A concise synthesis of fusaric acid and (S)-(+)-fusarinolic acid

Full text of DOI:10.1021/jo0013554

J . Org. Chem. 2001, 66, 605-608
605
Notes
A Con cise Syn th esis of F u sa r ic Acid a n d
(S)-(+)-F u sa r in olic Acid †
J inhua J . Song* and Nathan K. Yee
Department of Chemical Development, Boehringer Ingelheim
Pharmaceuticals, Inc., 900 Old Ridgebury Road,
P.O. Box 368, Ridgefield, Connecticut 06877-0368
F igu r e 1.
compounds 1 and 2, the reported syntheses generally
consisted of 5-10 steps. Most of them employed harsh
reaction conditions, low-temperature operations, and
undesirable reagents such as SeO2,8f KMnO4,8g,i NH2-
NH2,8c and Mg amalgam,8g which are not suitable for
large-scale synthesis.
The objective of this study was to develop a concise
and practical synthesis of these natural products and
their analogues to facilitate further pharmaceutical
evaluations. This has led us to devise a flexible synthetic
strategy, which employs the 2,5-dihalopyridine as a
template (Scheme 1). We envisioned that the sequential
coupling at C(2) and C(5) positions of the pyridine
ring would enable us to establish a unified and flex-
ible route to a range of fusaric acid derivatives. In
this paper, we wish to describe a concise synthesis of
fusaric acid and (S)-(+)-fusarinolic acid with a selective
carbonylation reaction of 2,5-dihalopyridine as the key
step.
jsong@rdg.boehringer-ingelheim.com
Received September 13, 2000
In tr od u ction
The 5-substituted-2-picolinic acids such as fusaric acid
(1) and (S)-(+)-fusarinolic acid (2) are a class of alkaloid
natural products with important biological activities
(Figure 1).1 In particular, fusaric acid (1) was shown to
be a potent inhibitor of dopamine â-hydroxylase in vitro
and in vivo and displayed notable antihypertensive
activity.2 Fusaric acid also exhibited marked antitumor
activity on human colon adenocarcinoma cell lines LoVo,
SW48, SW480, and SW742, as well as human mammary
adenocarcinoma cell line MDA-MB-468.3 Other biological
activities of fusaric acid and its derivatives include
neurogenic,4 wilting,5 and herbicidal activities,6 which
were summarized in a recent review article.7
To facilitate the biological investigation, a number of
synthetic approaches to fusaric acid (1) and its analogues,
including (S)-(+)-fusarinolic acid (2), have been devel-
oped.8 The target structures were either established by
construction of the pyridine ring via the Diels-Alder type
reactions8a,b,d or by elaboration of substituted pyridine
templates.8a,e-i Despite the rather simple structures of
Sch em e 1
† Dedicated to Professor Satoru Masamune for his enormous con-
tributions to organic chemistry.
Resu lts a n d Discu ssion
(1) (a) Grove, J . F.; J effs, P. W.; Mulholland, T. P. C. J . Chem Soc.
1958, 1236. (b) Steiner, K.; Graf, U.; Hardegger, E. Helv. Chim. Acta
1971, 54, 845.
(2) (a) Nagatsu, T.; Hidaka, H.; Kuzuya, H.; Takeya, K.; Umezawa,
H.; Takeuchi, T.; Suda, H. Biochem. Pharmacol. 1970, 19, 35. (b)
Hidaka, H.; Nagatsu, T.; Takeya, K. J . Antibiot. 1969, 22, 228. (c) Suda,
H.; Takeuchi, T.; Nagatsu, T.; Matsuzaki, M.; Matsumoto, I.; Umezawa,
H. Chem. Pharm. Bull. 1969, 17, 2377. (d) Langhals, E.; Langhals,
H.; Ruchardt, C. Liebigs Ann. Chem. 1982, 930.
(3) (a) Vesonder, R. F.; Gasdorf, H.; Peterson, R. E. Archiv. Environ.
Contam. Toxicol. 1993, 24, 473. (b) Fernandez-Pol, J . A.; Klos, D. J .;
Hamilton, P. D. Anticancer Res. 1993, 13, 57.
(4) (a) Rimando, A. M.; Porter, J . K. J . Toxicol. Environ. Health
1997, 50, 275. (b) Porter, J . K.; Bacon, C. W.; Wray, E. M.; Hagler, W.
M., J r. Nat. Toxins 1995, 3, 91. (c) Amano, H.; Goshima, Y.; Akema,
N.; Ueda, H.; Kubo, T.; Misu, Y. J . Pharmacobio-Dynamics 1989, 1,
18.
We first examined the possibility to use the com-
mercially available 2,5-dibromopyridine (3, Table 1) as
the template. The carbonylation reaction of 2,5-dibro-
mopyridine was previously reported to provide 5-bro-
mopyridine-2-carboxylic acid methyl ester (4) in 65%
yield after chromatography but the formation of diester
(5) was not mentioned.9 We repeated these experiments
and noticed that diester (5) was an unavoidable byprod-
uct under these reaction conditions. Presumably the
diester was formed through the further carbonylation of
the monoester via a sequential mechanism.10 In a typical
reaction, a mixture of compounds 4 and 5 was obtained
in a ratio of ∼6:1 at 88% conversion (Table 1, entry 1).
Isolation of the desired monoester from the mixture of
monoester, diester and unreacted starting material en-
tailed tedious chromatography, thus resulting in low
synthetic efficiency. When Pd(PPh3)2Cl2 was used as the
(5) Gaeumann, E.; Naef-Roth, S.; Kobel, H. Phytopath. Ztschr. 1952,
20, 1.
(6) Capasso, R.; Evidente, A.; Cutignano, A.; Vurro, M.; Zonno, M.
C.; Bottalico, A. Phytochemistry 1996, 41, 1035.
(7) Wang, H.; Ng, T. B. Life Sci. 1999, 65, 849.
(8) (a) Renslo, A.; Danheiser, R. L. J . Org. Chem. 1998, 63, 7840.
(b) Sagi, M.; Amano, M.; Konno, S.; Yamanaka, H. Heterocycles 1989,
29, 2249. (c) Reference 1a. (d) Waldner, A. Synth. Commun. 1989, 19,
2371. (e) Reference 2d. (f) Vogt, H.; Mayer, H. Tetrahedron Lett. 1966,
5887. (g) Tschesche, R.; Fuehrer, W. Chem. Ber. 1978, 111, 3502. (h)
Hardegger, E.; Nikles, E. Helv. Chim. Acta 1957, 40, 1016. (i) Plattner,
Pl. A.; Keller, W.; Boller, A. Helv. Chim. Acta 1954, 37, 1379.
(9) Chambers, R. J .; Marfat, A. Synth. Commun. 1997, 515.
(10) Diester formation (10%) was also observed in the Pd(PPh3)2Cl2
mediated carbonylative ester formation from 2,5-dibromo-3-methylpy-
ridine: Wu, G. G.; Wong, Y.-S.; Poirier, M. Org. Lett. 1999, 1, 745.
10.1021/jo0013554 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/30/2000

606 J . Org. Chem., Vol. 66, No. 2, 2001
Notes
Ta ble 1.
isolated yield
entry
X
ROH
conditions
time (h)
mono/di
(mono) (%)
1
2
3
4
5
6
7
8
Br
Br
Br
Br
I
I
I
I
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
PhCH2OH
Pd(OAc)2/dppfa/TEA/CH3CN/CO(60 psi)/60 °C
Pd(PPh3)2Cl2/TEA/CH3CN/CO(60 psi)/60 °C
Pd(PPh3)2Cl2/TEA/CH3CN/CO(60 psi)/60 °C
Pd(OAc)2/2,2′-dipyridyl/DBU/toluene/CO(60 psi)/65 °C
Pd(OAc)2/dppfa/TEA/CH3CN/CO(60 psi)/60 °C
Pd(OAc)2/2,2′-dipyridyl/DBU/toluene/CO(60 psi)/65 °C
Pd(PPh3)2Cl2/TEA/CH3CN/CO(60 psi)/60 °C
Pd(PPh3)2Cl2/TEA/CH3CN/CO(60 psi)/60 °C
8
15
48
46
6
46
15
15
6:1b
24:1
14:1
mono only
mono only
mono only
mono only
mono only
63
(50)c
(75)c
(<5)c
70
(10)c
97
93
a
b
dppf ) 1,1′-bis(diphenylphosphino)ferrocene. Ratio at 88% conversion. c Conversion measured by 1H NMR.
catalyst, the reaction was much slower and proceeded to
only 50% conversion after 15 h (4:5 ) 24:1, entry 2).
Prolonged heating led to the formation of more diester
(4:5 ) 14:1 at 75% conversion, entry 3). Recently, Wu et
al. reported that 2,2′-dipyridyl was an effective ligand
for the selective carbonylative amide formation from
2,5-dibromo-3-methylpyridine.10 Unfortunately, this
system was not successful when it was applied to
the carbonylative ester formation from 2,5-dibromo-
pyridine and the conversion was less than 5% even after
46 h (entry 4). This result was not surprising consider-
ing that the carbonylative amide formation is usually
more facile than the corresponding ester formation
due to the better nucleophilicity of amines than alco-
hols.10
To avoid the diester byproduct and to achieve a better
yield in the carbonylative ester formation reactions, we
turned our attention to 5-bromo-2-iodopyridine (6, Table
1). Despite its obvious advantages and potential utility,
this compound has not been employed in organic syn-
thesis and it was only briefly mentioned in one report.11
This compound was prepared in very low yield (∼30%)
by treatment of 2,5-dibromopyridine with refluxing HI,
but no experimental details or characterizations were
given. To secure the synthetic availability and to explore
the reactivity of this compound, we first developed an
efficient synthesis of 5-bromo-2-iodopyridine (6) via a
selective substitution reaction. Thus, when 2,5-dibromo-
pyridine (3) was heated with AcCl/NaI in refluxing
CH3CN,12 the iodo-bromo exchange occurred exclusively
at the C(2) position to furnish compound 6 in crystal-
line form in 85% yield without the need for chromatog-
raphy.
When 1,1′-bis(diphenylphosphino)ferrocene (dppf) was
used as the supporting ligand, the starting material was
completely consumed within 6 h to provide compound 4
in 70% isolated yield, along with some unidentified
byproducts. Attempts to use 2,2′-dipyridyl as the ligand
resulted in sluggish reactions (∼10% conversion after 46
h). To our delight, the use of Pd(PPh3)2Cl2 as the catalyst
dramatically improved the performance of the reaction
and pure monoester 4 was isolated with remarkable ease
in 97% yield (entry 7). It appeared that the use of an
iodide at the C(2) position not only enhanced the rate of
the first carbonylation reaction at the C(2) position but
also helped slow the subsequent carbonylation at the C(5)
position, thus avoiding the diester formation. More
detailed mechanistic studies are underway to understand
this interesting observation. The benzyl ester 7 was
obtained in 93% yield by using similar reaction conditions
(entry 8), and it was conveniently employed in the
synthesis of fusaric acid (1) and (S)-(+)-fusarinolic acid
(2). The benzyl ester was chosen for our synthesis because
this group can be easily removed by heterogeneous
hydrogenolysis, which would allow the isolation of the
polar and highly water soluble final products (1 and 2)
via a simple filtration.13
The bromo substituent at the C(5) position of the
pyridine ring served as a convenient handle to attach a
variety of appendages via transition metal mediated
cross-coupling reactions. Thus, compound 7 was readily
coupled with BuZnCl (generated in situ from BuMgBr
and ZnCl2
) under the catalysis of Pd(PPh ) Cl to give
3
2
2
the intermediate 8 (Scheme 2).14 Removal of benzyl group
by hydrogenolysis completed the synthesis of fusaric acid
(1).
The results of the carbonylation reaction with 5-bromo-
2-iodopyridine (6) are summarized in Table 1. The
progress of the reaction and the product ratios were
assessed by 1H NMR analysis of the crude reaction
mixtures. In all cases, no diester formation was observed.
For the synthesis of (S)-(+)-fusarinolic acid (2), the
palladium-catalyzed coupling of compound 7 with the
commercially available (S)-(-)-3-butyn-2-ol (9) provided
(13) In a previously reported synthesis (see ref 8a), isolation of
compound 2 from the aqueous solution required continuous liquid-
liquid extraction due to its high solubility in water.
(14) (a) For a review, see: Erdik, E. Tetrahedron 1992, 48, 9577.
(b) Okamoto, Y.; Yoshioka, K.; Yamana, T.; Mori, H. J . Organomet.
Chem. 1989, 369, 285.
(11) (a) Lehmann, U.; Henze, O.; Schluter, A. D. Chem., Eur. J . 1999,
5, 854. (b) Baker, W.; Curtis, R. F.; Edwards, M. G. J . Chem. Soc. 1951,
83.
(12) Corcoran, R. C.; Bang, S. H. Tetrahedron Lett. 1990, 31, 6757.

Notes
J . Org. Chem., Vol. 66, No. 2, 2001 607
5-Br om o-2-iod op yr id in e (6). 2,5-Dibromopyridine (3, 100
g, 0.42 mol) was suspended in acetonitrile (500 mL) at room
temperature. Sodium iodide (94 g, 0.63 mol) and acetyl chloride
(45 mL, 0.63 mol) were added. The reaction was refluxed for 3
h and was quenched with aqueous K2CO3 solution to pH ) 8.
Ethyl acetate (1.5 L) was added to extract the organic materials.
The organic layer was washed with saturated aqueous NaHSO3
solution (500 mL) and brine (500 mL), dried over MgSO4, and
concentrated to give a mixture of 6 and 3 (90:10). Re-subjection
of this crude material to the same conditions pushed the reaction
to completion. The same workup provided compound 611a as light
brown crystals (102 g, 85%): 1H NMR (CDCl3, 400 MHz) δ 8.44
Sch em e 2
(s, 1H), 7.60 (d, J ) 8.26 Hz, 1H), 7.44 (d, J ) 8.25 Hz, 1H); 13
C
NMR (CDCl3, 100 MHz) δ 152.2, 140.7, 136.5, 121.5, 115.6; mp
112.5-113.5 °C; HRMS calcd for the [M + 1]+ 283.8572, found
283.8568.
Sch em e 3
Ca r bon yla tion Rea ction w ith 5-Br om o-2-iod op yr id in e:
5-Br om op yr id in e-2-ca r boxylic Acid Meth yl Ester (4).9,17 To
a solution of compound 6 (0.5 g, 1.76 mmol) in CH3CN (6 mL)
in an autoclave were added TEA (0.37 mL, 2.64 mmol), MeOH
(2 mL), and Pd(PPh3)2Cl2 (37 mg, 0.05 mmol). The autoclave was
sealed, purged with CO twice, and pressured at 60 psi. The
reaction mixture was stirred vigorously and heated at 60 °C for
15 h before it was concentrated to give an oil which was subjected
to flash chromatography (30% ethyl acetate/hexanes) to yield
compound 4 (369 mg, 97%): mp 99.5-100.5 °C (lit.9 mp 96-97
°C; lit.17 mp 100-101 °C).
5-Br om op yr id in e-2-ca r boxylic Acid Ben zyl Ester (7).9
This compound was synthesized similarly in 93% yield: mp
89.0-90.0 °C (lit.9 mp 86-88 °C).
Ben zyl 5-n -Bu tylp yr id in e-2-ca r boxyla te (8). To a solution
of BuMgCl (2 M/THF, 1.37 mL, 2.73 mmol) in anhydrous THF
(8 mL) at room temperature was added ZnCl2 (1 M/ether, 3.0
mL, 3.0 mmol). After the reaction mixture was stirred for 15
min, Pd(PPh3)2Cl2 (48 mg, 0.068 mmol) was added followed by
the bromide 7 (400 mg, 1.37 mmol). The reaction mixture was
stirred at room temperature for 15 h before it was carefully
quenched with HCl (1 N) to pH ) 6. The aqueous layer was
extracted with CH2Cl2 (50 mL × 2), and the combined organic
layers were dried (MgSO4), filtered, concentrated, and used
directly as crude in the next step. Flash chromatography
provided compound 8 in pure form as an oil: 1H NMR (CDCl3,
400 MHz) δ 8.57 (d, J ) 1.63 Hz, 1H), 8.05 (d, J ) 7.98 Hz, 1H),
7.61 (dd, J ) 2.21, 7.98 Hz, 1H), 7.48 (d, J ) 8.18 Hz, 2H), 7.36
(m, 3H), 5.45 (s, 2H), 2.68 (t, J ) 7.56 Hz, 2H), 1.62 (m, 2H),
1.37 (m, 2H), 0.93 (t, J ) 7.32 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 165.2, 150.2, 145.6, 142.2, 136.5, 135.8, 128.6, 128.5,
128.3, 125.0, 67.3, 32.9, 32.7, 22.2, 13.8; HRMS calcd for the [M
+ 1]+ 270.1494, found 270.1489.
compound 10 smoothly in 92% yield (Scheme 3).15 The
simultaneous hydrogenolysis of benzyl ester and the
triple bond over Pd/C furnished (S)-(+)-fusarinolic acid
(2) in excellent yield.16 As expected, the use of a hetero-
geneous hydrogenation reaction in the last step of our
synthesis simplified isolation of the extremely polar and
water-soluble final products, thus avoiding the need for
the continuous solvent-aqueous extraction that was
encountered in a previously reported synthesis.8a
Con clu sion
In summary, we have developed an expedient synthesis
of naturally occurring alkaloids fusaric acid and (S)-(+)-
fusarinolic acid, which represents the most efficient
synthesis of these compounds to date (four steps with
overall yields of 55% and 70%, respectively). This syn-
thesis is based on a unified and flexible strategy using
5-bromo-2-iodopyridine (6) as a template and is readily
applicable to analogue synthesis. The carbonylative ester
formation of compound 6 was found to occur exclusively
at the C(2) position of the pyridine ring under the
catalysis of Pd(PPh3)2Cl2 to afford the monoester in
excellent yield, without the complication of the diester
formation. In addition, we reported a greatly improved
synthesis of 5-bromo-2-iodopyridine, which makes this
compound an attractive and more available template for
organic and materials synthesis.11a
F u sa r ic Acid (1).8a The crude 8 from above reaction was
dissolved in MeOH (5 mL) followed by the addition of Pd/C (10
wt %, 70 mg). The reaction mixture was shaken under hydrogen
(40 psi) at room temperature for 4 h. Filtration of the reaction
mixture afforded the crude product, which was purified by
recrystallization from CH2Cl2 and hexanes to yield fusaric acid
1
(1) (170 mg, 70% for two steps from 8). H NMR and 13C NMR
of the synthetic material were identical to those reported for the
natural product:8a 1H NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.14
(d, J ) 7.56 Hz, 1H), 7.75 (d, J ) 7.44 Hz, 1H), 2.73 (t, J ) 7.20
Hz, 2H), 1.60-1.70 (m, 2H), 1.35-1.45 (m, 2H), 0.95 (t, J ) 7.30
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.0, 147.9, 143.1, 145.0,
138.4, 124.2, 32.9, 32.8, 22.2, 13.8.
Ben zyl 5-(3-Hyd r oxy-bu t-1-yn yl)p yr id in e-2-ca r boxyla te
(10). To a solution of the alkyne 9 (0.57 g, 8.1 mmol), bromide
7 (1.58 g, 5.4 mmol), and TEA (1.1 mL, 8.1 mmol) in anhydrous
THF (35 mL) was added Pd(PPh3)4 (312 mg, 0.27 mmol). The
reaction mixture was heated at 70 °C for 15 h. The reaction was
quenched with saturated aqueous NaHCO3 solution and ex-
tracted with CH2Cl2 (100 mL × 2). The crude material was
purified by flash column chromatography (20% ethyl acetate/
hexanes) to yield 10 (1.4 g, 92%): 1H NMR (CDCl3, 400 MHz) δ
8.76 (d, J ) 1.64 Hz, 1H), 8.07 (d, J ) 8.00 Hz, 1H), 7.82 (dd, J
) 2.00, 8.10 Hz, 1H), 7.48 (m, 2H), 7.36 (m, 3H), 5.45 (s, 2H),
Exp er im en ta l Section
Gen er a l P r oced u r es. All reactions were performed in oven-
dried glassware under argon with magnetic stirring. All com-
mercial reagents were used as received. Flash chromatography
was performed using 230-400 mesh silica gel.
(15) Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993,
34, 6403.
(16) Spectroscopic properties of synthetic materials (1 and 2) were
identical to those reported for the natural products. 1H NMR spectrum
of the Mosher ester derived from compound 10 revealed only one
diastereomer, thus confirming the stereochemical integrity of the
stereogenic center.
(17) Campbell, A. D.; Chooi, S. Y.; Deady, L. W.; Shanks, R. W. Aust.
J . Chem. 1971, 24, 385.

608 J . Org. Chem., Vol. 66, No. 2, 2001
Notes
4.79 (m, 1H), 2.10 (br.s, 1H), 1.57 (d, J ) 6.60 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 165.7, 153.5, 153.4, 147.5, 140.9, 136.7,
130.0, 129.9, 129.8, 125.9, 124.8, 99.4, 81.2, 69.1, 59.8, 25.3; mp
MHz) δ 8.53 (d, J ) 1.6 Hz, 1H), 7.94 (d, J ) 8.1 Hz, 1H), 7.78
(d, J ) 8.1 Hz, 1H), 4.30-4.80 (br s, 1H), 3.53-3.61 (m, 1H),
2.62-2.82 (m, 2H), 1.60-1.67 (q, J ) 6.2 Hz, 2H), 1.08 (d, J )
6.0 Hz, 3H); 13C NMR (CD3OD, 100 MHz) δ 167.2, 149.5, 146.9,
80.5-81.5 °C; [R]25 ) -14.0° (c 0.5, MeOH); HRMS calcd for
D
the [M + 1]+ 282.1130, found 282.1147.
144.2, 140.0, 126.3, 67.7, 41.1, 30.2, 23.7; [R]25 ) +19.5° (c 1.5,
D
(S)-F u sa r in olic Acid (2).8a To a solution of 10 (752 mg, 2.68
mmol) in MeOH (10 mL) was added Pd/C (10 wt %, 75 mg). The
reaction mixture was shaken under hydrogen (40 psi) for 6 h.
Filtration of the reaction mixture and concentration of the
filtrate afforded the final product 28a (500 mg, 96%). 1H NMR
and 13C NMR of the synthetic material were identical to those
reported for the natural product:8a 1H NMR (DMSO-d6, 400
MeOH) [lit.8a [R]25 +20.5° (c 1.05, MeOH)].
D
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 6, 8 and 10. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0013554