Journal of Natural Products
Note
18.3, 16.2, −4.3; HRESIMS m/z 291.1781 [M + H]+ (calcd for
C17H27O2Si, 291.1780).
S. aureus. The more potent natural product, anaephene B (2),
displayed MIC values of 8 μg/mL against both B. cereus and S.
aureus. These MIC values are in line with those previously
reported by the isolation group.5 In addition, we demonstrated
that compounds 1 and 2 are active against MRSA, with MIC
values of 16 and 8 μg/mL, respectively. These results provide
evidence that this class of molecules serves as an excellent
starting point for the development and optimization of novel
antimicrobial agents effective against drug-resistant bacteria.
5-(3-((tert-Butyldimethylsilyl)oxy)phenyl)pentanal (7). To a
solution of 6 (325 mg, 1.12 mmol) in anhydrous EtOH (3.5 mL) was
added 10% palladium on carbon (25.0 mg, 0.0231 mmol), and the
flask was equipped with a H2 balloon. The reaction was then stirred at
rt for 48 h. The palladium on carbon was removed by filtration and
washed with EtOAc (10 mL) and then concentrated under reduced
pressure to afford a yellow oil. The crude oil was then taken up in
MeCN (1.6 mL), and 4 Å molecular sieves (0.25 g), N-
methylmorpholine N-oxide (144 mg, 1.23 mmol), and tetrapropy-
lammonium perruthenate (3.00 mg, 0.008 mmol) were added. The
reaction was stirred at rt for 6 h. The reaction mixture was then
concentrated under reduced pressure and purified by flash column
chromatography (4:1 hexanes/EtOAc) to yield 7 as a yellow oil
(0.103 g, 32% yield over two steps): 1H NMR (CDCl3, 500 MHz) δH
9.75 (s, 1H), 7.12 (t, J = 7.7 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 6.67−
6.65 (m, 2H), 2.58 (t, J = 7.0 Hz, 2H), 2.44 (td, J = 5.9, 2.2 Hz, 2H),
1.65 (m, 4H), 0.98 (s, 9H), 0.19 (s, 6H); 13C NMR (CDCl3, 125
MHz) δC 202.5, 155.8, 143.6, 129.3, 121.6, 120.3, 117.6, 43.9, 35.6,
30.9, 25.7, 21.8, 18.4, −4.2; HRESIMS m/z 293.1938 [M + H]+
(calcd for C17H29O2Si, 293.1937).
5-(Butylsulfonyl)-1-phenyl-1H-tetrazole (11). To a solution of
butanol (251 mg, 3.37 mmol) in THF (10 mL) were added PPh3
(970 mg, 3.71 mmol) and 1-phenyl-1H-tetrazole-5-thiol (660 mg,
3.71 mmol) at rt. The reaction mixture was then cooled to 0 °C, and
diisopropyl azodicarboxylate (0.73 mL, 3.7 mmol) was added
dropwise. The resulting mixture was warmed to rt and stirred for
16 h. The reaction was then concentrated under reduced pressure,
and the residue was purified by flash column chromatography (4:1
hexanes/EtOAc) to provide sulfide 9. Sulfide 9 (470 mg, 2.01 mmol)
was then dissolved in CH2Cl2 (10 mL) and cooled to 0 °C. Then
NaHCO3 (1.69 g, 20.1 mmol) and meta-chloroperbenzoic acid (730
mg, 4.20 mmol) were added. The resulting suspension was slowly
warmed to rt and stirred overnight. Then saturated NaHCO3 (10
mL) was added, and the aqueous layer was extracted with CH2Cl2 (3
× 10 mL). The combined organic layers were washed with brine (10
mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography
(3:2 hexanes/EtOAc) to afford 11 as a clear oil (362 mg, 56% yield
over two steps): 1H NMR (CDCl3, 500 MHz) δH 7.70−7.68 (m, 2H),
7.63−7.58 (m, 3H), 3.73 (t, J = 8.0 Hz, 2H), 1.97−1.91 (m, 2H),
1.57−1.50 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δC 153.7, 133.2, 131.6, 129.8, 125.2, 55.9, 24.0, 21.6, 13.5;
HRESIMS m/z 267.0916 [M + H]+ (calcd for C11H15N4O2S,
267.0916).
Table 1. MIC Values of Anaephene A (1), Anaephene B (2),
and Linezolid
compound
S. aureus
MRSA
B. cereus
anaephene A (1)
anaephene B (2)
linezolid
16 μg/mL
8 μg/mL
0.5 μg/mL
16 μg/mL
8 μg/mL
1 μg/mL
16 μg/mL
8 μg/mL
1 μg/mL
In conclusion, these are the first reported syntheses of
anaephenes A (1) and B (2) in the literature. The structures of
compounds 1 and 2 were confirmed by NMR and HRMS
analyses. The biological activities of the synthesized com-
pounds against S. aureus and B. cereus are in line with the
naturally obtained molecules. Additionally, we have demon-
strated that these natural products are active against MRSA.
The synthetic route reported herein is modular, which allows
for rapid diversification of the final products and permits the
development of structure−activity relationships. Together,
these results set the groundwork for further investigation and
optimization of this class of antibacterial natural products.
EXPERIMENTAL SECTION
■
1
General Experimental Procedures. H and 13C NMR spectra
were obtained on a Bruker 400 MHz Avance III spectrometer or
Bruker 500 MHz Avance III spectrometer in CDCl3 unless otherwise
noted. Chemical shifts are reported with the residual solvent peak
1
used as an internal standard (CDCl3 = 7.26 ppm for H and 77.16
ppm for 13C). All 2D NMR spectra, including COSY, HSQC, and
HMBC, were recorded in CDCl3. High-resolution mass spectra were
obtained using positive mode electrospray ionization (ESI+) on a
Thermo Scientific Q Exactive hybrid quadrupole-Orbitrap mass
spectrometer. Analytical HPLC was performed with a Thermo
Finnigan Surveyor HPLC utilizing a Thermo Scientific Hypersil
GOLD column (5 μm, 100 mm × 4.6 mm) run with 100% methanol
as the mobile phase at 1.0 mL/min. Reactions were monitored by
TLC analysis (silica gel 60 F254, 250 mm layer thickness) and
visualized with a 254 nm UV light. Flash column chromatography was
performed with silica gel 60 (230−400 mesh). All starting materials
and solvents were purchased from a commercial chemical company
and used as received.
5-(Hex-5-yn-1-ylsulfonyl)-1-phenyl-1H-tetrazole (12). To a
solution of 5-hexyn-1-ol (1.00 g, 10.2 mmol) in THF (85 mL) were
added PPh3 (3.74 g, 14.3 mmol) and 1-phenyl-1H-tetrazole-5-thiol
(2.36 g, 13.3 mmol) at rt. The reaction mixture was then cooled to 0
°C, and diisopropyl azodicarboxylate (3.20 mL, 16.3 mmol) was
added dropwise. The resulting mixture was warmed to rt and stirred
for 16 h. The reaction was then concentrated under reduced pressure,
and the residue was purified by flash column chromatography (4:1
hexanes/EtOAc) to provide the sulfide intermediate 10. The sulfide
10 (1.00 g, 3.88 mmol) was then dissolved in CH2Cl2 (34 mL) and
cooled to 0 °C. Then NaHCO3 (1.63 g, 19.4 mmol) and meta-
chloroperbenzoic acid (1.34 g, 8.53 mmol) were added. The resulting
suspension was slowly warmed to rt and stirred overnight. Then
saturated aqueous NaHCO3 (35 mL) was added, and the aqueous
layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were washed with brine (15 mL), dried (MgSO4), filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (3:2 hexanes/EtOAc) to afford 12 as a
5-(3-((tert-Butyldimethylsilyl)oxy)phenyl)pent-4-yn-1-ol (6).
To a solution of tert-butyl(3-iodophenoxy)dimethylsilane (547 mg,
1.64 mmol) in MeCN (7.5 mL) was added 4-pentyn-1-ol (151 mg,
1.80 mmol) followed by CuI (62.0 mg, 0.330 mmol) and
PdCl2(PPh3)2 (57.0 mg, 0.0810 mmol). The reaction was cooled to
0 °C, and then triethylamine (0.75 mL, 5.38 mmol) was added. The
reaction was slowly warmed to rt and stirred for 36 h. Upon
completion of the reaction, as determined by TLC analysis, the
reaction was filtered, concentrated under reduced pressure, and
purified by flash column chromatography (4:1 hexanes/EtOAc) to
1
afford 6 as a red oil (0.413 g, 87% yield): H NMR (CDCl3, 400
1
viscous oil (782 mg, 63% yield over two steps): H NMR (CDCl3,
MHz) δH 7.12 (t, J = 7.9 Hz, 1H), 6.98 (dt, J = 7.6, 1.2 Hz, 1H), 6.87
(t, J = 1.9 Hz, 1H), 6.76 (ddd, J = 8.2, 2.5, 1.0 Hz, 1H), 3.82 (t, J =
5.9 Hz, 2H), 2.5 (t, J = 6.9 Hz, 2H), 1.86 (p, J = 6.6 Hz, 2H), 1.5 (s,
1H), 0.98 (s, 9H), 0.19 (s, 6H); 13C NMR (CDCl3, 100 MHz) δC
155.6, 129.4, 124.9, 124.8, 123.3, 120.1, 89.2, 81.2, 62.0, 31.5, 25.8,
400 MHz) δH 7.70−7.68 (m, 2H), 7.63−7.60 (m, 3H) 3.38 (t, J = 7.8,
2H), 2.28 (td, J = 6.8, 2.7 Hz, 1H), 2.12 (p, J = 7.8 Hz, 2H), 1.99 (t, J
= 2.7 Hz, 1H), 1.73 (p, J = 7.3 Hz, 2H); 13C NMR (CDCl3, 100
MHz) δC 153.6, 133.2, 131.6, 129.9, 125.2, 82.8, 69.8, 55.7, 26.9, 21.4,
C
J. Nat. Prod. XXXX, XXX, XXX−XXX