A new efficient route for multigram asymmetric synthesis of alkannin and shikonin

Article abstract of DOI:10.1002/1521-3765(20020415)8:8<1795::AID-CHEM1795>3.0.CO;2-V

A short and convergent approach for the synthesis of alkannin, shikonin and shikalkin is presented. A Hauser-type annulation of cyanophthalide 26 with enone 7 affords the complete aromatic system in just one step with concomitant attachment of the entire side chain. Subsequent Corey's oxazaborolidine mediated asymmetric reduction of the above advanced intermediate, leads to the required isomer in high enantiomeric excess. Finally, a selective and high yielding deprotection protocol furnishes the title compounds as pure crystalline precipitates. Thus, a multigram synthesis of shikonin, alkannin and shikalkin is achieved in high yield and enantioselectivity.

Full text of DOI:10.1002/1521-3765(20020415)8:8<1795::AID-CHEM1795>3.0.CO;2-V

FULL PAPER
A New Efficient Route for Multigram Asymmetric Synthesis
of Alkannin and Shikonin
Elias A. Couladouros,*[a] Alexandros T. Strongilos,[a] Vassilios P. Papageorgiou,[b] and
Zoi F. Plyta[a]
Abstract: A short and convergent approach for the synthesis of alkannin, shikonin
and shikalkin is presented. A Hauser-type annulation of cyanophthalide 26 with
enone 7 affords the complete aromatic system in just one step with concomitant
attachment of the entire side chain. Subsequent Corey×s oxazaborolidine mediated
asymmetric reduction of the above advanced intermediate, leads to the required
isomer in high enantiomeric excess. Finally, a selective and high yielding deprotection
protocol furnishes the title compounds as pure crystalline precipitates. Thus, a
multigram synthesis of shikonin, alkannin and shikalkin is achieved in high yield and
enantioselectivity.
Keywords: asymmetric synthesis
Michael addition natural
products ¥ oxidation ¥ quinones
¥
¥
anticancer,[13] analgesic and antipyretic,[14] antithrombotic,[15]
immunostimulatory,[16] angiostatic[17] and wound healing prop-
erties.[18] From the chemical point of view, due to the high
chemical reactivity of the naphthazarin moiety, they are
difficult to handle and purify. For example, they are readily
polymerized upon treatment with acids, bases, heat or light
and they are susceptible to oxidation by exposure to air or
light.[9c] Even a simple chromatographic separation usually
results in substantial loss of material and irreversibly colored
silica. Consequently, the efficient preparation of these relatively
small molecules still presents a challenge. Nevertheless, to date,
most of the reported syntheses[19] use naphthazarin as starting
material. This approach usually results in long, non-versatile
synthetic schemes, which in most cases suffer of low yielding
deprotection operations and tedious purification of the final
products. In one of the shortest and most elegant synthesis of
shikonin and alkannin, reported by Nicolaou and Hepworth,
the final deprotection step proceeds in 80% yield albeit in
only 50% conversion, requiring chromatographic purification.[20]
An efficient and general synthetic scheme for naphthazarin
derivatives, suitable for multigram preparations, has to over-
come three main obstacles: a) To construct the fused aromatic
system in a general and convergent way avoiding the use of
the expensive and difficult to derivatize naphthazarin; b) to
secure an orthogonal protection of the hydroxyl and keto
groups of the aromatic rings inasmuch as deprotection of a
tetramethoxy precursor is inefficient and complicated.[21] The
ideal end-step should furnish the final product in pure form
without any need of chromatographic separation; c) to
introduce the side chain and establish the appropriate stereo-
chemistry in an efficient and straightforward way, suitable for
the construction of diversified analogues.
Introduction
The polyhydroxylated ring system of naphthazarin (1), is the
dominant structural characteristic of a number of natural
products exhibiting a wide spectrum of imposing biological
activities. Dynemicin A,[1] fredericamycin A,[2] fusarubin,[3]
bostrycoidin,[4] the novel antitumor antibiotics lomaiviticins A
and B,[5] the structurally related pigments heliquinomycin,[6] g-
rubromycin,[7] and purpuromycin,[8] as well as the antipode
pair alkannin/shikonin[9] (2/3, see below), are representative
examples of this group of compounds. The latter pair and their
OH
O
OH
O
OH
O
OH
OH
OH
O
OH
O
OH
O
1
2
3
closely related derivatives have recently attracted much
attention attributable to their omnifarious biological profile,
including antiinflammatory,[10] antibacterial,[11] antifungal,[12]
[a] Prof. E. A. Couladouros, A. T. Strongilos, Dr. Z. F. Plyta
Chemistry Laboratories, Agricultural University of Athens
Iera Odos 75, Athens 118.55 (Greece)
Fax : (‡301) 677-7849
and
Organic and Bioorganic Chemistry Laboratory
NCSR ™Demokritos∫ 153.10 Ag. Paraskevi Attikis
POB 60228, Athens (Greece)
E-mail: ecoula@mail.demokritos.gr
[b] Prof. V. P. Papageorgiou
Organic Chemistry Laboratory, Chemical Engineering Department
Aristotle University of Thessaloniki, 54006 Thessaloniki (Greece)
Chem. Eur. J. 2002, 8, No. 8
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1795

E. A. Couladouros et al.
FULL PAPER
O
O
OH
O
Results and Discussion
O
ref. [24]
i, ii
O
O
O
Two possible disconnections satisfying the above require-
ments are depicted in Scheme 1. Disconnection A appears to
be more versatile, employing commercially available starting
materials. From the practical point of view, it is suitable for the
preparation of derivatives with modified aromatic skeleton.
However, the resulting reaction sequence of this approach
towards alkannin and shikonin is relatively long. A detailed
investigation regarding this chemistry will be published
elsewhere. On the other hand, disconnection B, which is
presented herein, is shorter and more convergent.
HO
O
6
4
5
iii, iv
OMe
N
viii
v, vi, vii
Br
8
O
O
9
7
Scheme 2. Synthesis of enone 7. i) (CH3)2CHPPh3I, NaN(SiMe3)2, THF,
À10 ! 258C, 6.5 h, 65%; ii) (COCl)2, DMSO, Et3N, CH2Cl2, À78 ! 258C;
iii) CH3PPh3Br, NaN(SiMe3)2, THF, À10 ! 258C, 4 h, 68% (two steps);
iv) Amberlyst 15, THF/H2O, 6 h, 75%; v) KCN, DMF, 2 d, 258C, 86%;
vi) NaOH 2n, MeOH, reflux, 8 h, 90%; vii) MeONHMe ¥ HCl, CBr4,
Hauser
ˆ
pyridine, PPh3, CH2Cl2, 85%; viii) CH2 CHMgBr, THF, À208C, 20 min
Deprotection
annulation
oxidation
OPG2
then saturated aqueous NH4Cl solution, 61%.
PG1O
OH
O
O
B
R
2-iodo-propane and Swern oxidation, yielding intermediate 6.
The latter, upon methylenation of the aldehyde moiety and
controlled deprotection of the ketal by means of an acidic
resin, afforded acryloprenyl 7 in 16% total yield based on
tetronic acid. Alternatively, the same enone was prepared
from Weinreb amide 9,[25] which was synthesized via a known
and efficient reaction sequence[26, 27] from prenylbromide 8.
Vinylation of 9 with the appropriate Grignard reagent
furnished key intermediate 7 in 40% total yield based on
bromide 8.
According to literature,[28] the anion of sulfone 10, an 1,4-
dipole equivalent, was anticipated to be cyclized spontane-
ously to the corresponding bicyclic product 14 upon 1,4-
addition to enone 7 (Scheme 3). Unfortunately, addition of
Michael acceptor 7 to a solution of sulfone 10 pretreated with
OH
OH
PG1O
OPG2O
Asymmetric
reduction or
alkylation
Deprotection
oxidation
Stobbe
condensation
& oxidation
A
PG1O
O
O
O
H
+
OEt
OEt
A
B
PG1, PG2
PG1O
PG1O
protective
groups
-SO2Ph, -CN
-COAlkyl,
-CN, -COOMe
=
X
X
EWG
=
=
O
+
EWG
PG1O
O
Scheme 1. Retrosynthetic analysis for the target compounds.
Following this strategy, the entire carbon skeleton was
envisioned to be constructed in one step applying Hauser type
annulation[22] on a suitable functionalized Michael acceptor.
Thus, enone 7,[23] the synthesis of which is depicted in
Scheme 2, was targeted to be the critical building block.
Tetronic acid (4), after protection of the carbonyl group and
DIBAL reduction, was transformed to semiketal 5[24] which
was successively subjected to Wittig coupling with the ylide of
OMe
SO2Ph
i
+
O
O
10
O
OMe
7
OMe
OMe
OMe
OMe
SO2Ph
SO2Ph
O
O
O
O
O
O
Abstract in Greek:
11
12
OMe
OMe OH
SO2Ph
O
O
+
O
OMe
OMe OH
O
13
14
Scheme 3. Hauser annulation of sulfone 10 with enone 7. i) tBuOH, nBuLi,
0 ! À 788C then 7, À788C ! reflux.
tBuOLi at À788C, furnished almost exclusively 1,4-adduct 13.
Presumably, between the two possible enolate intermediates
11 and 12, the latter predominates due to its extended
conjugation. Since enolate 12 cannot be cyclized intramolec-
ularly, it is converted to ketone 13, after workup of the
reaction. Adduct 13 could not be transformed to the desired
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Alkannin and Shikonin
1795 1803
naphthazarine analogue 14, even after treatment with mild or
strong bases under a variety of conditions.[29] Interestingly,
ketone 14 could be isolated in low yields (5 10%) among
other by-products, when the reaction mixture was heated to
reflux, right after the addition of the Michael acceptor. These
observations suggested that cyclization could take place, only
if the kinetically favored enolate anion 11 was trapped by the
lactonic carbonylate before its conversion to the thermody-
namically stable form 12. The marginal solubility of sulfone 10
and presumably of the intermediate anion does not seem to
favor this reaction sequence.
OMe OTBS
OMe OTBS
i
+
19
OMe OH OTBS
OMe OTBSOH
22
21
OMe OTBS
OMe O
v or
vi
ii, iii,
iv
OMe OTBSOTBS
OMe O
R
24: R = OH
23
ref. [19e]
3
25: R = OTBS
On the other hand, the use of non enolizable Michael
acceptors should lead in better cyclization yields. Indeed,
coupling of acrylonitrile 15 or methyl acrylate 16 with 10,
afforded the corresponding partially protected naphthazar-
ines 17 and 18 in high yields (Scheme 4). Aldehydes 19 and 20
Scheme 5. Formal synthesis of (R)-(‡)-shikonin. i) (À)-Ipc2BAllyl, Et2O,
À1008C, then ethanolamine, 258C, 2 3 h, 84%; ii) TBSOTf, 2,6-lutidine,
CH2Cl2, 08C, 20 min, 96%; iii) OsO4, THF/H2O, NaIO4, 6 h;
iv) CH3CH(CH3)PPh3I, nBuLi, Et2O, 0 ! 258C, 3 h, 72% (two steps);
v) excess TBAF, THF, 258C, 15 min, 5% (23 ! 24); vi) CAN, CH3CN/H2O,
258C, 15 min, 92% (23 ! 25). (À)-Ipc2BAllyl ˆ (À)-B-allyldiisopinocam-
pheylborane, TBAF ˆ tetrabutylammonium fluoride, CAN ˆ ammonium
cerium(iv) nitrate.
OMe
OMe OPG
SO2Ph
i
+
O
R
R
equivalent 10, was subjected to coupling with enone 7, leading
to the desired compound 14 in significantly higher yields
(Scheme 6). Fine-tuning of the reaction conditions according
to the previously described considerations, resulted in a 90%
conversion of the Michael adduct 27 to the naphthazarine
system 14. This approach can be easily recognized to fulfil one
O
15: R = CN
OMe
OMe OPG
16: R = CO2Me
10
17: R = CN, PG = H
18: R = CO2Me, PG = H
19: R = CHO, PG = TBS
20: R = CHO, PG = Me
iv, iii,
v
ii, iii
Scheme 4. Hauser annulation of sulfone 10 with Michael acceptors 15 and
16. i) LDA, THF, 0 ! À788C then 15 or 16, 40 min; ii) (MeO)2SO2,
K2CO3, acetone, reflux, 6 h, 73% (based on 10); iii) DIBAL, CH2Cl2,
À788C, 1 h, 88% (17 ! 20), 95% (18 ! 19); iv) TBSOTf, 2,6-lutidine,
CH2Cl2, 08C, 15 min, 98%; v) NMO, cat. TPAP, CH2Cl2, 3 h, 97%.
DIBAL ˆ diisobutylaluminum hydride, TBSOTf ˆ tert-butyldimethylsilyl
OMe OH
OMe
OMe
CN
O
i
+
O
O
OMe OH
O
trifluoromethanesulfonate,
NMO ˆ 4-methylmorpholine
N-oxide,
OMe
OMe
CN
O
27
14
ii
TPAP ˆ tetrapropylammonium perruthenate.
OMe OAc
OMe OAc
O
were reached applying conventional chemistry on both, nitrile
17 and carboxylate 18. A suitable derivatization of the
aldehyde 20 towards the target molecules, has been reported
to be Brown×s asymmetric allylboration.[30] Following this
protocol, substrate 19 was successfully converted to advanced
intermediate 22 in high yield and 72% ee (Scheme 5). During
this reaction two products were monitored, the expected
alcohol 21 and the isomeric compound 22. Prolonged reaction
times, however, resulted exclusively in the isolation of the
migrated derivative 22. After silylation of alcohol 22, fully
protected shikonin 23 was prepared, within a high yielding
three-step sequence. Attempted deprotection of 23 with
excess TBAF, afforded only traces of the expected quinone
24. On the other hand, utilizing ammonium cerium(iv) nitrate
(CAN), partially desilylated quinone 25 was obtained in
almost quantitative yield. Since the deprotection of inter-
mediate 25, in moderate yield, has already been reported,[21]
this approach is a formal synthesis of compound 3. All
attempts to deprotect effectively compound 25 as well as
related model quinones were unsuccessful. Thus, in the
following final approach, the demethylation was planned
strategically to be carried out before unmasking the quinone
moiety.
+
26
OMe OAc O
OMe OAc OAc
28
29
Scheme 6. Hauser annulation of nitrile 26 with enone 7. i) LDA, THF,
À78 ! 08C then 7, 35 min, 60%; ii) MeCOCl, pyridine, CH2Cl2, 08C,
30 min.
of our primary objectives; to construct the entire carbon
skeleton of the target compound in one operation in relatively
high yield and multigram scale. Based on the experience
gained so far, a suitably protected precursor for both the
asymmetric reduction and the final deprotection operations
should be ketone 28. This intermediate, after reduction of the
carbonyl moiety, was anticipated to undergo complete and
selective demethylation and oxidation to the corresponding
exo-quinone. Subsequent saponification of the remaining
acetates, under fine-tuned experimental conditions, and con-
comitant in situ tautomerization should provide the target
compounds as pure crystalline precipitates. However, acety-
lation under basic conditions, strongly favored the enolisation
of 14 giving rise to mixtures of 28 and 29, whereas the
unwanted isomer predominated. Furthermore, esterification
under acidic conditions (AcOH/EDC) was also unsuccessful.
Consequently, we were opted for a more risky but delicate
Reconsidering Hauser×s annulation, cyanophthalide 26,[31]
which was more soluble than the originally used 1,4-dipole
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E. A. Couladouros et al.
FULL PAPER
approach by introducing the required asymmetry on the
unprotected precursor 14.
same result was obtained even when the temperature was
lowered to À1008C and the substrate was added to a
premixed solution of the catalyst and the borane. The
complete lack of enantioselectivity suggested that catalyst
30 did not participate at all in the above reduction. One
reasonable explanation is that the phenolic hydroxyl groups
are forming strong complexes with oxaborolidine 30 or/and
complex 31. Another possibility is a preferential complexation
of the borane with the substrate, followed by intramolecular
delivery of the hydride. In either case, the catalyst would be
excluded from the reduction complex intermediate. The use
of a Lewis acid such as B(OMe)3 as an in situ protective group
for the free phenols did not affect the ee of the product. The
problem was finally overcome, by adding one equivalent of
the substrate to a premixed solution of three equivalents of
both oxazaborolidine and catecholborane in toluene at
À788C. In this way, the targeted chiral alcohol 24 was isolated
in 80% yield and 83% ee, as was shown by 1H NMR
spectroscopy and HPLC analysis of corresponding MTPA
ester. Similarly, when BH3 ¥ THF was employed as the
reducing agent, the calculated enantioselectivities, using 0.1
or 3 equivalents of catalyst 30, were 30 and 90%, respectively.
In both cases the chemical yield was 77%. Despite the fact
that Corey×s oxazaborolidine is expensive, its effective
recovery assures a cost efficient scale up operation. Bearing
in mind that most of the biological properties of the two
enantiomers are independent of their stereochemistry,[10b]
reduction with NaBH4 is sufficient for large-scale production
of Shikalkin (trade name of their racemic mixture).
Chlorodiisopinocampheylborane (DIPCl),[32] was the first
reagent of choice, since it reduces acetophenones enantiose-
lectively and does not affect double bonds. In addition there is
precedent that it converts ortho-hydroxy-acetophenones[33]
into diols with high enantioselectivity. Thus, reaction of
ketone 14 with 2.1 molar equivalents of (‡)-DIPCl
(Scheme 7) furnished alcohol 24 in affordable enantioselec-
tivity (78%) and moderate chemical yield (40%). In a second
OMe OH
i
ii
24
OMe OH
O
RS
RL
14
Ph
Ph
O
O
-
B
B
N
L
N
O
+
O
Ph
Ph
RS
RS
B
H
L
H
B
L
RL
RL
L
24
Ph
Ph
H
H
Ph
Ph
L2BH
N
O
N
O
B
B
L
L
Final synthetic pathway: In summary, as it is depicted in
Scheme 8, synthons 26 and 7 have been efficiently converted
within two chemical steps to partially protected shikonin (24),
alkannin (32) or shikalkin (33) employing the appropriate
reduction protocol. Although these intermediates seem to be
one step away from the target compounds, it has been
demonstrated that any attempt to deprotect them directly will
end up to a catastrophe. It is, however, well known that
quinone/hydroquinone redox interconversions, as well as
naphthazarine tautomerizations, are quantitative operations.
As a result, a seven-step deprotection protocol which could be
performed in three chemical operations, including reduction
acetylation demethylation oxidation saponification tau-
tomerization neutralization was envisioned. To this end,
reduction and subsequent exhaustive acetylation of com-
pounds 24, 32 and 33 provided the corresponding triacetates
in nearly quantitative yields. To our delight, CAN-mediated
oxidative demethylation proceeded quantitatively, furnishing
BH
nBu
nBu
30
31
Scheme 7. Asymmetric reduction of compound 14. i) (‡)-DIPCl, pyridine,
THF, À208C, then ethanolamine, 258C, 20 h, 48%; ii) (S)-Corey×s catalyst,
catecholborane, toluene, À788C, then aqueous NaBO3 ¥ 4H2O, 20 h, 80%
or (S)-Corey×s catalyst, BH3 ¥ THF, toluene, À20 ! 08C then aqueous
NaBO3 ¥ 4H2O, 18 h, 77%. (‡)-DIPCl ˆ (‡)-B-chlorodiisopino-campheyl-
borane, (S)-Corey×s catalyst ˆ (S)-3,3-diphenyl-1-butyltetrahydro-3H-pyr-
rolo-[1,2-c][1,3,2]oxazaborole.
run, the reaction was performed in the presence of an
equimolar amount of pyridine, as a scavenger for the liberated
hydrogen chloride, yet, the chemical yield still did not exceed
50%. Alternatively, Corey×s oxazaborolidine catalyst[34] was
considered. Catecholborane and borane/tetrahydrofuran
complex (BH3 ¥ THF) which are the most commonly used
reducing agents for the CBS (Corey Bakshi Shibata) re-
duction were employed. The relative reactivity however, of
complex 31 with ketone versus phenolic hydroxyl groups, was
in question. Thus, treatment of 14 with 0.1 equivalents of
catalyst 30 and 2.0 equivalents of catecholborane in THF at
À788C for 6 h afforded, after in situ oxidation with NaBO3,
quinone 24 in 85% yield. The hydroquinone which was
actually formed by this reaction, during the work up was
partially oxidized by air to the corresponding quinone. To
avoid this implication it is preferable to oxidize it in situ, right
1
isomeric naphthazarine derivatives 34 36. Based on H and
13C NMR data, these deprotection products were shown to be
a mixture of the expected compounds 34 36 and their
isomeric endo-quinones (ratio ꢀ8:2, see Experimental Sec-
tion). The presence of the latter isomeric form was further
confirmed after comparison with spectroscopic data of
triacetylated shikonin prepared from an authentic shikonin
sample of natural source. However, due to the tautomeriza-
tion to the thermodynamically stable isomer, which is taking
place in the following step, the formation of this mixture did
not affect the total yield of the final compound. Finally,
1
before workup. H NMR analysis of the MTPA [a-methoxy-
a-(trifluoromethyl)-phenylacetyl] ester revealed that the
reduction proceeded with no enantioselectivity at all. The
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Alkannin and Shikonin
1795 1803
without further purification, unless stated otherwise. All reactions were
monitored by thin-layer chromatography (TLC) carried out on 0.25 mm
Merck silica gel plates (60 F254) using UV light as visualizing agent and
ethanolic phosphomolybdic acid or p-anisaldehyde solution and heat as
developing agents. Merck silica gel (60, particle size 0.040 0.063 mm) was
used for flash column chromatography. NMR spectra were recorded on
Bruker AMX-500, AMX-400 or AC-250 instruments. The following
abbreviations were used to explain NMR signal multiplicities: s ˆ singlet,
d ˆ doublet, t ˆ triplet, q ˆ quartet, m ˆ multiplet, dd ˆ double of doublets.
IR spectra were recorded on a Perkin Elmer 1600 series FT-IR or Nicolet
Magna system 550 FT-IR instruments. Optical rotations were recorded on a
Perkin Elmer 241 polarimeter. High resolution mass spectra (HRMS)
were recorded on a VG ZAB-ZSE mass spectrometer under fast atom
bombardment (FAB) conditions and matrix-assisted (MALDI-FTMS)
mass spectra were recorded on a PerSeptive Biosystems Voyager IonSpect
mass spectrometer. Melting points (m.p.) are uncorrected and were
recorded on a Gallenkamp melting point apparatus.
OMe
CN
OMe O
ii
+
O
O
O
26
OMe
OMe O
OMe O
OH
OH
7
24
32
iii
iv
i
OMe OH
OMe O
OMe OH
OMe OH
O
33
14
OMe OH OH
O
OAc
2-(3-Methyl-buten-2-yl)-[1,3]-dioxalane-2-carbaldehyde (6): A solution of
Me2CHPPh3I (6.19 g, 14.3 mmol) in anhydrous THF (24 mL) was treated
with (Me3Si)2NNa (1m solution in THF, 12.3 mL, 12.3 mmol) at À108C.
After 2 h, a solution of 5[24] (1.5 g, 10.3 mmol) in THF (10 mL) was added
dropwise at À108C and the reaction mixture was then stirred for 5 h at
258C. Upon completion of the reaction (monitored by TLC), a saturated
aqueous NH4Cl solution (30 mL) was added and the mixture was extracted
with Et2O (2 Â 60 mL). The organic extracts were washed with water
(30 mL), brine (30 mL), dried over Na2SO4 and finally concentrated under
reduced pressure. Purification of the crude product by flash column
chromatography (silica gel, hexanes/EtOAc 5:5), afforded [2-(3-methyl-
buten-2-yl)-[1,3]-dioxalan-2-yl]-methanol as a colorless oil (1.15 g, 65%).
Total yield
O
OAc R
R =
based on 26:
34.2%
(ee = 90%)
OAc
OAc
OAc
24
32
33
34
Shikonin (3)
Alkannin (2)
Shikalkin
v,vi,vii
vi,vii
viii
34.2%
(ee = 90%)
R =
35
36
R =
48.2%
Scheme 8. Synthesis of alkannin, shikonin, and shikalkin. i) LDA, THF,
À78 ! 08C then 7, 35 min, 60%; ii) 3 equiv (S)-Corey×s catalyst, 3 equiv
catecholborane, toluene, À788C then aqueous NaBO3 ¥ 4H2O, 20 h, 80%
or 3 equiv (S)-Corey×s catalyst, 3 equiv BH3 ¥ THF, toluene, À20 ! 08C
then aqueous NaBO3 ¥ 4H2O, 18 h, 77%; iii) 3 equiv (R)-Corey×s catalyst,
3 equiv catecholborane, toluene, À788C then aqueous NaBO3 ¥ 4H2O, 20 h,
80% or 3 equiv (R)-Corey×s catalyst, 3 equiv BH3 ¥ THF, toluene, À20 !
08C then aqueous NaBO3 ¥ 4H2O, 18 h, 77%; iv) NaBH4, MeOH, 08C;
v) Na2S2O4, Et2O/H2O; vi) Ac2O, Et3N, cat. DMAP, CH2Cl2, 5 h; vii) CAN,
CH3CN/H2O, 15 min, 34: yield ˆ 77.9% based on 24, 35: yield ˆ 77.6%
based on 32, 36: yield ˆ 86.5% based on 14; viii) 1m NaOH, 1 h, then acetic
acid to neutralization, 95%. DMAP ˆ 4-dimethylaminopyridine.
Rf ˆ 0.67 (hexanes/EtOAc 5:5); IR (neat): nÄ ˆ 3470, 2970, 2910, 1630, 1435,
1
1050 cmÀ1; H NMR (500 MHz, CDCl3, 258C): d ˆ 5.17 (m, 1H, CH), 4.00
ˆ
(s, 4H, OCH2CH2O), 3.53 (d, J ˆ 5.0 Hz, 2H, CH2OH), 2.38 (d, J ˆ 7.5 Hz,
ˆ
2H, CHCH2), 2.00 (brs, 1H, OH), 1.71 (s, 3H, Me), 1.62 (s, 3H, Me).
A solution of freshly distilled oxalylchloride (0.75 mL, 8.6 mmol) in
anhydrous CH2Cl2 (12.5 mL) was cooled at À788C and DMSO (1.15 mL,
16.2 mmol) was added dropwise. After 30 min a solution of [2-(3-methyl-
buten-2-yl)-[1,3]-dioxalan-2-yl]-methanol (1.15 g, 6.7 mmol) in CH2Cl2
(15 mL) was added dropwise and the mixture was stirred at À788C for
another 30 min. Finally Et3N (5.78 mL, 41.5 mmol) was added, the cooling
bath was removed and stirring was continued for 1 h. The reaction was then
quenched with a saturated aqueous NH4Cl solution (10 mL) and extracted
with Et2O (2 Â 50 mL). The combined organic extracts were washed with
brine (30 mL), dried over Na2SO4 and concentrated to afford crude 6,
which was used in the next step without any further purification.
saponification and tautomerization of the latter compounds
utilizing an 1m aqueous NaOH solution followed by careful
acidification with acetic acid in open air, provided the target
molecules as golden shiny deep red crystals which were
collected by simple filtration. The total chemical yield of all
operations from intermediates 24, 32, and 33 up to the final
pure crystalline products, was 75 to 80%.
6-Methyl-hepta-1,5-dien-3-one (7):
A solution of MePPh3Br (6.04 g,
16.9 mmol) in anhydrous THF (30 mL) was treated with (Me3Si)2NNa
(1m solution in THF, 25.4 mL, 25.4 mmol) at À108C. After 2 h, a solution of
the crude aldehyde 6 in THF (10 mL) was added and the mixture was
stirred at 258C approximately 2 h (monitored by TLC). The reaction was
quenched with a saturated aqueous NH4Cl solution (20 mL) and extracted
with Et2O (2 Â 50 mL). The combined organic extracts were washed with
brine (30 mL), dried over Na2SO4 and concentrated under reduced
pressure. The crude product was purified by flash column chromatography
(silica gel, pentane/Et2O 95:5) to afford 3-(3-methyl-buten-2-yl)-2-vinyl-
[1,3]-dioxalane as a colorless oil (764 mg, 68% based on [2-(3-methyl-
buten-2-yl)-[1,3]-dioxalan-2-yl]-methanol). Rf ˆ 0.54 (hexanes/EtOAc
Conclusion
In conclusion, a new method for the preparation of the title
compounds has been found. The approach is short, very
efficient and might find broad application in the synthesis of
many analogues of this family of compounds. More important,
this new synthetic method allows for the multigram scale
preparation of chemically and enantiomerically pure shikonin
or alkannin utilizing a very efficient deprotection protocol.
95:5); IR (neat): nÄ ˆ 3092, 2976, 2885, 1445, 1405, 1380, 1060, 859 cmÀ1
;
1H NMR (250 MHz, CDCl3, 258C): d ˆ 5.78 (dd, J ˆ 9.5, 7.2 Hz, 1H,
ˆ
ˆ
ˆ
CH2 CH), 5.40 (d, J ˆ 9.5 Hz, 1H, CH2 CH), 5.17 (m, 2H, CH2 CH,
ˆ
ˆ
Me2C CH), 3.96 (m, 4H, OCH2CH2O), 2.49 (d, J ˆ 7.2 Hz, 2H, CHCH2),
1.76 (s, 3H, Me), 1.62 (s, 3H, Me).
Amberlyst 15 (200 mg) was added to a solution of 3-(3-methyl-buten-2-yl)-
2-vinyl-[1,3]-dioxalane (250 mg, 1.48 mmol) in THF (15 mL) and water
(0.5 mL). The mixture was shaken for 6 h at 258C and then extracted with
Et2O (2 Â 60 mL). The combined organic extracts were washed with water
(2 Â 20 mL), brine (15 mL), dried over activated MgSO4 and concentrated
to 6 mL volume. The volatile crude product was used in the next step
without further purification.
Experimental Section
General techniques: All reactions were carried out under anhydrous
conditions and argon atmosphere using dry, freshly distilled solvents, unless
otherwise noted. Tetrahydrofuran (THF) and diethyl ether (ether) were
distilled from sodium/benzophenone, dichloromethane (CH2Cl2) from
P2O5 and toluene from sodium. Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous materials, unless stated other-
wise. All reagents were purchased at highest commercial quality and used
Alternatively, to a stirred solution of 9[26, 27] (407 mg, 2.59 mmol) in
anhydrous THF (23 mL) at À208C, was added dropwise a freshly prepared
Chem. Eur. J. 2002, 8, No. 8
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0947-6539/02/0808-1799 $ 20.00+.50/0
1799

E. A. Couladouros et al.
FULL PAPER
solution of vinylmagnesium bromide 1m in THF (3.1 mL, 3.10 mmol). The
mixture was stirred at the same temperature for 20 min and then a
saturated aqueous solution NH4Cl solution (3 mL) was added. The mixture
was then extracted with pentane (2 Â 10 mL) and the organic extracts were
dried over activated MgSO4 and concentrated to 10 mL volume. The
resulting solution of enone 7 was used for the Michael couplings without
further purification. Rf ˆ 0.89 (hexanes/EtOAc 8:2); IR (neat) (crude
product): nÄ ˆ 2964, 2929, 1690, 1621, 1448, 1402, 1298, 1109 cmÀ1; 1H NMR
NMR (250 MHz, CDCl3, 258C) (crude product): d ˆ 6.44 6.13 (m, 2H,
100.8, 91.6, 63.3, 56.0, 55.7; HRMS (FAB): calcd for C15H15ON: 274.1079
[M‡H] ; found 274.1090.
A solution of DIBAL 1.0m in CH2Cl2 (0.20 mL, 0.20 mmol) was added
‡
dropwise to
a stirred solution of 1,4,5,8-tetramethoxy-naphthalene-2-
carbonitrile (50.0 mg, 0.18 mmol) in CH2Cl2 (12 mL) at À788C. The
reaction mixture was stirred at the same temperature approximately 1 h
(monitored by TLC) and then quenched with MeOH (1 mL) followed by
addition of a saturated aqueous sodium potassium tartrate solution (8 mL)
and EtOAc (5 mL). The resulting mixture was stirred vigorously for
approximately 2 h whereupon the organic layer was separated and the
aqueous layer extracted with EtOAc (2 Â 8 mL). The combined organic
extracts were washed with brine (15 mL), dried over Na2SO4, concentrated
under pressure and the crude product was purified by flash column
chromatography (silica gel, hexanes/EtOAc 9:1) to afford 20 as yellow
crystalls (50.5 mg, 88%). All spectroscopic data were in accordance with
the reported ones (see ref. [19b]).
ˆ
ˆ
ˆ
CH CH2), 5.77 (d, J ˆ 10.0 Hz, 1H, CH2), 5.28 (m, 1H, CH CMe2), 3.25
ˆ
ˆ
(d, J ˆ 7.1 Hz, 2H, COCH2), 1.72 (s, 3H, CMe2), 1.61 (s, 3H, CMe2).
Coupling of sulfone 10 with enone 7: A solution of nBuLi 1.6m in hexanes
(0.18 mL, 0.30 mmol) was added dropwise to a stirred solution of tBuOH
(28 mL, 0.30 mmol) in anhydrous THF (2 mL) at 08C. The mixture was
stirred for 5 min and then the temperature was lowered to À788C followed
by addition of a solution of 10[22e] (40 mg, 0.12 mmol) in THF (22 mL). The
resulting yellow mixture was stirred at the same temperature for 20 min
followed by addition of a solution of 7 (29.6 mg, 0.24 mmol) in THF
(1.5 mL). Finally, temperature was raised up to reflux for 3 h and after
cooling the mixture to 258C, a saturated aqueous NH4Cl solution (5 mL)
was added. The mixture was extracted with EtOAc (2 Â 20 mL), the
combined organic extracts were washed with water (10 mL), brine (10 mL),
dried over Na2SO4 and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (silica gel, hexanes/
EtOAc 7:3) to afford 13 as a white solid (36.4 mg, 58%). Rf ˆ 0.31 (hexanes/
Preparation of aldehyde 19 from ester 18: A solution of ester 18 (120.0 mg,
0.43 mmol) in anhydrous CH2Cl2 (7 mL) was treated with 2,6-lutidine
(0.18 mL, 1.5 mmol) and TBSOTf (0.30 mL, 1.29 mmol) at 08C for 10 min.
The reaction mixture was then quenched with MeOH (0.3 mL) and a
saturated aqueous NH4Cl solution (5 mL) was added, followed by
extraction with EtOAc (2 Â 10 mL). The organic layer was washed with
brine (10 mL), dried over Na2SO4 and concentrated under reduced
pressure. The crude product was purified by flash column chromatography
(silica gel, hexanes/Et2O 9:1) to afford 1,4-bis-(tert-butyldimethylsilyloxy)-
EtOAc 5:5); IR (KBr): nÄ ˆ 2920, 1783, 1710, 1500, 1440, 1275 cmÀ1
;
5,8-dimethoxynaphthalene-2-carboxylic methyl ester as
a white solid
1H NMR (250 MHz, CDCl3, 258C): d ˆ 7.90 7.42 (m, 5H, SO2Ph), 7.10
(213.6 mg, 98%) upon prolonged drying under high vacuo. Rf ˆ 0.75
ˆ
(center of ABq, J ˆ 9.4 Hz, Dv ˆ 43.2 Hz, 2H, CHar), 5.15 (m, 1H, CH),
(hexanes/Et2O 8:2); m.p. 65 678C; IR (neat): nÄ ˆ 2951, 2857, 1739, 1608,
3.94 (s, 3H, OMe), 3.91 (s, 3H, OMe), 3.32 3.11 (m, 1H, CHHCH2CO),
1576, 1384, 1366, 1264, 1138, 1061, 930, 809 cmÀ1 1H NMR (500 MHz,
;
ˆ
2.95 (d, J ˆ 7.3 Hz, 2H, CH2CH ), 2.55 2.00 (m, 3H, CHHCH2CO), 1.68
CDCl3, 258C): d ˆ 7.18 (s, 1H, CHar), 6.73 (center of ABq, J ˆ 8.5 Hz, Dv ˆ
39.0 Hz, 2H, CHar), 3.88 (s, 3H, CO2Me), 3.84 (s, 3H, OMe), 3.82 (s, 3H,
OMe), 1.07 (s, 9H, tBuSi), 1.03 (s, 9H, tBuSi), 0.20 (s, 6H, Me2Si), 0.00 (s,
6H, Me2Si); 13C NMR (125.7 MHz, CDCl3, 258C): d ˆ 167.7, 152.0, 150.2,
146.8, 146.0, 123.9, 123.2, 119.9, 116.8, 107.5, 105.7, 55.7, 55.3, 51.8, 26.0, 25.9,
18.0, 18.2, À4.5, À5.1; HRMS (FAB): calcd for C26H42O6Si2: 507.2598
ˆ
ˆ
(s, 3H, CMe2), 1.50 (s, 3H, CMe2).
A second product isolated and characterized was the hydroxyketone 14 as
an orange yellow solid (6.1 mg, 8%). Rf ˆ 0.55 (hexanes/EtOAc 5:5); m.p.
108 1108C; IR (KBr): nÄ ˆ 3368, 2925, 1632, 1581, 1392, 1256, 1194, 1095,
1
1048, 866, 807 cmÀ1; H NMR (250 MHz, CDCl3, 258C): d ˆ 13.17 (s, 1H,
‡
OH), 9.14 (s, 1H, OH), 7.08 (s, 1H, CHar), 6.76 (center of ABq, J ˆ 8.7 Hz,
[M‡H] ; found 507.2614.
ˆ
Dv ˆ 32.9 Hz, 2H, CHar), 5.45 (m, 1H, CH), 3.95 (s, 3H, OMe), 3.92 (s,
A solution of DIBAL 1.0m in CH2Cl2 (0.87 mL, 0.86 mmol) was added
dropwise to a stirred solution of 1,4-bis-(tert-butyldimethylsilyloxy)-5,8-
dimethoxynaphthalene-2-carboxylic methyl ester (200.0 mg, 0.39 mmol) in
CH2Cl2 (20 mL) at À788C. The reaction mixture was stirred at the same
temperature approximately 15 min (monitored by TLC) and then
quenched with MeOH (1 mL) followed by addition of a saturated aqueous
sodium potassium tartrate solution (10 mL) and EtOAc (10 mL). The
resulting mixture was stirred vigorously approximately 2 h whereupon the
organic layer was separated and the aqueous extracted with EtOAc (2 Â
15 mL). The combined organic extracts were washed with brine (15 mL),
dried over Na2SO4, concentrated under reduced pressure and the crude
product was purified by flash column chromatography (silica gel, hexanes/
Et2O 7:3) to afford [1,4-bis-(tert-butyldimethylsilyloxy)-5,8-dimethoxy-
naphthalen-2-yl]-methanol as a colorless oil (177.4 mg, 95%). Rf ˆ 0.35
(hexanes/Et2O 7:3); IR (neat): nÄ ˆ 3445, 2929, 2856, 1602, 1373, 1258, 1062,
ˆ
3H, OMe), 3.71 (d, J ˆ 6.7 Hz, 2H, CH2), 1.75 (s, 3H, CMe2), 1.67 (s, 3H,
CMe2); 13C NMR (62.9 MHz, CDCl3, 258C): d ˆ 203.3, 155.3, 152.9, 149.3,
ˆ
135.6, 120.4, 118.0, 116.0, 115.0, 108.8, 108.6, 106.2, 56.6, 56.5, 39.6, 25.2,
‡
18.1; HRMS (MALDI): calcd for C18H20O5: 317.1383 [M‡H] ; found
317.1370.
Coupling of sulfone 10 with Michael acceptors 15 and 16: A suspension of
10 (250.0 mg, 0.75 mmol) in THF (90 mL) was added dropwise to a stirred
solution of LDA (2.24 mmol) in anhydrous THF (15 mL) at À788C. The
yellow suspension was stirred at the same temperature for 30 min and then
Michael acceptor 15 or 16 (2.24 mmol) was added in one portion. After
10 min the reaction mixture was quenched with a saturated aqueous NH4Cl
solution (10 mL) and temperature was raised to 258C under vigorous
stirring. The organic layer was separated and the aqueous layer was
extracted with EtOAc (2 Â 20 mL). The combined organic extracts were
washed with brine (50 mL), dried over Na2SO4 and concentrated under
reduced pressure. The crude ester 18 was purified by small column filtration
(silica gel, hexanes/Et2O 6:4) while nitrile 17 was not subjected to any
purification. Both 17 and 18 are easily oxidisable yellow oils.
1
926, 839 cmÀ1; H NMR (500 MHz, CDCl3, 258C): d ˆ 6.95 (s, 1H, CHar),
6.63 (s, 2H, CHar), 4.76 (d, J ˆ 3.5 Hz, 2H, CH2OH), 3.83 (s, 3H, OMe),
3.79 (s, 3H, OMe), 1.05 (s, 9H, tBuSi), 1.03 (s, 9H, tBuSi), 0.18 (s, 6H,
Me2Si), 0.00 (s, 6H, Me2Si); 13C NMR (125.7 MHz, CDCl3, 258C): d ˆ
150.6, 150.3, 146.5, 141.9, 128.7, 122.5, 121.5, 116.8, 105.0, 104.7, 60.8, 55.5,
55.2, 25.9, 25.8, 18.5, 18.3, À4.4, À4.5; HRMS (FAB) calcd for C25H42O5Si2:
Preparation of aldehyde 20 from nitrile 17: Nitrile 17 was dissolved in
anhydrous acetone (5.5 mL) and transferred into an autoclave. Then,
anhydrous K2CO3 (535.5 mg, 3.86 mmol) and (MeO)2SO2 (0.25 mL,
2.64 mmol) were added successively. The autoclave was sealed under
argon and the mixture was stirred at 658C for 6 h. Upon completion of the
reaction (monitored by TLC), water (15 mL) was added followed by
extraction with EtOAc (20 mL). The organic layer was washed with brine
(15 mL), dried over Na2SO4 and concentrated under reduced pressure. The
crude product was purified by flash column chromatography (silica gel,
hexanes/EtOAc 7:3) to afford 1,4,5,8-tetramethoxy-naphthalene-2-carbon-
itrile as a pale yellow crystalline solid (204.2 mg, 73% based on 10). Rf ˆ
0.75 (hexanes/EtOAc 5:5); m.p. 94 968C; IR (KBr): nÄ ˆ 2818, 2208, 1600,
‡
479.2649 [M‡H] ; found 479.2662.
A solution of [1,4-bis-(tert-butyldimethylsilyloxy)-5,8-dimethoxynaphtha-
len-2-yl]-methanol (160.4 mg, 0.34 mmol) in anhydrous CH2Cl2 (15 mL),
was treated with 4-methylmorpholine N-oxide (98.1 mg, 0.84 mmol) and
TPAP (23.5 mg, 0.07 mmol) at 258C for 3 h (the reaction progress was
monitored by TLC). The reaction mixture was then filtered through a pad
of silica gel (CH2Cl2) and the organic solvent was concentrated under
reduced pressure to afford 19 as a yellow oil (154.9 mg, 97%), which was
used in the next step without further purification. Rf ˆ 0.70 (hexanes/Et2O
7:3); IR (neat): nÄ ˆ 2955, 2858, 1678, 1605, 1574, 1516, 1392, 1372, 1259,
1074, 1059, 925, 841 cmÀ1; 1H NMR (400 MHz, CDCl3, 258C): d ˆ 10.40 (s,
1H, CHO), 7.15 (s, 1H, CHar), 6.78 (center of ABq, J ˆ 8.7 Hz, Dv ˆ
44.4 Hz, 2H, CHar), 3.84 (s, 3H, OMe), 3.83 (s, 3H, OMe), 1.07 (s, 9H,
tBuSi), 1.01 (s, 9H, tBuSi), 0.20 (s, 6H, Me2Si), 0.00 (s, 6H, Me2Si);
1580, 1260 cmÀ1
;
1H NMR (500 MHz, CDCl3, 258C): d ˆ 6.98 (center of
ABq, J ˆ 9.8 Hz, Dv ˆ 35.5 Hz, 2H, CHar), 6.83 (s, 1H, CHar), 3.96 (s, 6H,
OMe), 3.94 (s, 3H, OMe), 3.91 (s, 3H, OMe); 13C NMR (125.7 MHz,
CDCl3, 258C): d ˆ 153.5, 149.5, 144.4, 144.0, 124.1, 118.1, 115.9, 109.6, 101.5,
1800
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
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Chem. Eur. J. 2002, 8, No. 8

Alkannin and Shikonin
1795 1803
13C NMR (100.5 MHz, CDCl3, 258C): d ˆ 189.6, 152.2, 151.8, 150.8, 146.9,
130.9, 128.8, 124.6, 111.4, 109.2, 106.26, 55.9, 55.4, 25.9, 25.8, 18.5, À4.4,
mixture was stirred at 258C for 45 min. To the resulting deep red solution
was added dropwise at 08C a solution of the crude propionaldehyde in
Et2O (3 mL) and stirring was continued for 2 h at 258C. Upon completion
of the reaction (monitored by TLC), a saturated aqueous NH4Cl solution
(10 mL) was added and the mixture was extracted with EtOAc (2 Â 10 mL).
The organic extracts were washed with water (10 mL) and brine (10 mL),
dried over Na2SO4 and finally concentrated under reduced pressure.
Purification of the crude product by flash column chromatography (silica
gel, hexanes/EtOAc 95:5), afforded 23 as a colorless oil (80.9 mg, 72%
based on 1,4-bis-(tert-butyldimethylsilyloxy)-2-[1-(tert-butyldimethylsilyl-
oxy)-but-3-enyl]-5,8-dimethoxynaphthalene). Rf ˆ 0.85 (hexanes/EtOAc
8:2); IR (thin film): nÄ ˆ 2954, 2859, 1600, 1472, 1378, 1254, 1063, 928,
‡
À4.8; HRMS (FAB) calcd for C25H40O5Si2: 477.2493 [M‡H] ; found
477.2478.
4-(tert-Butyldimethylsilyloxy)-2-[1-(tert-butyldimethylsilyloxy)-but-3-en-
yl]-5,8-dimethoxynaphthalen-1-ol (22):
A solution of aldehyde 19
(140.1 mg, 0.29 mmol) in anhydrous ether (4 mL) was cooled to À1008C.
To this solution was added (À)-B-allyldiisopinocampheylborane (2.3 mL,
0.15m in pentane, 0.35 mmol) by cannulation during 15 min. (À)-B-
Allyldiisopinocampheylborane in pentane was typically prepared by the
adaptation of the original method reported by Brown.[35] Upon completion
of the addition, the mixture was stirred at the same temperature
approximately 30 min and then the reaction was quenched with MeOH
(0.3 mL). The mixture was then brought to 258C and ethanolamine
(1.5 mL) was added. Stirring was continued for 2 3 h followed by addition
of a saturated aqueous NH4Cl solution (5 mL) and EtOAc (8 mL). The
organic layer was separated and the aqueous layer was extracted with
EtOAc (2 Â 7 mL). The combined organic extracts were washed with brine
(10 mL), dried over Na2SO4 and concentrated under reduced pressure. The
crude product was purified by flash column chromatography (silica gel,
hexanes/EtOAc 7:3) to afford 22 as a colorless oil (127.9 mg, 84%). Rf ˆ
0.45 (hexanes/Et2O 7:3); [a]D25 ˆ ‡45.7 (c ˆ 1.0 in CHCl3); IR (neat): nÄ ˆ
3383, 2955, 2856, 1615, 1385, 1250, 1055, 902, 833 cmÀ1; 1H NMR (500 MHz,
CDCl3, 258C): d ˆ 9.66 (s, 1H, OH), 7.07 (s, 1H, CHar), 6.62 (center of ABq,
1
838 cmÀ1; H NMR (250 MHz, CDCl3, 258C): d ˆ 7.07 (s, 1H, CHar), 6.56
(center of ABq, J ˆ 8.6 Hz, Dv ˆ 11.5 Hz, 2H, CHar), 5.22 5.07 (m, 2H,
ˆ
CH, CH2CHOSi), 3.80 (s, 3H, OMe), 3.69 (s, 3H, OMe), 2.53 2.25 (m,
ˆ
ˆ
2H, CH2), 1.58 (s, 3H, CMe2), 1.43 (s, 3H, CMe2), 1.02 (s, 9H, tBuSi),
1.01 (s, 9H, tBuSi), 0.90 (s, 9H, tBuSi), 0.16 (s, 6H, Me2Si), 0.10 (s, 3H,
Me2Si), 0.05 (s, 3H, Me2Si), À0.06 (s, 3H, Me2Si), À0.07 (s, 3H, Me2Si);
13C NMR (62.9 MHz, CDCl3, 258C): d ˆ 151.1, 150.7, 145.9, 140.2, 133.3,
132.5, 128.3, 122.8, 121.0, 115.8, 106.5, 103.7, 69.1, 56.4, 55.4, 37.4, 26.1, 26.0,
25.9, 18.6, 18.4, 18.1, 17.9, 2.9, 2.8, 2.6, 2.4, 1.9.
Preparation of quinone 25 from 23: A solution of ammonium cerium(iv)
nitrate (301.5 mg, 0.55 mmol) in water (2 mL) was added dropwise to a
stirred solution of 23 (70.4 mg, 0.11 mmol) in CH3CN (5 mL) at 08C. The
reaction mixture was brought to 258C, stirred for additional 15 min and
then diluted with water (5 mL) and EtOAc (7 mL). The organic layer was
separated and the aqueous layer was extracted with EtOAc (2 Â 8 mL). The
combined organic extracts were washed with brine (10 mL), dried over
Na2SO4 and concentrated under reduced pressure. Small column filtration
of the crude product (silica gel, hexanes/EtOAc 7:3) afforded 25 as an
orange-yellow oil (43.6 mg, 92%). All spectroscopic data were in accord-
ance with the reported ones (see ref. [19e]).
ˆ
J ˆ 8.5 Hz, Dv ˆ 41.0 Hz, 2H, CHar), 5.90 5.80 (m, 1H, CH), 5.30 (t, J ˆ
ˆ
6.0 Hz, 1H, CH2CHO), 5.02 4.96 (m, 2H, CH2), 3.99 (s, 3H, OMe), 3.84
(s, 3H, OMe), 2.47 2.44 (m, 2H, CH2), 1.03 (s, 9H, tBuSi), 0.91 (s, 9H,
tBuSi), 0.19 (s, 3H, Me2Si), 0.17 (s, 3H, Me2Si), 0.06 (s, 3H, Me2Si), 0.00 (s,
3H, Me2Si); 13C NMR (125.7 MHz, CDCl3, 258C): d ˆ 151.9, 150.0, 143.9,
143.5, 135.6, 130.9, 128.8, 127.0, 120.3, 116.9, 116.5, 104.1, 103.4, 67.7, 55.4,
55.5, 43.3, 26.1, 26.0, 18.6, 18.2, À4.3, À4.4, À4.7, À5.1; HRMS (FAB) calcd
‡
for C28H46O5Si2: 651.1938 [M‡Cs] ; found 651.1918. Enantiomeric excess
(ee) of this compound was measured to be 72% by Mosher×s ester analysis
of final product 3 which is derived from this.
Coupling of nitrile 26 with enone 7: A solution of 26[31b] (500.0 mg,
2.28 mmol) in THF (25 mL) was added dropwise to a stirred solution of
LDA (4.56 mmol) in anhydrous THF (25 mL) at À788C. The yellow
solution was stirred at the same temperature for 30 min. The acetone/dry
ice bath was then replaced by an ice bath and enone 7 (424.9 mg, 3.4 mmol)
in THF (20 mL) was added in one portion. A dark red color appeared
immediately and after 5 min the reaction was quenched with a saturated
aqueous NH4Cl solution (40 mL) under vigorous stirring. The organic layer
was separated and the aqueous layer was extracted with EtOAc (2 Â
30 mL). The combined organic extracts were washed with brine (40 mL),
dried over Na2SO4 and the organic solvents were evaporated under reduced
pressure. The crude product was purified by flash column chromatography
(silica gel, hexanes/EtOAc 7:3 to 6:4) to afford 14 as an orange yellow solid
(433.0 mg, 60%, full data have been reported previously in this Exper-
imental Section). A second product isolated and characterized was the
Michael adduct 27 (94.0 mg, 12%) as a white solid. Rf ˆ 0.50 (hexanes/
EtOAc 5:5); m.p. 125 1278C; IR (KBr): nÄ ˆ 2927, 2843, 2248, 1788, 1713,
1,4-Bis-(tert-butyldimethylsilyloxy)-2-[1-(tert-butyldimethylsilyloxy)-4-
methyl-pent-3-enyl]-5,8-dimethoxynaphthalene (23):
A solution of 22
(107.8 mg, 0.21 mmol) in anhydrous CH2Cl2 (4 mL) was treated with 2,6-
lutidine (36.3 mL, 0.31 mmol) and TBSOTf (57.3 mL, 0.25 mmol) at 08C for
20 min. The reaction mixture was then quenched with MeOH (0.1 mL) and
a saturated aqueous NH4Cl solution (4 mL) was added followed by
extraction with EtOAc (2 Â 8 mL). The organic layer was washed with
brine (10 mL), dried over Na2SO4 and concentrated under reduced
pressure. The crude product was purified by flash column chromatography
(silica gel, hexanes/Et2O 9:1) to afford 1,4-bis-(tert-butyldimethylsilyloxy)-
2-[1-(tert-butyldimethylsilyloxy)-but-3-enyl]-5,8-dimethoxynaphthalene as
a colorless oil (126.3 mg, 96%). Rf ˆ 0.85 (hexanes/Et2O 7:3); [a]2D5 ˆ ‡7.8
(c ˆ 1.0 in CHCl3); IR (thin film): nÄ ˆ 2953, 2857, 1601, 1472, 1375, 1256,
1063, 928, 838 cmÀ1
;
1H NMR (500 MHz, CDCl3, 258C): d ˆ 7.07 (s, 1H,
CHar), 6.59 (center of ABq, J ˆ 8.5 Hz, Dv ˆ 17.5 Hz, 2H, CHar), 5.83 5.74
1
(m, 1H, CH), 5.24 (t, J ˆ 5.5 Hz, 1H, CH2CHOSi), 4.98 4.93 (m, 2H,
1512, 1443, 1283, 1021, 972, 825 cmÀ1; H NMR (500 MHz, CDCl3, 258C):
ˆ
ˆ
CH2), 3.83 (s, 3H, OMe), 3.73 (s, 3H, OMe), 2.51 2.47 (m, 2H, CH2), 1.06
d ˆ 7.07 (center of ABq, J ˆ 8.9 Hz, Dv ˆ 83.8 Hz, 2H, CHar), 5.30 5.18 (m,
ˆ
1H, CH), 3.93 (s, 3H, OMe), 3.91 (s, 3H, OMe), 3.08 (d, J ˆ 7.0 Hz, 2H,
(s, 9H, tBuSi), 1.03 (s, 9H, tBuSi), 0.94 (s, 9H, tBuSi), 0.20 (s, 3H, Me2Si),
0.19 (s, 3H, Me2Si), 0.14 (s, 3H, Me2Si), À0.03 (s, 3H, Me2Si), À0.04 (s, 3H,
Me2Si), À0.05 (s, 3H, Me2Si); 13C NMR (125.7 MHz, CDCl3, 258C): d ˆ
151.0, 150.7, 146.0, 140.2, 135.3, 132.8, 122.8, 121.0, 116.7, 115.7, 106.3, 103.8,
68.7, 56.3, 55.4, 43.1, 26.1, 26.0, 18.5, 18.4, 18.2, À3.5, À4.0, À4.2, À4.3,
ˆ
CH2CH ), 2.86 2.62 (m, 3H, CHHCH2), 2.22 2.13 (m, 1H, CHHCH2),
1.72 (s, 3H, CMe2), 1.60 (s, 3H, CMe2); 13C NMR (62.9 MHz, CDCl3,
258C): d ˆ 206.5, 165.0, 152.3, 147.6, 133.8, 119.0, 115.2, 114.5, 112.8, 75.6,
56.5, 56.4, 42.7, 36.2, 31.3, 25.7, 18.0; HRMS (MALDI): calcd for
ˆ
ˆ
‡
‡
À4.4, À4.5; HRMS (FAB): calcd for C28H46O5Si2: 633.3827 [M‡H] ; found
C19H21NO5: 366.1312 [M‡Na] ; found 366.1305.
633.3769.
Reduction of ketone 14 with Corey×s oxazaborolidine and catecholborane:
A solution of 1,4-bis-(tert-butyldimethylsilyloxy)-2-[1-(tert-butyldimethyl-
silyloxy)-but-3-enyl]-5,8-dimethoxynaphthalene (105.2 mg, 0.17 mmol) in a
1:1 mixture of THF/H2O (6 mL) was treated with a solution of OsO4 1% in
H2O (0.22 mL, 0.0085 mmol) and sodium periodate (145.4 mg, 0.68 mmol).
The mixture was stirred for 6 h at 258C and then diluted with water (10 mL)
and EtOAc (15 mL). The organic layer was separated and the aqueous
layer was extracted with EtOAc (3 Â 8 mL). The combined organic extracts
were washed with water (15 mL), brine (10 mL), dried over Na2SO4 and
concentrated under reduced pressure to afford crude 3-[1,4-bis-(tert-
butyldimethylsilyloxy)-5,8-dimethoxynaphthalen-2-yl]-3-(tert-butyldime-
thylsilyloxy)-propionaldehyde. Then, a solution of Me2CHPPh3I (110.2 mg,
0.26 mmol) in anhydrous Et2O (3 mL) was treated with nBuLi 1.6m in
hexane (0.14 mL, 0.22 mmol) at 08C. The ice bath was removed and the
A
mixture of (S)-3,3-diphenyl-1-butyltetrahydro-3H-pyrrolo-[1,2-c]-
[1,3,2]oxazaborole (Corey×s oxazaborolidine, 0.2m in toluene, 14.25 mL,
2.85 mmol) and catecholborane (1m in THF, 2.85 mL, 2.85 mmol) was
added dropwise at À788C to a solution of 14 (300.0 mg, 0.95 mmol) in
anhydrous toluene (25 mL). The reaction mixture was stirred at À788C for
8 h and then quenched with methanol (2 mL) at the same temperature
followed by addition of water (15 mL) and NaBO3 ¥ 4H2O (2.2 g,
14.25 mmol). The mixture was stirred vigorously overnight and then
extracted with EtOAc (2 Â 25 mL). The combined organic extracts were
washed successively with an 1n HCl solution (25 mL) for the recover of the
catalyst as a salt, water (2 Â 15 mL), brine (30 mL) and dried over Na2SO4.
The solvents were evaporated under reduced pressure and the crude
product was purified by flash column chromatography (silica gel, hexanes/
Chem. Eur. J. 2002, 8, No. 8
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0808-1801 $ 20.00+.50/0
1801

E. A. Couladouros et al.
FULL PAPER
EtOAc 5:5) to afford 24 as an orange oil (240.0 mg, 80%). Rf ˆ 0.30
(hexanes/EtOAc 5:5); [a]2D5 ˆ ‡19.4 (c ˆ 0.57 in CHCl3); IR (neat): nÄ ˆ
(250 MHz, CDCl3, 258C): d ˆ 7.17 7.05 (m, 1H, CHar), 6.74 (s, 2H, CHar),
ˆ
6.22 5.93 (m, 1H, CHOAc), 5.04 (t, J ˆ 7.4 Hz, 1H, CH), 3.81 (s, 6H,
3490, 2932, 1652, 1570, 1480, 1286, 1214, 1050, 829 cmÀ1
;
1H NMR
OMe), 2.68 2.41 (m, 2H, CH2), 2.34 (s, 3H, OAc), 2.31 (s, 3H, OAc), 2.01
(s, 3H, OAc), 1.63 (s, 3H, CMe2), 1.53 (s, 3H, CMe2); 13C NMR
(62.9 MHz, CDCl3, 258C): d ˆ 169.9, 169.7, 149.6, 149.3, 141.2, 135.2, 128.3,
121.5, 121.0, 118.8, 118.4, 118.2, 107.7, 107.4, 70.6, 68.9, 56.7, 33.6, 25.6, 21.0,
ˆ
ˆ
(250 MHz, CDCl3, 258C): d ˆ 7.30 (s, 2H, CHar), 6.78 (s, 1H, CHquin),
ˆ
5.16 (m, 1H, CH), 4.75 (m, 1H, CHOH), 3.94 (s, 6H, OMe), 2.60 (m, 1H,
ˆ
ˆ
CH2), 2.40 (m, 1H, CH2), 1.70 (s, 3H, CMe2), 1.60 (s, 3H, CMe2);
13C NMR (62.9 MHz, CDCl3, 258C): d ˆ 184.9, 153.8, 153.5, 150.4, 136.4,
133.7, 128.3, 120.4, 120.0, 118.9, 68.9, 56.7, 56.8, 35.4, 29.6, 25.9, 18.0; HRMS
‡
20.8, 20.7, 17.8; HRMS (MALDI): calcd for C24H28O8: 467.1676 [M‡Na] ;
found 467.1678.
‡
(MALDI): calcd for C18H20O5: 317.1383 [M‡H] ; found 317.1380. Enan-
A solution of ammonium cerium(iv) nitrate (1.23 g, 2.25 mmol) in water
(5 mL) was added dropwise to a stirred solution of either A, B or C
(200.0 mg, 0.45 mmol) in CH3CN (10 mL) at 08C. The reaction mixture was
brought to 258C, stirred for additional 15 min and then diluted with water
(15 mL) and EtOAc (15 mL). The organic layer was separated and the
aqueous layer was extracted with EtOAc (2 Â 10 mL). The combined
organic extracts were washed with brine (15 mL), dried over Na2SO4 and
concentrated under reduced pressure. Small column filtration of the crude
product (silica gel, hexanes/EtOAc 7:3) afforded 34, 35, and 36, respec-
tively, as yellow oils (177.2 mg, 95%). 34, 35, and 36: Rf ˆ 0.65 (hexanes/
EtOAc 7:3); [a]2D5 ˆ ‡54.0 (c ˆ 1.05 in CHCl3) for 34, [a]2D5 ˆ À54.0 (c ˆ
1.05 in CHCl3) for 35; IR (neat): nÄ ˆ 2938, 2853, 1771, 1735, 1611, 1462,
tiomeric excess (ee) of this compound was measured to be 83% yield by
Mosher×s ester analysis of final product 3 which is derived from this.
Reduction of ketone 14 with Corey×s oxazaborolidine and BH3 ¥ THF: A
mixture of (S)-3,3-diphenyl-1-butyltetrahydro-3H-pyrrolo-[1,2-c][1,3,2]ox-
azaborole (Corey×s oxazaborolidine, 0.2m in toluene, 14.25 mL, 2.85 mmol)
and BH3 ¥ THF (1m in THF, 2.85 mL, 2.85 mmol) was added dropwise to a
À208C solution of 14 (300.0 mg, 0.95 mmol) in anhydrous toluene (25 mL).
The reaction mixture was stirred at À208C for 1 h and then temperature
was raised to 08C. Stirring was continued approximately 6 h (reaction
progress was monitored by TLC) and then the reaction was quenched with
methanol (2 mL) at the same temperature followed by addition of water
(15 mL) and NaBO3 ¥ 4H2O (2.2 g, 14.25 mmol). The mixture was stirred
vigorously overnight and then extracted with EtOAc (2 Â 25 mL). The
combined organic extracts were washed successively with an 1n HCl
solution (25 mL) for the removal of the catalyst as a salt, water (2 Â 15 mL),
brine (30 mL) and dried over Na2SO4. The solvents were evaporated under
reduced pressure and the crude product was purified by flash column
chromatography (silica gel, hexanes/EtOAc 5:5) to afford 24 as an orange
oil (231.4 mg, 77%). [a]2D5 ˆ ‡27.3 (c ˆ 0.39 in CHCl3). Enantiomeric excess
(ee) of this compound was measured to be 90% yield by Mosher×s ester
analysis of final product 3 which is derived from this.
1368, 1214, 1048, 928, 812 cmÀ1 1H NMR (250 MHz, CDCl3, 258C): d
;
ˆ
(major isomer) ˆ 7.39 (s, 1H, CHar), 6.74 (s, 2H, CH CHquin), 6.02 5.89 (m,
ˆ
1H, CHOAc), 5.00 (t, J ˆ 7.4 Hz, 1H, CH), 2.54 2.37 (m, 2H, CH2), 2.43
ˆ
(s, 3H, OAc), 2.40 (s, 3H, OAc), 2.03 (s, 3H, OAc), 1.64 (s, 3H, CMe2),
ˆ
1.49 (s, 3H, CMe2); d (minor isomer) ˆ 7.33, 6.63, 5.89 5.81, 5.05, 2.56
2.27, 2.05, 1.63, 1.52; 13C NMR (62.9 MHz, CDCl3, 258C):
d (both
isomers) ˆ 183.2, 183.0, 182.9, 169.7, 169.1, 148.8, 147.7, 147.3, 147.6, 147.2,
142.5, 138.6, 138.3, 136.4, 136.0, 133.3, 131.0, 130.9, 124.5, 124.1, 117.6, 117.3,
69.2, 33.3, 32.6, 29.6, 25.7, 21.0, 20.8, 17.9, 17.7; HRMS (MALDI): calcd for
‡
C22H22O8: 437.1207 [M‡Na] ; found 437.1208.
Preparation of alkannin (2), shikonin (3) and shikalkin: Compounds 34, 35,
and 36 (100.0 mg, 0.24 mmol) were treated with an 1m NaOH solution
(5 mL) for 1 h at 258C and then were carefully acidified with glacial acetic
acid. The deep blue color disappeared and deep red crystalline solids
precipitated out of the reaction mixture. Simple filtration of the solids
afforded shikonin (3), alkannin (2), and shikalkin in crystalline form
(66.0 mg, 95%). Shikonin (3), alkannin (2), and shikalkin: Rf ˆ 0.35
(hexanes/EtOAc 7:3); m.p. 143 1458C; IR (thin film): nÄ ˆ 3456, 2926,
Hydroxy-quinone 32 was prepared in a similar manner by using (R)-3,3-
diphenyl-1-butyltetrahydro-3H-pyrrolo-[1,2-c][1,3,2]oxazaborole as a cata-
lyst. All data were identical with these of compound 24 except from [a]D25
À27.3 (c ˆ 0.39 in CHCl3).
ˆ
Reduction of ketone 14 with NaBH4: A solution of 14 (68.4 mg, 0.22 mmol)
in MeOH (4 mL) was cooled to 08C and NaBH4 (12.5 mg, 0.33 mmol) was
added. The mixture was stirred at this temperature approximately 20 min
(until no starting material was observed by TLC) and then diluted with
water (10 mL) and EtOAc (10 mL). The organic layer was separated and
the aqueous layer was extracted with EtOAc (2 Â 10 mL). The combined
organic extracts were washed with brine (2 Â 10 mL), dried over Na2SO4
and concentrated under reduced pressure to afford crude 33 which was
used in the next step without further purification.
1
1621, 1571, 1452, 1344, 1199, 1076, 776 cmÀ1; H NMR (250 MHz, CDCl3,
258C): d ˆ 12.60 (s, 1H, OHar), 12.50 (s, 1H, OHar), 7.19 (s, 2H, CHar), 7.16
ˆ
(s, 1H, CHquin), 5.20 (t, J ˆ 7.2 Hz, 1H, CH), 4.91 (dd, J ˆ 7.1, 4.1 Hz, 1H,
CHOH), 2.70 2.57 (m, 1H, CH2), 2.44 2.27 (s, 1H, CH2), 1.75 (s, 3H,
CMe2), 1.65 (s, 3H, CMe2); 13C NMR (62.9 MHz, CDCl3, 258C): d ˆ
180.6, 179.8, 165.5, 164.9, 151.4, 137.4, 132.4, 132.3, 131.8, 118.4, 112.0, 111.5,
68.3, 35.7, 25.9, 18.0; HRMS (MALDI): calcd for C22H22O8: 289.1070
ˆ
ˆ
Preparation of acetates 34 36: A saturated aqueous Na2S2O4 solution
(5 mL) was added to
a stirred solution of either 24 or 32 (from
‡
[M‡H] ; found 289.1074.
oxazaborolidine/BH3 ¥ THF reduction) (200.0 mg, 0.63 mmol) in Et2O
(20 mL), and the mixture was stirred vigorously for approximately
20 min (disappearance of the orange colour of the quinone). The organic
layer was then separated and the aqueous layer after being diluted with
water (10 mL) was extracted with EtOAc (2 Â 10 mL). The combined
organic extracts (being kept under argon atmosphere to avoid partial
oxidation of the trihydroxy intermediate) were washed with brine (15 mL),
dried over Na2SO4 and the solvents were evaporated under reduced
pressure. In the case of compound 33 the above procedure was skipped.
The crude mixture was then subjected to peracetylation with Ac2O (0.3 mL,
3.16 mmol), Et3N (0.7 mL, 5.04 mmol) and catalytic amount of DMAP in
CH2Cl2 (3 mL) at 258C for 5 h. The reaction was then quenched with an
aqueous saturated NaHCO3 solution (6 mL) and diluted with EtOAc
(10 mL). The organic layer was separated, washed with water (2 Â 10 mL),
brine (15 mL), dried over Na2SO4 and concentrated under reduced
pressure. The crude product was purified by flash column chromatography
(silica gel, hexanes/EtOAc 7:3) to afford (R)-acetic acid 4-acetoxy-3-(1-
acetoxy-4-methyl-pent-3-enyl)-5,8-dimethoxynaphthalen-1-yl ester (A),
(S)-acetic acid 4-acetoxy-3-(1-acetoxy-4-methyl-pent-3-enyl)-5,8-dime-
thoxynaphthalen-1-yl ester (B) or (R,S)-acetic acid 4-acetoxy-3-(1-ace-
toxy-4-methyl-pent-3-enyl)-5,8-dimethoxynaphthalen-1-yl ester (C), re-
spectively as pale yellow oils (for compounds A and B: 232.4 mg, 82%
based on 24 and 32, respectively; for compound C: 254.8 mg, 91% based on
14). A, B and C: Rf ˆ 0.47 (hexanes/EtOAc 5:5); [a]2D5 ˆ ‡50.8 (c ˆ 1 in
CHCl3) for A, [a]2D5 ˆ À50.8 (c ˆ 1 in CHCl3) for B; IR (neat): nÄ ˆ 2938,
Acknowledgement
The authors would like to thank P. N. Gerolymatos S.A. and the General
Secretary of the Ministry of Development of Greece for financial support
of this work. A.T.S. and Z.F.P. would also like to thank the Institute of
National Scholarships (IKY) for financial support.
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;
1H NMR
1802
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0808-1802 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 8

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Received: October 17, 2001 [F3618]
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