Journal of Natural Products
Note
131.5, 130.4, 130, 129.3, 126.4, 125.7, 121.6, 107.1, 56.6, 20; HRMS
(ESI) m/z 275.0686 [M + Na]+ (calcd for C16H12NaO3, 275.0684).
3-Hydroxy-8-methyl-1,4-phenanthrenedione (8). A mixture
of compound 7 (5 g, 20 mmol), NaOH (4.2 g, 105 mmol), H2O (700
mL), and EtOH (150 mL) was stirred at reflux for 1 h. After cooling,
the reaction mixture was acidified with 0.5 N HCl and extracted with
EtOAc (3 × 200 mL). The combined organic solution was washed
with H2O, dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo to provide crude 8, which was purified by column
chromatography to afford compound 8 (3.8 g, 79%) as a dark red
solid: mp 209−211 °C; 1H NMR (CDCl3, 400 MHz) δ 9.45 (1H, d, J
= 8.8 Hz, H-5), 8.46 (1H, d, J = 8.8 Hz, H-9), 8.26 (1H, d, J = 9.2 Hz,
H-10), 7.67−7.63 (1H, m, H-6), 7.49 (1H, d, J = 6.8 Hz, H-7), 6.33
(1H, s, H-2), 2.75 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ
184.6, 183.4, 161.2, 135.4, 134.2, 123.3, 131.5, 130.6, 129.6, 128.3,
125.4, 124.7, 121.6, 107.6, 19.7; HRMS (ESI) m/z 239.0710 [M + H]+
(calcd for C15H11O3, 239.0708).
via hydrolysis or demethylation. Compound III is considered
the crucial intermediate and is derived by a Diels−Alder
reaction from the substituted styrene IV and the 2-methoxy-
1,4-benzoquinone.
Thus, the synthesis of tanshinone I (1) starts with the
reaction between 2-methylstyrene (5) and 2-methoxy-1,4-
benzoquinone (6). The uncatalyzed Diels−Alder reaction
between 5 and 6 in toluene afforded compound 7 in 52%
yield. Subsequent demethylation of compound 7 using NaOH
in aqueous EtOH afforded compound 8 in 79% yield. In the
final step, the Feist−Benary reaction of compound 8 with
chloroacetone in HOAc−NH4OAc gave the target tanshinone I
(1), in 45% yield. The overall yield for the three-step synthesis
was approximately 18.5% (Scheme 2).
Tanshinone I (1). A round-bottomed flask was charged with
compound 8 (9.5 g, 40 mmol), toluene (1000 mL), HOAc (12 g, 200
mmol), NH4OAc (15.4 g, 200 mmol), chloroacetone (18.5 g, 200
mmol), and EtOH (200 mL), and the mixture was refluxed for 2 h in
the dark. After cooling, the reaction mixture was diluted with H2O
(200 mL) and extracted with EtOAc (3 × 200 mL). The combined
organic layer was washed with H2O, dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo to give a solid residue. The residue
was further purified using flash column chromatography (petroleum
ether−CH2Cl2, 3:1) to afford tanshinone I (1) (5.0 g, 45%) as a red
solid: mp 228−230 °C; 1H NMR (CDCl3, 400 MHz) δ 9.21 (1H, d, J
= 9.2 Hz, H-9), 8.25 (1H, d, J = 8.8 Hz, H-5), 7.75 (1H, d, J = 8.8 Hz,
H-4), 7.54−7.50 (1H, m, H-8), 7.32 (1H, d, J = 6.8 Hz, H-7), 7.28
(1H, s, H-2), 2.66 (3H, s, H-13), 2.27 (3H, s, H-12); 13C NMR
(CDCl3, 100 MHz) δ 183.3, 175.5, 161.1, 141.9, 135.1, 133.5, 132.8,
132.6, 130.6, 129.5, 128.2, 124.6, 122.9, 121.7, 120.4, 118.6, 19.8, 8.8;
HRMS (ESI) m/z 299.0685 [M + Na]+ (calcd for C18H12NaO3,
299.0684).
Scheme 2. Synthesis of Tanshinone I (1)
In summary, we have developed an efficient three-step total
synthesis of tanshinone I (1) using three straightforward steps.
Furthermore, compound 7 was synthesized in one step through
the Diels−Alder reaction between a 1,4-benzoquinone and a
styrene, a considerable improvement over current syntheses.
The synthesis reduced the number of toxic reagents and
lowered production costs through a higher overall yield, less
expensive reagents, and only three steps. This readily scaled
method should benefit further research on the biological
properties of tanshinone I (1).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
■
S
1H and 13C NMR spectra data for compounds 1 and 7
and 2D NMR spectra data for 7 (PDF)
AUTHOR INFORMATION
Corresponding Author
■
EXPERIMENTAL SECTION
General Experimental Procedures. Melting points were
determined using the X-4 micro melting point apparatus. NMR data
■
1
were obtained for H at 400 or 600 MHz and for 13C at 100 or 150
ORCID
MHz in a CDCl3 solution with tetramethylsilane as the internal
standard. ESI-HRMS data were obtained with a Waters SYNAPT G2
mass spectrometer. All reagents were obtained from commercial
sources and used without further purifications. Column chromatog-
raphy was carried out on silica gel (200−300 mesh). Thin-layer
chromatography was performed using commercially available HSGF
254 precoated plates.
Author Contributions
†N. Wu and W.-C. Ma contributed equally to this work.
Notes
The authors declare no competing financial interest.
3-Methoxy-8-methyl-1,4-phenanthrenedione (7).19 A mixture
of compound 5 (6.9 g, 50 mmol), compound 6 (35.4 g, 300 mmol),
and anhydrous toluene (500 mL) in a sealed autoclave was heated to
200 °C for 6 h. After cooling, the reaction mixture was purified by
column chromatography (petroleum ether−CH2Cl2, 5:2) and
recrystallization using EtOAc to provide compound 7 (7.6 g, 52%)
ACKNOWLEDGMENTS
■
This research work was supported by grants from Department
of Science and Technology of Sichuan Province (project no.
2012FZ0011).
1
as an orange solid: mp 222−225 °C; H NMR (CDCl3, 600 MHz) δ
REFERENCES
9.39 (1H, d, J = 8.4 Hz, H-5), 8.38 (1H, d, J = 9 Hz, H-9), 8.21 (1H, d,
J = 8.4 Hz, H-10), 7.63−7.60 (1H, m, H-6), 7.46 (1H, d, J = 6.6 Hz,
■
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