Synthesis of (+)-makassaric acid, a protein kinase MK2 inhibitor

Article abstract of DOI:10.1016/j.tet.2010.06.023

Description of the first synthesis of (+)-makassaric acid, an important kinase MK2 inhibitor. The key step was a Barton/McCombie radical deoxygenation. (+)-Makassaric acid has been synthesized from (-)-sclareol, through a Barton/McCombie reaction.

Full text of DOI:10.1016/j.tet.2010.06.023

Tetrahedron 66 (2010) 6008e6012
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Synthesis of (þ)-makassaric acid, a protein kinase MK2 inhibitor
*
P. Basabe , M. Martín, O. Bodero, A. Blanco, I.S. Marcos, D. Díez, J.G. Urones
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca. Plaza de los Caídos 1-5, 37008 Salamanca. Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 May 2010
Received in revised form 7 June 2010
Accepted 8 June 2010
Description of the first synthesis of (þ)-makassaric acid, an important kinase MK2 inhibitor. The key step
was a Barton/McCombie radical deoxygenation.
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 12 June 2010
Keywords:
Makassaric acid
Subersic acid
Meroterpenoids
Protein kinase inhibitors
Barton/McCombie
1. Introduction
total synthesis of (ꢀ)-subersic acid was carried out by Stille coupling,
between a stannane aromatic derivative of p-hydroxybenzoic acid
(ꢀ)-Subersic acid, 1, was isolated recently from the Papua New
Guinean sponge Suberea sp. and exhibited biological activity as an
inhibitor of human 15-lipooxygenase.1
The stereochemistry of this sponge-derived was established as
(5R,10R),1, by total synthesis, by Mori et al.2 The main strategy of this
synthesis is the coupling of a sulfone derivative of a decalin obtained
from (S)-3-hydroxy-2,2-dimethylcyclohexanone and an aromatic
prenylated derivative obtained from p-hydroxybenzoic acid. Another
and the allyl trifluoroacetate derivative of the diterpene unitobtained
from (8aR)-bicyclofarnesol by Akita et al.3 In addition, the synthesis of
(þ)-subersic acid, 2, was achieved by coupling of an aromatic lithium
derivative of p-hydroxybenzoic acid and an diterpene allyl bromide
obtained from the natural product sclareol by us.4 Later, in 2004,
Andersen et al.5 isolated (þ)-subersic acid, 2 and (þ)-makassaric acid,
3, from the marine sponge Acanthodendrilla sp. The two mer-
oterpenoids 2 and 3 were inhibitors of the protein kinase MK2 (Fig.1).
HO
HO
COOH
COOH
COOH
H
OH
H
H
H
1
2
3
(-)-subersic acid
Suberea sp.
(+)-subersic acid
Acanthodendrilla sp.
(+)-makassaric acid
Acanthodendrilla sp.
MK2 inhibitor
15-lipoxygenase inhibitor
MK2 inhibitor
Figure 1. Some meroterpenoids with biological activity.
* Corresponding author. Tel.: þ34 923294474; fax: þ34 923294574; e-mail ad-
dress: pbb@usal.es (P. Basabe).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.023

P. Basabe et al. / Tetrahedron 66 (2010) 6008e6012
6009
The biological activities of all of these meroterpenes are related
to the control of antiinflammatory processes. Inflammation repre-
sents a host defence response to traumatisms, infections, ischemia,
toxics or autoimmune injuries.6
Inflammatory stimuli activate many intracellular signalling
pathways. Among them, the p38 MAPK is considered to be a central
regulator of inflammation.7 Subsequently, efforts have been made
to search for MK2 inhibitors from natural products, and we, par-
ticularly, became interested in synthesizing (þ)-makassaric acid, 3.
After NMR studies and mainly based on ROESY experiments,
NOEs between H-15 and H-7 , H-14 and Me-17, we concluded that
the configuration for 7 at C-15 is (S) Scheme 3.
b
With alcohol 7 in our hands, the next requirement for the syn-
thesis of (þ)-makassaric acid was the deoxygenation at C-15.
Our first attempt was to carry out the deoxygenation through the
Huang-Millon procedure11 (Scheme 4). Oxidation of 7 with TPAP
under standard conditions12 led to ketone 8 with excellent yield.
However, treatment of ketone 8 with KOH/H2NNH2 failed to afford
the desired hydrazone that would yield our target molecule, 10.
An alternative approach was the formation of the dithiane 9 from
ketone 8, which would be subsequently reduced with Ni-Raney.
However, again, reaction of 8 with bistrimethylsilylethanedithioldid
not lead to the requested intermediate.
2. Results and discussion
Scheme 1 shows our synthetic plan for (þ)-makassaric acid: the
target molecule 3 was to be constructed by the coupling of the
diterpenic moiety, aldehyde 4 and an aromatic lithium derivative 5,
appropriately protected. The last compound can be provided by
lithiation of the bromoderivative 6.
Those results confirm the difficulty to access to the carbonyl
group in 8.
Finally, the Barton/McCombie13 radical deoxygenation was the
chosen procedure. Consequently, alcohol 7 was first converted into
the xanthate 11. Treatment of 11 with tri-n-butyl tin hydride in
refluxing toluene yielded compound 10.
COOH
Selective deprotection of 10 with p-TsOH/MeOH and subsequent
oxidation of the resulting benzylic alcohol with PDC/DMF led to al-
dehyde 13. Further oxidation of 13 with sodium chlorite and removal
H
HO
H
of the remaining protecting group afforded compound 3 (Scheme 5).
22
The spectroscopic data of 3, as well as its optical rotation [a]
D
3
þ8.5 (c 0.20, MeOH) are identical to those described for the natural
product (þ)-makassaric acid,5
[
a]
22 þ7.3 (c 0.54, MeOH).
D
3. Conclusions
CH2OTHP
CH2OTHP
CHO
It can be concluded that this is the first, short and efficient
synthesis of (þ)-makassaric acid, a highly promising protein kinase
MK2 inhibitor. The synthesis is very versatile and can lead to the
synthesis of many analogues of (þ)-makassaric acid to carry out
SAR studies, aimed to improve their activity.
+
H
Li
Br
H
OMOM
OMOM
4
5
6
Scheme 1. Retrosynthetic analysis of (þ)-makassaric acid.
4. Experimental
4.1. General
Aldehyde 4 was a key intermediate in our previous synthesis of
luffolide8 and it was obtained from methyl isoanticopalate, which
has been obtained from (ꢀ)-sclareol9 (Scheme 2). Moreover, this
compound has been used in the synthesis of several biologically
active spongianes.10
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available and were used without fur-
HO
Ref. 9
OH
Ref. 8
CHO
COOMe
H
H
H
(-)-sclareol
H
H
methyl isoanticopalate
4
Scheme 2. Synthesis of the diterpenic moiety.
Compound 5 can be obtained by lithiation of the bromoder-
ivative 6, as previously mentioned (Scheme 1). This compound had
already been used by us in the synthesis of (þ)-subersic acid.4
The coupling of 4 and the lithium derivative 5 was accomplished
through a nucleophilic addition. Treatment of 6 with t-BuLi led to
the lithiated arene unit, which was added ‘in situ’ to the aldehyde 4
(Scheme 3).
In these conditions alcohol 7 was obtained in quantitative yield.
The reaction took place with total diastereofacial selection, leading
only to the expected Felkin-Anh diastereoisomer.
ther purification. IR spectra were recorded on a BOMEM 100 FTIR or
an AVATAR 370 FTIR Thermo Nicolet spectrophotometers. 1H and
13C NMR spectra were performed in CDCl3 and referenced to the
residual peak of CHCl3 at
respectively, using Varian 200 VX and Bruker DRX 400 instruments.
Chemical shifts are reported in parts per million and coupling
d 7.26 ppm and d
77.0 ppm, for 1H and 13C,
d
constants (J) are given in hertz. MS were performed at a VG-TS 250
spectrometer at 70 eV ionising voltage. Mass spectra are presented
as m/z (% rel int.). HRMS were recorded on a VG Platform (Fisons)
spectrometer using chemical ionisation (ammonia as gas) or Fast

6010
P. Basabe et al. / Tetrahedron 66 (2010) 6008e6012
Scheme 3. Reagents and conditions: (a) t-BuLi, THF, ꢀ78 ꢁC, 3 h, 100%.
CH2OTHP
CH2OTHP
a
H
H
O
OMOM
OH OMOM
H
H
8
7
b
c
CH2OTHP
OMOM
CH2OTHP
OMOM
S
H
H
S
H
H
9
10
Scheme 4. Reagents and conditions: (a) TPAP, NMO, DCM, molecular sieves 4 Å, 1.5 h, 100%; (b) KOH/H2NNH2, ethylene glycol, 175 ꢁC, 20 h, 230 ꢁC, 3 h; (c) ZnI2, 1,2-bis-
trimethylsylilethanedithiol, Et2O, ꢀ20 ꢁC to rt.
CH2OTHP
b
CH2OTHP
OMOM
R
CH2OTHP
a
H
H
H
O
S
OMOM
SMe
OH OMOM
H
H
H
10
11
7
c
COOH
f
H
H
OH
OMOM
H
H
3
12 R = CH2OH
13 R = CHO
14 R = COOH
d
e
(+)
-Makassaric acid
Scheme 5. Reagents and conditions: (a) NaHMDS, CS2, MeI, THF, ꢀ78 ꢁC, (100%); (b) AIBN, n-Bu3SnH, 120 ꢁC, 1.5 h, (67%); (c) p-TsOH, MeOH, 2.5 h, rt, (85%); (d) PDC, DMF, 14 h, rt,
(100%); (e) NaClO2, t-BuOH, 2-methyl-2-butene, NaH2PO4, 2 h, rt, (86%); (f) HCl 6 M, THF, 4 h, 50 ꢁC, (65%).
Atom Bombardment (FAB) technique. For some of the samples,
QSTAR XL spectrometer was employed for electrospray ionization
(ESI). Optical rotations were determined on a Perkin/Elmer 241
polarimeter in 1 dm cells. Diethyl ether and THF were distilled from
sodium, and dichloromethane was distilled from calcium hydride
under argon atmosphere.
stirring for 3 h, saturated NH4Cl was added, and the reaction mix-
ture was extracted with EtOAc. The organic extracts were dried
with Na2SO4 and concentrated under reduced pressure. The crude
was a yellowish oil that was purified by chromatography on silica
gel, affording 7 (144 mg, 100%).
4.2.1. Compound 7. IR (film): 3473, 2940, 1727, 1612, 1587, 1511,
4.2. Coupling reaction of 4 and 6 to yield 7
1464, 1386, 923, 816 cmꢀ1 1H NMR (400 MHz)
; d: 7.65 (1H, d,
J¼1.6 Hz), 7.18 (1H, dd, J¼8.0,1.6 Hz), 7.03 (1H, d, J¼8.0 Hz), 5.55 (1H,
s), 5.30 (1H, s), 5.20 (2H, s), 4.72 (1H, d, J¼11.7 Hz), 4.65 (1H, m), 4.46
(1H, d, J¼11.7 Hz), 3.92 (1H, m), 3.53 (1H, m), 3.47 (3H, s), 2.65 (1H, s),
2.30e2.15 (2H, m), 1.95e0.98 (18H, m), 1.55 (3H, s), 1.13 (3H, s), 0.94
(3H, s), 0.88 (3H, s), 0.84 (3H, s), OH not observed; 13C NMR
To a solution of 6 (730 mg, 2.2 mmol) in THF (7 mL), a solution of
t-BuLi in pentane (1.7 M mg, 1.94 mL, 3.1 mmol) was added, under
argon atmosphere and at ꢀ78 ꢁC. After 15 min, a solution of 4
(133 mg, 0.46 mmol) in THF (4.1 mL) was added via cannula. After

P. Basabe et al. / Tetrahedron 66 (2010) 6008e6012
6011
(100 MHz)
d
: 153.0, 134.2, 132.8, 130.5,128.1,127.3,126.6, 113.0, 97.1,
J¼14.0, 2.0 Hz), 2.41 (1H, dd, J¼8.0, 2.0 Hz), 1.98e0.85 (20H, m), 1.55
93.7, 68.5, 67.3, 62.1, 59.0, 56.7, 56.2, 55.3, 41.9, 41.7, 40.1, 38.0, 37.3,
33.4, 33.1, 30.5, 25.5, 24.6, 22.3, 21.7, 19.4, 19.0, 18.5, 16.3, 16.2;
EIHRMS: calcd for C34H52O5Na (MþNa): 563.3707, found 563.3714.
(3H, s), 0.95 (3H, s), 0.88 (3H, s), 0.87 (3H, s), 0.83 (3H, s).
4.6. Reaction of 10 with p-TsOH to yield 12
4.3. Oxidation of 7 with TPAP to yield 8
A solution of 10 (62 mg, 0.12 mmol) in p-TsOH/MeOH (25%,
15 mL) was stirred at room temperature during 2.5 h. The reaction
was monitored by TLC and when it finished, water was added and it
was extracted with EtOAc. The organic phase was washed with
NaHCO3 6% and brine. It was dried over Na2SO4 and the solvent was
removed under reduced pressure. The desired compound 12
(44 mg, 85% yield) was obtained as a colourless oil.
To a solution of 7 (36 mg, 6.58 mmol) in DCM (1.42 mL), 4 Å
molecular sieves (61 mg, 500 mg/mmol), NMO (30 mg, 0.22 mmol)
and TPAP (4 mg, 6.4 mmol) were added. The reaction mixture was
stirred at room temperature. After 1.5 h the reaction had finished
according to TLC. Then, it was diluted with DCM and filtered over
silica gel and CeliteÔ. The solvent was removed under pressure to
yield 8 (51 mg, 100%).
4.6.1. Compound 12. IR (film): 3373, 2929, 2847, 1740, 1609, 1499,
1448, 1384, 1244, 1151, 1009, 922, 821 cmꢀ1; 1H NMR (400 MHz)
d:
4.3.1. Compound 8. IR (film): 2937, 2848, 1679 cmꢀ1
(400 MHz)
;
1H NMR
7.28 (1H, d, J¼1.7 Hz), 7.12 (1H, dd, J¼8.4, 1.7 Hz), 7.03 (1H, d, J¼8.4),
5.35 (1H, s), 5.19 (2H, s), 4.60 (2H, d, J¼6 Hz), 3.49 (3H, s), 2.79 (1H,
dd, J¼15.2, 9.6 Hz), 2.59 (1H, dd, J¼15.2, 1.6 Hz), 2.41 (1H, dd, J¼9.6,
1.6 Hz), 2.0 (1H, m), 1.90 (2H, m), 1.70e0.85 (10H, m), 1.42 (3H, s),
1.25 (1H, m), 0.91 (3H, s), 0.89 (3H, s), 0.88 (3H, s), 0.83 (3H, s), OH
d
: 7.40 (1H, dd, J¼9.2, 2.0 Hz), 7.39 (1H, d, J¼2.0 Hz), 7.13
(1H, d, J¼9.2 Hz), 5.56 (1H, s), 5.28 (1H, d, J¼6.8 Hz), 5.20 (1H, d,
J¼6.8 Hz), 4.72 (1H, d, J¼12.0 Hz), 4.65 (1H, m), 4.47 (1H, d,
J¼12.0 Hz), 4.22 (1H, s), 3.89 (1H, m), 3.50 (1H, m), 3.48 (3H, s),
1.95e0.90 (20H, m) 1.64 (3H, s), 0.91 (3H, s), 0.88 (3H, s), 0.78 (3H,
not observable; 13C NMR (100 MHz)
d: 154.5, 135.4, 133.8, 133.1,
s), 0.78 (3H, s); 13C NMR (100 MHz)
d
: 205.7, 154.1, 133.9, 131.8,
128.5, 125.3, 122.0, 114.0, 94.6, 65.3, 56.2, 56.1, 55.2, 54.8, 42.0, 41.1,
39.9, 37.3, 37.0, 33.4, 33.1, 25.7, 22.7, 22.1, 21.7, 18.9, 18.5, 15.6, 14.7;
EIHRMS: calcd for C29H44O3Na (MþNa): 463.3183, found 463.3173.
131.7, 131.3, 129.1, 124.2, 114.8, 97.6, 94.3, 67.9, 67.1, 62.3, 56.4, 56.3,
54.8, 42.8, 41.8, 39.7, 38.5, 37.6, 33.4, 33.2, 30.5, 25.4, 22.6, 21.9, 21.6,
19.4, 18.5, 18.4, 15.8, 15.6; EIHRMS: calcd for C34H50O5Na (MþNa):
561.3550, found 561.3552.
4.7. Oxidation of 12 with PDC to yield 13
4.4. Reaction of 7 with CS2 to yield 11
To a solution of 12 (17 mg, 0.04 mmol) in DMF (1 mL), PDC
(105 mg, 0.28 mmol) was added, and it was stirred under argon
atmosphere for 14 h at room temperature. Then it was cooled with
ice and water was added. After extraction with EtOAc, the organic
phase was dried over Na2SO4 and the solvent was evaporated,
yielding 13 (23 mg, 100% yield).
To a solution of 7 (11 mg, 0.02 mmol) in THF (0.45 mL), cooled to
ꢀ78 ꢁC, sodium hexamethyldisylazide (1.0 M in THF, 0.68 mL,
0.68 mmol) was added under argon atmosphere. The reaction
mixture was stirred for 30 min at 0 ꢁC and then CS2 (0.1 ml,
1.71 mmol) was added. The reaction mixture is stirred for 2.5 h
longer and after this time MeI (0.1 ml, 1.18 mmol) was added. It was
allowed to stir during 2 h and then it was quenched with ice and
extracted with EtOAc. The organics were washed with HCl 0.5 M
and brine, dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by chromatography on silica gel
affording the desired compound 11 as an oil (16 mg, 100% yield).
4.7.1. Compound 13. 1H NMR (200 MHz)
d: 9.9 (1H, s), 7.82 (1H, d,
J¼2.0 Hz), 7.65 (1H, dd, J¼8.0, 2.0 Hz), 7.18 (1H, d, J¼8.0 Hz), 5.35
(1H, s), 5.29 (2H, s), 3.50 (3H, s), 2.70 (1H, dd, J¼15.2, 9.6 Hz), 2.59
(1H, dd, J¼15.2, 1.6 Hz), 2.47 (1H, dd, J¼9.6, 1.6 Hz), 2.01e0.85 (14H,
m), 1.39 (3H, s), 0.91 (3H, s), 0.89 (3H, s), 0.88 (3H, s), 0.83 (3H, s).
4.8. Oxidation of 13 with NaClO2 to yield 14
4.4.1. Compound 11. IR (film): 2924,1496,1441,1198,1059, 812, 668,
655 cmꢀ1; 1H NMR (400 MHz)
d: 7.65 (1H, d, J¼8.8 Hz), 7.15 (1H, dd,
To a solution of 13 (22 mg, 0.05 mmol) in t-BuOH (0.65 mL) and 2-
metyl-2-butene (0.13 mL), 0.18 mL of a solution of NaH2PO4 (6 g in
44 mL H20) and NaClO2 5% (0.12 mL, mmol) were added. The solution
was stirred for 2 h at room temperature. After this time it was acid-
ulated with HCl 2 N and extracted with Et2O. The organics were
washed with water and dried over Na2SO4. After removal of the sol-
vent, compound14 (19 mg, 86%yield)wasobtained asacolourlessoil.
J¼8.8, 2.2 Hz), 7.05 (1H, d, J¼8.8 Hz), 5.57 (1H, s), 5.25(1H, s), 5.23(1H,
s), 4.68 (1H, d, J¼11.8 Hz), 4.64 (1H, m), 4.44 (1H, d, J¼11.8 Hz), 3.90
(1H, m), 3.56 (1H, m) 3.50 (3H, s), 2.65 (1H, s), 2.40 (1H, m), 2.36 (3H,
s), 1.85e0.85 (19H, m), 1.64 (3H, s), 1.35 (1H, m) 1.04 (3H, s), 0.91 (3H,
s), 0.87 (3H, s), 0.83 (3H, s); 13C NMR (100 MHz)
d: 189.2,153.6,132.5,
132.0, 130.7, 130.4, 127.8, 126.6, 113.2, 96.9, 93.8, 68.3, 62.1, 59.1, 56.6,
56.2, 55.9, 42.5, 41.8, 41.6, 40.1, 38.9, 37.4, 33.4, 33.1, 30.6, 25.5, 24.9,
22.6, 21.6, 19.4, 19.0, 18.5, 16.2, 15.9, 13.0; EIHRMS: calcd for
C36H54O5S2Na (MþNa): 653.3305, found 653.3327.
4.8.1. Compound 14. IR (film): 2928, 2852, 1686, 1604,1499,1265,
1080, 923, 735 cmꢀ1
;
1H NMR (400 MHz)
d
: 8.03 (1H, d, J¼1.9 Hz),
7.09 (1H, dd, J¼8.6, 1.9 Hz), 7.10 (1H, d, J¼8.6 Hz), 5.35 (1H, s), 5.27
(2H, s), 3.51 (3H, s), 2.79 (1H, dd, J¼15.5, 9.6 Hz), 2.62 (1H, dd,
J¼15.5, 1.6 Hz), 2.45 (1H, dd, J¼9.6, 1.6 Hz), 2.05e0.85 (14H, m),
1.40 (3H, s), 0.91 (3H, s), 0.89 (3H, s), 0.89 (3H, s), 0.82 (3H, s),
4.5. Reaction of 11 with n-Bu3SnH to yield 10
To a solution of 11 (18 mg, 0.03 mmol) in toluene (0.44 mL),
AIBN (1 mg, 0.027 mmol) and n-Bu3SnH (0.1 ml, 0.37 mmol) were
added. The reaction mixture was stirred under argon atmosphere
and at 120 ꢁC for 1.5 h. Then it was cooled down and directly sub-
jected to chromatography on silica gel to obtain 10 (10 mg, 67%) as
a colourless oil.
COOH not observable; 13C NMR (100 MHz)
d: 171.7, 159.3, 135.0,
133.0, 131.6, 129.3, 122.3, 122.1, 113.0, 94.2, 56.4, 56.0, 55.1, 54.5,
41.1, 41.9, 39.9, 37.3, 37.0, 33.4, 33.1, 25.7, 22.7, 22.2, 21.7, 18.9, 18.6,
15.6, 14.7; EIHRMS: calcd for C29H42O4Na (MþNa): 477.2975,
found 477.2958.
4.5.1. Compound 10. 1H NMR (200 MHz)
d
: 7.10 (1H, d, J¼1.8 Hz), 7.10
4.9. Reaction of 14 with HCl 6 M to yield makassaric acid
(1H, dd, J¼1.8, 8.8 Hz), 7.02 (1H, d, J¼8.8 Hz), 5.37 (1H, s), 5.19 (2H, s),
4.70 (1H, d, J¼11.8 Hz), 4.69 (1H, m), 4.45 (1H, d, J¼11.8 Hz), 3.90 (1H,
m), 3.57 (1H, m)3.48(3H, s), 2.77 (1H, dd, J¼14.0, 8.0 Hz), 2.60(1H, dd,
To a solution of 14 (20 mg, 0.04 mmol) in THF (0.5 mL), 0.5 mL
of HCl 6 M were added and the reaction mixture was stirred for

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P. Basabe et al. / Tetrahedron 66 (2010) 6008e6012
4 h at 50 ꢁC. When the reaction finished it was allowed to reach
room temperature and then poured over a saturated solution of
NaCl. The mixture was extracted with EtOAc. The organic phase
was dried over Na2SO4 and the solvent was evaporated. The crude
was purified by chromatography on silica gel to afford 3 (12 mg,
65% yield). The data were coincident with the ones of
(þ)-makassaric acid.
References and notes
1. Carroll, J.; Jonsson, E. N.; Ebel, R.; Hartman, M. S.; Holman, T. R.; Crews, P. J. Org.
Chem. 2001, 66, 6847.
2. Tanada, Y.; Mori, K. Eur. J. Org. Chem. 2003, 848.
3. Arima, Y.; Kinoshita, M.; Akita, H. Tetrahedron: Asymmetry 2007, 18, 1701.
4. Basabe, P.; Diego, A.; Delgado, S.; Díez, D.; Marcos, I. S.; Urones, J. G. Tetrahedron
2003, 59, 9173.
5. Williams, D. E.; Tellier, J. B.; Liu, J.; Tahir, A.; Van Soest, R.; Andersen, R. J. J. Nat.
Prod. 2004, 67, 2127.
6. Zang, J.; Shen, B.; Lin, A. Trends Pharmacol. Sci. 2007, 28, 286.
7. (a) Kumar, S.; Boehm, J.; Lee, J. C. Nat. Rev. Drug Discov. 2003, 2, 717; (b) Zarubin,
T.; Han, J. Cell. Res. 2005, 15, 11; (c) Kratcht, M.; Saklatvala, J. Cytokine 2002, 20,
91; (d) Schnieven, G. L. Curr. Top Med. Chem. 2005, 5, 921; (e) Saklatvala, J. Curr.
Opin. Pharmacol. 2004, 4, 372.
20
20
4.9.1. Makassaric acid (3). [
0.2, MeOH); IR (film): 3368, 2927, 2850, 1683, 1603, 1442, 1385,
1276 cmꢀ1 1H NMR (400 MHz)
a
]
þ6.5 (c 0.2, CHCl3); [
a
]
þ8.5 (c
D
D
;
d
: 8.02 (1H, d, J¼1.8 Hz), 7.82 (1H,
dd, J¼8.3, 1.8 Hz), 6.78 (1H, d, J¼8.3 Hz), 5.36 (1H, s), 2.67 (1H, dd,
J¼15.0, 9.5 Hz), 2.64 (1H, d, J¼15.0 Hz), 2.47 (1H, s), 2.05e0.85 (14H,
m), 1.41 (3H, s), 0.92 (3H, s), 0.89 (3H, s), 0.89 (3H, s), 0.82 (3H, s),
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signals for COOH and OH are not visible; 13C NMR (100 MHz)
d:
171.3, 158.2, 134.7, 132.3, 130.1, 129.3, 122.5, 121.5, 115.1, 56.0, 55.0,
54.1, 41.9, 41.1, 39.8, 37.2, 37.0, 33.4, 33.1, 25.7, 22.7, 22.3, 21.7, 18.9,
18.5, 15.6, 14.7; EIHRMS: calcd for C27H38O3 (Mþ): 410.2743, found
410.2748.
Acknowledgements
The authors would like to thank Junta de Castilla y León for the
financial support (GR178 and SA063A07), MICINN (CTQ2009-
11557) and for the doctoral fellowships awarded to A.B. and O.B.