LETTER
New Methodologies for the Synthesis of 3-Acylpyridone Metabolites
PhD Thesis; Loughborough University: UK, 2008.
657
logue of the natural product pretenellin B, a biosynthetic
precursor of tenellin (2a) isolated from B. bassiana, and
20a is a lower homologue.7 Interestingly, B. bassiana has
been shown to demonstrate chain length infidelity, and a
3-acyltetramic acid with the side chain of 20a, prototenel-
lin B, has been isolated.
(9) For our first-generation approach, see: (a) Jones, R. C. F.;
Bhalay, G.; Carter, P. A.; Duller, K. A. M.; Dunn, S. H.
J. Chem. Soc., Perkin Trans. 1 1999, 765. (b) Jones, R. C.
F.; Duller, K. A. M.; Vulto, S. I. E. J. Chem. Soc., Perkin
Trans. 1 1998, 411. (c) Jones, R. C. F.; Duller, K. A. M.
ARKIVOC 2002, (viii), 34.
(10) (a) Natale, N. R.; McKenna, J. I.; Niou, C.; Borth, M. J. Org.
Chem. 1985, 50, 5660. (b) Grünanger, P.; Vita-Finzi, P.
Isoxazoles: The Chemistry of Heterocyclic Compounds, Part
1, Vol. 49; Wiley-Interscience: New York, 1991, 324.
(11) Stork, G.; McMurry, J. E. J. Am. Chem. Soc. 1967, 89, 5461.
(12) Phan, X. T.; Shannon, P. J. J. Org. Chem. 1983, 48, 5164.
(13) Typical Procedure
Synthesis of 3-Methyl-7-phenyl-5H-isoxazolo[4,3-
c]pyridin-4-one (12a)
Pd(PPh3)4 (4.2 mg, 0.004 mmol) was added to degassed 1,4-
dioxane (10 mL), followed by iodopyridone 11 (20 mg, 0.07
mmol). The solution was purged with N2 for 10 min at 23 °C.
Phenylboronic acid (13 mg, 0.1 mmol) in EtOH (10 mL) and
aq Na2CO3 (2 M, 0.02 mL, 0.14 mmol) were degassed with
N2, and added sequentially. The mixture was heated at reflux
for 18 h under an N2 atmosphere, cooled, H2O (50 mL)
added, and the mixture was extracted with EtOAc (3 × 50
mL). The combined organic layers were washed with brine
(50 mL), dried (MgSO4), filtered, and evaporated under
reduced pressure to a brown oil purified by silica column
chromatography eluting with EtOAc–light PE (bp 40–
60 °C) (1:1 v/v) to leave title compound 12a, white solid (10
mg, 67%); mp 253.5–254 °C. IR (CH2Cl2): nmax = 3245,
2959, 1676, 1629, 1404 cm–1. 1H NMR (400 MHz, CDCl3):
d = 2.86 (3 H, s, CH3), 7.33 (1 H, d, J = 6.0 Hz, NHCH), 7.36
(1 H, t, J = 7.2 Hz, ArCH), 7.43 (2 H, m, ArCH), 7.75 (2 H,
d, J = 7.2 Hz, ArCH), 8.72 (1 H, br, NH). 13C NMR (100
MHz, CDCl3): d = 13.0 (CH3), 108.6, 112.5 (2 × C), 127.3,
128.0, 128.8, 129.1 (4 × CH), 133.2, 158.8, 161.7, 174.2
(4 × C). HRMS–FAB: m/z calcd for C13H11N2O2: 227.0822;
found: 227.0825 [MH+].
Figure 3 X-ray crystal structure of reduction product 19 (disorder
in phenyl ring; crystallographic numbering)
We have thus demonstrated a flexible route to elaboration
of a core isoxazolo[4,3-c]pyridin-2-one scaffold, as
masked forms of diverse 3-acylpyridin-2-ones of biologi-
cal interest. Further studies towards natural and unnatural
derivatives are ongoing.
Acknowledgment
We thank the Open University (studentship to G.L.), Loughborough
University (studentships to C.L. & A.K.C.) and Syngenta for addi-
tional support (A.K.C.), Dr. N. B. Carter for helpful discussions,
and the EPSRC Mass Spectrometry Service Centre (Swansea) for
some high-resolution MS data.
References and Notes
(14) Typical Procedure
Synthesis of 3-(2-Phenylethenyl)-5H-isoxazolo[4,3-
c]pyridin-4-one (14a)
(1) (a) El Basyouni, S. H.; Brewer, D.; Vining, L. C. Can. J. Bot.
1968, 46, 441. (b) Wat, C.-K.; McInnes, A. G.; Smith, D. G.
Can. J. Chem. 1977, 55, 4090.
(2) Cheng, Y.; Schneider, B.; Riese, U.; Schubert, B.; Li, Z.;
Hamburger, M. J. Nat. Prod. 2004, 67, 1854.
(3) (a) Schmidt, K.; Gunther, W.; Stoyanova, S.; Schubert, B.;
Li, Z.; Hamburger, M. Org. Lett. 2002, 4, 197. (b) Schmidt,
K.; Riese, U.; Li, Z.; Hamburger, M. J. Nat. Prod. 2003, 66,
378.
(4) (a) Takahashi, S.; Kakinuma, N.; Uchida, K.; Hashimoto, R.;
Yanagisawa, T.; Nakagawa, A. J. Antibiot. 1998, 51, 596.
(b) Takahashi, S.; Kakinuma, N.; Uchida, K.; Hashimoto,
R.; Yanagisawa, T.; Nakagawa, A. J. Antibiot. 1998, 51,
1051.
To 3-methyl-5H-isoxazolo[4,3-c]pyridin-4-one (6, 100 mg,
0.66 mmol) in THF (20 mL) at –78 °C under N2 was added
BuLi (0.6 mL of a 2.5 M solution in hexanes, 1.45 mmol)
and the solution stirred for 1 h before benzaldehyde (1.0 mL,
0.99 mmol) was added. Stirring was continued for 5 min at
–78 °C, before the mixture was quenched with H2O (20 mL),
acidified with HCl (2 M, 20 mL) and extracted with EtOAc
(2 × 30 mL). The combined organic layers were washed with
brine (30 mL), dried (MgSO4), filtered, and evaporated
under reduced pressure to a yellow oil purified by silica
column chromatography, eluting with EtOAc–light PE (bp
40–60 °C) (1:1 v/v) to afford hydroxy adduct 13a (106 mg,
63%), pale yellow solid; mp 180–182 °C. IR (CH2Cl2):
(5) Matsumoto, M.; Minato, H. Tetrahedron Lett. 1976, 42,
3827.
n
max = 3395, 3131, 2962, 1675, 1643, 1457 cm–1. 1H NMR
[400 MHz, (CD3)2SO]: d = 3.55 (2 H, d, J = 7.7 Hz, CHCH2),
5.19 (1 H, m, CH2CH), 5.74 (1 H, d, J = 4.9 Hz, CHOH),
6.38 (1 H, d, J = 7.6 Hz, NHCHCH), 7.15 (1 H, dd, J = 7.6,
5.7 Hz, NHCH), 7.39–7.46 (5 H, m, ArCH), 10.15 (1 H, br,
NH). 13C NMR [100 MHz, (CD3)2SO]: d = 36.9 (CH2), 70.4,
92.6 (2 × CH), 108.5 (C), 125.6, 127.3, 128.2, 134.1 (4 ×
CH), 144.4, 157.3, 158.9, 174.8 (4 × C). HRMS (EI):
m/z calcd for C14H13N2O3: 257.0921; found: 257.0924
[MH+]. To 13a (130 mg, 0.51 mmol) in PhMe (30 mL) was
added TsOH (96 mg, 0.51 mmol) and the mixture heated at
reflux overnight under Dean–Stark conditions. Water (20
mL) was added to the cooled mixture, and it was extracted
(6) For leading references, see: Dolle, R. E.; Nicolaou, K. C.
J. Am. Chem. Soc. 1985, 107, 1691.
(7) (a) Halo, L. M.; Marshall, J. M.; Yakasai, A. A.; Song, Z.;
Butts, C. P.; Crump, M. P.; Heneghan, M.; Bailey, A. M.;
Simpson, T. J.; Lazarus, C. M.; Cox, R. J. ChemBioChem
2008, 9, 585. (b) Halo, L. M.; Heneghan, M. N.; Yakasai,
A. A.; Song, Z.; Williams, K.; Bailey, A. M.; Cox, R. J.;
Lazarus, C. M.; Simpson, T. J. J. Am. Chem. Soc. 2008, 130,
17988.
(8) (a) Jones, R. C. F.; Dawson, C. E.; O’Mahony, M. J.; Patel,
P. Tetrahedron Lett. 1999, 40, 4085. (b) Jones, R. C. F.;
Pillainayagam, T. A. Synlett 2004, 2815. (c) Law, C. C. M.
Synlett 2010, No. 4, 654–658 © Thieme Stuttgart · New York