Total synthesis of lithospermic acid using Fe-catalyzed Cross-Dehydrogenative-Coupling reaction and Pd-catalyzed ester-directed C–H olefination

Article abstract of DOI:10.1016/j.tet.2018.08.028

The total synthesis of lithospermic acid has been accomplished employing two C–H activation reactions as key steps. Fe-catalyzed Cross-Dehydrogenative-Coupling reaction was used for the rapid construction of benzofuran framework. Pd-catalyzed ester-direct

Full text of DOI:10.1016/j.tet.2018.08.028

Accepted Manuscript
Total synthesis of lithospermic acid using Fe-catalyzed Cross-Dehydrogenative-
Coupling reaction and Pd-catalyzed ester-directed C-H olefination
Yong Zheng, Weibin Song, Yefu Zhu, Bole Wei, Lijiang Xuan
PII:
S0040-4020(18)30992-X
10.1016/j.tet.2018.08.028
TET 29748
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 June 2018
Revised Date: 14 August 2018
Accepted Date: 20 August 2018
Please cite this article as: Zheng Y, Song W, Zhu Y, Wei B, Xuan L, Total synthesis of lithospermic acid
using Fe-catalyzed Cross-Dehydrogenative-Coupling reaction and Pd-catalyzed ester-directed C-H
olefination, Tetrahedron (2018), doi: 10.1016/j.tet.2018.08.028.
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ACCEPTED MANUSCRIPT
of lithospermic acid
reaction
Total
synthesis
using
and
Fe-catalyzed
Pd-catalyzed
Cross-Dehydrogenative-Coupling
ester-directed C-H olefination
Yong Zheng, Weibin Song, Yefu Zhu, Bole Wei and Lijiang Xuan
*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, 501 Haike Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China
*Corresponding Author. Email: ljxuan@mail.shcnc.ac.cn
The total synthesis of lithospermic acid has been accomplished employing two C-H activation
reactions as key steps. Fe-catalyzed Cross-Dehydrogenative-Coupling reaction was used for the
rapid construction of benzofuran framework. Pd-catalyzed ester-directed C-H olefination allowed
the efficient assembly of the dihydrobenzofuran ester and acrylate moieties.
1. Introduction
Lithospermic acid (Figure 1) is originally isolated from Lithospermum ruderale in 1963, and its
gross structure was fully elucidated in 1975.1,2 It is one of the pharmaceutically active components
of traditional Chinese medical plant Danshen (Salvia miltiorrhiza), which is used for the treatment
of cardiovascular and cerebrovascular diseases.3 Recently, lithospermic acid has been shown to
exhibit HIV-1 integrase inhibition activity (IC50 = 1.4 ꢀM).4
Owing to its remarkable biological profiles, limited availability from natural sources, and
intriguing structural features, total synthesis of lithospermic acid have spurred considerable
interest of the synthetic community. In 2005, Ellman and Bergman group reported the first total
synthesis of (+)-lithospermic acid by exploiting Rh-catalyzed asymmetric intramolecular C-H
alkylation as a key step.5 Yu group also achieved total synthesis of lithospermic acid via
Rh-catalyzed carbene C-H insertion and a late-stage Pd-catalyzed intermolecular C-H olefination.6
Since then, Coster, Ghosh and Hyu groups have completed their total synthesis respectively.7-9 It is
still highly desirable to develop a concise synthetic route to lithospermic acid analogues for the
evaluation of their potentials as lead compounds in drug research.
Recently, metal-catalyzed C-H activation has emerged as a powerful and economical tool for the
total synthesis of natural products, owing to its remarkable potential for step and atom economy.10
Our group has recently accomplished the first total synthesis of salvianoic acid A by employing
Ru-catalyzed C-H olefination as a key step.11 As part of our interest to explore synthesis and
1

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structural modification of bioactive compounds from Salvia miltiorrhiza, we herein report a
concise total synthesis of lithospermic acid using two C-H activation reactions as key steps.
Fe-catalyzed Cross-Dehydrogenative-Coupling (CDC) was utilized for the rapid construction of
benzofuran skeleton.12 The dihydrobenzofuran ester and acrylate fragments were coupled by
Pd-catalyzed ester-directed C-H olefination.13
Figure 1. (+)-Lithospermic acid (1)
Scheme 1. Retrosynthetic analysis of heptamethyl lithospermic acid (2).
2. Results and discussion
Our retrosynthetic analysis is depicted in Scheme 1. We envisioned that hepatmethyl lithospermic
acid 2 could be assembled from dihydrobenzofuran ester 3 and acrylate subunit 4 by Pd-catalyzed
ester-directed C-H olefination. Alcohol 5 was synthesized through metal-participated asymmetric
reaction of 7 with the optically pure 2,3-epoxypropionate 6, which has been reported in our
previous work.11 Dihydrobenzofuran ester 3 was prepared via Mg-NH4Cl reduction of benzofuran
ester 8. Construction of 8 could be achieved by Fe-catalyzed CDC reaction of phenol 9 with
β-keto ester 10.
We initially began to synthesize benzofuran ester 8 from 2-methoxylphenol 9 and β-keto ester 10
by Fe-catalyzed CDC reaction. Disappointedly, by using FeCl3·6H2O as catalyst and (t-BuO)2 as
oxidant, the desired product 8 resulted in 5% yield (Table1, entry 1). Other Fe catalysts and
2

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oxidants failed to afford the desired product (Table1, entries 2-4). When oxygen was used as
oxidant, 8 would be obtained in 20% yield (Table1, entry 5). The yield was increased to 35%
when 1,10-phenanthroline was added as ligand (Table1, entry 6). Using other ligands, such as
2,2’-bipyridine and pyridine, did not further improve the yield (Table1, entries 7 and 8). All
attempts to synthesize 8 by CDC reaction in acceptable yield were in vain. We suspected that the
unsatisfactory yield of 8 arose from the presence of ortho-methoxyl group in phenol 9. We then
turned our attention to other 2-substituted phenols. Gratifyingly, the reaction between phenol 9a
and β-keto ester 10 gave 8a in 72% yield (Table1, entry 9). 2-bromophenol 9b, reacting with 10
under FeCl3 and (t-BuO)2 conditions, afforded the desired product 8b in 55% yield (Table1, entry
10). The yield was improved to 64% by adding 1,10-phenanthroline as ligand (Table1, entry 11).
Having successfully prepared benzofuran ester 8b, we next examined the possibility of
transforming 8b into 8 (Scheme 2). Fortunately, Ullman coupling of 8b with MeONa in the
presence of CuBr proceeded smoothly to furnish the desired product in 78% yield. Reduction of
benzofuran ester 8 under Mg and NH4Cl in MeOH successfully gave the corresponding
(±)-trans-dihydrobenzofuran ester 3 in 67% yield without affecting ester group.
Table 1. Optimization of Fe-catalyzed CDC reactiona
Entry
R
Catalyst
Oxidant
(t-BuO)2
(t-BuO)2
(t-BuO)2
t-BuOOH
O2
Ligand
Yield (%)b
1
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
FeCl3·6H2O
FeSO4
5
2
trace
trace
0
3
Fe(acac)3
4
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
5
20
35
19
10
72
55
6
O2
1,10-phenanthroline
2,2’-bipyridine
pyridine
7
O2
8
O2
9
(t-BuO)2
(t-BuO)2
(t-BuO)2
10
Br
11
Br
1,10-phenanthroline 64
aReaction conditions: phenol (0.3 mmol), 10 (0.2 mmol), Fe catalyst (10 mol%),
oxidant (0.3 mmol) or O2 (1 atm), ligand (20 mol %), DCE (2 mL), 100 °C, 12 h.
bIsolated yield.
With (±)-dihydrobenzofuran ester 3 in hand, we next investigated Pd-catalyzed C-H olefination
for coupling of (±)-dihydrobenzofuran ester 3 and acrylate 4. In Yu’s previous work, carboxylic
acid group was employed as directing group for a late stage C-H olefination to construct the
lithospermic acid.6 Inspired by examples of phenylacetic ester-directed C-H olefination, we
envisioned that phenylacetic ester group in (±)-3 could be utilized as directing group for C-H
3

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olefination, which avoids preparing acid by hydrolysis of ester.13 To test our hypothesis,
dihydrobenzofuran ester 3 and methyl acrylate 11 were chosen as standard substrates to test the
C-H olefination. To our delight, the coupling product 12 was obtained in 17% yield with Pd(OAc)2
and Ag2CO3 in HFIP (Table 2, entry 1). Further optimization of ligand revealed that the yield of 12
was improved to 81 % when Ac-Gly-OH was used as the ligand (Table 2, entries 2-4). Other silver
salts gave lower yields than Ag2CO3 for the C-H olefination (Table 2, entries 5-7).
Scheme 2. Synthesis of (±)-dihydrobenzofuran ester 3
Table 2. Optimization of Pd-catalyzed ester-directed C-H olefinationa
Entry
Ag salt
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
Ag2O
ligand
Yield(%)b
1
2
3
4
5
6
7
17
81
68
54
46
43
61
Ac-Gly-OH
Ac-Ala-OH
Ac-Leu-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
AgNO3
aReaction conditions: 3 (0.2 mmol), 11 (0.4 mmol), Pd(OAc)2 (5 mol%), Ag salt (0.4 mmol),
ligand (20 mol%), HFIP (2 mL), air, 90 °C, 48 h.
bIsolated yield.
4

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Scheme 3. Total synthesis of lithospermic acid 1.
Having established the optimized conditions for Pd-catalyzed C-H olefination, we returned to the
total synthesis of 1 (Scheme 3). C-H Olefination of (±)-trans-dihydrobenzofuran ester 3 with
acrylate subunit 4 under the standard conditions to provide the desired coupling product 2 and its
diastereomer 13. Single diastereomer 2 could be separated in 34% yield from the mixtures of 2
and 13 by preparative HPLC. Next, treatment of 2 with Me3SnOH in DCE provided diacid 14 in
85% yield.14 Finally, subsequent removal of methyl groups in diacid 14 with TMSI-quinoline gave
the natural product (+)-lithospermic acid 1.
3. Conclusions
In summary, we have accomplished the total synthesis of lithospermic acid starting from
2-bromophenol, involving two metal-catalyzed C-H activation reactions. Fe-catalyzed
Cross-Dehydrogenative-Coupling was utilized for the rapid construction of dihydrobenzofuran
ester fragment. The dihydrobenzofuran ester and acrylate fragments were coupled by Pd-catalyzed
ester-directed C-H olefination. This work provides a concise method towards the synthesis of
lithospermic acid, which would facilitate further studies on the synthesis and biological evaluation
of lithospermic acid analogues.
4. Experimental section
5

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4.1. General information
All the reagents were used without further purification. The solvents were dried by the standard
methods. 1H and 13C NMR spectra were recorded on a Bruker NMR spectrometer with TMS as an
internal standard. HRESIMS was measured on an Agilent G6224A TOF spectrometer. TLC was
performed on pre-coated silica gel GF254 plates (Qingdao Marine Chemical Factory). Column
chromatography was performed on silica gel (200−300 mesh, Qingdao Marine Chemical Factory).
Visualization was carried out with UV or anisaldehyde staining.
4.2. Methyl 7-bromo-2-(3,4-dimethoxyphenyl)benzofuran-3-carboxylate (8b)
To a solution of 10 (4 mmol, 1.01 g) and 9b (6 mmol, 720 mg) in DCE (10 mL) was added
FeCl3·6H2O (10 mol%, 108 mg), 1,10-phenantroline (20 mol%, 144 mg) and (t-BuO)2 (8 mmol,
1.2 g) under N2. The mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled to
room temperature and sat. NaHCO3 was added. The mixture was extracted by DCM for three
times. The organic layers were combined, and dried over Na2SO4, filtered, and concentrated in
vacuo. The resulting residue was purified by silica gel column chromatography (petroleum
ether:ethyl acetate) to give 8b as white powder (998 mg, 64%).
1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 8.0, 1.1 Hz, 1H), 7.71 – 7.64 (m, 2H), 7.40 (dd, J =
7.9, 1.1 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.86
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.3, 161.3, 151.2, 150.5, 148.5, 128.6, 128.0, 125.2,
123.3, 121.8, 121.5, 112.6, 110.6, 108.3, 103.7, 56.1, 56.0, 51.8. HRMS-ESI (m/z): calcd for
C18H15BrNaO5 [M + Na]+ 413.0001, found 413.0000.
4.3. Methyl 2-(3,4-dimethoxyphenyl)-7-methoxybenzofuran-3-carboxylate (8)
8b (0.5 mmol, 185 mg), CuBr (0.05 mmol, 12 mg), freshly prepared NaOMe (2 mmol, 216 mg),
MeOH (1 mL), and anhydrous DMF (3 mL) were added into sealed tube under N2. The mixture
was stirred at 130 °C for 24 h. The reaction mixture was cooled to room temperature and sat.
NH4Cl was added. The mixture was extracted by EtOAc for three times. The organic layers were
combined, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was
purified by silica gel column chromatography (petroleum ether:ethyl acetate) to give 8 as white
powder (133 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 7.75 – 7.72 (m, 2H), 7.64 (dt, J = 7.9, 1.5
Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 9.0 Hz, 1H), 6.88 (dd, J = 8.0, 1.0 Hz, 1H), 4.05 (s,
3H), 4.00 (s, 3H), 3.98 (s, 3H), 3.96 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.6, 161.0, 150.8,
6

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148.4, 145.1, 142.9, 129.0, 124.6, 123.1, 122.0, 114.7, 112.5, 110.5, 108.1, 107.1, 56.1, 56.0, 56.0,
51.6. HRMS-ESI (m/z): calcd for C19H18NaO6 [M + Na]+ 365.1001, found 365.1000.
4.4. (±)-Methyl 2-(3,4-dimethoxyphenyl)-7-methoxy-2,3-dihydrobenzofuran-3-carboxylate
(3)
To a solution of 8 (1.2 mmol, 410 mg) in THF (15 mL) and MeOH (15 mL) was added freshly
activated magnesium turning (3.6 mmol, 86 mg) and NH4Cl (2.4 mmol, 127 mg) under N2. The
mixture was stirred at -15 °C for 5 h, and then stirred at room temperature for 24 h. Reaction was
cooled to -15 °C before sat. NH4Cl was added. The mixture was extracted by EtOAc for three
times. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo.
The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl
acetate) to give (±)-3 as yellow oil (276 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 7.10 – 6.72 (m,
6H), 6.08 (d, J = 8.4 Hz, 1H), 4.36 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H),
3.81 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 171.2, 149.2, 147.8, 144.6, 132.5, 125.1, 121.5, 118.8,
117.0, 112.5, 111.1, 109.3, 86.6, 56.1, 56.0, 56.0, 55.9, 52.7. HRMS-ESI (m/z): calcd for
C19H20NaO6 [M + Na]+ 367.1158, found 367.1156.
4.5. (R)-3-(3,4-dimethoxyphenyl)-1-methoxy-1-oxopropan-2-yl acrylate (4)
To a solution of alcohol (2 mmol, 480 mg) and acrylic acid (3 mmol, 258 mg) in DCM (20 mL)
was added DMAP (4 mmol, 488 mg) and EDCI (4 mmol, 764 mg) under N2. The reaction mixture
was stirred at room temperature for 24 h. After completion of reaction, 1N HCl was added at 0 °C.
The mixture was extracted by EtOAc for three times. The organic layers were combined, dried
over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel
column chromatography (petroleum ether:ethyl acetate) to give 4 as colorless oil (517 mg, 88%).
1H NMR (400 MHz, CDCl3) δ 6.75-6.81 (m, 3H), 6.45 (d, J = 17.2 Hz, 1 H), 6.12-6.19 (m, 1H),
5.89 (d, J = 10.4 Hz, 1 H), 5.26-5.29 (m, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.74 (s, 3H), 3.07-3.19
(m, 2H). 13C NMR (100 MHz, CDCl3) δ 169.9, 165.1, 148.6, 147.9, 131.9, 128.1, 127.4, 121.3,
112.3, 111.1, 73.2, 55.8, 52.4, 37.1. HRMS-ESI (m/z): calcd for C15H18NaO6 [M + Na]+ 317.1001,
found 316.9997.
4.6.
(±)-methyl
2-(3,4-dimethoxyphenyl)-7-methoxy-4-((E)-3-methoxy-3-oxoprop-1-en-1-yl)-2,3-dihydrobenz
ofuran-3-carboxylate (12)
7

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(±)-3 (0.2 mmol, 69 mg), methyl acrylate 11 (0.4 mmol, 35 mg), Ag2CO3 (0.4 mmol, 110 mg),
Ac-Gly-OH (20 mol%, 10 mg), Pd(OAc)2 (5 mol%, 5 mg) and HFIP (2 mL) was added into sealed
tube. The mixture was stirred at 90 °C for 48 h. After the reaction was cooled to room temperature,
the mixture was filtered by Celite and concentrated in vacuo. The resulting residue was purified by
silica gel column chromatography (petroleum ether:ethyl acetate) to give 12 as colorless oil (70
mg, 81%). 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 15.9 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 6.91
(dd, J = 7.8, 1.1 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.83 (d, J = 8.3 Hz,
1H), 6.29 (d, J = 15.9 Hz, 1H), 6.04 (d, J = 5.8 Hz, 1H), 4.49 (d, J = 5.8 Hz, 1H), 3.95 (s, 3H),
3.87 (s, 3H), 3.86 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 171.86,
167.41, 149.29, 149.23, 148.43, 146.19, 141.12, 132.29, 125.00, 124.52, 120.56, 118.08, 117.35,
112.94, 111.11, 108.73, 87.53, 56.18, 55.96, 52.89, 51.70. HRMS-ESI (m/z): calcd for
C23H24NaO8 [M + Na]+ 451.1363, found 451.1382.
4.7. (2S,3S)-methyl
2-(3,4-dimethoxyphenyl)-4-((E)-3-(((R)-3-(3,4-dimethoxyphenyl)-1-methoxy-1-oxopropan-2-
yl)oxy)-3-oxoprop-1-en-1-yl)-7-methoxy-2,3-dihydrobenzofuran-3-carboxylate (2)
(±)-3 (0.2 mmol, 69 mg), 4 (0.4 mmol, 118 mg), Ag2CO3 (0.4 mmol, 110 mg), Ac-Gly-OH (20
mol%, 10 mg), Pd(OAc)2 (5 mol%, 5 mg) and HFIP (2 mL) was added into sealed tube. The
mixture was stirred at 90 °C for 48 h. After the reaction was cooled to room temperature, the
mixture was filtered by celite and concentrated in vacuo. The resulting residue was subjected to
HPLC (YMC Diol-NP column, 150 mm × 20 mm, 5 µm particle size, 5:95 to 15:85
i-PrOH:hexanes over 65 min at 9 mL/min, detection: UV at 254 nm) to afford 2 (43 mg, 34%).
1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 15.9 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 6.86-6.90 (m,
3H), 6.82 (d, J = 8.5 Hz, 1H), 6.75-6.79 (m, 3H), 6.32 (d, J = 16Hz, 1H), 6.02 (d, J = 5.6 Hz, 1H),
5.31 (dd, J = 8.5, 5.5 Hz, 1H), 4.45 (d, J = 5.6 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H),
3.83 (s, 3H), 3.83 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 3.16 (dd, J = 14.3, 4.7 Hz, 1H), 3.09 (dd, J =
14.3, 8.2 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 171.80, 170.40, 166.21, 149.39, 149.32, 148.86,
148.55, 148.13, 146.49, 142.58, 132.39, 128.41, 125.07, 124.44, 121.53, 120.98, 118.13, 116.52,
112.98, 112.46, 111.20, 112.20, 108.81, 87.57, 73.19, 56.27, 56.04, 56.00, 56.00, 55.96, 55.92,
52.94, 52.47, 37.23. HRMS-ESI (m/z): calcd for C34H36NaO12 [M + Na]+ 659.2099, found
659.2099. [α]D23 = +139 (c 0.39, CH2Cl2), lit. [α]D = +134.5 (c 0.49, CH2Cl2),5 [α]D25 = +131.9 (c
0.079, CH2Cl2).7 Melting point: 58-59 °C.
8

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4.8.
(2S,3S)-4-((E)-3-((R)-1-carboxy-2-(3,4-dimethoxyphenyl)ethoxy)-3-oxoprop-1-en-1-yl)-2-(3,4
-dimethoxyphenyl)-7-methoxy-2,3-dihydrobenzofuran-3-carboxylic acid (14)
To a solution of 2 (0.068 mmol, 43 mg) in DCE (2 mL) was added Me3SnOH (0.34 mmol, 61 mg).
The reaction mixture was stirred at 90 °C for 20 h. After completion of reaction, 1N HCl was
added at 0 °C. The mixture was extracted by DCM for three times. The organic layers were
combined, dried over Na2SO4, filtered through a small pad of silica gel, and concentrated in vacuo.
The resulting residue purified by silica gel column chromatography (hexanes:EtOAc:HOAc
1:1:0.005) to give diacid 14 as white solid (35 mg, 85%). 1H NMR (500 MHz, CD3COCD3) δ 7.84
(d, J = 16.0 Hz, 1H), 7.38 (d, J = 8.6, 1H), 7.07 (d, J = 1.9 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.98
– 6.91 (m, 3H), 6.89 – 6.82 (m, 2H), 6.42 (d, J = 16 Hz, 1H), 6.06 (d, J = 5.1 Hz, 1H), 5.25 (dd, J
= 8.5, 4.2 Hz, 1H), 4.58 (d, J = 5.1 Hz, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H),
3.74 (s, 3H) , 3.19 (dd, J = 14.3, 4.2 Hz, 1H), 3.09 (dd, J = 14.3, 8.5 Hz, 1H). 13C NMR (126 MHz,
CD3COCD3) δ 172.97, 171.16, 166.49, 150.57, 150.11, 149.49, 149.35, 147.40, 143.07, 133.92,
130.00, 126.99, 125.30, 122.56, 121.39, 118.83, 117.27, 114.31, 114.26, 112.71, 112.65, 110.59,
88.18, 73.75, 60.54, 56.50, 56.42, 56.11, 56.00, 37.62. HRMS-ESI (m/z): calcd for C32H32NaO12
[M + Na]+ 631.1786, found 631.1781. [α]D23 = +170.2 (c 0.51, CH2Cl2).
4.9. Lithospermic acid (1)
14 (0.049 mmol, 30 mg) and trimethylsilylquinolinium iodide (50 equiv, 806 mg) was added into a
seal tube. The reaction mixture was stirred at 130 °C for 3 h. The reaction was cooled to room
temperature, and 1N HCl was added slowly. The mixture was extracted by EtOAc for four times.
The combined organic layers were dried by Na2SO4, filtered and concentrated under vacuum. The
resulting residue was subjected to HPLC separation (YMC C18 column, MeCN:H2O:TFA
10:90:0.1 to 50:50:0.1 over 60 min at 1 mL/min, detection: UV at 254 nm). The collected fractions
1
were concentrated under reduced pressure to give 1 as yellow powder (5.8 mg, 22%). H NMR
(500 MHz, CD3COCD3) δ 7.85 (d, J = 16.0 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 6.89 (d, J = 8.5 Hz,
1H), 6.88 (m, 1H), 6.86 (d, J = 1.7 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.80 (dd, J = 8.2, 1.8 Hz,
1H), 6.73 (d, J = 8.0 Hz, 1H), 6.67 (dd, J = 8.0, 1.9 Hz, 1H), 6.38 (d, J = 15.9 Hz, 1H), 5.98 (d, J
= 4.7 Hz, 1H), 5.18 (dd, J = 8.6, 4.0 Hz, 1H), 4.53 (d, J = 4.7 Hz, 1H), 3.10 (dd, J = 14.4, 4.0 Hz,
1 H), 3.01 (dd, J = 14.3, 8.6 Hz, 1H). 13C NMR (126 MHz, MeOD) δ 175.07, 173.43, 168.10,
9

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148.81, 146.62, 146.06, 145.25, 144.08, 133.74, 129.18, 127.59, 124.56, 121.95, 121.66, 118.24,
117.57, 116.36, 116.31, 113.38, 88.74, 74.70, 57.48, 37.89. HRMS-ESI (m/z): calcd for
23
23
C27H22NaO12 [M + Na]+ 561.1003, found 561.1005. [α]D = +71 (c 0.16, MeOH), lit. [α]D
=
+68.3 (c 0.8, CD3OD),6 [α]D23 = +75 (c 0.2, MeOH).8 Melting point: 180-182°C.
Acknowledgements
We are grateful to the National Natural Science Foundation of China (No.81602995) for financial
support.
Supplementary data
Supplementary data related to this article can be found at
References and notes
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