60 mg, 0.23 mmol), anhyd quinoline (1 mL)
and CuO (22 mg), were heated under Ar atmosphere to 215 °C for
15 min. The reaction mixture was cooled to r.t. and poured into aq
HCl (5 mL, 10%), and extracted with Et2O (3 × 10 mL). The organic
Synthesis 2005, No. 4, 527–529 © Thieme Stuttgart · New York