Synthesis of siloxy-α-lapachone derivatives by chemo- and regioselective Diels-Alder reactions of 3-methylene-1,2,4-naphthotriones with silyl enol ethers

Article abstract of DOI:10.1055/s-2008-1042950

o-Quinone methides, generated in situ from the Knoevenagel condensation of 2-hydroxy-1,4-naphthoquinone with aliphatic and aromatic aldehydes, take part in chemoselective hetero-Diels-Alder reactions with silyl enol ethers to give a series of siloxy-containing naphtho[2,3-b]pyran-5,10-dione (α-lapachone) derivatives in moderate to high yield. These reactions regioselectively gave α-lapachone derivatives with an acetal structure. This regioselectivity can be rationalized by considering the frontier molecular orbital interactions of the o-quinone methide with the silyl enol ether, and by taking into account the energetically more favorable pathway leading to a zwitterion-like transition state of lower energy in a Michael addition between the two reactants. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042950

1182
PAPER
Synthesis of Siloxy-a-Lapachone Derivatives by Chemo- and Regioselective
Diels–Alder Reactions of 3-Methylene-1,2,4-naphthotriones with Silyl Enol
Ethers
S
ynthesis of Siloxy
a
-
a
-Lapach
-
one
D
eri
Q
vative
s
uan Peng,a,b Yun Liu,a Zhi-Feng Lu,a Yong-Miao Shen,a Jian-Hua Xu*a
a
Department of Chemistry, Nanjing University, Nanjing 210093, P. R. of China
Fax +86(25)83317761; E-mail: xujh@nju.edu.cn
Department of Chemistry, Chongqing Normal University, Chongqing 400047, P. R. of China
b
Received 1 May 2007; revised 21 January 2008
the recently rapidly developing research area of cancer
chemoprevention as a promising tool in cancer control,14
quinone compounds have proven to be one of the most im-
portant classes of potential cancer chemopreventing
Abstract: o-Quinone methides, generated in situ from the
Knoevenagel condensation of 2-hydroxy-1,4-naphthoquinone with
aliphatic and aromatic aldehydes, take part in chemoselective
hetero-Diels–Alder reactions with silyl enol ethers to give a series
of siloxy-containing naphtho[2,3-b]pyran-5,10-dione (a-lapa- agents (antitumor promoters).15 Extensive studies of a
chone) derivatives in moderate to high yield. These reactions regio-
large variety of quinone compounds points to the 1,4- and
selectively gave a-lapachone derivatives with an acetal structure.
1,2-naphthoquinones, including a- and b-lapachones, as
This regioselectivity can be rationalized by considering the frontier
privileged structures,16 with the 1,4-naphthoquinones
molecular orbital interactions of the o-quinone methide with the
having great cancer-preventing potential.17 Structure–
silyl enol ether, and by taking into account the energetically more
activity relationship studies in lapachones have shown
that structural modification to the redox center (the qui-
none functionality)13a and the C-ring,13a,16b leads to signif-
icant changes in bioactivities and are important in the
search for possible lead compounds with more potent
pharmaceutical activity and less toxicity. Lapachones are
minor components in plants and are not easily available in
large quantities from natural sources. This fact, and the
need for unnatural analogues, demands the development
of convenient and versatile synthetic methods for lapa-
chones.
favorable pathway leading to a zwitterion-like transition state of
lower energy in a Michael addition between the two reactants.
Key words: a-lapachone, o-quinone methide, silyl enol ether,
Diels–Alder reaction, regioselectivity
Naturally occurring naphthoquinones comprise an impor-
tant class of natural products with a wide range of biolog-
ical activity1,2 arising from their ability to cause DNA
modification via redox cycling of the quinone moiety and
the generation of reactive oxygen species.2c,3 In the struc-
turally diverse naphthoquinone natural products, dihydro-
pyranonaphthoquinones (a- and b-lapachones) have
attracted special attention because of their promising anti-
tumor ability,4 among various other bioactivities. Hetero-
cyclic naphthoquinones of the lapachone family are found
as minor components in the stem bark of many trees of the
Tabebuia genus in Central and South America.5 a-Lapa-
chones have a wider distribution than b-lapachones, and
are additionally found in Ekmanianthe longiflora in
America6 and in Capalta ovata trees in many east Asian
countries.7 Of these pyranonaphthoquinones, b-lapachone
derivatives have so far received the most extensive inves-
tigations, mainly owing to their stronger antitumor activi-
ty.8 However, more recent investigations have shown that
a-lapachone is an effective DNA topoisomerase II inhibi-
tor and is a potential lead compound for the development
of drugs for the treatment of multidrug resistant cell lines
with low expressions of topoisomerase II.9 In addition, a-
There are several synthetic approaches to a- and b-lapa-
chones (Scheme 1).
1. Acid-catalyzed cyclization of lapachol or its derivatives
(equation 1).18 The lapachol derivative itself needs to be
synthesized by alkylation of the lithium salt of 2-hydroxy-
1,4-naphthoquinone (1) with an alkyl bromide. Although
this reaction has been the subject of intensive investiga-
tion,18b,19 the yield of the lapachol products has never ex-
ceeded 50% due to the complication of O-alkylation.19 In
a very recent report, lapachol was prepared by palladium-
catalyzed [Pd(PPh3)4] alkylation of quinone 1 with 3-
methylbut-2-en-1-ol in 43% yields.20
2. Michael addition of quinone 1 to a,b-unsaturated com-
pounds, followed by acid-catalyzed cycloketalization of
the Michael adduct (equation 2).21 In these cyclization re-
actions, only a-lapachone derivatives were formed in
moderate overall yields.
lapachone derivatives possess their own special biological 3. Base-catalyzed addition reaction of quinone 1 with an
activities ranging across antibacterial,10 antipsoriatic,11 a,b-unsaturated aldehyde, followed by electrocyclization
antifungal12 and trypanosidal13 activity. Furthermore, in of the adduct (equation 3).22 Ten lapachone derivatives
have been prepared using this reaction sequence in mod-
erate to high yield (40–90%). The resulting dehydro-a-
SYNTHESIS 2008, No. 8, pp 1182–1192
Advanced online publication: 18.03.2008
DOI: 10.1055/s-2008-1042950; Art ID: F07707SS
x
x
.
x
x
.2
0
0
8
lapachones can then be converted to the a-lapachones by
palladium-catalyzed hydrogenation.
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Siloxy-a-Lapachone Derivatives
1183
O
O
O
O
O
OH
O
HCl
H2SO4
(1)
H2O, 25 °C
H2O, 25 °C
O
O
β-lapachone
α-lapachone
lapachol
O
O
O
O
OMe
OH
OH
OH
O
pyridine
reflux
MeOH
(2)
+
H+
O
O
O
O
O
O
O
H
O
ethylenediamine
diacetate
O
O
– H2O
+
O
O
OH
O
O
O
(3)
O
Scheme 1 Synthetic approaches to a- and b-lapachones
4. Knoevenagel condensation of quinone 1 with formalde- groups,28 hydrolysis of the siloxy-containing a-lapachone
hyde, followed by Diels–Alder reaction of the o-quinone derivatives would provide easy access to an additional se-
methide intermediate with a 1,3-diene or an enol ether.23 ries of 1,4-naphthoquinone derivatives. To our knowl-
Mixtures of a- and b-lapachone derivatives were formed edge, this is the first report on the use of silyl enol ethers
in moderate to high total yields (30–95%). The last proto- as dienophiles in the inverse-electron-demand Diels–
col represents a new example of the increasing synthetic Alder reactions of any o-quinone methide.
applications of the novel tandem reaction sequence of
Knoevenagel condensation of an o-hydroxyquinone with
Benzaldehyde, formaldehyde and butyraldehyde have
been used as the aldehydes in the Knoevenagel condensa-
tion with 2-hydroxy-1,4-naphthoquinone (1) to give the
corresponding o-quinone methides I (Scheme 2), II
(Scheme 3)and III (Scheme 4), respectively. The o-
quinone methides were allowed to participate in cycload-
an aldehyde, followed by hetero-Diels–Alder reaction of
the o-quinone methide24 with an electron-rich alkene, in
the synthesis of heterocyclic natural products and their
analogues.25
Taking into account the ready availability of the starting ditions with the silyl enol ethers in refluxing dioxane so-
materials, the synthetic efficiency in respect of product lution. The silyl enol ethers employed were a-
yields, the versatility in allowing structural modification (trimethylsiloxy)styrene (2a), 2-(trimethylsiloxy)propene
of the product, and the simple one-pot procedures, we en- (2b), 1-(trimethylsiloxy)cyclohexene (2c) and (Z)-1-(tri-
visioned that this last synthetic strategy would be more methylsiloxy)-1-butene (2d). The results of these reac-
advantageous for the synthesis of lapachone derivatives. tions are summarized in Scheme 2, Scheme 3 and
In particular, since the aldehyde in the Knoevenagel con- Scheme 4.
densation and the alkene in the Diels–Alder reaction can
be changed, the introduction of different substituents at
the C-ring can be easily achieved. However, only formal-
Reaction of o-quinone methide I, derived from quinone 1
and benzaldehyde, with silyl enol ether 2a afforded two
products: 3a (27% yield) and 4a (18% yield). The struc-
tures of both were determined by X-ray crystallographic
analysis; it turns out that 3a and 4a constitute a pair of
diastereomeric a-lapachone derivatives (Figure 1 and
dehyde as the aldehyde and 1,3-dienes and a few enol
ethers as the alkene, have been applied so far.23 We report
here the synthesis of a series of silicon-containing a-lapa-
chone derivatives by the Diels–Alder reaction of the o-
Figure 2). Since b-Lapachone derivatives were not found
quinone methides derived from 1 with silyl enol ethers.
as products in this reaction, the [4+2] cycloaddition of I
Silyl enol ethers are highly electron-rich alkenes and are
with the silyl enol ether must occur exclusively at one of
excellent dienophiles in inverse-electron-demand Diels–
the 1-oxadiene units [the O(4)=C(3)–C(2)=C(1) moiety,
see Scheme 2]. Compounds 3a and 4a have distinguish-
able differences in their physical and spectroscopic prop-
erties. The trans-isomer 3a has a lower polarity than the
Alder reactions.26 Use of the special biological activity of
organosilicon compounds in the design of new drugs has
aroused considerable recent attention.27 Furthermore,
since silyl serves as a protecting group for hydroxy
Synthesis 2008, No. 8, 1182–1192 © Thieme Stuttgart · New York

1184
D.-Q. Peng et al.
PAPER
O
O
4
O
3
2
OH
dioxane
reflux
PhCHO
+
1
Ph
O
O
1
I
O
O
Ph
O
O
O
Ph
O
OSiMe3
Ph
I
+
+
Ph
OSiMe3
Ph
OSiMe3
2a
3a 27%
4a 18%
O
O
Ph
O
O
Ph
O
Ph
OSiMe3
Me
+
I
+
+
Me
OSiMe3
Me
OSiMe3
OH
O
O
O
O
2b
3b 22%
4b 5%
5b 32%
O
Ph
OSiMe3
I
I
+
O
OH
O
2c
3c 22%
O
Ph
O
O
Ph
Et
Et
Et
OSiMe3
H
+
+
H
O
OSiMe3
O
OSiMe3
O
2d
3d
4d 33%
Scheme 2 Reaction of o-quinone methide I with silyl enol ethers 2a–d
cis-isomer 4a, thus, 3a is eluted before 4a in the chro-
1
matographic separation. In the H NMR spectra, the two
methylene protons in 3a not only absorb at higher field
strength (d = 1.92 and 2.62 ppm) than those in 4a (d = 2.37
and 2.71 ppm), but also have a larger Dd value (Dd for the
two methylene protons is 0.70 ppm) than that in 4a (Dd =
0.34 ppm). In the IR spectra, 3a has a strong C–O stretch-
ing band at 1260 cm–1, while 4a has the strong C–O band
at 1201 cm–1.
Reactions of o-quinone methide I with silyl enol ether 2b,
similarly gave two diastereomeric cycloaddition products
3b (22% yield) and 4b (5% yield), and a hydrolysis prod-
uct 5b (32% yield). The steric structure of trans-3b was
also established by an X-ray crystallographic analysis.29
Again, trans-3b had lower polarity than the cis-isomer 4b.
Their spectroscopic data display similar regular differ-
ences as for compounds 3a and 4a. In the 1H NMR spec-
tra, the methylene protons in 3b lie at higher field strength
(d = 1.87 and 2.40 ppm) with a larger Dd value (0.53 ppm)
than in 4b, where the methylene protons absorb at lower
field (d = 2.25 and 2.41 ppm) with a smaller Dd value
(0.16 ppm). In the IR spectra, 3b has a strong C–O stretch-
ing band at 1265 cm–1, while the corresponding C–O band
in 4b is at 1179 cm–1. 1H NMR data reveal that 5b occurs
Figure 1 ORTEP drawing of 3a (CCDC 641918)
cleanly in the open-chain keto-form in chloroform-d solu-
tion, and the phenol proton absorbs at d = 7.60 ppm.
In the reactions of o-quinone methide I with silyl enol
ether 2c, only a hydrolysis product 3c (22% yield) was ob-
tained. This exists in chloroform-d solution as a pair of
diastereomeric cyclic hemiacetals in a ratio of 1:0.31. The
reaction of o-quinone methide I with silyl enol ether 2d,
afforded 3d and 4d as diastereomers (total yield 33%).
Synthesis 2008, No. 8, 1182–1192 © Thieme Stuttgart · New York

PAPER
Synthesis of Siloxy-a-Lapachone Derivatives
1185
Figure 3 ORTEP drawing of 4d (CCDC 641920)
Figure 2 ORTEP drawing of 4a (CCDC 641919)
roform-d solution, with the hydroxy proton absorption
occurring at d = 7.75 ppm in H NMR spectrum and the
1
three carbonyl carbon absorptions at d = 199.9, 185.1 and
181.6 ppm in the 13C NMR spectrum. Reactions of o-
quinone methide II with silyl enol ether 2b, gave the ex-
pected cycloadduct 6b (43% yield) and a hydrolysis prod-
Compound 3d was not fully separated from 4d during the
column chromatographic separation, however, a pure
sample of 4d was obtained and its steric structure was
shown by an X-ray crystallographic analysis (Figure 3).
1
uct 7b (36% yield). Again, H NMR data show that 7b
Reaction of quinone 1, paraformaldehyde and silyl enol
ether 2a in refluxing dioxane, gave products 6a (31%
yield) and 7a (40% yield). While 6a is the Diels–Alder cy-
cloadduct, 7a is a hydrolysis product of 6a. NMR data for
7a showed that it was in the open-chain keto-form in chlo-
exists in chloroform-d6 solution cleanly in the open-chain
keto-form, with the phenol proton absorption at d = 7.59
ppm. In the reaction of o-quinone methide II with silyl
enol ether 2c, products 6c (21% yield) and 7c (45% yield)
O
O
OH
O
dioxane
+
(CH2O)n
reflux
O
O
II
1
O
O
O
O
O
OSiMe3
Ph
Ph
II
II
II
II
+
+
+
+
+
Ph
OSiMe3
O
OH
2a
6a 31%
7a 40%
O
O
O
OSiMe3
Ph
Me
+
Me
OSiMe3
O
OH
O
O
2b
6b 43%
7b 36%
O
O
OSiMe3
+
O
O
OSiMe3
OH
O
O
2c
6c 21%
7c 45%
O
O
Et
Et
Et
H
OSiMe3
H
+
O
O
OSiMe3
OH
O
O
7d 28%
2d
6d 45%
Scheme 3 Reaction of o-quinone methide II with silyl enol ethers 2a–d
Synthesis 2008, No. 8, 1182–1192 © Thieme Stuttgart · New York

1186
D.-Q. Peng et al.
PAPER
O
O
O
O
OH
dioxane
reflux
PrCHO
+
Pr
O
1
III
O
O
Pr
O
O
O
Pr
O
OSiMe3
Ph
III
+
Ph
+
Ph
OSiMe3
OSiMe3
2a
8a 46%
8b 19%
O
Pr
Et
Et
OSiMe3
III
+
O
OH
H
H
O
2d
9a
81%
Scheme 4 Reaction of o-quinone methide III with silyl enol ethers 2a and 2d
were formed. 1H NMR data show that 7c in chloroform-d the electron-deficient QMs with the highly electron-rich
solution exists as a mixture of the cyclic hemiacetal and its silyl enol ethers, the preferential FMO interaction should
open-chain keto-form in a ratio of ~1:0.7. In the keto- be the LUMO(QM)–HOMO(2) interaction. Calculated FMO
form, the phenol proton absorption occurs at d = 7.94 energies of both methods show that this FMO interaction
ppm. A similar reaction of o-quinone methide II with silyl pair indeed has a much smaller energy gap than the HO-
enol ether 2d, gave cycloadduct 6d (45% yield) and hy- MO(QM)–LUMO(2) interaction for all the QM–silyl ether
1
drolysis product 7d (28% yield). H NMR data showed combinations. The requirement of maximum positive
that 7d in chloroform-d solution exists as a mixture of two orbital overlap in the predominant LUMO(QM)–HOMO(2)
diastereomeric cyclic hemiacetals in a ratio of 1:0.7, to- interaction predicts the regioselectivity, which is rational-
gether with a trace amount of the open-chain aldehyde ized by HF calculation. However, in the DFT calculation,
form.
the relative magnitudes of the atomic coefficients at C(1)
and O(4) in QM II and III are the reverse of those ob-
tained through the HF calculation. However, since the two
coefficients at C(1) and O(4) are rather close in magni-
tude, the FMO interaction consideration could not give a
definite prediction of the regioselectivity for the reactions
of QM II and III with silyl enol ethers 2a–d.
Reaction of the o-quinone methide III, derived from
quinone 1 and butyraldehyde, with silyl enol ether 2a, fur-
nished two diastereomeric cycloaddition products 8a
(46% yield) and 8b (19% yield) without formation of any
hydrolysis product. The steric configurations of 8a and 8b
were assigned by comparison of their spectral data with
those of compounds 3a and 4a mentioned above. A simi- Considering the [4+2] cycloaddition of the QM with the
lar reaction of o-quinone methide III with silyl enol ether enol ether as proceeding in a highly asynchronic fashion
2d gave the hydrolysis product 9a (81% yield) as the sole by a Michael addition pathway via a zwitterion-like tran-
1
product. The H NMR spectrum reveals that 9a exists in sition state, would provide an alternative mechanistic ra-
chloroform-d solution as a pair of diastereomeric cyclic tionalization of the observed regioselectivity (Scheme 5).
hemiacetals in a roughly 1:1 ratio. In accordance with this,
Nucleophilic attack of the silyl enol ether at the exocyclic
13
the C NMR spectrum reveals four carbonyl carbon ab-
methylene carbon atom would proceed via the energeti-
sorptions at d = 184.8, 184.7, 181.3 and 180.7 ppm.
cally more favorable pathway, leading to the more stable
As seen in Scheme 2, Scheme 3 and Scheme 4, all the cy- A with the positive charge delocalized to the oxygen
cloadditions between the o-quinone methides (QMs) I– atom, rather than the regioisomeric B with a localized pos-
III and the silyl enol ethers 2a–d, are regioselective and itive charge at C(6). This rationale of the observed regio-
give products with an acetal structure only. We have not selectivity is supported by recent computational studies
observed the formation of other regioisomers throughout on the inverse-electron-demand Diels–Alder reactions of
this series of reactions. To gain insight into this regiose- o-quinone methides31 and electron-deficient hetero-
lectivity, HF and DFT (B3LYP) calculations of the QMs dienes32 with highly electron-rich alkenes such as enol
I–III and the silyl enol ethers 2a–d have been carried out ethers. These computational results suggest that the [4+2]
using a 6-31G (d) basis set.30 The frontier molecular orbit- cycloadditions take place with a large charge-transfer
al (FMO) properties are outlined in Figure 4 and Figure 5. from the alkene to the QM via a zwitterionic transition
In the inverse-electron-demand Diels–Alder reactions of state,31,32 and the ortho-approach of the enol ether to QMs
Synthesis 2008, No. 8, 1182–1192 © Thieme Stuttgart · New York

PAPER
Synthesis of Siloxy-a-Lapachone Derivatives
1187
0.10082
(0.41753)
O
O
Ph
O
O
O
O
Pr
0.00772
O
0.01449
(0.28740)
1
0.10180
0.01074
2
(0.36261)
(0.42103)
(0.28728)
Ph
Pr
3
–0.13723
(0.20473)
–0.00927
O –0.01134
O (0.26977)
O
O
O
4
(0.28576)
–0.12796
(0.22711)
–0.01467
(0.27694)
O
O
O
II
I
III
EHOMO = –0.32870 a.u. EHOMO = –0.36165 a.u.
EHOMO = –0.32879 a.u.
EHOMO = –0.35748 a.u.
LUMO = 0.03980 a.u.
EHOMO = –0.35722 a.u.
ELUMO = 0.04007 a.u.
ELUMO = 0.03277 a.u.
ELUMO = 0.02639 a.u.
E
LUMO = 0.02626 a.u.
E
OSiMe3
0.31730
(–0.37049)
0.36109
(0.37928)
OSiMe3
OSiMe3
Et
OSiMe3
0.39436
(0.58970)
0.19420
0.30033
0.27483
(–0.35243)
0.34196
(–0.17445)
0.30426
(0.24795)
(–0.61920)
(0.29812)
Ph
H
H
2a
2b
2c
2d
EHOMO = –0.30482 a.u.
ELUMO = 0.12029 a.u.
EHOMO = –0.32132 a.u.
ELUMO = 0.20117 a.u.
E
E
HOMO = –0.32186 a.u.
LUMO = 0.20152 a.u.
EHOMO = –0.33080 a.u.
ELUMO = 0.19867 a.u.
Figure 4 FMO energies and atomic orbital coefficients calculated by HF (in parentheses are the LUMO orbital coefficients)
O
Ph
O
O
O
O
Pr
–0.09865
(0.23610)
O
0.04290
(0.23766)
–0.05627
(0.32186)
1
–0.10233
(0.32968)
–0.06517
(0.29050)
2
Ph
Pr
3
0.39397
0.37943
(0.24375)
4 O
0.37153
O
O
O
O
(0.29843)
(0.28289)
0.39073
(0.26882)
–0.31490
(0.29067)
O
O
O
O
II
I
III
EHOMO = –0.24665 a.u. EHOMO = –0.24670 a.u.
E
EHOMO = –0.24926 a.u.
ELUMO = –0.10692 a.u.
EHOMO = –0.25578 a.u.
LUMO = –0.10921 a.u. ELUMO = –0.10954 a.u. ELUMO = –0.11485 a.u.
EHOMO = –0.24802 a.u.
ELUMO = –0.10650 a.u.
OSiMe3
OSiMe3
0.24079
(–0.22755)
OSiMe3
0.29419
(–0.48312)
0.32184
Et
0.35012
(–0.47891)
OSiMe3
0.29013
(0.53275)
0.37722
(0.50496)
(-0.47896)
0.34956
(0.34146)
0.37898
(0.51554)
Ph
H
H
2a
2b
EHOMO = –0.21759 a.u.
2c
2d
HOMO = –0.20924 a.u.
LUMO = 0.04694 a.u.
EHOMO = –0.21568 a.u.
LUMO = –0.02256 a.u.
EHOMO = –0.21241 a.u.
ELUMO = 0.04205 a.u.
E
E
E
ELUMO = 0.03982 a.u.
Figure 5 FMO energies and atomic orbital coefficients calculated by DFT (in parentheses are the LUMO orbital coefficients)
O
O
O
O
R
R
O
O
O
R
OSiMe3
OSiMe3
OSiMe3
+
O
O
A
O
O
2
1
6
5
R
3
OSiMe3
4
O
B
Scheme 5 Alternative mechanistic rationalization
(leading to the product in which the a-carbon atom of the tion of 2-hydroxy-1,4-naphthoquinone (1) with aliphatic
enol ether is bonded to the oxygen atom in QM) is ener- and aromatic aldehydes, take part in [4+2] reactions with
getically more feasible than the meta-approach pathway silyl enol ethers 2a–d selectively at one of the 1-oxadiene
(leading to the regioisomeric product with the a-carbon units [the O(4)=C(3)–C(2)=C(1) unit, Scheme 2] to give a
atom of the enol ether linked to the exocyclic methylene series of previously unknown siloxy-containing a-lapa-
carbon atom in QM).
chone derivatives in moderate to high yields. These reac-
tions are also regioselective and give only the products
with an acetal structure. Therefore, these highly chemo-
In summary, we have shown that the o-quinone methides
I–III, generated in situ from the Knoevenagel condensa-
Synthesis 2008, No. 8, 1182–1192 © Thieme Stuttgart · New York

1188
D.-Q. Peng et al.
PAPER
Anal. Calcd for C28H26O4Si: C, 74.01; H, 5.73. Found: C, 74.03; H,
5.70.
and regioselective hetero-Diels–Alder cycloadditions
provide a convenient and efficient one-pot synthesis of si-
loxy-containing a-lapachone derivatives, with different
C-ring-substitution patterns, from readily available start-
ing materials.
4a
Yield: 165 mg (18%); yellow solid; mp 180–181 °C.
IR (KBr): 2960, 1682, 1655, 1618, 1568, 1496, 1450, 1373, 1201,
963, 932, 847, 774, 692 cm–1.
Petroleum ether (PE), where used, had a boiling range of 60–90 °C.
Melting points were recorded using a Keyi XT3A microscopic
melting point apparatus and are uncorrected. 1H NMR spectra were
measured on a Bruker DPX 300 spectrometer at 300 MHz with
CDCl3 as solvent unless otherwise stated. The chemical shifts (d)
are reported in ppm relative to the residual deuterated solvent sig-
nal, and coupling constants (J) are given in Hz. 13C NMR spectra
were measured on a Bruker Avance 300 spectrometer at 75 MHz or
with a Bruker Avance 400 spectrometer at 100 MHz with CDCl3 as
solvent. IR spectra were recorded with a Shimadzu IR 440 spec-
trometer as a KBr pellet. Mass spectra were taken on a VG ZAB-HS
spectrometer in the EI ionization mode (70 eV). Elemental analyses
were performed with a Perkin–Elmer 240C analyzer. For X-ray
crystallographic analysis, the X-ray diffraction intensities and the
unit-cell parameters were determined on a Enraf–Nonius CAD-4
diffractometer, employing graphite-monochromated (MoKa) radia-
tion (l = 0.71073 Å) and operating in the w/2q scan mode. Data col-
lection and cell refinement were performed with CAD-4 software.
Structures were solved by direct methods and refined by full matrix
least squares on F2 with SHELXTL. Non-hydrogen atoms were re-
fined by anisotropic displacement parameters and the positions of
all H-atoms were fixed geometrically and included in estimated po-
sitions using a riding model.
1H NMR (300 MHz, CDCl3): d = –0.17 (s, 9 H), 2.37 (dd, J = 7.2,
14.5 Hz, 1 H), 2.71 (dd, J = 4.0, 14.3 Hz, 1 H), 4.22 (dd, J = 3.9, 7.0
Hz, 1 H), 7.21–7.39 (m, 8 H), 7.54 (dd, J = 9.7, 1.7 Hz, 2 H), 7.73–
7.77 (m, 2 H), 8.02–8.04 (m, 1 H), 8.18–8.20 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 183.7, 179.5, 154.5, 142.9, 142.7,
134.2, 133.2, 132.2, 131.1, 128.5, 128.4, 128.2, 127.5, 126.5, 126.4,
126.0, 125.4, 123.1, 101.5, 43.2, 34.7, 1.1.
MS (EI): m/z (%) = 454 (2) [M+], 378 (7), 364 (12), 287 (18), 274
(31), 246 (26), 233 (33), 189 (27), 105 (79), 84 (5), 75 (100), 44 (8);
Anal. Calcd for C28H26O4Si: C, 74.01; H, 5.73. Found: C, 74.05; H,
5.78.
trans-2-Methyl-4-phenyl-2-(trimethylsiloxy)-3,4-dihydro-2H-
naphtho[2,3-b]pyran-5,10-dione (3b), cis-2-Methyl-4-phenyl-2-
(trimethylsiloxy)-3,4-dihydro-2H-naphtho[2,3-b]pyran-5,10-di-
one (4b), and 2-Hydroxy-3-(3-oxo-1-phenylbutyl)-1,4-naphtha-
lenedione (5b)
A mixture of 2-hydroxy-1,4-naphthoquinone (1; 348 mg, 2 mmol),
silyl enol ether 2b (782 mg, 6 mmol) and benzaldehyde (849 mg, 8
mmol) in anhydrous dioxane (20 mL) was refluxed under an argon
atmosphere for 18 h until complete conversion of 1 was observed
(TLC). Workup as described above gave the products 3b, 4b and
5b.
Crystallographic data (excluding structure factors) for the structures
in this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication numbers CCDC
641918, CCDC 641919 and CCDC 641920. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK [Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk].
3b
Yield: 175 mg (22%); yellow solid; mp 136–138 °C.
IR (KBr): 2947, 1682, 1654, 1609, 1595, 1577, 1493, 1364, 1265,
1177, 998, 849, 769, 727 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.16 (s, 9 H), 1.74 (s, 3 H), 1.87
(dd, J = 11.9, 13.7 Hz, 1 H), 2.40 (dd, J = 6.9, 13.7 Hz, 1 H), 4.18
(dd, J = 6.8, 11.8 Hz, 1 H), 7.21–7.31 (m, 5 H), 7.67–7.69 (m, 2 H),
7.91–7.93 (m, 1 H), 8.12–8.15 (m, 1 H).
anti-2,4-Diphenyl-2-(trimethylsiloxy)-3,4-dihydro-2H-naph-
tho[2,3-b]pyran-5,10-dione (3a) and cis-2,4-Diphenyl-2-(tri-
methylsiloxy)-3,4-dihydro-2H-naphtho[2,3-b]pyran-5,10-
dione (4a)
MS (EI): m/z (%) = 392 (1) [M+], 302 (23), 274 (16), 246 (15), 225
A mixture of 2-hydroxy-1,4-naphthoquinone (1; 348 mg, 2 mmol),
silyl enol ether 2a (1.15 g, 6 mmol) and benzaldehyde (849 mg, 8
mmol) in anhydrous dioxane (20mL) was refluxed under an argon
atmosphere for 18 h until complete conversion of 1 was observed
(TLC). The solvent was removed under reduced pressure, and the
residual solid was separated by flash chromatography on silica gel
column (PE–EtOAc, gradient elution) to give the products 3a and
4a.
(25), 189 (13), 84 (38), 75 (100).
Anal. Calcd for C23H24O4Si: C, 70.41; H, 6.12. Found: C, 70.44; H,
6.15.
4b
Yield: 38 mg (5%); yellow solid; mp 114–116 °C.
IR (KBr): 2994, 2960, 1676, 1650, 1616, 1594, 1578, 1376, 1331,
1267, 1256, 1179, 1099, 993, 847 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.05 (s, 9 H), 1.67 (s, 3 H), 2.25
(dd, J = 7.3, 14.0 Hz, 1 H), 2.41 (dd, J = 5.0, 14.0 Hz, 1 H), 4.26
(dd, J = 4.9, 7.2 Hz, 1 H), 7.16–7.29 (m, 5 H), 7.70–7.73 (m, 2 H),
8.01–8.04 (m, 1 H), 8.14–8.17 (m, 1 H).
3a
Yield: 241 mg (27%); yellow solid; mp 163–165 °C.
IR (KBr): 2955, 1678, 1652, 1611, 1573, 1486, 1260, 1166, 1020,
931, 843, 756, 700, 528 cm–1.
1H NMR (300 MHz, CDCl3): d = –0.05 (s, 9 H), 1.92 (dd, J = 12.0,
14.1 Hz, 1 H), 2.62 (dd, J = 6.7, 14.1 Hz, 1 H), 4.37 (dd, J = 6.7,
12.0 Hz, 1 H), 7.19–7.28 (m, 5 H), 7.37–7.41 (m, 3 H), 7.65–7.73
(m, 4 H), 7.93–7.96 (m, 1 H), 8.12–8.17 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 183.6, 179.8, 153.9, 143.4, 142.6,
134.1, 133.1, 132.3, 130.9, 128.6, 128.5, 128.3, 127.2, 126.5, 126.4,
126.2, 125.5, 125.2, 100.7, 46.9, 36.2, 1.0.
MS (EI): m/z (%) = 392 (1) [M+], 302 (28), 274 (16), 246 (15), 225
(35), 189 (14), 115 (6), 84 (11), 75 (100), 49 (11), 44 (17).
Anal. Calcd for C23H24O4Si: C, 70.41; H, 6.12. Found: C, 70.40; H,
6.18.
5b
Yield: 203 mg (32%); yellow solid; mp 143–145 °C.
MS (EI): m/z (%) = 454 (1) [M+], 378 (4), 274 (16), 246 (14), 233
(13), 189 (15), 105 (50), 84 (19), 75 (100), 49 (17).
IR (KBr): 3480, 2961, 2935, 2850, 1673, 1647, 1618, 1591, 1574,
1492, 1366, 1260, 1149, 1092, 976, 945, 875, 756, 727 cm–1.
Synthesis 2008, No. 8, 1182–1192 © Thieme Stuttgart · New York

PAPER
Synthesis of Siloxy-a-Lapachone Derivatives
1189
1H NMR (300 MHz, CDCl3): d = 2.18 (s, 3 H), 3.27 (dd, J = 6.0,
17.8 Hz, 1 H), 3.77 (dd, J = 9.7, 17.8 Hz, 1 H), 4.98 (dd, J = 6.0, 9.7
Hz, 1 H), 7.20–7.32 (m, 3 H), 7.47 (d, J = 7.5 Hz, 2 H), 7.60 (s,
1 H), 7.66 (t, J = 7.5 Hz, 1 H), 7.72 (t, J = 7.5 Hz, 1 H), 8.08 (dd,
J = 7.5, 19.0 Hz, 2 H).
atmosphere for 18 h until complete conversion of 1 was observed
(TLC). Workup as described above gave the products 6a and 7a.
6a
Yield: 233 mg (31%); yellow solid; mp 78–80 °C.
MS (EI): m/z (%) = 320 (22) [M+], 278 (100), 261 (24), 202 (24),
178 (11), 115 (32), 105 (26), 91 (17), 77 (43), 43 (96).
IR (KBr): 2961, 2938, 1679, 1649, 1631, 1592, 1578, 1448, 1383,
1339, 1261, 1224, 1199, 1138, 1056, 997, 950, 870, 844, 721, 699
cm–1.
1H NMR (300 MHz, CDCl3): d = –0.04 (s, 9 H), 1.70–1.80 (m, 1 H),
2.32–2.36 (m, 1 H), 2.72–2.77 (m, 2 H), 7.39–7.44 (m, 3 H), 7.62
(d, J = 7.2 Hz, 2 H), 7.72–7.76 (m, 2 H), 8.12–8.16 (m, 2 H).
Anal. Calcd for C20H16O4: C, 75.00; H, 5.00. Found: C, 75.03; H,
5.06.
4a-Hydroxy-12-phenyl-2,3,4,4a,12,12a-hexahydro-1H-ben-
zo[b]xanthene-6,11-dione (3c)
A mixture of 2-hydroxy-1,4-naphthoquinone (1; 348 mg, 2 mmol),
silyl enol ether 2c (1.02 g, 6 mmol) and benzaldehyde (849 mg, 8
mmol) in anhydrous dioxane (20 mL) was refluxed under an argon
atmosphere for 18 h until the reaction was complete (TLC). Workup
as described above gave the product 3c.
MS (EI): m/z (%) = 378 (53) [M+], 350 (7), 288 (11), 231 (12), 191
(34), 177 (30), 105 (100), 75 (54), 44 (26).
Anal. Calcd for C22H22O4Si: C, 69.84; H, 5.82. Found: C, 69.80; H,
5.88.
7a
Yield: 161 mg (22%); yellow solid; mp 220–222 °C.
Yield: 246 mg (40%); green solid; mp 168–170 °C.
IR (KBr): 3442, 2952, 2928, 2853, 1670, 1658, 1610, 1595, 1578,
1494, 1452, 1364, 1338, 1266, 1200, 1177, 1095, 956, 892, 724,
700 cm–1.
1H NMR (300 MHz, CDCl3): d (major diastereomer) = 1.65–1.71
(m, 5 H), 2.05–2.07 (m, 2 H), 2.33–2.41 (m, 2 H), 4.66 (d, J = 6.6
Hz, 1 H), 7.13–7.28 (m, 2 H), 7.48 (d, J = 7.5 Hz, 1 H), 7.62–7.75
(m, 3 H), 7.93–7.94 (m, 1 H), 8.06–8.11 (m, 2 H).
MS (EI): m/z (%) = 360 (44) [M+], 343 (18), 342 (13), 289 (5), 231
(100), 202 (15), 177 (11), 149 (11), 115 (21), 105 (19), 91 (12), 77
(19), 44 (40).
IR (KBr): 3362, 2931, 1683, 1664, 1641, 1591, 1578, 1460, 1377,
1352, 1271, 1215, 1055, 974, 861, 746, 725, 690 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.03 (t, J = 7.2 Hz, 2 H), 3.33 (t,
J = 7.2 Hz, 2 H), 7.49 (t, J = 7.5 Hz, 2 H), 7.57 (t, J = 7.5 Hz, 1 H),
7.71 (td, J = 7.5, 1.5 Hz, 1 H), 7.75 (s, 1 H), 7.77 (td, J = 7.5, 1.5
Hz, 1 H), 7.98 (dd, J = 1.3, 7.5 Hz, 2 H), 8.09–8.13 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 199.9, 185.1, 181.6, 154.1, 136.9,
135.3, 133.6, 133.5, 133.2, 130.0, 129.0, 128.6, 127.2, 126.6, 123.5,
37.4, 18.8.
MS (EI): m/z (%) = 306 (15) [M+], 201 (3), 173 (6), 159 (2), 127 (6),
105 (100), 77 (65), 51 (20).
Anal. Calcd for C23H20O4: C, 76.67; H, 5.56. Found: C, 76.63; H,
5.62.
Anal. Calcd for C19H14O4: C, 74.51; H, 4.58. Found: C, 74.56; H,
4.62.
(2a,3a,4b)-3-Ethyl-4-phenyl-2-(trimethylsiloxy)-3,4-dihydro-
2H-naphtho[2,3-b]pyran-5,10-dione (3d) and (2a,3a,4a)-3-Eth-
yl-4-phenyl-2-(trimethylsiloxy)-3,4-dihydro-2H-naphtho[2,3-
b]pyran-5,10-dione (4d)
A mixture of 2-hydroxy-1,4-naphthoquinone (1; 348 mg, 2 mmol),
silyl enol ether 2d (866 mg, 6 mmol) and benzaldehyde (849 mg, 8
mmol) in anhydrous dioxane (20 mL) was refluxed under an argon
atmosphere for 18 h until complete conversion of 1 was observed
(TLC). Workup as described above gave the products 3d (not fully
separated from 4d) and 4d.
2-Methyl-2-(trimethylsiloxy)-3,4-dihydro-2H-naphtho[2,3-
b]pyran-5,10-dione (6b) and 2-Hydroxy-3-(3-oxobutyl)-1,4-
naphthalenedione (7b)
A mixture of 2-hydroxy-1,4-naphthoquinone (1; 348 mg, 2 mmol),
silyl enol ether 2b (782 mg, 6 mmol) and paraformaldehyde (240
mg, 8 mmol) in anhydrous dioxane (20 mL) was refluxed under an
argon atmosphere for 18 h until complete conversion of 1 was ob-
served (TLC). Workup as described above gave the products 6b and
7b.
4d
Yield: 267mg (33%); yellow solid; mp 135–136 °C.
6b
Yield: 273 mg (43%); yellow solid; mp 117–118 °C.
IR (KBr): 2962, 2924, 1676, 1650, 1619, 1602, 1583, 1454, 1423,
1328, 1294, 1261, 1101, 1026, 972, 936, 887, 849, 803, 707, 667
cm–1.
IR (KBr): 2990, 2943, 1679, 1645, 1617, 1594, 1578, 1418, 1380,
1305, 1267, 1254, 1198, 1082, 1005, 946, 896, 841, 727 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.12 (s, 9 H), 1.00 (t, J = 7.5 Hz,
3 H), 1.13–1.26 (m, 1 H), 1.51–1.60 (m, 1 H), 2.05–2.07 (m, 1 H),
4.20 (d, J = 6.9 Hz, 1 H), 5.74 (s, 1 H), 7.18–7.75 (d, J = 6.3 Hz,
3 H), 7.33 (d, J = 6.6 Hz, 2 H), 7.63–7.70 (m, 2 H), 7.94–7.97 (m,
1 H), 8.11–8.16 (m, 1 H).
MS (EI): m/z (%) = 406 (80) [M+], 377 (26), 316 (39), 262 (24), 233
(27), 178 (9), 129 (71), 105 (34), 73 (100), 45 (23).
1H NMR (300 MHz, CDCl3): d = 0.15 (s, 9 H), 1.67–1.69 (m, 1 H),
1.72 (s, 3 H), 2.07–2.13 (m, 1 H), 2.59–2.70 (m, 2 H), 7.66–7.74
(m, 2 H), 8.11 (dd, J = 6.6, 1.3 Hz, 2 H).
MS (EI): m/z (%) = 316 (33) [M+], 301 (29), 274 (15), 258 (46), 130
(17), 115 (40), 102 (13), 75 (65), 73 (100).
Anal. Calcd for C17H20O4Si: C, 64.56; H, 6.33. Found: C, 64.55; H,
6.52.
Anal. Calcd for C24H26O4Si: C, 70.94; H, 6.40. Found: C, 70.89; H,
6.48.
7b
Yield: 177 mg (36%); yellow-green solid; mp 140–142 °C.
2-Phenyl-2-(trimethylsiloxy)-3,4-dihydro-2H-naphtho[2,3-
b]pyran-5,10-dione (6a) and 2-Hydroxy-3-(3-oxo-3-phenylpro-
pyl)-1,4-naphthalenedione (7a)
A mixture of 2-hydroxy-1,4-naphthoquinone (1; 348 mg, 2 mmol),
silyl enol ether 2a (1.15 g, 6 mmol) and paraformaldehyde (240 mg,
8 mmol) in anhydrous dioxane (20 mL) was refluxed under an argon
IR (KBr): 3326, 3066, 2917, 1699, 1671, 1640, 1591, 1578, 1560,
1371, 1347, 1269, 1212, 1184, 1070, 971, 941, 849, 729, 691 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.24 (s, 3 H), 2.77 (t, J = 7.0 Hz,
2 H), 2.88 (t, J = 7.0 Hz, 2 H), 7.59 (s, 1 H), 7.68–7.80 (m, 2 H),
8.11 (td, J = 1.5, 8.7 Hz, 2 H).
Synthesis 2008, No. 8, 1182–1192 © Thieme Stuttgart · New York

1190
D.-Q. Peng et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 208.6, 185.0, 181.5, 154.0, 135.3,
133.4, 129.9, 127.1, 126.6, 123.2, 42.1, 30.0, 18.3.
MS (EI): m/z (%) = 330 (35) [M+], 301 (17), 244 (34), 188 (27), 158
(21), 129 (59), 115 (31), 73 (100).
MS (EI): m/z (%) = 244 (33) [M+], 202 (100), 173 (29), 159 (39),
115 (30), 105 (30), 77 (40), 43 (80).
Anal. Calcd for C18H22O4Si: C, 65.45; H, 6.67. Found: C, 65.52; H,
6.75.
Anal. Calcd for C14H12O4: C, 68.85; H, 4.92. Found: C, 68.87; H,
5.05.
7d
Yield: 146 mg (28%); yellow solid; mp 105–106 °C.
4a-(Trimethylsiloxy)-2,3,4,4a,12,12a-hexahydro-1H-ben-
zo[b]xanthene-6,11-dione (6c) and 4a-Hydroxy-2,3,4,4a,12,12a-
hexahydro-1H-benzo[b]xanthenes-6,11-dione (7c)
A mixture of 2-hydroxy-1,4-naphthoquinone (1; 348 mg, 2 mmol),
silyl enol ether 2c (1.02 g, 6 mmol) and paraformaldehyde (240 mg,
8 mmol) in anhydrous dioxane (20 mL) was refluxed under an argon
atmosphere for 18 h until complete conversion of 1 was observed
(TLC). Workup as described above gave the products 6c and 7c.
IR (KBr): 3423, 2924, 1688, 1641, 1625, 1590, 1579, 1333, 1306,
1198, 970, 943, 722 cm–1.
1H NMR (300 MHz, CDCl3): d (two cyclic hemiacetals in a ratio of
1:0.7) = 0.99–1.10 (m, 5.1 H), 1.50–1.86 (m, 5.1 H), 2.34 (dd,
J = 12.3, 18.3 Hz, 1 H), 2.60 (dd, J = 3.3, 18.3 Hz, 0.7 H), 2.80 (t,
J = 5.7 Hz, 1 H), 2.86 (t, J = 5.1 Hz, 0.7 H), 5.62 (d, J = 3.1 Hz,
0.7 H), 5.78 (d, J = 2.9 Hz, 1 H), 7.66–7.76 (m, 3.4 H), 8.10 (d,
J = 8.2 Hz, 2.8 H).
13C NMR (100 MHz, CDCl3): d (two cyclic hemiacetals) = 184.3,
184.2, 180.5, 180.0, 152.1, 152.0, 134.1, 133.2, 133.1, 132.1, 132.0,
131.0, 126.4, 126.3, 126.2, 126.1, 122.8, 121.6, 96.6, 94.9, 36.9,
36.3, 24.0, 23.2, 19.6, 19.5, 11.4, 11.3.
MS (EI): m/z (%) = 258 (28) [M+], 230 (18), 188 (49), 159 (18), 115
(15), 105 (25), 77 (28), 44 (100).
6c
Yield: 153 mg (21%); yellow oil.
IR (KBr): 2937, 2859, 1679, 1650, 1623, 1597, 1579, 1447, 1386,
1336, 1306, 1266, 1251, 1201, 1183, 1145, 1109, 950, 903, 881,
845, 723 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.11 (s, 9 H), 1.11–1.32 (m, 2 H),
1.53–1.73 (m, 5 H), 1.95–2.01 (m, 1 H), 2.37–2.46 (m, 2 H), 2.82
(dd, J = 6.6, 18.6 Hz, 1 H), 7.66–7.74 (m, 2 H), 8.08–8.12 (m, 2 H).
Anal. Calcd for C15H14O4: C, 69.77; H, 5.43. Found: C, 69.72; H,
5.46.
MS (EI): m/z (%) = 356 (35) [M+], 340 (7), 231 (23), 217 (20), 170
(51), 127 (37), 75 (100), 43 (83).
trans-2-Phenyl-4-propyl-2-(trimethylsiloxy)-3,4-dihydro-2H-
naphtho[2,3-b]pyran-5,10-dione (8a) and cis-2-Phenyl-4-pro-
pyl-2-(trimethylsiloxy)-3,4-dihydro-2H-naphtho[2,3-b]pyran-
5,10-dione (8b)
Anal. Calcd for C20H24O4Si: C, 67.42; H, 6.74. Found: C, 67.47; H,
6.78.
A mixture of 2-hydroxy-1,4-naphthoquinone (1; 348 mg, 2 mmol),
silyl enol ether 2a (1.15 g, 6 mmol) and butyraldehyde (577mg, 8
mmol) in anhydrous dioxane (20 mL) was refluxed under an argon
atmosphere for 18 h until complete conversion of 1 was observed
(TLC). Workup as described above gave the products 8a and 8b.
7c
Yield: 255 mg (45%); yellow solid; mp 180–182 °C.
IR (KBr): 3443, 2946, 2852, 1661, 1652, 1617, 1593, 1447, 1377,
1304, 1250, 1180, 1139, 1025, 963, 936, 837, 792, 720, 684 cm–1.
1H NMR (300 MHz, CDCl3): d (cyclic hemiacetal form) = 1.21–
8a
3.02 (m, 11 H), 7.65–7.78 (m, 2 H), 8.08–8.10 (m, 2 H).
Yield: 383 mg (46%); yellow oil.
MS (EI): m/z (%) = 284 (100) [M+], 266 (33), 213 (32), 175 (59),
159 (23), 105 (34), 77 (40).
IR (KBr): 2960, 2927, 1680, 1653, 1610, 1578, 1449, 1378, 1331,
1261, 1203, 1171, 1039, 938, 887, 846, 723, 701 cm–1.
1H NMR (300 MHz, CDCl3): d = –0.10 (s, 9 H), 0.88 (t, J = 7.2 Hz,
3 H), 1.24–1.44 (m, 3 H), 1.79 (dd, J = 3.6, 9.2 Hz, 1 H), 1.91–2.08
(m, 1 H), 2.44 (dd, J = 6.8, 13.9 Hz, 1 H), 3.12–3.27 (m, 1 H), 7.37–
7.42 (m, 3 H), 7.63 (dd, J = 7.8, 1.2 Hz, 2 H), 7.71–7.76 (m, 2 H),
8.11 (td, J = 1.3, 8.4 Hz, 2 H).
MS (EI): m/z (%) = 420 (9) [M+], 377 (2), 287 (6), 228 (3), 192 (9),
177 (47), 115 (16), 105 (100), 75 (41), 45 (21).
Anal. Calcd for C17H16O4: C, 71.83; H, 5.63. Found: C, 71.80; H,
5.68.
cis-3-Ethyl-2-(trimethylsiloxy)-3,4-dihydro-2H-naphtho[2,3-
b]pyran-5,10-dione (6d) and 3-Ethyl-2-hydroxy-3,4-dihydro-
2H-naphtho[2,3-b]pyran-5,10-dione (7d)
A mixture of 2-hydroxy-1,4-naphthoquinone (1; 348 mg, 2 mmol),
silyl enol ether 2d (866 mg, 6 mmol) and paraformaldehyde (240
mg, 8 mmol) in anhydrous dioxane (20 mL) was refluxed under an
argon atmosphere for 18 h until complete conversion of 1 was ob-
served (TLC). Workup as described above gave the products 6d and
7d.
Anal. Calcd for C25H28O4Si: C, 71.43; H, 6.67. Found: C, 71.48; H,
6.81.
8b
Yield: 158 mg (19%); yellow solid; mp 95–96 °C.
6d
IR (KBr): 2961, 2934, 1681, 1648, 1615, 1595, 1578, 1449, 1380,
1340, 1249, 1203, 1176, 1119, 960, 877, 848, 758, 699 cm–1.
Yield: 299 mg (45%); yellow solid; mp 93–95 °C.
IR (KBr): 2961, 2937, 1677, 1651, 1623, 1592, 1577, 1459, 1369,
1331, 1299, 1254, 1195, 1022, 970, 953, 865, 844, 727 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.18 (s, 9 H), 1.01 (t, J = 7.5 Hz,
3 H), 1.42–1.54 (m, 2 H), 1.67–1.77 (m, 1 H), 2.24 (dd, J = 12.4,
18.1 Hz, 1 H), 2.76 (dd, J = 5.4, 18.0 Hz, 1 H), 5.63 (s, 1 H), 7.66–
7.74 (m, 2 H), 8.10 (dd, J = 1.7, 7.2 Hz, 2 H).
1H NMR (300 MHz, CDCl3): d = –0.05 (s, 9 H), 1.01 (t, J = 7.2 Hz,
3 H), 1.45–1.84 (m, 4 H), 1.98–2.02 (m, 1 H), 2.50 (d, J = 15.0 Hz,
1 H), 2.95–2.99 (m, 1 H), 7.32–7.42 (m, 3 H), 7.59 (d, J = 7.9 Hz,
2 H), 7.69–7.77 (m, 2 H), 8.10 (t, J = 7.5 Hz, 2 H).
MS (EI): m/z (%) = 420 (74) [M+], 377 (21), 213 (8), 192 (42), 177
(30), 105 (100), 75 (38), 45 (22).
13C NMR (100 MHz, CDCl3): d = 184.4, 179.8, 152.4, 133.8, 133.0,
132.1, 131.1, 126.2, 126.1, 122.6, 95.1, 37.7, 24.0, 19.8, 11.1, –0.2.
Anal. Calcd for C25H28O4Si: C, 71.43; H, 6.67. Found: C, 71.38; H,
6.75.
Synthesis 2008, No. 8, 1182–1192 © Thieme Stuttgart · New York

PAPER
Synthesis of Siloxy-a-Lapachone Derivatives
1191
3-Ethyl-2-hydroxy-4-propyl-3,4-dihydro-2H-naphtho[2,3-
b]pyran-5,10-dione (9a)
A mixture of 2-hydroxy-1,4-naphthoquinone (1; 348 mg, 2 mmol),
silyl enol ether 2d (866 mg, 6 mmol) and butyraldehyde (577 mg, 8
mmol) in anhydrous dioxane (20 mL) was refluxed under an argon
atmosphere for 18 h until complete conversion of 1 was observed
(TLC). Workup as described above gave the product 9a.
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Yield: 485 mg (81%); yellow solid; mp 158–160 °C.
IR (KBr): 3373, 2955, 1684, 1611, 1575, 1458, 1268, 1200, 1168,
992, 971, 941, 721 cm–1.
1H NMR (300 MHz, CDCl3): d (two diastereomeric hemiacetals,
1:1 ratio) = 0.92–1.03 (m, 12 H), 1.38–2.16 (m, 14 H), 2.79 (d,
J = 9.0 Hz, 1 H), 3.01 (d, J = 8.4 Hz, 1 H), 5.67 (s, 1 H), 5.75 (s,
1 H), 7.65–7.76 (m, 4 H), 7.92–8.11 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 184.8, 184.7, 181.3, 180.7, 153.3,
151.2, 134.7, 134.5, 132.9, 132.8, 131.1, 126.7, 126.0, 125.2, 97.8,
96.0, 40.6, 38.7, 37.3, 34.7, 34.3, 32.8, 25.2, 21.2, 20.8, 18.2, 14.4,
12.3.
MS (EI): m/z (%) = 300 (32) [M+], 272 (34), 229 (64), 187 (100),
176 (35), 159 (68), 115 (47), 105 (52), 77 (57), 45 (40).
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Anal. Calcd for C18H20O4: C, 72.00; H, 6.67. Found: C, 72.05; H,
6.72.
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Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China [NSFC 20572044]. Partial support from the Modern
Analytical Center at Nanjing University is also appreciated.
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