Synthesis of methyl 1-hydroxy-6-oxo-2-cyclohexenecarboxylate, a component of salicortin and tremulacin, and the monomer of idesolide

Article abstract of DOI:10.1021/jo701512w

(Chemical Equation Presented) We have developed a short and practical first synthesis of methyl 1-hydroxy-6-oxo-2-cyclohexenecarboxylate (2), which has been known as a component of salicortin and tremulacin since 1970. Birch reduction of the SEM ether of methyl salicylate followed by oxidation of the intermediate enolate with (-)-camphorsulfonyloxaziridine afforded the SEM enol ether of 2. Hydrolysis of the SEM enol ether afforded 2. We did not observe the dimerization of either racemic or optically enriched 2 to give idesolide (1).

Full text of DOI:10.1021/jo701512w

Synthesis of Methyl
1-Hydroxy-6-oxo-2-cyclohexenecarboxylate, a
Component of Salicortin and Tremulacin, and the
Monomer of Idesolide
Amie M. Richardson, Chun-Hsing Chen, and
Barry B. Snider*
Department of Chemistry MS 015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
FIGURE 1. Selected naturally occurring 1-hydroxy-6-oxo-2-cyclo-
hexenecarboxylate esters.
ReceiVed July 11, 2007
idescarpin (3b),8 tremulacin (3c),7 cochinchiside B (3d),9 and
4-hydroxytremulacin (3e).3 Although the structures of salicortin
and tremulacin were assigned in 1970,7 the synthesis of the
densely functionalized 1-hydroxy-6-oxo-2-cyclohexenecarboxy-
late moiety has not been reported. This ring system is somewhat
unstable, undergoing dehydration in dilute hydrochloric acid to
give salicylate esters (4) and ring cleavage with NaOMe in
MeOH to provide diester 5 (see Scheme 1).7 Hydrolysis of 3a
with aqueous base or pig/rabbit liver esterase yields a â-keto
acid that decarboxylates to provide hydroxycyclohexenone 6,
which is readily oxidized to form catechol (7).7,10
We have developed a short and practical first synthesis of
methyl 1-hydroxy-6-oxo-2-cyclohexenecarboxylate (2), which
has been known as a component of salicortin and tremulacin
since 1970. Birch reduction of the SEM ether of methyl
salicylate followed by oxidation of the intermediate enolate
with (-)-camphorsulfonyloxaziridine afforded the SEM enol
ether of 2. Hydrolysis of the SEM enol ether afforded 2.
We did not observe the dimerization of either racemic or
optically enriched 2 to give idesolide (1).
SCHEME 1. Reactions of Salicortin (3a)
Kim and co-workers recently isolated idesolide (1) from the
fruits of Idesia polycarpa Maxim (see Figure 1).1 The seeds of
this tree have been used as an insecticide in Korea, and the
leaves have hemostatic activity. The structure of idesolide was
determined spectroscopically and by X-ray crystallography.
Idesolide (1) is a hemiketal/ketal dimer of methyl 1-hydroxy-
6-oxo-2-cyclohexenecarboxylate (2). The monomer 2 has also
been isolated from several sources, including Idesia polycarpa.2-4
Both 1 and 2 inhibit lipopolysaccharide-induced NO production
in BV2 microglia at micromolar concentrations.1,4
We were intrigued by the isolation of both the monomer 2
and the dimer idesolide (1) that apparently do not easily
equilibrate with each other. 3-Hydroxybicyclo[2.2.1]heptan-2-
one (8) dimerizes at room temperature overnight or at 4 °C for
1 week to provide the symmetrical dimer 9 whose structure was
determined crystallographically (see Scheme 2).11 The structures
of other related dimers have been inferred from their sym-
metry.12 Laurencione (10) formed the unsymmetrical dimer 11,
whose structure was shown by X-ray crystal structure determi-
nation to be analogous to that of idesolide (1).13 Other dimers
The 1-hydroxy-6-oxo-2-cyclohexenecarboxylate moiety is
also a significant component of several important willow and
poplar glycosides that are related to the discovery and develop-
ment of aspirin.5,6 It is a component of salicortin (3a),7
(1) Kim, S. H.; Sung, S. H.; Choi, S. Y.; Chung, Y. K.; Kim, J.; Kim,
Y. C. Org. Lett. 2005, 7, 3275-3277.
(8) Chou, C.-J.; Lin, L.-C.; Tsai, W.-J.; Hsu, S.-Y.; Ho, L.-K. J. Nat.
Prod. 1997, 60, 375-377.
(2) Ekabo, O. A.; Farnsworth, N. R.; Santisuk, T.; Reutrakul, V. J. Nat.
Prod. 1993, 56, 699-707.
(9) Ishikawa, T.; Nishigaya, K.; Takami, K.; Uchikoshi, H.; Chen, I.-S.;
Tsai, I.-L. J. Nat. Prod. 2004, 67, 659-663.
(3) Rasmussen, B.; Nkurunziza, A.-J.; Witt, M.; Oketch-Rabah, H. A.;
Jaroszewski, J. W.; Stærk, D. J. Nat. Prod. 2006, 69, 1300-1304.
(4) Kim, S. H.; Jang, Y. P.; Sung, S. H.; Kim, Y. C. Planta Med. 2007,
73, 167-179.
(5) Jeffreys, D. Aspirin: The Remarkable Story of a Wonder Drug;
Bloomsbury: New York, 2004.
(10) (a) Julkunen-Tiitto, R.; Meier, B. J. Nat. Prod. 1992, 55, 1204-
1212. (b) Ruuhola, T.; Julkunen-Tiitto, R.; Vainiotalo, P. J. Chem. Ecol.
2003, 29, 1083-1097.
(11) Jauch, J.; Schurig, V.; Walz, L. Z. Kristallogr. 1991, 196, 255-
260.
(6) Mahdi, J. G.; Mahdi, A. J.; Mahdi, A. J.; Bowen, I. D. Cell Prolif.
2006, 39, 147-155.
(7) (a) Pearl, I. A.; Darling, S. F. Tetrahedron Lett. 1970, 11, 3827-
3830. (b) Pearl, I. A.; Darling, S. F. Phytochemistry 1971, 10, 3161-3166.
(12) Shurvell, H. F.; Petelenz, B. U.; Hester, R. E.; Girling, R. B. J.
Mol. Struct. 1982, 84, 11-23.
(13) Bernart, M. W.; Gerwick, W. H.; Corcoran, E. E.; Lee, A. Y.;
Clardy, J. Phytochemistry 1992, 31, 1273-1276.
10.1021/jo701512w CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/15/2007
J. Org. Chem. 2007, 72, 8099-8102
8099

have been suggested to have structures analogous to 1 and 11
and oxygenation of the intermediate analogous to 16. Although
the TBS enol ether of 19 could probably be cleaved under mild
conditions to give 2, Birch reduction/oxidation of TBS ether
1818 failed to give 19.
on the basis of the lack of symmetry in their 1H NMR spectra.14
SCHEME 2. Dimerization of r-Hydroxyketones
SCHEME 4. Birch Reduction/Oxidation Provides Enol
Ether 17
We decided to synthesize methyl 1-hydroxy-6-oxo-2-cyclo-
hexenecarboxylate (2) because (1) this functionally dense
molecule has never been prepared, although it has been known
as a component of salicortin and tremulacin since 1970;7 (2)
recent reports indicate that it inhibits NO production;1,4 and (3)
the isolation of both 2 and the dimer idesolide (1) with no
apparent equilibration deserved further study.1,4
The hydroxylation of methyl 2-oxocyclohexanecarboxylate
(12) to give methyl 1-hydroxy-2-oxocyclohexanecarboxylate
(13) can be easily achieved with molecular oxygen and Ce-
(III), Co(II), or Mn(II) (see Scheme 3).15 We hoped that we
could carry out a similar transformation starting with methyl
6-oxo-1-cyclohexenecarboxylate (14).16 Unfortunately, this and
a variety of other approaches to 2 were unsuccessful.
We then decided to investigate the Birch reduction/oxidation
of SEM ether 21 with the expectation that the enol ether product
could be cleaved with fluoride under mild conditions that would
not destroy product 2. Reaction of methyl salicylate (20) with
SEM chloride and (i-Pr)2EtN in CH2Cl2 at 25 °C for 20 h
afforded the desired SEM ether 21 in 99% yield (see Scheme
5).19 Birch reduction of SEM ether 21 followed by trapping the
intermediate with (-)-camphorsulfonyloxaziridine gave 22 in
55% yield with low enantiomeric excess. Unfortunately, all
attempts to convert 22 to 2 using a variety of fluoride protocols
gave either unreacted 22, methyl salicylate (20) resulting from
deprotection and dehydration of 22, or complex mixtures.
Finally, we were delighted to find that cleavage of the SEM
enol ether of 22 with MgBr2•OEt2 in Et2O/nitromethane20
afforded the desired product 2 in 71% yield.
SCHEME 3. Unsuccessful Approach to 2
SCHEME 5. Synthesis of Methyl
1-Hydroxy-6-oxo-2-cyclohexenecarboxylate (2)
Eventually, we noted that Schultz had prepared enol ether
17 by the Birch reduction of methyl 2-methoxybenzoate (15)
followed by trapping intermediate 16 with camphorsulfonylox-
aziridine to give 17 in 50-60% yield and 30% ee (see Scheme
4).17 Simple hydrolysis of the enol ether would provide the
desired product 2. However, 2 is known to be unstable to the
acidic conditions required to hydrolyze enol ethers, and all
attempts to hydrolyze 17, including those using soft Hg(II) or
Pd(II) salts, gave either unreacted 17, methyl 2-methoxybenzoate
(15) resulting from dehydration of 17, or complex mixtures.
Therefore, we needed a protecting group that is sufficiently labile
to be removed without the decomposition of the desired product
2 but robust enough to be compatible with the Birch reduction
(14) (a) Duggan, J. C.; Urry, W. H.; Schaefer, J. Tetrahedron Lett. 1971,
4197-4200. (b) Heyns, K.; Ko¨ll, P. Chem. Ber. 1971, 104, 3835-3841.
(c) Heyns, K.; Ko¨ll, P. Chem. Ber. 1973, 106, 611-622. (d) Yates, P.;
Langford, G. E. Can. J. Chem. 1981, 59, 344-355. (e) Freimund, S.;
Ko¨pper, S. Carbohydr. Res. 1998, 308, 195-200. (f) Andersen, S. M.;
Lundt, I.; Marcussen, J.; Yu, S. Carbohydr. Res. 1999, 320, 250-256.
(15) (a) Christoffers, J.; Werner, T.; Frey, W.; Baro, A. Eur. J. Org.
Chem. 2003, 4879-4886. (b) Baucherel, X.; Levoirier, E.; Uziel, J.; Juge,
S. Tetrahedron Lett. 2000, 41, 1385-1387. (c) Christoffers, J. J. Org. Chem.
1999, 64, 7668-7669.
The spectral data of 2 are identical to those previously
reported.2,3 However, we were unable to observe the formation
of the dimer idesolide (1) under a wide variety of conditions. It
is important to note that synthetic 2 is almost racemic ([R]D
-7), while natural 2 is presumably optically pure ([R]D -185).
(18) Nagarathnam, D.; Cushman, M. Tetrahedron 1991, 47, 5071-5076.
(19) Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343-
(16) Kato, M.; Kamat, V. P.; Yoshikoshi, A. Synthesis 1988, 699-701.
(17) Schultz, A. G.; Harrington, R. E.; Holoboski, M. A. J. Org. Chem.
1992, 57, 2973-2976.
3346.
(20) Vakalopoulos, A.; Hoffmann, H. M. R. Org. Lett. 2000, 2, 1447-
1450.
8100 J. Org. Chem., Vol. 72, No. 21, 2007

may be obtained from the Birch reduction/oxidation of 15 and
21. In an attempt to improve the enantioselectivity, we examined
the oxidation of 15 using the more bulky oxidant dichlorocam-
phorsulfonyloxaziridine.22 No 17 was obtained, indicating that
this reaction is sensitive to the steric bulk of the oxidant. We
then considered procedures for the kinetic resolution of 2.
Tanyeli and co-workers reported hydrolytic kinetic resolution
of methyl 1-methyl-2-methoxy-2,5-cyclohexadienecarboxylate
with pig liver esterase afforded the recovered ester in 36% yield
and 93% ee.23 We therefore treated racemic 2 with pig liver
esterase in pH 7 phosphate buffer at 6 °C for 5-10 days. This
afforded catechol and optically enriched 2 in 10% yield and
85% ee as determined by chiral GC analysis (see Scheme 6).
The hydrolysis product decarboxylates to give hydroxyketone
6, which is completely oxidized to catechol under these
conditions. The oxidation may be catalyzed by impurities in
the liver alcohol dehydrogenase. This optically enriched sample
of 2 also failed to dimerize to idesolide on standing at 0-
25 °C for several days.
SCHEME 6. Hydrolytic Kinetic Resolution of 2
Kim and co-workers did not note any interconversion of
idesolide (1) and monomer (2) during their solution spectro-
scopic studies. This suggests that there is a significant kinetic
barrier to the formation/decomposition of idesolide (1), which
is both a ketal and a hemiketal. Our failure to observe the
formation of idesolide (1) from either racemic or optically
enriched 2 suggests that we have not achieved the same
conditions that result in dimerization of 2 to give 1 in the fruits
of Idesia polycarpa.
In conclusion, we have developed a short and practical first
synthesis of methyl 1-hydroxy-6-oxo-2-cyclohexenecarboxylate
(2), which has been known as a component of salicortin and
tremulacin since 1970. We did not observe the dimerization of
either racemic or optically enriched 2 to give idesolide (1).
FIGURE 2. Three-dimensional representation and molecular structure
of 2 established by X-ray structure determination.
The relative stereochemistry of the two halves of idesolide is
identical, indicating it is formed from a single enantiomer of 2.
Dimerization of 2 should be favored at high concentration by
Le Chatelier’s principle and at low temperatures based on
entropic considerations. Therefore, we kept a neat sample of 2
at 0-25 °C for several days. However, under these conditions,
the racemic monomer, mp 70-72 °C, crystallized.
The structure of 2 was confirmed by X-ray crystallography.
Compound 2 crystallizes in the racemic space group P21/c, with
Z ) 4, indicating that there are two molecules of each
enantiomer in the unit cell. Figure 2 shows four symmetry-
related molecules of 2. There is a hydrogen bond from the
alcohol of one enantiomer to the ketone of the other O1-H11‚
‚‚O2 [x, 3/2 - y, z - 1/2; O‚‚‚O, 2.857 Å, O-H‚‚‚O, 155.4°].
Inspection of Figure 2 reveals that the complete hydrogen bond
set is an infinite zigzag chain, graph set C(5),21 that propagates
along the c-axis of the unit cell.
Synthetic, racemic monomer 2 did not dimerize to give any
idesolide (1) under a wide variety of conditions, including
storage neat at 0-100 °C and stirring in D2O with or without
MgCl2. We suspected that this might be a result of the fact that
racemic 2 crystallizes under the conditions (high concentration,
low temperature) that should favor dimerization, whereas
natural, optically pure 2 has been reported only as an oil. We
therefore investigated routes to optically enriched 2.
Schultz reported that 17 was formed in about 30% ee.17
However, chiral GC analysis revealed that our sample of 2 was
virtually racemic, indicating that different enantiomeric excesses
Experimental Section
Methyl 2-(((2-Trimethylsilyl)ethoxy)methoxy)benzoate (21).
2-(Trimethylsilyl)ethoxymethyl chloride (1.42 mL, 8 mmol) was
added to a solution of methyl salicylate (609 mg, 4 mmol) in dry
CH2Cl2 (2 mL) under N2 and cooled to 0 °C. Diisopropylamine
(2.79 mL, 16 mmol) was added over 5 min. The solution was
warmed to 25 °C and stirred for 20 h. The solution was poured
into ice-cold water (20 mL), and the mixture was extracted with
Et2O (3 × 20 mL). The combined Et2O extracts were washed with
water and brine, dried over MgSO4, and concentrated under reduced
pressure. Flash chromatography on MeOH-deactivated silica gel
(6:1 hexanes/EtOAc) afforded 1.127 g (99%) of 21 as a colorless
oil: 1H NMR (CDCl3) δ 7.75 (br d, 1, J ) 8 Hz), 7.41 (ddd, 1, J
) 8, 8, 2 Hz), 7.21 (br d, 1, J ) 8 Hz), 7.00 (ddd, 1, J ) 8, 8, 2
Hz), 5.29 (s, 2), 3.87 (s, 3), 3.79 (t, 2, J ) 8.2 Hz), 0.94 (t, 2, J )
8.2 Hz), -0.02 (s, 9); 13C NMR (CDCl3) δ 166.5, 156.7, 133.1,
131.2, 121.14, 121.10, 116.2, 93.3, 66.4, 51.8, 17.9, -1.6 (3 C);
IR (neat) 2953, 2897, 1733, 1601, 1490, 1454, 1434, 1299, 1250,
(22) Davis, F. A.; Weismiller, M. C. J. Org. Chem. 1990, 55, 3715-
3717.
(21) Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystallogr., Sect.
B: Struct. Sci. 1990, 46, 256-262.
(23) Tanyeli, C.; Sezen, B.; Demir, A. S.; Alves, R. B.; Arseniyadis, S.
Tetrahedron: Asymmetry 1999, 10, 1129-1133.
J. Org. Chem, Vol. 72, No. 21, 2007 8101

1130, 1080, 991, 860, 836, 757; HRMS (TOF MS ES+) calcd for
NaC14H22O4Si (MNa+) 305.1185, found 305.1200.
silica gel (0.5% MeOH in CH2Cl2) afforded 60 mg (71%) of 2 as
a light yellow oil. The oil was kept neat at 0 °C for 1-2 days,
yielding off-white crystals that were washed with Et2O: mp 70-
72 °C; [R]23D -7.11 (c 0.61, CHCl3); {lit.3 [R]25D -185.9 (c 0.59,
CHCl3)}; 1H NMR (CDCl3) δ 6.13 (ddd, 1, J ) 10.0, 3.6, 3.6 Hz),
5.79 (d, 1, J ) 10.0 Hz), 4.23 (s, 1, OH), 3.80 (s, 3), 3.00 (ddd, 1,
J ) 14.0, 6.8, 6.8 Hz), 2.77-2.64 (m, 2), 2.62-2.55 (m, 1); 13C
NMR (CDCl3) δ 205.4, 170.3, 131.9, 127.5, 77.9, 53.4, 35.1, 26.9;
IR (neat) 3462, 2956, 1727, 1439, 1253, 1224, 1140, 1103, 914,
733; HRMS (TOF MS ES+) calcd for C8H10O4 (M+) 170.0579,
found 170.0580. The spectral data are identical to those previously
reported.3 Chiral GC analysis (80 °C, 4 min, 1 °C/min to 200 °C,
tR(major) ) 59.74 min, tR (minor) ) 59.25) indicated 1-2% ee.
Enzymatic Hydrolysis of Methyl 1-Hydroxy-6-oxocyclohex-
2-enecarboxylate (2). Racemic methyl 1-hydroxy-6-oxocyclohex-
2-enecarboxylate (2) (25 mg, 0.15 mmol) was chilled to 6 °C in
aqueous phosphate buffer (pH ∼ 7, 0.5 mL). Pig liver esterase (3
mg, 20 units/mg) was added, and the mixture was stirred at 6 °C
for 8 days. The mixture was diluted with water (5 mL) and CH2-
Cl2 (5 mL), and the layers were separated. The aqueous layer was
extracted with CH2Cl2 (2 × 5 mL). The combined extracts were
washed with 10% aqueous NaHCO3 (to remove catechol) and brine,
dried over MgSO4, and concentrated under reduced pressure. Flash
chromatography on MeOH-deactivated silica gel (10:1 hexanes/
EtOAc) yielded 3 mg (10%) of 2 as a colorless oil in 85% ee as
determined by chiral GC analysis (80 °C, 4 min, 1 °C/min to
200 °C, tR(major) ) 59.74 min, tR (minor) ) 59.25). The oil was
stored neat at 25 °C for 4 weeks. NMR analysis did not reveal any
idesolide (1) formation.
Methyl 1-Hydroxy-2-((2-(trimethylsilyl)ethoxy)methoxy)-
cyclohexa-2,5-dienecarboxylate (22). Anhydrous NH3 (5 mL) was
added to a dried three-neck flask equipped with a condenser at
-78 °C under N2. tert-Butyl alcohol (0.1 mL, 1 mmol) and a
solution of 21 (282 mg, 1 mmol) in anhydrous THF (2.5 mL) were
added. Lithium metal (42 mg, 6 mmol) was added until a dark
blue solution was achieved, and the solution was stirred for 15 min.
Piperylene was added to the reaction dropwise until the blue
coloration disappeared, and (-)-(2S,8aR)-(camphorylsulfonyl)-
oxaziridine (413 mg, 1.8 mmol) in DME (4 mL) was immediately
added to the solution. After 30 min, excess solid NH4Cl was added,
and the mixture was allowed to warm to 25 °C. CH2Cl2 was added,
and the mixture was filtered. After concentration at reduced
pressure, Et2O was added to the resulting residue. The mixture was
filtered through a MgSO4 plug, and the filtrate was concentrated
under reduced pressure. Flash chromatography on MeOH-deacti-
vated silica gel (10:1 hexanes/EtOAc to 3:1 hexanes/EtOAc)
afforded 165 mg (55%) of 22 as a colorless oil: [R]23D -4 (c 1.275,
1
CHCl3); H NMR (CDCl3) δ 6.11 (ddd, 1, J ) 9.8, 3.2, 3.2 Hz),
5.66 (br d, 1, J ) 9.8 Hz), 5.37 (dd, 1, J ) 3.4, 3.4 Hz), 5.02 (d,
1, J ) 6.6 Hz), 5.07 (d, 1, J ) 6.6 Hz), 3.90 (s, 1, OH), 3.78 (s, 3),
3.65 (t, 2, J ) 8.2 Hz), 2.90 (br, 2, w1/2 ) 0.90), 0.94 (t, 2, J ) 8.2
Hz), 0.01 (s, 9); 13C NMR (CDCl3) δ 174.1, 149.5, 129.0, 125.1,
100.0, 92.4, 71.4, 66.1, 53.3, 26.6, 17.9, -1.5 (3 C); IR (neat) 3513,
2953, 2894, 1740, 1690, 1249, 1168, 1079, 860, 836; HRMS (TOF
MS ES+) calcd for NaC14H24O5Si (MNa+) 323.1291, found
323.1302.
Methyl 1-Hydroxy-6-oxo-2-cyclohexenecarboxylate (2). Et2O
(2 mL) was added to MgBr2•OEt2 (1.033 g, 4 mmol), and the
mixture was stirred at 25 °C until no solid MgBr2•OEt2 remained
(approximately 15 min) and two liquid phases were present.
Nitromethane (763 mg, 12.5 mmol) was added to the two-phase
system, resulting in a one-phase solution. The solution was added
to 22 (150 mg, 0.5 mmol) in 2 mL of Et2O, and the resulting
solution was stirred at 25 °C for 2 h. The solution was diluted with
EtOAc (10 mL) and water (10 mL). The layers were separated,
and the aqueous layer was saturated with solid NaCl followed by
extraction with EtOAc (3 × 15 mL). The combined organic layers
were washed with brine, dried over MgSO4, and concentrated under
reduced pressure. Flash chromatography on MeOH-deactivated
Acknowledgment. We are grateful to the National Institutes
of Health (GM-50151) for support of this work. We thank the
National Science Foundation for the partial support of this work
through Grant CHE-0521047 for the purchase of an X-ray
diffractometer. We thank Prof. Bruce M. Foxman, Brandeis
University, for assistance with the X-ray structure determination.
Supporting Information Available: Copies of 1H and 13C NMR
spectral data, and X-ray crystallographic data (CIF file) for 2. This
material is available free of charge via the Internet at http://pubs.
acs.org.
JO701512W
8102 J. Org. Chem., Vol. 72, No. 21, 2007