First asymmetric synthesis of CJ-14877 and its enantiomer and their interleukin-1β inhibitory activities

Article abstract of DOI:10.1016/j.bmcl.2009.02.064

A potent antiinflammatory methyl picolinate alkaloid CJ-14877 [(+)-1] and its enantiomer (-)-1 were synthesized in two steps starting from commercially available methyl 5-bromopicolinate. The synthesis includes microwave-assisted Suzuki coupling reaction

Full text of DOI:10.1016/j.bmcl.2009.02.064

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1876–1878
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Bioorganic & Medicinal Chemistry Letters
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First asymmetric synthesis of CJ-14877 and its enantiomer and their
interleukin-1b inhibitory activities
Yutaka Aoyagi a, Yoshiyuki Adachi b, Shunta Akagi a, Naohito Ohno b, Koichi Takeya a,
*
a Natural Products and Medicinal Chemistry, School of Pharmacy, Tokyo University of Pharmacy & Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
b Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy & Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A potent antiinflammatory methyl picolinate alkaloid CJ-14877 [(+)-1] and its enantiomer (À)-1 were
synthesized in two steps starting from commercially available methyl 5-bromopicolinate. The synthesis
includes microwave-assisted Suzuki coupling reaction and Sharpless asymmetric dihydroxylation.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 23 January 2009
Revised 17 February 2009
Accepted 18 February 2009
Available online 21 February 2009
Keywords:
CJ-14877
Antiinflammatory
Interleukin-1b inhibitory activities
Suzuki coupling
Sharpless asymmetric dihydroxylation
A methyl picolinate derivative having a C3 unit on C-5, CJ-14877
[(+)-1], and its family (2–4) are potent cytokine inhibitors isolated
from a fermentation broth of a fungus basidiomycetes (Fig. 1).1
Isolation of (+)-1 was reported also from a culture filtrate of a fun-
gus, Hirsutella nivea BCC 2594, a pathogen of insects.2 These com-
pounds are shown to inhibit lipopolysaccharide (LPS)-induced
production of interleukin-1b without decreasing the leucine
uptake.1 However, the structure–activity relationship is not known
yet. To obtain new antiinflammatory drugs of this series, we stud-
ied synthesis of (+)-1. We established a facile two step synthesis of
(+)-1 and its enantiomer (À)-1, by the synthetic strategy shown in
Scheme 1: stereoselective preparation of (+)-1 and its enantiomer
(À)-1 by Sharpless asymmetric dihydroxylation3 of compound 5,
which may be obtained via Suzuki coupling reaction4 between
(E)-prop-1-enylboronic acid with commercially available methyl
5-bromopicolinate (6).5
The present paper reports detailed procedure of this method.
First, the Suzuki coupling reaction of 6 with (E)-prop-1-enylboronic
acid (7) was carried out under several reaction conditions (Table 1).
A mixture of 6 and 7 was heated at 80 °C for 0.5 h under an Argon
atmosphere to give the corresponding coupling product 5 in 84%
yield (entry 6). Prolonged reaction time gave no further improve-
ment in the yield (entries 7 and 8). Recently, microwave has come
to be used as an efficient heating procedure.6 A microwave-as-
sisted Suzuki coupling reaction was described by Sharma et al.,7
which we applied to the present scheme. When the reaction
mixture was heated by means of microwave at 140 °C for 5 min,
the reaction proceeded to give the corresponding coupling product
5 in 87% yield (entry 15).8 When (Z)-prop-1-enylboronic acid (8)
was employed as the substrate, the coupling product 9 was
obtained in 93% yield (entry 16). By the Sharpless asymmetric
dihydroxylation (AD) of the coupling product 5 using AD-mix-a 9
,
diol (+)-1 was obtained in quantitative yield,10 whose spectral
and physical data were identical to those of natural (+)-1. The
OH
OH
OH
O
OAc
O
N
N
O
O
1
CJ-14877 [(+)- ]
CJ-14897 ( )
2
OAc
OH
OAc
O
OH
OH
N
N
O
O
CJ-15336 ( )
1
3
CJ-14877 [(+)- ]
* Corresponding author. Tel.: +81 426 76 3007; fax: +81 426 77 1436.
E-mail address: takeyak@ps.toyaku.ac.jp (K. Takeya).
Figure 1. Natural cytokine production inhibitors CJ-14877 [(+)-1] and their
analogues.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.064

Y. Aoyagi et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1876–1878
1877
Table 2
OH
IL-1b production inhibitory activity (%) induced with LPS
AD-mix-α
AD-mix-β
Compounds
Concentration (
0.1
lM)
OH
O
0.01
1.0
10
N
O
1
(+)-1
(À)-1
À9.5
13.8
4.3
39.6
10.6
49.8
À7.5
9.1
O
CJ-14877 [(+)- ]
N
OH
O
5
OH
N
O
Suzuki coupling
O
1
(-)-
Br
O
O
N
methyl 5-bromopicolinate (6)
Scheme 1. Synthetic strategy for preparation of (+)-1 and its enantiomer (À)-1
from 6.
Figure 2. Effect of (+)-1 and its enantiomer (À)-1 on IL-1b production induced with
LPS (100 ng).
When AD-mix-b9 was employed as an oxidant in the dihydroxyla-
tion reaction of 5, instead of AD-mix-
obtained also in very high yield and with very high enantiomeric
a
, the enatiomer (À)-1 was
excess (Scheme 2).
Scheme 2. Asymmetric dihydroxylation of 5.
The both of CJ-14877 [(+)-1] and its enantiomer [(À)-1] were
evaluated for inhibitory activities of LPS-stimulated IL-1b produc-
tion by human PBMC.12 The results was shown in Table 2 and
Figure 2. CJ-14877 [(+)-1] inhibited IL-1b production depending
enatiomeric excess of this product was calculated by using the
chiral column OD-HPLC system and was shown to be 97% ee.11
Table 1
Palladium-mediated coupling reactions of methyl 5-bromopicolinate (6) with (E)- or (Z)-prop-1-enylboronic acids (7 or 8)
Br
Suzuki Coupling
+
B
OH
O
O
10 mol% Pd(PPh3)4
K2CO3 (3 eq.) / DMF
N
N
OH
6
O
O
7 (E)
8 (Z )
5 (E )
9 (Z )
Entriesa
Boronic acids (3.0 equiv)
Reaction temp (°C)
Reaction time (h)
Products
Yields (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
8
rt
rt
50
50
5
24
1
5
5 min
0.5
1
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
9
70 (12)b
65 (15)b
58 (28)b
87
50 (MW)c
80
20 (61)b
84
80
80
85
85
5
80 (MW)c
80 (MW)c
120 (MW)c
120 (MW)c
120 (MW)c
130 (MW)c
140 (MW)c
140 (MW)c
5 min
5 min  2
5 min
10 min
5 min  2
5 min
5 min
5 min
43 (46)b
53 (26)b
73 (20)b
88 (5)b
87
80 (5)b
87 (1)b
93
a
Ref. 8.
b
c
The yields in parenthesis means the recovery of the starting material.
MW: microwave irradiation.

1878
Y. Aoyagi et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1876–1878
0.28 mmol), and dry DMF (1.0 mL) was heated at 140 °C by using
a
on the substrate level and the inhibition ratio was 49.8% at 10
On the other hand, its enantiomer [(À)-1] showed no IL-1b produc-
tion inhibitory activity at 10 M. That indicated that the stereo-
chemistry on C-7 and C-8 of compound 1 are important on the
activity.
In summary, an effective and facile two step synthesis of
CJ-14877 ((+)-1) and its enantiomer [(À)-1] from commercially
available methyl 5-bromopicolinate (6) was successfully estab-
lished for the first time. Preparation of a series of synthetic
analogues is now in progress.
lM.
microwave apparatus (at 2.45 GHz, Discover, CEM Co., North Carolina, USA)
for 5 min. After dilution with H2O (10 mL), the mixture was extracted with
AcOEt (10 mL Â 3), and the extract was washed with H2O (10 mL Â 3), dried
over MgSO4, filtered, and evaporated in vacuo to give an oily residue, which
was purified by MPLC (hexanes:AcOEt = 1:2). The yield of the resulting
coupling product 5 was 85%. Compound 5: Colorless amorphous solid, mp
67–68 °C (MeOH). 1H NMR (400 MHz, CDCl3) d 8.61 (1H, d, 2.0), 8.02 (1H, d,
8.2), 7.71 (1H, dd, 8.2, 2.0), 6.48–6.36 (2H, m), 3.96 (3H, s), 1.91 (3H, d, 5.0). 13C
NMR (100 MHz, CDCl3) d 165.6 (s), 147.6 (d), 145.6 (s), 136.6 (s), 132.9 (d),
131.3 (d), 126.8 (d), 125.0 (d), 52.7 (q), 18.7 (q). IR (film): mmax 1738 (C@O),
1708 (C@C) cmÀ1. HRMS (ESI): Calculated for C10H12NO2 (M++H): 178.0868.
Found: 178.0860. Compound 9: Colorless viscous oil. 1H NMR (500 MHz, CDCl3)
d 8.67 (1H, d, 1.7), 8.11 (1H, d, 6.6), 7.74 (1H, dd, 6.6, 1.7), 6.44 (1H, m), 6.05
(1H, dq, 9.4, 5.8), 4.01 (3H, s), 1.93 (3H, dd, 5.8, 1.4). 13C NMR (125 MHz, CDCl3)
d 165.7 (s), 150.0 (d), 145.4 (s), 136.7 (s), 136.4 (d), 131.6 (d), 125.6 (d), 124.7
l
Acknowledgments
(d), 52.8 (q), 14.8 (q). IR (film):
Calculated for C10H12NO2 (M++H): 178.0868. Found: 178.0870.
9. AD-mix- and -b (Cat. No. 392758-10G and 392766-10G) were purchased from
m
max 1741 (C@O), 1721 (C@C) cmÀ1. HRMS (ESI):
This work was supported by a Grant-in-aid for Scientific
Research (C) from the Ministry of Education, Culture, Sports, Sci-
ence, and Technology of Japan.
a
Aldrich Co. (MI).
10. General procedure for Sharpress asymmetric dihydroxylation:
A mixture of
compound
5 (0.03 g, 0.169 mmol), AD-mix-a (0.237 g, 0.169 mmol), and
AcNH2 (0.016 g, 0.169 mmol) in tBuOH–H2O (1:1, 2.1 mL) was stirred at
room temperature for 6 h. After addition of satd Na2SO3 (10 mL), the mixture
was extracted with AcOEt (10 mL Â 3), and the extract was dried over MgSO4,
filtered, and evaporated in vacuo to give an oily residue, which was purified by
MPLC (CHCl3/MeOH = 15:1) to give (+)-1 in a quantitative yield. The spectral
and physical data of the product were identical to those of natural CJ-14877
reported by Ichikawa et al.1
References and notes
1. Ichikawa, K.; Hirai, H.; Ishiguro, M.; Kambara, T.; Kato, Y.; Kim, Y. J.; Kojima, Y.;
Matsunaga, Y.; Nishida, H.; Shiomi, Y.; Yoshikawa, N.; Kojima, N. J. Antibiot.
2001, 54, 703.
2. Isaka, M.; Palasarn, S.; Sriklung, K.; Kocharin, K. J. Nat. Prod. 2005, 68, 1680.
3. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
4. Suzuki, A. Chem. Commun. 2005, 4759. and the references cited therein..
5. Methyl 5-bromopicolinate (5) was purchased from Combi-Blocks Co. (Cat. No.
CA-4117). The starting material can also be prepared by the procedure reported
by Song et al. (J. Org. Chem. 2001, 66, 605.).
6. Lidström, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
and the references cited therein..
7. Sharma, A. K.; Gowdahalli, K.; Krzeminski, J.; Amin, S. J. Org. Chem. 2007, 72,
8987.
11. The percentage of enantiomeric excess (% ee) values of (+)- and (À)-1 were
calculated on the basis of HPLC analysis. (Analytical conditions: column:
CHIRALCEL OD-H (Daisel Co., Ltd, 0.46 Â 15 cm), elution: n-hexane–iPrOH
(85:15), at flow rate of 0.6 mL/min, detection: UV (270 nm)). Retention time
(tR): 29.0 min for [(+)-1]; 33.6 min for [(À)-1].
12. Human peripheral blood mononuclear cells (PBMC) in RPMI1640 medium
containing 10% fetal bovine serum were cultured with various concentration of
the compounds in the presence of 100 ng/ml lipopolysaccharides (LPS, E. coli
B4) for 24 h. The human IL-1b concentration in the culture supernatant was
measured by ELISA in accordance with the protocol of the manufacturer
(eBioscience, Inc.).
8. General procedure for microwave-assisted Suzuki coupling reaction: A mixture of
methyl 5-bromopicolinate (0.02 g, 0.093 mmol), (E)-prop-1-enylboronic acid
(0.023 g, 0.28 mmol), Pd(PPh3)4 (0.01 g, 0.0093 mmol), K2CO3 (0.039 g,