An efficient multigram synthesis of alkannin and shikonin

Article abstract of DOI:10.1002/ejoc.201101505

The concise and efficient total syntheses of alkannin (1) and shikonin (2), based on the resolution of a key acid intermediate, are achieved with excellent enantiomeric excesses and high overall yields (99 % ee, 15.6 % for 1 and 99.8 % ee, 11.9 % for 2). The key steps of the synthetic strategy involve the convenient synthesis and separation of a pair of amide diastereoisomers and the mild hydrolysis of the amide to remove the amine chiral auxiliary, together with an efficient deprotection sequence of the methyl protecting groups. The concise and efficient syntheses of alkannin and shikonin remained elusive until recently. We have developed a new method of resolution for achieving the syntheses of alkannin (1) and shikonin (2) in excellentenantiomeric excesses (≥ 99 % ee for 1 and ≥ 99.8 % ee for 2) and high yields (27.5 %) with low cost, which is practical for use in large-scale preparation. Copyright

Full text of DOI:10.1002/ejoc.201101505

FULL PAPER
DOI: 10.1002/ejoc.201101505
An Efficient Multigram Synthesis of Alkannin and Shikonin
Rubing Wang,[a] Shanshan Zhou,[a] Hudagula Jiang,[a] Xiaogang Zheng,[a] Wen Zhou,[a] and
Shaoshun Li*[a]
Keywords: Natural products / Total synthesis / Chiral resolution / Chiral auxiliaries
The concise and efficient total syntheses of alkannin (1) and
shikonin (2), based on the resolution of a key acid intermedi-
ate, are achieved with excellent enantiomeric excesses and
high overall yields (99% ee, 15.6% for 1 and 99.8% ee,
11.9% for 2). The key steps of the synthetic strategy involve
the convenient synthesis and separation of a pair of amide
diastereoisomers and the mild hydrolysis of the amide to re-
move the amine chiral auxiliary, together with an efficient
deprotection sequence of the methyl protecting groups.
Introduction
Alkannin (1) and shikonin (2), a pair of enantiomers
which are extracted and identified from the roots of
Alkanna tinctoria in Europe and Lithospermum
erythrorhizon in the Orient, have been used independently
for many centuries as natural red dyes and as crude drugs
capable of accelerating wound healing.[1] Over the past few
decades, the two natural products and their derivatives have
been reported to have a wide variety of biological and phar-
macological activities, such as immunostimulatory,[2] anti-
bacterial,[3] anti-inflammatory,[4] antiviral,[5] analgesic,[6]
angiostatic,[7] antithrombotic,[8] and antitumor[1,9] proper-
ties. Though these natural products can be isolated from
many species of Boraginaceae, both as the free alcohols and
as ester derivatives, their enantiomeric ratios vary not only
with their habitats and species but also with their different
derivatives,[10] as has been previously confirmed in our
lab.[11] Thus, extraction and purification of 1 and 2 from
natural resources proved unsatisfactory, because of inef-
ficiency and providing products with low optical purity, and
could not meet the demands. However, the syntheses of 1
and 2 have attracted the attention of many researchers.[10,12]
Because of the high chemical reactivity of the naphthazarin
moiety,[1] the concise and efficient syntheses of 1 and 2 re-
mained elusive until recently, although their molecular
structures are seemingly simple. This, in combination with
the excellent biological properties of these natural products,
motivated us to investigate new and efficient total syntheses.
Results and Discussion
Most successful syntheses reported for 1 and 2 involved
using 1,4,5,8-tetramethoxynaphthalene derivatives[12a–12f]
and were based on asymmetric syntheses[10,12d,12f,12i,12k,13]
from over the past thirty years. The final deprotection se-
quences to reveal the naphthazarin moiety had poor yields,
and the reagents were costly. The chiral reagents and inter-
mediates were either expensive or difficult to obtain, and
the enantioselectivity was very disappointing. One of the
shortest and most elegant syntheses, which adopted a new
protecting system (i.e., the methylene protecting group), was
reported by Nicolaou. However, the final deprotection step,
proceeding by electrolysis, resulted in low yields and was
difficult to scale up, to say nothing of the possibilities for
large-scale preparation.[10] Furthermore, the Weinreb amide
used in this route was difficult to synthesize.
A practical and efficient synthetic route for alkannin (1)
and shikonin (2) had to overcome several obstacles, such as:
(1) to apply a resolution method without using an expensive
chiral reagent, so that it would be more suitable for large-
scale preparation and (2) to obtain the product with high
optical purity, providing the possibility for new drug devel-
opment in the future.
According to the retrosynthetic analysis in Scheme 1, we
designed and obtained a racemic acid, whose structure is
very similar to α-hydroxyphenylacetic acid (mandelic acid).
The resolution of mandelic acid has already been fully ex-
plored and may provide some ideas for our resolution. We
then expected to achieve a pair of chiral acids through a
[a] School of Pharmacy, Shanghai Jiao Tong University,
Shanghai, 200240, P. R. China
Fax: +86-21-34204775
E-mail: ssli@sjtu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101505.
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three-step protocol, which includes salt formation with a
chiral amine, recrystallization, and dissociation. However,
some chiral amines, such as (S)-1-phenylethylamine, 10,11-
dimethoxystrychnine, chinine, and cinchonine, have proved
impracticable for the formation of salts with the racemic
acid.
Scheme 2. The synthesis of key diastereomers 5, 6 and 7, 8. Rea-
gents and conditions: (a) Zn, BrCH2CO2C2H5, dry THF (tetra-
hydrofuran), room temp., 1 h, then 1,4,5,8-tetramethoxy-2-naphth-
aldehyde, room temp., 1 h, 92%; (b) NaOH (2 m solution), room
temp., 1 h, then HCl (6 m solution), 99%; (c) (S)-1-phenylethyl-
amine, BOP [bis(2-oxo-3-oxazolidinyl)phosphane], TEA (triethyl-
amine), dry DMF (dimethylformamide), room temp., 3 h, 5 (54%),
6 (41%); (d) TBDPSCl, imidazole, DMAP [4-(dimethylamino)pyr-
idine], room temp., 24 h, 96%.
Scheme 1. The retrosynthetic analysis of alkannin (1) and shikonin
(2) to achieve a racemic acid.
(H2O, see Scheme 4). The optimum reaction conditions for
Luckily, the condensation of racemic acid 4 and (S)-1- each step, such as temperature, time, and ratio of the rea-
phenylethylamine gave rise to two diastereomers (i.e., 5 and gents, were explored. Compound 9 was reduced to corre-
6), which were easily separated by one-step column sponding aldehyde 10 with DIBALH (diisobutylaluminum
chromatography on silica gel (petroleum ether/ethyl acetate, hydride). A Wittig-type elongation of the resulting aldehyde
3:2), because of the approximate double gap in their polarit- using the ylide of 2-bromopropane afforded fully protected
ies (Scheme 2). The secondary hydroxy groups in the two 11. The deprotection of the side-chain hydroxy group pro-
diastereomers (i.e., 5 and 6) were protected using tert-butyl- vided key chiral intermediate 12 with a high enantio-
diphenylsilyl chloride (TBDPSCl) to produce 7 and 8, selectivity (Ն99.8% ee). Many derivatives of 2 have been
which could easily be purified further by recrystallization synthesized based on 12.
to ensure the optical purity. The starting material 1,4,5,8-
After 12 was obtained, target molecule 2 could be pro-
tetramethoxy-2-naphthaldehyde was synthesized in good duced in two steps by the reported literature pro-
yield according to our reported procedures.[14] Racemic acid cedures[12c,12d,12f,12g,12i] in 20% yield. This included oxi-
4 was obtained by a Reformatsky reaction and subsequent dation by ammonium cerium(IV) nitrate (CAN) followed
hydrolysis.
by deprotection of the second pair of methyl protecting
The other synthetic steps starting from 7 to produce 1 groups with harsh and costly reagents (AgIIO, HNO3) that
are the same as those from 8 to produce 2. We used the were impractical for large-scale preparation. However, the
synthesis of 2 as our example. The hydrolysis of amide 8 to monosubstitution derivatives of naphthazarin (isomers A
obtain ester derivative 9 was one of the most difficult steps and B) have been reported to rapidly tautomerize and favor
(Scheme 3). After a series of experiments, we found the best A by virtue of the stabilizing effect of the electron-donating
hydrolysis method, occurring in 80% yield and using a one- alkyl group[10,15] (Scheme 5). Based on Couladouros’ re-
pot three-step procedure which included chlorination [PCl5, port,[12k] the synthesis of 2 was achieved according to three
py (pyridine)], etherification (CH3OH), and hydrolysis chemical operations in high yield (65%) with an excellent
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An Efficient Multigram Synthesis of Alkannin and Shikonin
Scheme 3. The synthesis of key chiral intermediate 12. Reagents
and conditions: (a) PCl5, pyridine, dry CH2Cl2, 0 °C, 8 h, then dry
CH3OH, –20 °C, 1 h, then H2O, room temp., 12 h, 80%; (b) DI-
BALH, dry CH2Cl2, –78 °C, 12 h, 90%; (c) Ph3PCH(CH3)2Br,
nBuLi, dry Et2O, 0 °C, 30 min, then 10, room temp., 2 h, 75%;
(d) TBAF (tetra-n-butylammonium fluoride), dry THF, room
temp., 3 h, 95%.
Scheme 6. The deprotection of the methyl protecting groups on
naphthazarin moiety. Reagents and conditions: (a) Ac2O, Et3N,
DMAP, dry CH2Cl2, room temp., 20 min, then CAN, CH2Cl2,
room temp., 15 min, 13 (25%), 14 (67%); (b) Zn, Ac2O, Et3N,
DMAP, 2 h, room temp., 15 (76%), 16 (86%); (c) CAN, CH3CN,
room temp., 10 min, then NaOH (1 m solution), 6 h, then HCl
(10% solution), 85%.
Conclusions
Based on the practical synthesis and separation of a pair
of amide diastereomers and their successful hydrolysis, we
have demonstrated a new method of resolution to synthe-
size alkannin (1) and shikonin (2) in excellent enantiomeric
excesses and high yields (99% ee, 15.6% for 1 and 99.8% ee,
11.9% for 2) under mild conditions. (S)-1-phenylethylam-
ine, the chiral reagent used for the resolution, is inexpensive
and, therefore, practical for use in large-scale preparation.
This groundbreaking development, together with the valu-
able approach for the deprotection of the methyl protecting
groups on the naphthazarin core, has allowed us to com-
plete the concise and practical syntheses of the two enantio-
mers alkannin (1) and shikonin (2). This research not only
marks a breakthrough in the history of alkannin and
shikonin syntheses, but also is of great benefit to the re-
search and development of alkannin and shikonin and their
analogs as new drugs.
Scheme 4. The plausible hydrolysis mechanism of amide 8.
enantioselectivity (Ն99.8% ee) (Scheme 6). The preparation
included acetylation–oxidation, reduction–acetylation, and
oxidation–hydrolysis–neutralization–tautomerization reac-
tions.
Experimental Section
General Methods: All solvents and reagents were purified by stan-
dard techniques. Crude products were purified by column
chromatography on silica gel of 100–200 mesh. NMR spectroscopic
Scheme 5. Tautomerization of isomers A and B.
Eur. J. Org. Chem. 2012, 1373–1379
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data were recorded with a Mercury 300 (Varian) or AVANCE 400
(Bruker) spectrometers. Chemical shifts in 1H and 13C spectra were
recorded with tetramethylsilane as an internal standard. Mass spec-
tra were recorded with a Shimadzu LCMS-2010EV mass spectrom-
eter. HRMS were recorded with a Waters Q-TOF Premier mass
spectrometer. The HPLC system was equipped with a UV/Vis de-
tector (G1315C/D), an Agillent 1200 series G1322A IV pump, and
software for process control and data handling (Agilent ChemSt-
ation for LC 3D Systems). The chiral HPLC column used was a
Sino-chiral OD column, no. 0A02014-C [packed with cellulose-
tris(3,5-dimethylphenyl carbamate)], purchased from FunSea
(S)-3-Hydroxy-N-[(S)-1-phenylethyl]-3-(1,4,5,8-tetramethoxynaphth-
alen-2-yl)propanamide (5) and (R)-3-Hydroxy-N-[(S)-1-phenylethyl]-
3-(1,4,5,8-tetramethoxynaphthalen-2-yl)propanamide (6): To a solu-
tion of 4 (50.4 g, 0.15 mol), BOP (66.4 g, 0.15 mol), TEA (16.7 g,
0.165 mol), and DMAP (0.015 mol) in dry DMF (200 mL) was
added (S)-1-phenylethylamine (18.2 g, 0.15 mol) dropwise, and the
mixture was stirred for 3 h at room temperature. After the comple-
tion of reaction, the reaction mixture was diluted with cold water
(200 mL), and the resulting solution was extracted with EtOAc
(3ϫ300 mL). The combined organic layers were washed with brine
(300 mL), dried with anhydrous Na2SO4, and concentrated under
Beijing Technology Co. Ltd. (Beijing, China), 150ϫ4.6 mm. The vacuum to furnish the residue which was purified by silica gel col-
separations were also conducted at ambient temperature. The mo-
bile phase was degassed before application.
umn chromatography (PE/EtOAc, 3:2) to give 5 (33.8 g, 54%) and
6 (27.5 g, 41%) as light yellow foamy solids. Data for diastereomer
5: IR (KBr): νmax = 3468, 3066, 2929, 2835, 1643, 1600, 1543, 1454,
˜
1362, 1257, 1074, 832, 802, 757, 701 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.35–7.26 (m, 5 H, Ar), 7.12 (s, 1 H, Ar), 6.82 (s, 2 H,
Ar), 6.01 (d, J = 4.5 Hz, 1 H, CHOHCONH), 5.52 (dd, J = 8.7,
2.7 Hz, 1 H, NHCHCH3), 5.14–5.02 (m, 1 H, CHOHCONH), 3.95
(s, 3 H, ArOCH3), 3.94 (s, 3 H, ArOCH3), 3.89 (s, 3 H, ArOCH3),
3.74 (s, 3 H, ArOCH3), 2.77–2.57 (m, 2 H, CH2), 1.39 (d, J =
6.9 Hz, 3 H, NHCHCH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
171.5 (C=O), 153.5 (CnaphOCH3), 151.3 (CnaphOCH3), 150.1
(CnaphOCH3), 145.7 (CnaphOCH3), 143.0 (CAr), 133.2 (CArH), 128.6
(CArH), 127.2 (CArH), 126.0 (CnaphCH), 122.4 (Cnaph), 120.1
(Cnaph), 108.3 (CnaphH), 107.1 (CnaphH), 105.6 (CnaphH), 65.9
(COH), 62.5 (OCH3), 57.8 (OCH3), 57.0 (OCH3), 56.5 (OCH3),
48.8 (CHCH3), 43.4 (CH2CO), 21.8 (CH3) ppm. HRMS: calcd. for
C25H29NO6 439.1995; found 439.1990. Data for diastereoisomer 6:
Ethyl 3-Hydroxy-3-(1,4,5,8-tetramethoxynaphthalen-2-yl)propano-
ate (3): Ethyl bromoacetate (167.0 g, 1.0 mol) was added dropwise
to the solution of zinc powder (117.0 g, 1.8 mol) in dry THF
(300 mL) over a period of 1 h, as the solution gently heated to
reflux under a nitrogen atmosphere. The mixture was stirred for an
additional 1 h at room temperature. Then, a solution of 1,4,5,8-
tetramethoxynaphthalene-2-carbaldehyde (138.1 g, 0.5 mol) in
THF (300 mL) was added to the mixture over 10 min at room tem-
perature. After being stirred for 1 h, the reaction mixture was
quenched with cold HCl (5% solution, 200 mL), and the resulting
mixture was extracted with ethyl acetate (3ϫ400 mL). The com-
bined organic layers were washed with NaHCO3 (2ϫ200 mL) and
brine (300 mL), dried with Na2SO4, and then evaporated under
reduced pressure. Thus, the obtained crude residue was purified
over silica gel [PE (petroleum ether)/EtOAc, 1:2) to give 3 (167.5 g,
0.46 mol, 92%) as a light yellow oil. 1H NMR (300 MHz, CDCl3):
δ = 7.04 (s, 1 H, Ar), 6.75 (s, 2 H, Ar), 5.58 (dd, J = 9.6, 2.7 Hz, 1
H, CHOHCH2), 4.13 (dd, J = 14.4, 7.2 Hz, 2 H, CH2CH3), 3.89
(s, 3 H, ArOCH3), 3.86 (s, 3 H, ArOCH3), 3.83 (s, 3 H, ArOCH3),
3.70 (s, 3 H, ArOCH3), 2.85–2.63 (m, 2 H, CH2CO2CH2), 1.21 (t,
J = 7.2 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
172.6 (C=O), 153.3 (CnaphOCH3), 151.1 (CnaphOCH3), 149.9
(CnaphOCH3), 145.7 (CnaphOCH3), 132.4 (CnaphCH), 122.3 (Cnaph),
119.9 (Cnaph), 108.0 (CnaphH), 107.3 (CnaphH), 105.0 (CnaphH), 65.0
(CHOH), 62.4 (OCH3), 60.5 (CH2CH3), 57.5 (OCH3), 56.7
(OCH3), 56.6 (OCH3), 42.4 (CH2COOCH2CH3), 13.9 (CH3) ppm.
MS (ESI): m/z = 397 [M + Na]+.
IR (KBr): ν
= 3468, 3066, 2928, 2834, 1627, 1600, 1543, 1454,
˜
max
1362, 1256, 1074, 834, 800, 757, 701 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.20–7.08 (m, 6 H, Ar), 6.82 (s, 2 H, Ar), 6.08 (d, J =
7.5 Hz, 1 H, CHOHCONH), 5.54 (d, J = 6.0 Hz, 1 H,
NHCHCH3), 5.12–5.03 (m, 1 H, CHOHCONH), 3.94 (s, 3 H, Ar-
OCH3), 3.90 (s, 3 H, ArOCH3), 3.88 (s, 3 H, ArOCH3), 3.76 (s, 3
H, ArOCH3), 2.77–2.57 (m, 2 H, CH2), 1.45 (d, J = 6.9 Hz, 3 H,
NHCHCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.7 (C=O),
153.5 (CnaphOCH3), 151.4 (CnaphOCH3), 150.1 (CnaphOCH3), 145.6
(CnaphOCH3), 143.0 (CAr), 133.3 (CArH), 128.5 (CArH), 127.1
(CArH), 125.8 (CnaphCH), 122.4 (Cnaph), 120.2 (Cnaph), 108.3
(CnaphH), 107.2 (CnaphH), 105.6 (CnaphH), 66.0 (COH), 62.5
(OCH3), 57.9 (OCH3), 56.9 (OCH3), 56.6 (OCH3), 48.8 (CHCH3),
43.3 (CH2CO), 21.9 (CH3) ppm. HRMS: calcd. for C25H29NO6
439.1995; found 439.1990.
3-Hydroxy-3-(1,4,5,8-tetramethoxynaphthalen-2-yl)propanoic Acid
(4): To a solution of 3 (72.9 g, 0.2 mol) in methanol (400 mL) was
added NaOH (2 m solution, 400 mL) dropwise, and the mixture
was stirred for 2 h at room temperature. After completion of the
reaction, most of the methanol was evaporated under reduced pres-
sure. Then, the obtained crude residue was extracted with CH2Cl2
(3ϫ150 mL). The aqueous phase was carefully acidified with HCl
(6 m solution) to pH = 5 at 0–5 °C, and the nearly white solid pre-
cipitated out of the reaction mixture. Simple filtration and drying
afforded 4 (66.5 g, 0.2 mol, 99%) as an off-white solid; m.p. 50–
54 °C; ref.[12d] m.p. 51–52 °C. 1H NMR [300 MHz, DMSO (di-
methyl sulfoxide)]: δ = 7.10 (s, 1 H, Ar), 6.86 (dd, J = 18.9, 8.7 Hz,
2 H, Ar), 5.53 (t, J = 7.2 Hz, 1 H, CHOHCH2), 3.84 (s, 3 H, Ar-
OCH3), 3.82 (s, 3 H, ArOCH3), 3.76 (s, 3 H, ArOCH3), 3.67 (s, 3
H, ArOCH3), 2.76 (d, J = 6.3 Hz, 2 H, CH2) ppm. 13C NMR
(75 MHz, DMSO): δ = 172.5 (C=O), 152.9 (CnaphOCH3), 151.0
(S)-3-(tert-Butyldimethylsilyloxy)-N-[(S)-1-phenylethyl]-3-(1,4,5,8
tetramethoxynaphthalen-2-yl)propanamide (7): To a cooled (0 °C)
solution of 5 (22 g, 0.05 mol), DMAP (1.22 g, 0.01 mol), and imid-
azole (6.80 g, 0.1 mmol) in dry CH2Cl2 (300 mL) was added drop-
wise a solution of tert-butyldiphenylsilyl chloride (9.04 g, 0.06 mol)
in dry CH2Cl2 (50 mL), and the mixture was stirred for 24 h. After
the completion of reaction, the mixture was diluted with water
(200 mL), and the resulting solution was extracted with CH2Cl2
(3ϫ200 mL). The combined organic layers were washed with brine
(3ϫ200 mL), dried with anhydrous Na2SO4, and evaporated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (PE/EtOAc, 5:1) to give 7 which was puri-
fied further by recrystallization (PE/EtOAc, 4:1) to afford suffi-
ciently pure 7 (26.5 g, 96%) as off-white crystals; m.p. 135–137 °C.
(CnaphOCH3), 149.8 (CnaphOCH3), 145.2 (CnaphOCH3), 134.7 IR (KBr): ν
= 3374, 2929, 2855, 1670, 1603, 1529, 1461, 1360,
˜
max
(CnaphCH), 122.1 (Cnaph), 119.3 (Cnaph), 108.2 (CnaphH), 108.0 1259, 1216, 1072, 1013, 951, 834, 777, 700 cm–1
.
1H NMR
(CnaphH), 105.9 (CnaphH), 63.8 (CHOH), 62.1 (OCH3), 57.1 (300 MHz, CDCl3): δ = 7.17–7.09 (m, 5 H, Ar), 6.89 (s, 1 H, Ar),
(OCH3), 56.8 (OCH3), 56.6 (OCH3), 44.0 (CH2) ppm. MS (ESI):
m/z = 359 [M + Na]+.
6.70 (dd, J = 10.5, 9 Hz, 2 H, Ar), 6.06 (d, J = 7.2 Hz, 1 H,
CHOHCONH), 5.57 (dd, J = 7.8, 3.3 Hz, 1 H, NHCHCH3), 5.06–
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An Efficient Multigram Synthesis of Alkannin and Shikonin
4.97 (m, 1 H, CHOHCONH), 3.80 (s, 3 H, ArOCH3), 3.78 (s, 3 H, (R)-3-(tert-Butyldimethylsilyloxy)-3-(1,4,5,8-tetramethoxynaphth-
ArOCH3), 3.72 (s, 3 H, ArOCH3), 3.66 (s, 3 H, ArOCH3), 2.59– alen-2-yl)propanal (10): To a cooled (–78 °C) solution of 9 (4.39 g,
2.41 (m, 2 H, CH2), 1.38 (d, J = 6.9 Hz, 3 H, NHCHCH3), 0.78 0.01 mmol) in dry CH2Cl2 (60 mL) was added DIBALH (20% in
(s, 9 H, tBuHSi), –0.04 (s, 3 H, CH3Si), –0.25 (s, 3 H, CH3Si) ppm.
toluene, 10 mL, 0.012 mol), and the reaction mixture was stirred at
1 3 C NMR (100 MHz, CDCl3 ): δ = 169.4 (C=O), 153.2 –78 °C for 12 h. Then, the reaction mixture was quenched with a
(CnaphOCH3), 151.4 (CnaphOCH3), 150.3 (CnaphOCH3), 145.4 saturated solution of ammonium chloride (10 mL), and the re-
(CnaphOCH3), 143.4 (CAr), 134.2 (CArH), 128.5 (CArH), 127.2 sulting mixture was extracted with CH2Cl2 (2ϫ100 mL). The com-
(CArH), 126.2 (CnaphCH), 122.7 (Cnaph), 120.1 (Cnaph), 108.0 bined organic layers were washed with brine (200 mL), dried with
(CnaphH) 107.9 (CnaphH), 106.0 (CnaphH), 66.7 (CH), 62.4 (OCH3), anhydrous Na2SO4, and concentrated under vacuum to furnish the
57.6 (OCH3), 57.1 (OCH3), 56.8 (OCH3), 48.8 (CH2), 47.3 residue which was purified by silica gel column chromatography
1
(CHCH3), 25.8 [C(CH3)3], 21.9 (CHCH3), 18.0 [C(CH3)3], –4.78 (PE/EtOAc, 5:1) to afford 10 (3.9 g, 90%) as a light yellow oil. H
(CSi), –5.07 (CSi) ppm. HRMS: calcd. for C31H43NO6Si 553.2860;
found 553.2856.
NMR (300 MHz, CDCl3): δ = 9.84 (s, 1 H, CH2CHO), 7.10 (s, 1
H, Ar), 6.83 (s, 2 H, Ar), 5.80–5.76 (m, 1 H, CHOHCH2), 3.94 (s,
6 H, 2 ArOCH3), 3.90 (s, 3 H, ArOCH3), 3.79 (s, 3 H, ArOCH3),
2.84–2.70 (m, 2 H, CH2), 0.90 (s, 9 H, tBuHSi), 0.11 (s, 3 H,
CH3Si), –0.09 (s, 3 H, CH3Si) ppm. 13C NMR (100 MHz, CDCl3):
δ = 200.9 (CHO), 153.3 (CnaphOCH3), 151.3 (CnaphOCH3), 150.0
(CnaphOCH3), 144.8 (CnaphOCH3), 133.6 (CnaphCH), 120.0 (Cnaph),
107.8 (CnaphH), 107.6 (CnaphH), 105.3 (CnaphH), 64.8 (COH), 62.2
(OCH3), 57.3 (OCH3), 56.7 (OCH3), 56.6 (OCH3), 53.1 (CH2), 25.5
[C(CH3)3], 17.9 [C(CH3)3], –4.83 (CSi), –5.28 (CSi) ppm. MS (ESI):
m/z = 435 [M + H]+.
(R)-3-(tert-Butyldimethylsilyloxy)-N-[(S)-1-phenylethyl]-3-(1,4,5,8-
tetramethoxynaphthalen-2-yl)propanamide (8): Following the same
procedure as described for 7, 8 was obtained as white crystals; m.p.
124–125.5 °C. IR (KBr): νmax = 3371, 2927, 2849, 1640, 1597, 1538,
˜
1456, 1361, 1257, 1196, 1077, 1012, 946, 834, 780, 697 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 7.25–7.17 (m, 5 H, Ar), 6.98 (s, 1
H, Ar), 6.74 (s, J = 9.0, 2.1 Hz, 2 H, Ar), 6.13 (d, J = 6.9 Hz, 1 H,
CHOHCONH), 5.60 (dd, J = 7.8, 3.0 Hz, 1 H, NHCHCH3), 5.08–
4.99 (m, 1 H, CHOHCONH), 3.84 (s, 3 H, 2 ArOCH3), 3.82 (s, 6
H, ArOCH3), 3.73 (s, 3 H, ArOCH3), 2.65–2.47 (m, 2 H, CH2),
1.40 (d, J = 6.9 Hz, 3 H, NHCHCH3), 0.75 (s, 9 H, tBuHSi), –0.08
(s, 3 H, CH3Si), –0.22 (s, 3 H, CH3Si) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.3 (C=O), 153.2 (CnaphOCH3), 151.4 (CnaphOCH3),
(R)-tert-Butyldimethyl-[4-methyl-1-(1,4,5,8-tetramethoxynaphth-
alen-2-yl)pent-3-enyloxy]silane (11): To a cooled (0 °C) solution of
Ph3PCH(CH3)2Br (3.85 g, 0.01 mol) in dry Et2O (100 mL) was
added n-butyllithium (2.5 m in hexane, 3.2 mL, 8 mmol) dropwise
150.3 (CnaphOCH3), 145.4 (CnaphOCH3), 143.2 (CAr), 134.1 (CArH), under a nitrogen atmosphere, and the mixture was stirred for
128.5 (CArH), 127.2 (CArH), 126.4 (CnaphCH), 122.7 (Cnaph), 120.1 30 min at 0 °C. Then, a solution of 10 (2.17 g, 5 mmol) in dry Et2O
(Cnaph), 107.9 (CnaphH), 106.1 (CnaphH), 66.6 (CH), 62.4 (OCH3), (50 mL) was added dropwise, and the mixture was stirred for 2 h
57.5 (OCH3), 57.0 (OCH3), 56.9 (OCH3), 48.8 (CH2), 47.1 at room temperature. After completion of the reaction, the mixture
(CHCH3), 25.7 [C(CH3)3], 21.7 (CHCH3), 18.0 [C(CH3)3], –4.86 was quenched by the slow addition of water (50 mL), and the re-
(CSi), –5.20 (CSi) ppm. HRMS: calcd. for C31H43NO6Si 553.2860;
found 553.2858.
sulting solution was extracted with EtOAc (2ϫ100 mL). The com-
bined organic layers were washed with brine (200 mL), dried with
anhydrous Na2SO4, and concentrated under vacuum to furnish the
crude residue which was purified by silica gel column chromatog-
raphy (PE/EtOAc, 5:1) to afford 11 (1.73 g, 75%) as a yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.15 (s, 1 H, Ar), 6.79 (dd, J =
11.6, 8.8 Hz, 2 H, Ar), 5.34–5.26 (m, 2 H, CHOHCH2 and CH=C),
3.96 (s, 3 H, ArOCH3), 3.91 (s, 3 H, ArOCH3), 3.89 (s, 3 H, Ar-
OCH3), 3.79 (s, 3 H, ArOCH3), 2.50–2.35 (m, 2 H, CH2), 1.72 (s,
3 H, CH3), 1.60 (s, 3 H, CH3), 0.92 (s, 9 H, tBuHSi), 0.08 (s, 3 H,
CH3Si), –0.08 (s, 3 H, CH3Si) ppm. 13C NMR (100 MHz, CDCl3):
δ = 153.0 (CnaphOCH3), 151.6 (CnaphOCH3), 150.3 (CnaphOCH3),
145.2 (CnaphOCH3), 136.0 (C=CH), 133.1 (CnaphCH), 122.6
(Cnaph), 121.7 (C=CH), 119.9 (Cnaph), 107.8 (CnaphH), 107.6
(CnaphH), 106.7 (CnaphH), 69.4 (COH), 62.3 (OCH3), 57.5 (OCH3),
57.1 (OCH3), 56.9 (OCH3), 38.7 (CH2), 25.8 [C(CH3)3], 18.2
[C(CH3)3], –4.70 (CSi), –4.89 (CSi) ppm. MS (ESI): m/z = 483 [M
+ Na]+.
(R)-Methyl 3-(tert-Butyldimethylsilyloxy)-3-(1,4,5,8-tetrameth-
oxynaphthalen-2-yl)propanoate (9): To a cooled (0 °C) solution of
phosphorus pentachloride (33.3 g, 0.16 mol) in dry CH2Cl2
(250 mL) was added pyridine (12.64 g, 0.32 mol) dropwise. After
stirring for 30 min, 8 (22.1 g, 0.04 mol) was added, and the mixture
was stirred for 8 h at 0 °C. Then, the reaction temperature was
cooled to –30 °C, and dry methanol (200 mL) was added slowly
keeping the reaction temperature below –20 °C. The solution
turned dark red and was stirred for 1 h at –20 °C. Then, water
(300 mL) was added, and the mixture was stirred at room tempera-
ture and was monitored by TLC. After completion of the reaction
(12 h), the mixture was extracted with CH2Cl2 (3ϫ200 mL). The
combined organic layers were washed with brine (3 ϫ200 mL),
dried with anhydrous Na2SO4, and concentrated under vacuum to
furnish the residue which was purified by silica gel column
chromatography (PE/EtOAc, 5:1) to afford 9 (14.8 g, 80%) as a
yellow oil. IR (KBr): ν
= 2953, 2929, 2855, 1742, 1601, 1463,
(R)-4-Methyl-1-(1,4,5,8-tetramethoxynaphthalen-2-yl)pent-3-en-1-ol
˜
max
1363, 1256, 1165, 1079, 1015, 954, 833, 779 cm–1
(300 MHz, CDCl3): δ = 7.10 (s, 1 H, Ar), 6.82 (s, 2 H, Ar), 5.75–
5.71 (m, 1 H, CHOHCH2), 3.94 (s, 6 H, 2 ArOCH3), 3.90 (s, 3 H, mixture was stirred at room temperature and was monitored by
.
1H NMR (12): To a solution of 11 (2.3 g, 5 mmol) in dry THF (40 mL) was
added tetra-n-butyl ammonium fluoride (2.61 g, 10 mmol), and the
ArOCH3), 3.81 (s, 3 H, ArOCH3), 3.72 (s, 3 H, CH2CO2CH3),
2.77–2.61 (m, 2 H, CH2), 0.88 (s, 9 H, tBuHSi), 0.07 (s, 3 H,
TLC. After completion of the reaction (3 h), the mixture was
quenched by the addition of water (50 mL), and the resulting solu-
CH3Si), –0.11 (s, 3 H, CH3Si) ppm. 13C NMR (100 MHz, CDCl3): tion was extracted with EtOAc (3ϫ50 mL). The combined organic
δ = 171.4 (C=O), 153.3 (CnaphOCH3), 151.4 (CnaphOCH3), 150.2
phases were washed with brine (50 mL), dried with anhydrous
(CnaphOCH3), 145.1 (CnaphOCH3), 134.1 (CnaphCH), 122.5 (Cnaph), Na2SO4, and concentrated under vacuum to furnish the residue
120.0 (Cnaph), 107.9 (CnaphH), 107.8 (CnaphH), 105.6 (CnaphH), 66.4 which was purified by silica gel column chromatography (PE/
(COH), 62.4 (OCH3), 57.5 (OCH3), 56.9 (OCH3), 56.7 (OCH3), EtOAc, 2:1) to afford 12 (1.64 g, 95%) as a yellow oil. 1H NMR
51.4 (OCH3), 45.3 (CH2), 25.6 [C(CH3)3], 18.0 [C(CH3)3], –4.75
(CSi), –5.34 (CSi) ppm. HRMS: calcd. for C24H36Si 464.2230;
found 464.2226.
(300 MHz, DMSO): δ = 7.04 (s, 1 H, Ar), 6.82 (s, J = 8.7, 16.5 Hz,
2 H, Ar), 5.22–5.31 (m, 2 H, CHOHCH2 and CH=C), 3.82 (s, 3
H, ArOCH3), 3.80 (s, 3 H, ArOCH3), 3.76 (s, 3 H, ArOCH3), 3.61
Eur. J. Org. Chem. 2012, 1373–1379
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1377

R. Wang, S. Zhou, H. Jiang, X. Zheng, W. Zhou, S. Li
FULL PAPER
(s, 3 H, ArOCH3), 2.41–2.28 (m, 2 H, CH2), 1.62 (s, 3 H, CH3),1.50 (CArOCH3), 149.4 (CArOCH3), 141.3 (CArOCOCH3), 135.3
(s, 3 H, CH3) ppm. 13C NMR (75 MHz, DMSO): δ = 152.5
(CArCH), 130.1 (C=CH), 121.6 (CArOCOCH3), 121.1 (C=CH),
(CnaphOCH3), 150.9 (CnaphOCH3), 149.6 (CnaphOCH3), 145.3 118.8 (CArH), 118.5 (CAr), 118.3 (CAr), 107.8 (CArH), 107.5 (CArH),
(CnaphOCH3), 135.5 (CH=C), 131.7 (CnaphCH), 121.9 (Cnaph), 70.6 (CHOCOCH3), 56.8 (OCH3), 56.7 (OCH3), 33.6 (CH2), 25.7
121.4 (CH=C), 119.0 (Cnaph), 108.2 (CnaphH), 107.7 (CnaphH), 106.4 (CH3), 21.1 (CH3), 20.9 (CH3), 20.8 (CH3), 17.8 (CH3) ppm. MS
(CnaphH), 66.2 (COH), 61.9 (OCH3), 57.0 (OCH3), 56.8 (OCH3), (ESI): m/z = 467 [M + Na]+.
56.5 (OCH3), 37.1 (CH2), 25.5 (CH3), 17.6 (CH3) ppm. MS (ESI):
(R)-6-(1-Acetoxy-4-methylpent-3-enyl)-5,8-dimethoxynaphthalene-
m/z = 369 [M + Na]+. HPLC (Sino-chiral OD Chiralpak AD-H;
1,4-diyl Diacetate (16): To a stirred solution of 14 (174 mg,
hexane/iPrOH, 60:40; flow rate = 0.8 mL/min; λ = 220 nm): tR
9.59 min; 99.8% ee.
=
0.5 mmol), Ac2O (8 mL), Et3N (2 mL), and DMAP (6.1 mg,
0.05 mmol) was added Zn powder (325 mg, 5 mmol) at 5 °C, and
(R)-1-(5,8-Dimethoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-meth- the reaction mixture was stirred for 2 h at 20 °C. Then, the mixture
ylpent-3-enyl Acetate (13) and (R)-1-(1,4-Dimethoxy-5,8-dioxo-5,8-
dihydronaphthalen-2-yl)-4-methylpent-3-enyl Acetate (14): To a
solution of 12 (346 mg, 1 mmol), pyridine (0.16 mL, 2 mmol), and
was poured into water (15 mL), and the resulting solution was ex-
tracted with EtOAc (3ϫ30 mL). The organic layers were washed
with saturated aqueous NaHCO3 (3ϫ30 mL) and brine (30 mL)
DMAP (24.4 mg, 0. 2 mmol) in dry CH2Cl2 (10 mL) was added and then concentrated under vacuum to obtain a residue which
Ac2O (0.19 mL, 2 mmol) at 0 °C, and the mixture was stirred for
was purified by silica gel column chromatography (PE/EtOAc, 5:1)
20 min at room temperature. Then, a solution of CAN (1.37 g, to afford 16 (191 mg, 86 %) as a light yellow oil. 1H NMR
2.5 mmol) in water (10 mL) was added dropwise to the reaction
mixture which was stirred for 15 min at room temperature. After
completion of the reaction, the mixture was diluted with water, and
the resulting solution was extracted with CH2Cl2 (3ϫ20 mL). The
combined organic layers were washed with brine (20 mL), dried
with anhydrous Na2SO4, and concentrated under vacuum to fur-
nish the residue which was purified by silica gel column chromatog-
(400 MHz, CDCl3): δ = 7.09 (dd, J = 25.6, 8.4 Hz, 2 H, Ar), 6.83
(s, 1 H, Ar), 6.30–6.24 (m, 1 H, CHOCOCH3), 5.10 (t, J = 7.2 Hz,
1 H, CH=C), 3.90 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 2.60–2.44
(m, 2 H, CH2), 2.35 (s, 3 H, ArOCOCH3), 2.34 (s, 3 H, ArOC-
OCH3), 2.09 (s, 3 H, CHOCOCH3), 1.67 (s, 3 H, CH3), 1.54 (s, 3
H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.1 (C=O),
170.0 (C=O), 169.2 (C=O), 151.9 (CArOCH3), 145.2 (CArOC-
raphy (PE/EtOAc, 2:1) to afford 13 (89 mg, 25%) as a red oil and OCH3), 144.7 (CArOCOCH3), 143.7 (CArOCH3), 134.9 (C=CH),
14 (240 mg, 67%) as a yellow oil. Data for 13: 1H NMR (400 MHz,
131.5 (CArCH), 123.6 (C=CH), 121.1 (CAr), 120.3 (CAr), 119.4
CDCl3): δ = 7.24 (s, 2 H, Ar), 6.57 (s, 1 H, Hquin), 5.85–5.82 (m, 1 (CArH), 118.6 (CArH), 105.0 (CArH), 70.4 (CHOCOCH3), 62.6
H, CHOCOCH3), 5.05–5.01 (m, 1 H, CH=C), 3.86 (s, 6 H, 2
OCH3), 2.53–2.48 (m, 1 H, CH2), 2.39–2.34 (m, 1 H, CH2), 2.03
(OCH3), 56.5 (OCH3), 34.6 (CH2), 25.6 (CH3), 21.2 (CH3), 20.8
(CH3), 20.6 (CH3), 17.7 (CH3) ppm. MS (ESI): m/z = 467 [M +
Na]+.
(s, 3 H, OCOCH3), 1.58 (s, 3 H, CH3), 1.49 (s, 3 H, CH3) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 184.4 (Cquin=O), 183.3 (Cquin=O),
169.5 (C=O), 153.7 (CArOCH3), 153.3 (CArOCH3), 148.0
(CquinCH), 135.5 (CquinH), 133.1 (C=CH), 120.8 (CAr), 120.6
(CArH), 120.3 (CArH), 120.2 (C=CH), 117.9 (CAr), 69.6 (CHOC-
OCH3), 56.6 (OCH3), 32.6 (CH2), 25.5 (CH3), 20.8 (CH3), 17.8
(CH3) ppm. Data for 14: 1H NMR (400 MHz, CDCl3): δ = 7.20 (s,
1 H, Ar), 6.66 (s, 2 H, Hquin), 6.05–6.02 (m, 1 H, CHOCOCH3),
5.02 (t, J = 7.2 Hz, 1 H, CH=C), 3.87 (s, 3 H, OCH3), 3.80 (s, 3
H, OCH3), 2.45–2.37 (m, 2 H, CH2), 2.02 (s, 3 H, OCOCH3), 1.56
(s, 3 H, CH3), 1.42 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 184.1 (Cquin=O), 183.6 (Cquin=O), 169.4 (C=O), 155.6
(CArOCH3), 150.1 (CArOCH3), 143.9 (CquinH), 138.3 (CquinH),
137.3 (CArCH), 135.0 (C=CH), 124.7 (C=CH), 119.7 (CArH), 117.8
(CAr), 116.5 (CAr), 70.0 (CHOCOCH3), 61.5 (OCH3), 56.2 (OCH3),
33.5 (CH2), 25.2 (CH3), 20.5 (CH3), 17.3 (CH3) ppm. MS (ESI):
m/z = 381 [M + Na]+.
(R)-5,8-Dihydroxy-2-(1-hydroxy-4-methylpent-3-enyl)naphthalene-
1,4-dione (Shikonin, 2): To a stirred solution of 15 (67 mg,
0.15 mmol) and 16 (177 mg, 0.4 mmol) in CH3CN (10 mL) was
added a solution of CAN (1.37 g, 2.5 mmol) in water (5 mL) drop-
wise until the solution turned dark red. The solution was stirred
for 15 min at room temperature. Then, NaOH (1 m solution, 5 mL)
was added, and the reaction mixture was stirred for 2 h and then
carefully acidified with HCl (10% solution) to neutralize the mix-
ture. The deep blue color disappeared and turned deep red. The
mixture was extracted with EtOAc (3ϫ20 mL) and brine (20 mL)
and then concentrated under vacuum to obtain the residue which
was purified by silica gel column chromatography (PE/EtOAc,
10:1) to afford 2 (135 mg, 85%) as a red powder; m.p. 145–147 °C;
1
ref.[12k] m.p. 143–145 °C. H NMR (400 MHz, CDCl3): δ = 12.58
(s, 1 H, ArOH), 12.48 (s, 1 H, ArOH), 7.19–7.16 (m, 3 H, Ar and
Hquin), 5.20 (dd, J = 8.0, 6.8 Hz, 1 H, CH=C), 4.93–4.90 (m, 1 H,
ArCHOH), 2.39–2.32 (m, 2 H, CH2), 1.76 (s, 3 H, CH3), 1.65 (s, 3
H, CH3) ppm. 13C NMR (75 MHz, DMSO): δ = 180.6 (C=O),
179.7 (C=O), 164.0 (CArOH), 163.4 (CArOH), 153.6 (CArCH),
132.9 (CArH), 131.8 (CH=C), 131.7 (CArH), 131.6 (CArH), 120.4
(CH=C), 111.7 (CAr), 111.2 (CAr), 66.4 (COH), 35.3 (CH2), 25.5
(CH3), 17.7 (CH3) ppm. HPLC (Sino-chiral OD Chiralpak AD-
(R)-2-(1-Acetoxy-4-methylpent-3-enyl)-5,8-dimethoxynaphthalene-
1,4-diyl Diacetate (15): To a stirred solution of 13 (79 mg,
0.22 mmol), Ac2O (5 mL), Et3N (1 mL), and DMAP (2.4 mg,
0.02 mmol) was added Zn powder (143 mg, 2.2 mmol) at 5 °C, and
the reaction mixture was stirred for 4 h at 20 °C. Then, the mixture
was poured into water (10 mL), and the resulting solution was ex-
tracted with EtOAc (3ϫ20 mL). The organic layers were washed
with saturated aqueous NaHCO3 (3ϫ20 mL) and brine (20 mL)
and then concentrated under vacuum to furnish the crude residue
which was purified by silica gel column chromatography (PE/
H; hexane/iPrOH, 9:1; flow rate = 0.6 mL/min; λ = 516 nm): tR
10.58 min; 99.8% ee (shikonin, 2).
=
Supporting Information (see footnote on the first page of this arti-
cle): Characterisation data for all the products and copies of 1H
NMR, 13C NMR and HPLC data.
1
EtOAc, 4:1) to afford 15 (74 mg, 76%) as a yellow oil. H NMR
(300 MHz, CDCl3): δ = 7.17–7.11 (m, 1 H, Ar), 6.78 (s, 2 H, Ar),
6.19–6.00 (m, 1 H, CHOCOCH3), 5.08–5.03 (m, 1 H, CH=C), 3.85
(s, 6 H, OCH3), 2.63–2.46 (m, 2 H, CH2), 2.38 (s, 3 H, ArOC-
OCH3), 2.36 (s, 3 H, ArOCOCH3), 2.04 (s, 3 H, CHOCOCH3),
1.66 (s, 3 H, CH3), 1.56 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,
Acknowledgments
This work was supported by the National Natural Science Founda-
CDCl3): δ = 170.1 (C=O), 169.9 (C=O), 169.8 (C=O), 149.7 tion of China (NSFC) (grant numbers 30973604 and 91013012),
1378
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1373–1379

An Efficient Multigram Synthesis of Alkannin and Shikonin
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Received: October 15, 2011
Published Online: January 11, 2012
Eur. J. Org. Chem. 2012, 1373–1379
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1379