One-pot synthesis of fused-tetracyclic scaffolds employing a Lewis acid promoted domino reaction of naphthoquinones

Article abstract of DOI:10.1055/s-0030-1260073

The facile synthesis of tetracyclic molecular frameworks employing a Lewis acid promoted domino reaction of naphthoquinones with hydroxy- and amino-functionalized cross-conjugated trienes is reported. The reaction cascade involves a heterocyclization via hemiacetal or imine formation, and an intramolecular Diels-Alder cycloaddition. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260073

PAPER
2321
One-Pot Synthesis of Fused-Tetracyclic Scaffolds Employing a Lewis Acid
Promoted Domino Reaction of Naphthoquinones
F
used-Tetracyclic
a
Scaffolds
f
r
om
N
aph
s
thoquinon
i
es ne Bendiabdellah, Isabel Villanueva-Margalef, Antonio Misale, Kazi S. Nahar, Mohammad R. Haque,
David E. Thurston, Giovanna Zinzalla*
Cancer Research UK Protein–Protein Interactions Drug Discovery Research Group, The School of Pharmacy, University of London,
29–39 Brunswick Square, London, WC1N 1AX, UK
Fax +44(20)77535964; E-mail: giovanna.zinzalla@pharmacy.ac.uk
Received 2 March 2011; revised 3 May 2011
of the antibiotic BE-43472B.5 Grieco and co-workers de-
Abstract: The facile synthesis of tetracyclic molecular frameworks
scribed an intermolecular process instead, promoted by
employing a Lewis acid promoted domino reaction of naphtho-
quinones with hydroxy- and amino-functionalized cross-conjugated
trienes is reported. The reaction cascade involves a heterocycliza-
HCl in aqueous media on benzoquinones.6 Furthermore,
the domino process described here provides a facile entry
tion via hemiacetal or imine formation, and an intramolecular to novel polycyclic scaffolds as useful synthetic interme-
Diels–Alder cycloaddition.
diates not previously available.
Key words: tetracyclic scaffolds, naphthoquinone, Lewis acid pro-
moted domino reaction, intramolecular Diels–Alder cycloaddition
linear synthesis illustrated in Scheme 1.7 This commenced
The cross-conjugated trienes 17–20 were prepared by the
with formation of aldehydes 5–8, followed by addition of
5-bromopenta-1,3-diene in the presence of indium and
sulfonylation of the resulting secondary alcohols, and then
b-elimination, and removal of the protecting groups.
Many potent and selective protein–protein interaction
(PPI) inhibitors are naturally occurring molecular frame-
works that possess tetra- or pentacyclic fused rings con-
taining at least one phenyl system.1 This confers a rigid
3-D geometry crucial for target selectivity. Endocyclic ni-
trogen and/or oxygen atoms are often present in these
frameworks.1 In order to discover novel PPI inhibitors ca-
pable of downregulating the Hypoxia Inducible Factor 1
(HIF-1) signaling pathway,2 our synthetic efforts have fo-
cused on tetracyclic scaffolds utilizing the Diels–Alder
(DA) cycloaddition for the efficient and stereospecific
construction of fused-carbocyclic rings. For the prepara-
tion of tetracycline mimetics as potential inhibitors of the
HIF-1 dimerization event,3 we describe herein a Lewis
acid promoted domino process involving intramolecular
DA cycloaddition and heterocyclic cyclization via hemi-
acetal or imine formation. This process takes advantage of
intramolecularity and Lewis acid catalysis in Diels–Alder
reactions4 to enhance reactivity, regioselectivity, and ste-
reoselectivity, and access formation of a polyheterocyclic
ring system in one pot. Previous work by Fallis4c,d and
Ward4a,b has shown the synthetic potential of LA-tether
X
O
n
a)
b)
X
X
HO
H
OH
n
n
Br
1, 2: X = OTBS
3, 4a: X = NHBoc
n = 2, 1
5, 6: X = OTBS
7, 8: X = NHBoc
n = 2, 1
9, 10: X = OTBS
11, 12: X = NHBoc
n = 2, 1
n
d)
X
17, 18: X = OH
n = 2, 1
HO
n
c)
e)
n
19, 20: X = NH2
n = 2, 1
H2N
13, 14: X = OTBS
15, 16: X = NHBoc
n = 2, 1
Scheme 1 Synthesis of cross-conjugated trienes. Reagents and con-
ditions: a) Dess–Martin periodinane, CH2Cl2, 0 °C, 30 min, 65–99%;
b) In, DMF, 10 °C, 3 h, 72–90%; c) i. MsCl, Et3N, 0 °C, 1 h, ii. DBU,
toluene, 60 °C, 5–18 h, 65–92% over 2 steps; d) TBAF, THF, r.t., 18
controlled DA reactions using cross-conjugated triene and h, 96%; e) TFA, CH2Cl2, 50 °C, 18 h, 45–55% (a Compound 4 is com-
mercially available).
diene alcohol derivatives, respectively.
In our studies, oxygen and nitrogen-based derivatives of
Preparation of the novel tetracyclic scaffolds was carried
out in the first instance with trienes 17 and 17a with 2-me-
thyl-1,4-naphthoquinone (21) and 5-hydroxy-2-methyl-
1,4-naphthoquinone (22) (Table 1). A range of Lewis
acids was investigated to synthesize tetrahydro-2H-an-
thra[9,1-bc]pyran-7-ones. BF3·OEt2 and ZrCl4 proved to
be the best catalysts to afford the desired scaffold in high
yields (Table 1). It is important to highlight that the dou-
ble-DA product coming from the DA cycloaddition of 23
with another molecule of triene was not observed.7,8 In the
case of BF3, an excess of the triene 17 was reacted with 21
cross-conjugated trienes and dienes were employed with
asymmetrically substituted naphthoquinones in the Lewis
acid promoted domino process. A Lewis acid catalyzed
domino process involving an intramolecular DA reaction
on quinone systems has not been previously reported in
the literature. Thermal conditions have been explored by
Nicolaou on a naphthoquinone derivative in the synthesis
SYNTHESIS 2011, No. 14, pp 2321–2333
x
x.
x
x
.
2
0
1
1
Advanced online publication: 16.06.2011
DOI: 10.1055/s-0030-1260073; Art ID: N24311SS
© Georg Thieme Verlag Stuttgart · New York

2322
Y. Bendiabdellah et al.
PAPER
with two equivalents of the catalyst (Table 1, entry 1). The
reaction progressed to completion at –45 °C in five hours,
and under these optimized conditions 23 was isolated in
82% yield.9 When the reaction was performed using
ZrCl4, 23 was obtained in 81% yield (entry 2). Under the
optimized conditions two equivalents of the catalyst were
required for full consumption of the starting material as
with BF3, but the reaction progressed faster and at a lower
temperature. When employing Sc(OTf)3, less catalyst was
required (0.5 equiv) and the reaction went to completion
in two hours as with ZrCl4 (entry 3), but 23 was obtained
in a lower yield (65%). The reaction using AlCl3 gave a
complex mixture of products, from which 23 was isolated
in a modest 50% yield (entry 4). Traces of the double-DA
product were also observed.8 Low yields were obtained by
using SnCl4 and TiCl4 (entries 5 and 6). The domino reac-
tion was also attempted with LiClO4/Et2O as Lewis acid,10
but in this case the double-DA adduct 24 was the major
product (40% yield, entry 7; see the experimental section
and Supporting Information). We speculate that no hemi-
acetal formation occurred, thus the DA cycloaddition did
not go through a tether mechanistic pathway4a,b resulting
therefore in the formation of mainly the double-DA ad-
duct. Reverse regioselectivity was observed in the double-
DA cycloaddition compared to the domino process (see
Supporting Information), which also suggested that hemi-
acetal formation did not occur. Finally, the thermal DA re-
action was investigated for the sake of comparison (entry
8) where 23 was formed only in a trace amount.
Table 1 Summary of Optimized Reaction Conditions for the Syn-
thesis of the Anthra[9,1-bc]pyranone Scaffold9
R2
R1
O
R1
O
HO
R2
4
1
17 and 17a (1.5 equiv)
Lewis acid
low temperature
CH2Cl2
O
O
( )
21 R1 = H
17 R2 = CH=CH2
17a R2 = H
23 R1= H, R2 = CH=CH2
22 R1 = OH
25 R1= H, R2 = H
26 R1= OH, R2 = CH=CH2
Entry Lewis acid
Equiv Temp Time (h)Yield Product
(°C)
–45
–78
0
(%)
82
81
65
50
34
14
1
2
BF3·OEt2
ZrCl4
2
5
2
23
23
23
23
23
23
–
2
3
Sc(OTf)3
AlCl3
0.5
1
2
4
–78
–45
–45
r.t.b
80
3
5
SnCl4
2
5
6
TiCl4
2
5
c
7
LiClO4/Et2O 12a
3
–
d
8
–
–
120
24
2.5
–
–
9
Sc(OTf)3
BF3·OEt2
0.5
0.5
0
50
75
25e
10
0
26
Diene 17a was also investigated, but as expected based on
stabilizing secondary orbital interactions, it was less reac-
tive (entry 9). In this case only the use of Sc(OTf)3 al-
lowed the isolation of 25. Plumbagin (22) was then
employed to prepare the tetrahydroanthra[9,1-bc]pyran-7-
one analogue 26. Use of BF3 in the reaction with 17 re-
quired a higher temperature (0 °C) than for naphthoqui-
none 21 to afford the tetracyclic scaffold in good yield
(75%, entry 10).
a A 5 M LiClO4/Et2O solution was used as the reaction solvent.
b Addition of LiClO4/Et2O solution at 0 °C.
c Double-DA product 24 was obtained in 40% yield.
d Traces of 23 observed by LC-MS.
e No product was obtained by using BF3·OEt2 or ZrCl4.
moted under thermal reaction conditions (Tables 1 and 2,
entries 8 and 5, respectively).
The sequence of the domino process is proposed to com-
mence with formation of the hemiacetal (i.e., a ‘covalent
tether’) at the C-4 position (Scheme 2), followed by in-
tramolecular Diels–Alder cycloaddition to give the fused-
cyclic hemiacetal, which then undergoes elimination to
afford the conjugated enol ether system. The driving force
of the reaction, and regiocontrol of hemiacetal formation,
is thought to be the formation of the thermodynamically
favored skeleton containing the conjugated enol ether sys-
tem. This process is promoted by the Lewis acid, which
facilitates both formation of the hemiacetal intermediate
and the intramolecular [4+2] cycloaddition with full ste-
reospecific control (endo transition state). The hemiacetal
formation (i.e., ‘covalent tether’) as the initial intermedi-
ate also ensures exclusive formation of the mono-DA ad-
duct. As anticipated by this reaction sequence, formation
of the opposite regioisomer, namely the fused-cyclic
hemiacetal derivative B, or solely the Diels–Alder adduct,
was not observed.
The reaction of 21 with triene 18 was then investigated for
the formation of the dihydro-2H-anthra[9,1-bc]furan-7-
one scaffold 27 (Table 2). Use of Sc(OTf)3 (0.5 equiv) al-
lowed the formation of the desired tetracyclic compound
as a single product in good yield at 0 °C over 4.5 hours
(65%, Table 2, entry 1). Preparation of 27 was also carried
out using ZrCl4 (entry 2). The reaction proceeded in a sim-
ilar reaction time to Sc(OTf)3, but required more catalyst
(1 equiv), and the desired product was formed in lower
yield (55%). AlCl3 afforded 27 in poor yield and the reac-
tion resulted in complex mixtures of by-products. No re-
action was observed employing BF3 or LiClO4/Et2O, and
the use of TiCl4 or SnCl4 resulted in complex reaction
mixtures. When the domino reaction was carried out un-
der thermal conditions (both conventional and microwave
heating), 27 was isolated in very low yield (15%, entry 5).
In all cases Lewis acid catalysis afforded the desired tet-
racyclic scaffold as a single diastereoisomer and with full
regioselectivity, and BF3 and Sc(OTf)3 proved to be the
best catalysts overall. The domino process was not pro-
With regard to the intramolecular versus intermolecular
mechanistic pathway, it is significant that no reaction oc-
Synthesis 2011, No. 14, 2321–2333 © Thieme Stuttgart · New York

PAPER
Fused-Tetracyclic Scaffolds from Naphthoquinones
2323
of the hemiacetal (‘covalent tether’) could explain the de-
crease in reactivity and selectivity. However, the factors
responsible for the different reactivities of the Lewis acids
are still unclear. We can only speculate that the domino
process is best promoted by the Lewis acid that enhances
the formation of the hemiacetal. In the case of BF3 this
catalyst displays unusual regioselective features in Diels–
Alder reactions of benzo- and naphthoquinones.11 For this
reason, it is suggested that in the reaction with naphtho-
quinone 21, BF3 preferentially chelates the oxygen atom
of the C-4 carbonyl where steric factors take precedence
over electronic ones, thus promoting formation of the
thermodynamically favored enol 23. However, for naph-
thoquinone 22 hemiacetal formation is promoted at both
the C-1 carbonyl (i.e., BF3 chelation) and C-4 carbonyl
(i.e., intramolecular hydrogen bonding) positions. Thus,
an equilibrium between the regiomeric hemiacetals at C-1
and C-4 may be possible, which could explain why a high-
er temperature is required.
Table 2 Summary of Optimized Reaction Conditions for the Syn-
thesis of the Anthra[9,1-bc]furanone Scaffold9
HO
18 (1.5 equiv)
O
O
4
1
Lewis acid
low temperature
CH2Cl2
O
O
21
( )-27
Entry Lewis acida
Equiv
0.5
1
Temp (°C) Time (h) Yield (%)
1
2
3
4
5
Sc(OTf)3
ZrCl4
0
4.5
5
65
55
25
–45 to –25
–78
AlCl3
2
5
d
LiClO4/Et2O
–
12b
–
r.t.c
6
–
80
120
15
a No product was obtained by using BF3·OEt2, SnCl4, or TiCl4.
b A 5 M LiClO4/Et2O solution was used as the reaction solvent.
c Addition of LiClO4/Et2O solution at 0 °C.
In order to gather additional experimental data to support
the proposed mechanistic pathway, 21 and 22 were react-
ed with the methyl ether derivative 17b (Scheme 3) where
only formation of the DA adduct was possible. The reac-
tions were conducted in the conditions optimized for
formation of the tetracyclic scaffold 23. Tricyclic com-
pounds 28 and 29 were obtained as single regioisomers.
d Traces of 27 observed by LC-MS.
LA
HO
R1
O
O
R2
R1
n
HO
R2
4
1
+
OMe
MeO
O
O
O
O
LA
H
17b
intramol. DA
(1.5 equiv)
BF3⋅OEt2 (2 equiv)
CH2Cl2
LA
H
–45 °C, 5 h
O
O
R1
O
O
R1
O
n
n
O
H
21
( )-28, 85%
R2
R2
– H2O
fast
OH
O
OH
O
17b
H
(1.5 equiv)
( )-A
O
BF3⋅OEt2 (2 equiv)
CH2Cl2
R1
O
Formation of B resulting from
hemiacetal formation at the C-1
carbonyl was not observed.
–45 °C, 15 h
O
H
O
4
1
Note:
22
( )-29, 55%
OMe
R2
Scheme 3 Synthesis of 28 and 299
HO
( )-B
O
n
R1 = H, alkyl, OH; R2 = alkenyl, alkyl; n = 1, 2
In both cases, the regiochemical outcome was in accord
with the chelation features of BF3 in Diels–Alder reac-
tions with naphthoquinones as discussed above.11 There-
fore, the reversed regioselective outcome of the DA
reaction for compound 29 compared to 26 supports the re-
action sequence illustrated in Scheme 2.
Scheme 2 Proposed mechanistic pathway of the domino process
curred between 21 and 17 using MeMgBr. This bidentate
Lewis acid afforded the best reactivity in the intermolec-
ular Diels–Alder reaction pathway via a ‘noncovalent
temporary tether’ as reported by Ward and co-workers.4a,b
This experimental data combined with the fact that forma-
tion of the noncovalent temporary tether was not possible
when using BF3 (a monodentate Lewis acid), supported
the reaction sequence proposed in Scheme 2. In the case
of other Lewis acids, where the noncovalent tether path-
way is plausible, equilibrium between this and formation
Application of the domino process to the synthesis of
hetero-tetracyclic skeletons containing an endocyclic
nitrogen atom was then investigated via reaction of naph-
thoquinone 21 with the 1-amino-functionalized triene 19
(Table 3). Using Sc(OTf)3, the anthra[9,1-bc]pyridine tet-
racyclic skeleton 30 was obtained in good yield (70%,
Table 3, entry 1). Two equivalents of the Lewis acid and
Synthesis 2011, No. 14, 2321–2333 © Thieme Stuttgart · New York

2324
Y. Bendiabdellah et al.
PAPER
15 hours were required for full consumption of the naph-
thoquinone. As envisaged, product 30 resulted from pref-
erential Lewis acid chelation to the most electron-rich
carbonyl, thus promoting imine formation at the C-1 posi-
tion. Use of LiClO4 and AlCl3 afforded product 30 with
shorter reaction times but in lower yields (55% and 20%,
respectively, entries 2 and 3). Employing ZrCl4, a trace of
the product was detected by LC-MS. No reactivity was
observed with BF3·OEt2, TiCl4, or SnCl4. The reaction
was also carried out under thermal conditions (both con-
ventional and microwave heating) and, as expected, no re-
activity was observed after five days at 80 °C. The
reaction was also investigated using Brønsted acid cataly-
sis in aqueous medium (5 M HCl, 2.5 equiv) for the sake
of comparison with the domino reaction involving an in-
termolecular pathway on benzoquinone systems reported
by Grieco.6 Compound 30 was isolated in 50% yield from
a complex mixture after heating at 50 °C for 2.5 hours.
Lewis acid catalysis was confirmed to provide formation
of the desired product in good yield.
OH
O
N
H
6a
OH
O
O
( )-31a, 29%
19 (2.5 equiv)
+
Sc(OTf)3 (3 equiv)
CH2Cl2, 0 °C, 24 h
OH
O
H
6a
22
N
( )-31b, 65%
Scheme 4 Synthesis of anthra[9,1-bc]pyridine 309
Table 4 Synthesis of the Tricyclic Skeleton 329
NHBoc
O
H
Table 3 Summary of Optimized Reaction Conditions for the Syn-
thesis of the Anthra[9,1-bc]pyridine Scaffold9
BocHN
O
O
O
O
H2N
O
O
H
( )-32
15
19 (1.5 equiv)
+
Lewis acid
Lewis acid
CH2Cl2, 0 °C
NHBoc
CH2Cl2, 0 °C or r.t.
N
O
21
21
( )-30
H
Entry Lewis acida
Equiv
2
Temp (°C) Time (h) Yield (%)
O
H
1
2
3
4
5
Sc(OTf)3
0
r.t.c
0
15
6
70
55
20
H
O
O
LiClO4/Et2O 12b
( )-33
AlCl3
ZrCl4
–
2
2
–
4
Entry Triene Lewis acid LA
Time
(equiv) (h)
Yield
(%)
d
–20
80
6
–
(equiv)
32
33
3
120
–
a No product was obtained by using BF3·OEt2, TiCl4, or SnCl4.
b A 5 M LiClO4/Et2O solution was used as the reaction solvent.
c Addition of LiClO4/Et2O solution at 0 °C.
1
2
1.5
2.5
Sc(OTf)3
BF3·OEt2
1.5
5
2.5
36
70
25
a
19
d Traces of product observed by LC-MS.
a Recovered 21: 25%.
Triene 19 proved to be much less reactive with 22 where
3 equivalents of catalyst and a prolonged reaction time
were required for full consumption of 22 to form the tet-
racyclic compound in a good yield (Scheme 4). Due to the
prolonged reaction time, racemization at the C-6a position
of 31a was observed (monitored by LC-MS), with forma-
tion of the cis-31a and trans-31b diastereoisomers in an
approximate ratio of 1:2.
good yield using Sc(OTf)3 as Lewis acid, with only traces
of the double DA adduct 33 formed. With BF3 the reaction
proceeded poorly (Table 4, entry 2). Also, the larger
amount of Lewis acid and longer reaction time promoted
the second DA cycloaddition with formation of a 1.3:1 ra-
tio of 32/33. The structures and relative stereochemistries
for all the nitrogen-based scaffolds were unambiguously
determined by 1D and 2D NMR experiments (including
NOESY).9
Reaction of 21 with the N-Boc-protected triene 15 pro-
ceeded to give the opposite regiochemistry to compound
30 (Table 4). In this case, imine formation is not possible
and so steric factors control the regioselectivity of the in-
termolecular DA reaction. Product 32 was obtained in
Formation of the anthra[9,1-bc]pyrrole scaffold 34 was
also investigated (Table 5). Reaction of 21 with triene 20
in the presence of Sc(OTf)3 required 3 equivalents of
Sc(OTf)3, 2 equivalents of triene, and 18 hours at room
Synthesis 2011, No. 14, 2321–2333 © Thieme Stuttgart · New York

PAPER
Fused-Tetracyclic Scaffolds from Naphthoquinones
2325
temperature for complete consumption of the starting ma-
terial. This afforded 34 in moderate yield (55%, Table 5,
entry 1). Use of other Lewis acids did not enhance the re-
activity (entries 2 and 3). Full regio- and diastereoselec-
tivity were again achieved, and the regio-outcome was
opposite to that observed for 30. In this case, the regiose-
lectivity for the synthesis of the tetracyclic scaffold via
hemiaminal formation followed by intramolecular DA re-
action is controlled by steric factors, due to formation of
the fused nitrogen-based five-membered ring in product
34. Under thermal conditions no reactivity was observed
(entry 4). Also, no reaction was observed under aqueous
HCl reaction conditions for the preparation of product
type 34 in the case of 21 and 22.6
O
O
O
35a,b
N
R
(5 equiv)
O
23
H
toluene, 70 °C
O
N
O
R
( )-36a, R = H, 95%
( )-36b, R = (CH2)2COOH, 90%
Scheme 5 Synthesis of fused polycyclic skeletons9
teraction area where the size and complexity of molecular
frameworks are known to be critical.1 Furthermore, a
domino process provides a facile entry to intermediates
for the synthesis of complex polycyclic compounds.
Also in the case of the nitrogen-based tetracyclic scaffold,
Lewis acid catalysis afforded the desired product as a sin-
gle diastereoisomer and with full regioselectivity, and
Sc(OTf)3 proved to be the best catalyst overall. The dom-
ino process was not promoted under thermal reaction con-
ditions (Tables 3 and 5, entries 5 and 4, respectively).
Reagents and solvents used were obtained from commercial sourc-
es, unless otherwise indicated. Reactions requiring anhydrous con-
ditions were conducted in glassware, which had been oven-dried
overnight. All reactions were carried out under dry N2 and in anhy-
drous conditions, unless H2O was used as solvent or co-solvent. All
reactions were monitored by analytical TLC performed using the in-
dicated solvent on E. Merck silica gel 60 F254 plates (0.25 mm).
TLC plates were visualized using UV light (254 or 360 nm) and/or
staining with a cerium sulfate/ammonium molybdate solution or ba-
sic KMnO4 followed by heating. LC-MS was also used to monitor
the progress of reactions. Solvents were removed by rotary evapo-
ration at or below 40 °C and products further dried using low-pres-
sure vacuum pumps. Compounds with low boiling points such as
bromopentadiene, pentadienol, and the trienes were dried at 30 °C/
100 mmHg. An immersion cooler was used to perform overnight re-
actions at very low temperatures (e.g., –45 °C). Purification of com-
pounds was achieved by column chromatography using Merck
Flash silica gel 60 (230–400 mesh). IR spectra were recorded using
neat conditions on a PerkinElmer Spectrum 1000 FT IR Spectro-
photometer. 1H and 13C NMR spectra were acquired at 300 K using
a Bruker Avance 400 NMR spectrometer at 400 MHz or 500 MHz
Table 5 Synthesis of Anthra[9,1-bc]pyrrole Scaffold9
H2N
N
O
H
20 (2 equiv)
+ 21 (30%)
Lewis acid
CH2Cl2, r.t., 18 h
O
O
( )-34, 55%
21
Entry
Lewis acida Equiv
Temp (°C) Time (h) Yield (%)
1
2
3
4
Sc(OTf)3
ZrCl4
SnCl4
–
5
5
3
–
r.t.b
r.t.b
r.t.b
80
18
18
55
10
10
–
1
for H NMR and 100 MHz or 125 MHz for 13C NMR. Chemical
shifts (d) are quoted in ppm and referenced to CDCl3 (residual
18
CHCl3 signal 1H d = 7.26, 13C d = 77.2 or DMSO-d6 residual
1
1
DMSO signal H d = 2.54, 13C d = 40.45). Multiplicities in the H
NMR spectra are quoted as: s = singlet, d = doublet, q = quartet,
m = multiplet, dd = double doublet, ddd = double double doublet,
dt = double triplet, td = triple doublet, ddt = double double triplet.
Mass spectroscopy data were collected using a Waters Micromass
ZQ instrument coupled to a Waters 2695 HPLC with a Waters 2996
PDA. Waters Micromass ZQ parameters used were: capillary, 3.38
kV; cone, 35 V; extractor, 3.0 V; source temperature, 100 °C; de-
solvation temperature, 200 °C; cone flow rate, 50 L/h; desolvation
flow rate, 250 L/h. High-resolution mass spectra (HRMS) were ob-
tained on a Waters Micromass QTOF Global in positive W-mode
using metal-coated borosilicate glass tips to introduce samples into
the instrument coupled with LC using electrospray (ES) ionization
and time-of-flight (TOF) mass spectrometry.
120
a No product was obtained using BF3·OEt2, AlCl3, LiClO4/Et2O, or
TiCl4.
b Addition of the Lewis acid at 0 °C.
With these novel scaffolds in hand, the formation of more
complex structures was investigated for the preparation of
tetracycline mimetics as potential inhibitors of the HIF-
1a:HIF-1b protein–protein interaction. For example, the
scaffold 23 was reacted with symmetric dienophiles 35a
and 35b in toluene in a thermal DA cycloaddition to form
the novel fused-polycyclic compounds 36a and 36b, con-
taining endocyclic oxygen and nitrogen atoms. The poly-
cyclic products were both isolated as single diastereo-
isomers in good yields (Scheme 5).
Synthesis of Dienes and Cross-Conjugated Trienes
TBS Monoprotection of Diols; General Procedure
Propanediol or ethanediol (80.5 mmol, 1 equiv) was diluted with
THF (150 mL, 0.5 M) at 0 °C and powdered imidazole (13.14 g, 193
mmol, 2.4 equiv) was added to the solution under dry, inert condi-
tions. Upon stirring, powdered tert-butyldimethylsilyl chloride
(13.51 g, 76.5 mmol, 0.95 equiv) powder was added to the mixture.
The reaction was left to stir at r.t. for 18 h. The crude was filtered
on a pad of silica gel and washed with EtOAc (3 × 30 mL), then con-
centrated at 40 °C/100 mm Hg. The concentrated solution was sep-
In summary, the domino reaction described here provides
a powerful synthetic tool to access novel heterotetracy-
clic-fused skeletons in a one-pot synthesis, and in a regio-
and diastereospecific manner. These complex skeletons
should find use in the preparation of compound libraries
for drug discovery, in particular in the protein–protein in-
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2326
Y. Bendiabdellah et al.
PAPER
arated by column chromatography on silica gel using n-hexane and
EtOAc (4:1) to give the desired product as a colorless oil (98% pu-
rity assessed by NMR analysis and TLC).
EtOAc (20:1) to afford the desired compounds (98% purity assessed
by NMR analysis and TLC).
3-(tert-Butyldimethylsilyloxy)propanal (5)
The reaction time was 1.5 h and compound 9 was isolated as a col-
orless oil; yield: 3.21 g (75%); Rf = 0.14 (n-hexane–EtOAc, 20:1).
3-(tert-Butyldimethylsilyloxy)propan-1-ol (1)
Yield: 8.74 g (60%); Rf = 0.15 (n-hexane–EtOAc, 4:1).
IR (neat): 3453, 2922, 2356 cm–1.
IR (neat): 2928, 2366, 1715, 1253, 1102 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.83–3.74 (4 H, m, H-1,3), 2.76 (1
H, s, OH), 1.74 (2 H, q, J = 5.7 Hz, H-2), 0.90 [9 H, s, C(CH3)3],
0.04 [6 H, s, Si(CH3)2].
1H NMR (400 MHz, CDCl3): d = 9.80 (1 H, s, H-1), 3.98 (2 H, t,
J = 6.0 Hz, H-3), 2.59 (2 H, td, J = 26.0, 2.1 Hz, H-2), 0.88 [9 H, s,
C(CH3)3], 0.07 [6 H, s, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 62.5 (C-1/3), 61.9 (C-1/3), 34.0
(C-2), 25.8 [C(CH3)3], 25.6 [C(CH3)3], –5.8 [Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 201.9 (C-1), 57.4 (C-3), 46.5 (C-
2), 25.8 [C(CH3)3], 18.2 [C(CH3)3], –5.5 [Si(CH3)2].
Spectroscopic data are in accordance with those reported in the lit-
erature.4c
HRMS: m/z calcd for C9H20O2Si + H: 189.1311; found: 189.1316
[M + H]+.
Spectroscopic data are in accordance with those reported in the lit-
erature.4c
3-(tert-Butyldimethylsilyloxy)ethan-1-ol (2)
Yield: 7.68 g (57%); Rf = 0.17 (n-hexane–EtOAc, 4:1).
IR (neat): 2928, 2360, 1417, 1253 cm–1.
3-(tert-Butyldimethylsilyloxy)ethanal (6)
The reaction time was 1 h and compound 6 was isolated as a color-
less oil; yield: 2.57 g (65%); Rf = 0.16 (n-hexane–EtOAc, 20:1).
IR (neat): 2917, 2849, 2365, 1739, 1263, 733 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.71 (1 H, dt, J = 6.4, 0.7 Hz, H-
1), 3.70 (1 H, d, J = 5.0 Hz, H-1), 3.72–3.61 (2 H, m, H-2), 0.91 [9
H, s, C(CH3)3], 0.08 [6 H, s, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 64.1 (C-1/3), 63.7 (C-1/3), 25.9
[C(CH3)3], 18.3 [C(CH3)3], –5.3 [Si(CH3)2].
1H NMR (400 MHz, CDCl3): d = 9.70 (1 H, s, H-1), 4.20 (2 H, d,
J = 0.8 Hz, H-2), 0.93 [9 H, s, C(CH3)3], 0.11 [6 H, s, Si(CH3)2].
Spectroscopic data are in accordance with those reported in the lit-
erature.12
13C NMR (100 MHz, CDCl3): d = 202.3 (C-1), 69.6 (C-2), 25.7
[C(CH3)3], 18.3 [C(CH3)3], –5.4 [Si(CH3)2].
HRMS: m/z calcd for C8H18O2Si + H: 175.1154; found: 175.1158
N-Boc-propanol (3)
[M + H]+.
Amino alcohol 1 (0.50 g, 6.7 mmol, 0.51 mL) was diluted with THF
(15 mL, 0.4 M) and transferred to a three-necked flask. The solution
was cooled to 0 °C and K2CO3 (0.92 g, 6.7 mmol, 1 equiv) and di-
tert-butyl dicarbonate (1.74 g, 7.9 mmol, 1.2 equiv) were added to
the mixture, which was allowed to warm up to r.t. and left vigorous-
ly stirring for 18 h. The reaction mixture was concentrated under re-
duced pressure and diluted with EtOAc (35 mL). The EtOAc layer
was then washed with H2O (3 × 15 mL) and brine (10 mL), and the
combined aqueous phases were extracted with EtOAc (3 × 15 mL).
The combined organic solutions were dried (MgSO4) and concen-
trated under vacuum. The crude mixture was then purified by col-
umn chromatography on silica gel using n-hexane and EtOAc (1:1).
Compound 3 was isolated as a clear colorless oil; yield: 1.03 g
(88%) (98% purity assessed by NMR and LC-MS analysis); Rf =
0.27 (Et2O).
Spectroscopic data are in accordance with those reported in the lit-
erature.14
tert-Butyl 3-Oxopropylcarbamate (7)
The reaction time was 1 h and compound 7 was isolated as a color-
less oil; yield: 2.95 g (75%); Rf = 0.4 (Et2O).
IR (neat): 2976, 2357, 1702, 1506, 1264 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.81 (1 H, s, H-3), 4.91 (1 H, s,
NH), 3.49–3.36 (2 H, m, H-1), 2.74–2.65 (2 H, m, H-2), 1.42 [9 H,
s, C(CH3)3].
13C NMR (100 MHz, CDCl3): d = 201.5 (C-3), 155.8 (COO), 79.5
[C(CH3)3], 44.3 (C-2), 34.0 (C-1), 28.4 [C(CH3)3].
Spectroscopic data are in accordance with those reported in the lit-
erature.15
IR (neat): 3349, 2934, 2330, 1682, 1164 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.74 (1 H, s, NH), 3.66 (2 H, q,
J = 5.8 Hz, H-3), 3.29 (2 H, q, J = 6.0 Hz, H-1), 1.66 (2 H, q,
J = 5.9 Hz, H-2), 1.45 [9 H, s, C(CH3)3].
13C NMR (100 MHz, CDCl3): d = 155.8 (COO), 79.7 [C(CH3)3],
59.2 (C-1), 36.8 (C-3), 32.9 (C-2), 28.4 [C(CH3)3].
tert-Butyl 2-Oxoethylcarbamate (8)
The reaction time was 30 min and compound 8 was isolated as a col-
orless oil; yield: 3.57 g (99%); Rf = 0.65 (Et2O).
IR (neat): 2977, 2356, 1686, 1630 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.63 (1 H, s, H-2), 5.23 (1 H, s,
NH), 4.05 (2 H, d, J = 4.6 Hz, H-1), 1.44 [9 H, s, C(CH3)3].
Spectroscopic data are in accordance with those reported in the lit-
erature.13
13C NMR (100 MHz, CDCl3): d = 197.5 (C-2), 156.0 (COO), 51.7
(C-1), 31.9 [C(CH3)3], 28.6 [C(CH3)3].
Aldehydes 5–8; General Procedure
Under N2 flow and at 0 °C, Dess–Martin periodinane (10.1 g, 23.8
mmol, 1.05 equiv) was added in one portion to a solution of alcohol
(22.7 mmol) in CH2Cl2 (50 mL, 0.4 M). The reaction mixture was
left stirring for 30 min to 1.5 h, then quenched with sat. aq NaHCO3/
Na2S2O3 (1:1, 30 mL) and stirred at r.t. for 30 min. The aqueous lay-
er was separated from the organic and extracted with Et2O (3 × 20
mL). The combined organic solutions were washed with H2O
(3 × 20 mL) and brine (20 mL), dried (MgSO4), filtered, and con-
centrated under reduced pressure. The crude mixture was purified
by flash column chromatography on silica gel using n-hexane and
MS (EI): m/z (%) = 158.27 (M+ – 1, 20), 171.34 (M+ + 12, 80).
HRMS: m/z calcd for C7H13NO3 + H: 160.0974; found: 160.0978
[M + H]+.
Anal. Calcd for C7H13NO3: C, 52.82; H, 8.23; N, 8.80. Found: C,
52.62; H, 8.06; N, 8.69.
Spectroscopic data are in accordance with those reported in the lit-
erature.16
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Fused-Tetracyclic Scaffolds from Naphthoquinones
2327
Allylation of Aldehydes; General Procedure
HRMS: m/z calcd for C13H23NO3 + Na: 264.1576; found: 264.1578
The 5-bromopenta-1,3-diene (18.9 mmol, 1.5 equiv), prepared ac-
cording to the procedure of Prevost,17 was added to a solution of al-
dehyde (12.6 mmol, 1 equiv) in DMF (65 mL, 0.2 M). The reaction
mixture was then cooled to 0 °C and In powder (100 mesh, 1.49 g,
25.2 mmol, 2 equiv) was added portionwise under vigorous stirring.
After 3 h, the reaction was allowed to warm to 10 °C, diluted with
CH2Cl2 (65 mL) and poured into Et2O (195 mL) forming a cloudy
mixture. This was filtered on a pad of silica gel and washed with
Et2O (3 × 30 mL). The solvent was removed under reduced pressure
and the crude residue was purified by flash column chromatography
on silica gel using n-hexane and Et2O (4:1). Compounds 9–12 were
isolated as colorless oils (98% purity assessed by NMR and LC-MS
analysis).
[M + Na]+.
1-(N-Boc)-3-vinylpent-4-en-2-ol (12)
Yield: 2.06 g (72%); Rf = 0.6 (n-hexane–Et2O, 1:9).
IR (neat): 3361, 2977, 2360, 1682, 1512, 1392, 1366, 1246 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.89–5.75 (2 H, m, H-3a,4), 5.22–
5.11 (4 H, m, H-3b/5), 4.93 (1 H, s, NH), 3.63 (1 H, td, J = 7.4 Hz,
H-2), 3.40 (1 H, ddd, J = 14.0, 6.7, 2.5 Hz, H-1), 3.03 (1 H, ddd,
J = 14.1, 8.1, 5.1 Hz, H-1), 2.82 (1 H, m, H-3), 2.47 (1 H, s, OH),
1.44 [9 H, s, C(CH3)3].
13C NMR (100 MHz, CDCl3): d = 157.0 (COO), 136.9 (C-3b,5),
117.7 (C-3a,4), 66.2 (C-2), 53.4 (C-3), 44.8 (C-1), 31.9 [C(CH3)3],
28.7 [C(CH3)3].
1-(tert-Butyldimethylsilyloxy)-4-vinylhex-5-en-3-ol (9)
Yield: 2.91 g (90%); Rf = 0.48 (n-hexane–Et2O, 4:1).
MS (EI): m/z (%) = 228.46 (M+ + 1, 10), 250.42 (M+ + 23, 90).
HRMS: m/z calcd for C12H21NO3 + Na: 250.1419; found: 250.1427
IR (neat): 3462, 2956, 2364, 1253, 1086 cm–1.
[M + Na]+.
1H NMR (400 MHz, CDCl3): d = 5.90 (1 H, ddd, J = 17.5, 10.6 Hz,
H-4a/5), 5.83 (1 H, ddd, J = 17.3, 10.9, 7.5 Hz, H-4a/5), 5.18–5.09
(4 H, m, H-4b,6), 3.89 (1 H, dt, J = 10.1, 5.0 Hz, H-3), 3.92–8.76 (2
H, m, H-1), 2.81 (1 H, q, J = 7.0 Hz, H-4), 1.85–1.71 (2 H, m, H-2),
0.90 [9 H, s, C(CH3)3], 0.07 [6 H, s, Si(CH3)2].
Anal. Calcd for C12H21NO3: C, 63.41; H, 9.31; N, 6.16. Found: C,
63.54; H, 9.21; N, 6.26.
Cross-Conjugated Trienes; General Procedure
Et3N (23.4 mmol, 2 equiv) was added at r.t. to a solution of the sec-
ondary alcohol (11.7 mmol, 1 equiv) in CH2Cl2 (45 mL, 0.25 M).
MsCl (17.5 mmol, 1.5 equiv) was then added dropwise at –50 °C.
The cooling bath was removed and the reaction was left to reach 0
°C and stirred for 1 h. The reaction mixture was then poured into
half sat. aq NaHCO3 (40 mL). The separated aqueous layer was then
extracted with Et2O (3 × 30 mL), dried (MgSO4), and concentrated
under reduced pressure. The methyl sulfonate salt formed was used
in the next reaction without further purification. The sulfonate salt
was dissolved in benzene (45 mL, 0.27 M) and then DBU (12.9
mmol, 1.05 equiv) was added. The mixture was heated at 80 °C for
5–18 h. The excess of solvent was removed under reduced pressure
and the crude residue was purified by column chromatography on
silica gel using n-hexane. The hexane fractions were concentrated
under reduced pressure (40 °C/50 mm Hg). Trienes 13–16 were iso-
lated as clear colorless oils (98% purity assessed by NMR analysis
and TLC).
13C NMR (100 MHz, CDCl3): d = 137.8 (C-5/4a), 137.3 (C-5/4a),
116.7 (C-4b/6), 116.4 (C-4b/6), 73.6 (C-3), 62.6 (C-1), 54.7 (C-4),
35.8 (C-2), 25.8 [C(CH3)3], 18.1 [C(CH3)3], –5.6 [Si(CH3)2].
MS (EI): m/z (%) = 238.88 (M+ – 18, 100), 256.89 (M+, 20).
HRMS: m/z calcd for C14H28O2Si + H: 257.1937; found: 257.1928
[M + H]+.
Spectroscopic data are in accordance with those reported in the lit-
erature.4c
1-(tert-Butyldimethylsilyloxy)-3-vinylpent-4-en-2-ol (10)
Yield: 2.29 g (75%); Rf = 0.50 (n-hexane–Et2O, 4:1).
IR (neat): 2927, 2360, 1636, 1471, 1107 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.92 (1 H, dt, J = 17.4, 8.8 Hz, H-
3a/4), 5.80 (1 H, dt, J = 17.8, 8.8 Hz, H-3a/4), 5.16–5.08 (4 H, m,
H-3b,5), 3.68–3.54 (2 H, m, H-1), 3.51 (1 H, m, H-2), 2.90 (1 H, q,
J = 7.4 Hz, H-3), 2.41 (1 H, d, J = 3.9 Hz, OH), 0.90 [9 H, s,
C(CH3)3], 0.07 [6 H, s, Si(CH3)2].
tert-Butyldimethyl(4-vinylhexa-3,5-dienyloxy)silane (13)
Yield: 2.57 g (92%); Rf = 0.8 (CH2Cl2).
13C NMR (100 MHz, CDCl3): d = 137.2 (C-3a/4), 116.6 (C-3b/5),
73.4 (C-2), 65.2 (C-1), 53.4 (C-3), 25.9 [C(CH3)3], 18.2 [C(CH3)3],
–5.4 [(CH2)2].
IR (neat): 2954, 2362, 1471, 1253, 1096 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.49 (1 H, dd, J = 18.2, 10.6 Hz,
H-4a/5), 6.40 (1 H, dd, J = 17.4, 10.7 Hz, H-4a/5), 5.64 (1 H, t,
J = 7.6 Hz, H-3), 5.30 (1 H, dd, J = 1.9, 1.3 Hz, H-4b/6), 5.32–5.22
(2 H, m, H-4b/6), 5.03 (1 H, dd, J = 10.6, 1.5 Hz, H-4b/6), 3.66 (2
H, t, J = 6.8 Hz, H-1), 2.45 (2 H, q, J = 7.1 Hz, H-2), 0.89 [9 H, s,
C(CH3)3], 0.05 [6 H, s, Si(CH3)2].
MS (EI): m/z (%) = 242.86 (M+, 10), 224.92 (M+ – 18, 100).
HRMS: m/z calcd for C13H26O2Si + Na: 265.1600; found: 265.1611
[M + Na]+.
13C NMR (100 MHz, CDCl3): d = 138.5 (C-4), 137.8 (C-3), 132.1
(C-5/4a), 128.5 (C-5/4a), 117.4 (C-4b/6), 114.0 (C-4b/6), 62.7 (C-
1), 32.1 (C-2), 25.9 [C(CH3)3], 18.4 [C(CH3)3], –5.3 [Si(CH3)2].
tert-Butyl 3-Hydroxy-4-vinylhex-5-enylcarbamate (11)
Yield: 1.98 g (65%); Rf = 0.15 (EtOAc–n-hexane, 1:1).
IR (neat): 3351, 2977, 2353, 1682, 1508, 1166 cm–1.
MS (EI): m/z (%) = 239.17 (MH+, 15), 123.29 (M+ – 116, 15).
1H NMR (400 MHz, CDCl3): d = 5.90–5.72 (2 H, m, H-4a,5), 5.21–
5.10 (4 H, m, H-4b,6), 4.92 (1 H, br s, NH), 3.63 (1 H, td, J = 6.2,
2.7 Hz, H-3), 3.46 (1 H, m, H-1), 3.17 (1 H, dd, J = 13.7, 5.4 Hz, H-
1), 2.81 (1 H, q, J = 7.4 Hz, H-4), 2.73 (1 H, br s, OH), 1.65 (1 H,
m, H-2), 1.52 (1 H, m, H-2), 1.46 [9 H, s, C(CH3)3].
13C NMR (100 MHz, CDCl3): d = 157.0 (COO), 137.7 (C-5/4a),
136.5 (C-5/4a), 117.7 (C-6/4b), 116.5 (C-6/4b), 79.5 [C(CH3)3],
71.2 (C-3), 54.5 (C-4), 37.3 (C-1), 35.2 (C-2), 20.2 [C(CH3)3].
HRMS: m/z calcd for C14H26OSi + H: 239.1831; found: 239.1822
[M + H]+.
tert-Butyldimethyl(3-vinylpenta-2,4-dienyloxy)silane (14)
Yield: 2.10 g (80%); Rf = 0.8 (CH2Cl2).
IR (neat): 2928, 2363, 1471, 1253, 1096 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.43 (2 H, dd, J = 17.8, 10.9 Hz,
H-3a,4), 5.76 (1 H, t, J = 6.8 Hz, H-2), 5.43–5.31 (2 H, m, H-3b,5),
5.26 (1 H, dd, J = 17.6, 1.8 Hz, H-3b/5), 5.13 (1 H, dd, J = 10.7, 1.0
MS (EI): m/z (%) = 79.09 (M+ – 162), 241.57 (M+, 10), 264.55 (M
+ Na+, 5).
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2328
Y. Bendiabdellah et al.
PAPER
Hz, H-3b/5), 4.39 (2 H, d, J = 6.8 Hz, H-1), 0.90 [9 H, s, C(CH3)3],
0.07 [6 H, s, Si(CH3)2].
J = 10.7, 1.3 Hz, H-4b/6), 3.71 (2 H, dd, J = 11.7, 6.2 Hz, H-1),
2.51 (2 H, dd, J = 13.9, 6.7 Hz, H-2), 1.40 (1 H, br s, OH).
13C NMR (100 MHz, CDCl3): d = 142.8 (C-3), 138.2 (C-2), 134.6
(C-4/3a), 126.5 (C-4/3a), 118.4 (C-3b/5), 115.7 (C-3b/5), 69.4 (C-
1), 25.9 [C(CH3)3], 18.3 [C(CH3)3], –5.3 [Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 139.6 (C-4), 137.6 (C-5/4a),
131.8 (C-5/4a), 127.6 (C-3), 118.0 (C-4b/6), 114.5 (C-4b/6), 62.4
(C-1), 31.8 (C-2).
MS (EI): m/z = 224.92 (M+, 100%).
MS (EI): m/z (%) = 124.34 (M+, 5), 104.90 (M+ – 19, 20).
HRMS: m/z calcd for C13H24OSi + H: 224.1596; found: 221.1178
4-Vinylpenta-2,4-dien-1-ol (18)
Yield: 1.17 g (96%); Rf = 0.20 (CH2Cl2).
[M+ – 3].
1-(N-Boc)-4-vinylhexa-3,5-diene (15)
Yield: 1.70 g (65%); Rf = 0.26 (CH2Cl2).
IR (neat): 3350, 2976, 2357, 1682, 1506, 1163 cm–1.
IR (neat): 3318, 2361, 1601, 1417, 986 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.42 (2 H, dd, J = 17.8, 10.9 Hz,
H-3a,4), 5.77 (1 H, t, J = 6.8 Hz, H-2), 5.35 (2 H, m, H-3b,5), 5.26
(1 H, dd, J = 17.6, 1.8 Hz, H-3b/5), 5.13 (1 H, dd, J = 10.7, 1.0 Hz,
H-3b/5), 4.35 (2 H, d, J = 6.8 Hz, H-1), 1.47 (1 H, br s, OH).
13C NMR (100 MHz, CDCl3): d = 139.2 (C-3), 137.5 (C-3/3a),
131.3 (C-4/3a), 129.9 (C-2), 119.2 (C-3b/5), 115.7 (C-3b/5), 59.5
(C-1).
1H NMR (400 MHz, CDCl3): d = 6.46 (1 H, dd, J = 17.3, 11.0 Hz,
H-4a/5), 6.39 (1 H, dd, J = 16.9, 10.3 Hz, H-4a/5), 5.56 (1 H, t,
J = 7.7 Hz, H-3), 5.31 (1 H, d, J = 11.1 Hz, H-4b/6 cis), 5.28 (2 H,
d, J = 17.5 Hz, H-4b,6 trans), 5.06 (1 H, d, J = 10.7 Hz, H-4b/6 cis),
4.53 (1 H, br s, NH), 3.20 (2 H, q, J = 6.1 Hz, H-1), 2.41 (2 H, q,
J = 7.1 Hz, H-2), 1.44 [9 H, s, C(CH3)3].
13C NMR (100 MHz, CDCl3): d = 155.8 (COO), 139.3 (C-4), 137.6
(C-5/4a), 131.7 (C-5/4a), 128.3 (C-3), 117.9 (C-6/4b), 114.5 (C-6/
4b), 79.5 [C(CH3)3], 40.0 (C-1), 28.7 (C-2), 28.4 [C(CH3)3].
MS (EI): m/z (%) = 110.86 (M+, 85), 96.4 (M+ – 17, 55).
HRMS: m/z calcd for C7H10O + H: 111.0810; found: 111.0813 [M
+ H]+.
MS (EI): m/z (%) = 168.22 (M+ – 55, 75), 224.30 (MH+, 15).
Removal of the Boc Protecting Group; General Procedure
Trifluoroacetic acid (32.8 mmol, 4 equiv) was added at 0 °C to a so-
lution of N-Boc protected triene (8.2 mmol, 1 equiv) in CH2Cl2 (35
mL, 0.2 M). The mixture was left to stir at 50 °C for 18 h. The so-
lution was then left to cool at r.t. and activated Amberlyst A-21
(7.14 g, 8 equiv) was added. The heterogeneous mixture was stirred
at r.t. for 1 h. Amberlyst was filtered off and the filtrate was concen-
trated at 40 °C/40 mm Hg. The crude mixture was purified by flash
column chromatography on silica gel using EtOAc and Et3N
(9.5:0.5). Amines 19 and 20 were obtained as clear yellow oils (98%
purity assessed by NMR and LC-MS analysis).
HRMS: m/z calcd for C13H21NO2 + Na: 246.1470; found: 246.1480
[M + Na]+.
Anal. Calcd for C13H21NO2: C, 69.92; H, 9.48; N, 6.27. Found: C,
69.91; H, 9.54; N, 5.99.
1-(N-Boc)-3-vinylpenta-2,4-diene (16)
Yield: 1.60 g (65%); Rf = 0.3 (CH2Cl2).
IR (neat): 2976, 1689, 1505, 1391, 1365, 1247, 1180 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.53–6.38 (2 H, m, J = 17.6, 11.1
Hz, H-3b/5), 5.58 (1 H, t, J = 7.0 Hz, H-2), 5.38–5.09 (4 H, m, H-
3b/5), 4.55 (1 H, s, NH), 3.92 (2 H, t, J = 3.2 Hz, H-1), 1.44 [9 H, s,
C(CH3)3].
13C NMR (100 MHz, CDCl3): d = 156.1 (COO), 137.7 (C-3), 131.6
(C-3a,4), 128.1 (C-2), 119.5 (C-3b/5), 115.8 (C-3b/5), 39.0 (C-1),
31.2 [C(CH3)3], 28.8 [C(CH3)3].
4-Vinylhexa-3,5-dien-1-amine (19)
Yield: 0.75 g (55%); Rf = 0.26 ( EtOAc–Et2NH, 9.5:0.5).
IR (neat): 2935, 2365, 1684, 1166 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.43 (1 H, dt, J = 17.2, 11.4 Hz,
H-4a/5), 6.34 (1 H, ddd, J = 17.4, 10.6, 6.8 Hz, H-4a/5), 5.55 (1 H,
q, J = 6.5 Hz, H-3), 5.34–5.16 (3 H, m, H-4b/6), 4.98 (1 H, dd,
J = 10.7, 6.1 Hz, H-4b/6 cis), 2.73 (2 H, t, J = 6.8 Hz, H-1), 2.31 (2
H, q, J = 7.1 Hz, H-2), 1.38 (2 H, br s, NH2).
13C NMR (100 MHz, CDCl3): d = 138.8 (C-4), 137.4 (C-5/4a),
131.7 (C-5/4a), 129.2 (C-3), 117.5 (C-4b/6), 113.9 (C-4b/6), 41.7
(C-1), 29.4 (C-2).
MS (EI): m/z = 232.50 (M+ + 23, 10%).
HRMS: m/z calcd for C12H19NO2 + Na: 232.1313; found: 232.1320
[M + Na]+.
Anal. Calcd for C12H19NO2: C, 68.87; H, 9.15; N, 6.69. Found: C,
68.8; H, 9.37; N, 6.91.
MS (EI): m/z (%) = 124.17 (MH+, 25), 107.14 (M+ – 17, 35).
Removal of the TBS Protecting Group; General Procedure
Bu4NF (5.8 g, 22.2 mmol, 1 M in THF, 2 equiv) was added at 0 °C
to a solution of TBSO-protected triene (11.1 mmol, 1 equiv) in THF
(55 mL, 0.2 M). The mixture was left to stir at r.t. for 18 h. The ex-
cess of solvent was removed under reduced pressure and the crude
residue dissolved in CH2Cl2 (40 mL), washed with sat. aq NaHCO3
(3 × 25 mL), H2O (3 × 25 mL), and brine (25 mL), dried (MgSO4),
and concentrated under reduced pressure. The crude mixture was
purified by column chromatography on silica gel using n-hexane
and CH2Cl2 (4:1). Alcohols 17 and 18 were isolated as colorless oils
(98% purity assessed by NMR analysis and TLC).
HRMS: m/z calcd for C8H13N + H: 124.1126; found: 124.1120 [M
+ H]+.
3-Vinylpenta-2,4-dien-1-amine (20)
Yield: 0.54 g (45%); Rf = 0.20 (EtOAc–Et2NH, 9.5:0.5).
IR (neat): 3260, 2922, 2357, 1661, 988 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.45 (1 H, dd, J = 15.7, 9.2 Hz, H-
3a/4), 6.38 (1 H, dd, J = 15.7, 8.8 Hz, H-3a/4), 5.67 (1 H, t, J = 7.0
Hz, H-2), 5.32 (1 H, ddd, J = 11.1, 1.8, 1.0 Hz, H-3b/5), 5.30 (1 H,
dd, J = 17.4, 1.6 Hz, H-3b/5), 5.25 (1 H, dd, J = 17.6, 1.8 Hz, H-3b/
5), 5.08 (1 H, ddd, J = 10.7, 1.5, 0.4 Hz, H-3b/5), 3.48 (2 H, d,
J = 7.0 Hz, H-1), 1.36 (2 H, s, NH2).
13C NMR (100 MHz, CDCl3): d = 137.7 (C-3a/4), 137.3 (C-3),
133.0 (C-2), 131.6 (C-3a/4), 118.3 (C-3b/5), 114.8 (C-3b/5), 39.8
(C-1).
4-Vinylhexa-3,5-dien-1-ol (17)
Yield: 1.32 g (96%); Rf = 0.18 (CH2Cl2).
IR (neat): 3318, 2879, 2367, 1629, 1417 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.50 (1 H, dd, J = 17.2, 11.7 Hz,
H-4a/5), 6.41 (1 H, dd, J = 17.4, 10.7 Hz, H-4a/5), 5.64 (1 H, t,
J = 7.6 Hz, H-3), 5.41–5.25 (3 H, m, H-4b/6), 5.07 (1 H, dd,
MS (EI): m/z = 106.08 (M+ – 3, 100%).
Synthesis 2011, No. 14, 2321–2333 © Thieme Stuttgart · New York

PAPER
Fused-Tetracyclic Scaffolds from Naphthoquinones
2329
HRMS: m/z calcd for C7H11N + H: 110.0970; found: 110.0966 [M
(1SR,4aRS,9aSR)-5-Hydroxy-1-(2¢¢-methoxyethyl)-9a-methyl-
2-vinyl-1,4,4a,9a-tetrahydroanthracene-9,10-dione (29)
2-Methyl-5-hydroxynaphthoquinone (22; 20 mg, 0.11 mmol, 1
equiv) and methoxytriene 17b (22 mg, 0.16 mmol, 1.5 equiv) in
CH2Cl2 (1 mL, 0.11 M) were added to a sealed glass tube. The mix-
ture was cooled at –45 °C, and then BF3·OEt2 (49.5 mg, 0.026 mL,
0.21 mmol, 2 equiv) was added very slowly. The reaction mixture
was left to stir at this temperature for 15 h, and then quenched with
ice water (5 mL), and the organic and aqueous phases were separat-
ed. The latter was extracted with CH2Cl2 (3 × 5 mL). The combined
organic phases were washed with H2O (5 mL) and brine (5 mL),
dried (MgSO4), and concentrated under reduced pressure. The
crude mixture was purified by flash column chromatography on sil-
ica gel using n-hexane and Et2O (80:20) to afford 29 (19.2 mg, 55%)
as a yellow oil (98% purity assessed by NMR and LC-MS analysis);
Rf = 0.55 (Et2O–n-hexane, 2:1).
+ H]+.
Cross-Conjugated Triene 17b
Ag2O (260.0 mg, 1.12 mmol, 2 equiv) and MeI (2.25 mmol, 4 equiv,
1.12 mL, 2 M in THF) were added to a vigorously stirred solution
of 17 (70.0 mg, 0.56 mmol, 1 equiv) in CH2Cl2 (3 mL, 0.2 M). The
reaction mixture was left to stir at r.t. for 48 h. This was then filtered
on a thin pad of Celite and washed with CH2Cl2 (3 × 10 mL). The
crude mixture was then concentrated under reduced pressure and
purified by column chromatography on silica gel using n-hexane
and CH2Cl2 (1:1). Compound 17b was obtained in 70% yield (54
mg) as a colorless oil (98% purity assessed by NMR analysis and
TLC); Rf = 0.28 (n-hexane–CH2Cl2, 50:50).
IR (neat): 3297, 2926, 2358, 1641, 1015 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.47 (1 H, dd, J = 17.5, 11.4 Hz,
H-4a/5), 6.39 (1 H, dd, J = 17.4, 10.7 Hz, H-4a/5), 5.63 (1 H, t,
J = 7.5 Hz, H-3), 5.38–5.22 (2 H, m, H-4b/6), 5.25 (1 H, m, H-4b/
6), 5.03 (1 H, dd, J = 10.7, 1.6 Hz, H-4b/6), 3.42 (2 H, q, J = 6.8 Hz,
H-1), 3.34 (3 H, s, OCH3), 2.49 (2 H, q, J = 7.0 Hz, H-2).
13C NMR (100 MHz, CDCl3): d = 138.6 (C-4), 137.8 (C-5/4a),
131.8 (C-5/4a), 128.2 (C-3), 117.7 (C-4b/6), 114.2 (C-4b/6), 72.2
(CH3), 58.6 (C-1), 30.9 (C-2).
IR (neat): 2926, 1690, 1641, 1577, 1452, 1370, 1333, 1266 cm–1.
1H NMR (500 MHz, CDCl3): d = 11.89 (1 H, s, OH), 7.68 (1 H, dd,
J = 7.6, 1.4 Hz, H-8), 7.64 (1 H, t, J = 7.8 Hz, H-7), 7.24 (1 H, dd,
J = 8.1, 1.4 Hz, H-6), 6.37 (1 H, dd, J = 17.5, 10.9 Hz, H-1¢), 5.75
(1 H, t, J = 3.8 Hz, H-3), 5.30 (1 H, d, J = 17.6 Hz, H-2¢), 5.02 (1 H,
d, J = 10.9 Hz, H-2¢), 3.65 (1 H, dd, J = 9.8, 7.1 Hz, H-4a), 3.44 (1
H, ddd, J = 9.4, 8.0, 6.0 Hz, H-2¢¢), 3.37 (1 H, ddd, J = 9.4, 6.6, 5.6
Hz, H-2¢¢), 3.15 (1 H, dd, J = 4.7, 2.5 Hz, H-1), 3.13 (3 H, s, OCH3),
2.71 (1 H, ddd, J = 20.4, 7.1, 4.2 Hz, Hb-4), 2.65 (1 H, ddd,
J = 20.5, 9.9, 3.8 Hz, Ha-4), 1.90 (1 H, dddd, J = 14.1, 7.8, 6.5, 5.0
Hz, H-1¢¢), 1.64 (1 H, ddt, J = 13.7, 7.5, 6.0 Hz, H-1¢¢), 1.11 (3 H, s,
CH3).
MS (EI): m/z (%) = 139.18 (MH+, 50), 133.10 (M+ – 5, 25).
HRMS: m/z calcd for C9H14O – H: 137.0966; found: 137.0656 [M
– H]+.
13C NMR (150 MHz, CDCl3): d = 205.3 (C-10), 198.7 (C-9), 160.7
(C-5), 139.3 (C-2), 139.2 (C-1¢), 136.6 (C-77), 133.5 (C-8a), 125.4
(C-3), 123.5 (C-6), 119.0 (C-8), 117.1 (C-4b), 111.5 (C-2¢), 71.0 (C-
2¢¢), 58.9 (OCH3), 50.8 (C-9a), 44.8 (C-4a), 37.2 (C-1), 34.5 (C-1¢¢),
23.1 (C-4¢), 21.4 (CH3).
Synthesis of the Tricyclic Scaffolds
(1RS,4aRS,9aSR)-1-(2¢¢-Methoxyethyl)-4a-methyl-2-vinyl-
1,4,4a,9a-tetrahydroanthracene-9,10-dione (28)
2-Methylnaphthoquinone (21; 30 mg, 0.17 mmol, 1 equiv) and
methoxytriene 17b (36 mg, 0.26 mmol, 1.5 equiv) in CH2Cl2 (1.5
mL, 0.12 M) were added to a sealed glass tube. The mixture was
cooled at –45 °C, and then BF3·OEt2 (49.5 mg, 0.043 mL, 0.35
mmol, 2 equiv) was added very slowly. The reaction mixture was
left to stir at this temperature for 7 h, and then quenched with ice
water (5 mL), and the organic and aqueous phases were separated.
The aqueous solution was extracted with CH2Cl2 (3 × 5 mL). The
combined organic phases were then washed with H2O (5 mL) and
brine (5 mL), dried (MgSO4), and concentrated under reduced pres-
sure. The crude mixture was purified by flash column chromatogra-
phy on silica gel using n-hexane and Et2O (80:20) to afford the
compound 28 (46.0 mg, 85%) as a yellow oil (98% purity assessed
by NMR and LC-MS analysis); Rf = 0.42 (n-hexane–Et2O, 1:1).
MS (EI): m/z (%) = 327.69 (MH+, 25), 295.63 (M+ – 32, 100).
HRMS: m/z calcd for C20H22O4 + H: 327.1596; found: 327.1610 [M
+ H]+.
tert-Butyl 2-[(3RS,6aRS,12aSR)-6a-Methyl-7,12-dioxo-4-vinyl-
3,6,6a,7,12,12a-hexahydroanthracen-3-yl]ethylcarbamate (32)
and (5aR,8R,8aS,14aR,15aS,15bS)-8-(2¢-N-tert-Butyloxycarbo-
nyl)-5a,14a-dimethyl-5a,6,8,8a,15,15a-hexahydrohexaphene-
5,9,14,16(14aH,15bH)-tetraone (33)
Procedure 1: 2-Methylnaphthoquinone (21; 39 mg, 0.23 mmol, 1
equiv) and a solution of triene 15 (75 mg, 0.34 mmol, 1.5 equiv) in
CH2Cl2 (1 mL, 0.2 M) were added to a sealed glass tube. The mix-
ture was then cooled to 0 °C and Sc(OTf)3 (165 mg, 0.34 mmol, 1.5
equiv) was added in one portion. The reaction mixture was left to
stir at this temperature for 2.5 h, then quenched with ice water (5
mL), and the organic and aqueous phases were separated. The latter
was extracted with CH2Cl2 (3 × 5 mL). The combined organic phas-
es were washed with H2O (5 mL) and brine (5 mL), dried (MgSO4),
and concentrated under reduced pressure. The crude mixture was
purified by flash column chromatography on silica gel using n-hex-
ane and Et2O (8:2) to afford 32 (63 mg, 70%) and 33 (2 mg, 3%) as
yellow oils (98% purity assessed by NMR and LC-MS analysis).
IR (neat): 2915, 2359, 1685, 1247, 628 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.12–8.08 (2 H, m, H-6,7), 7.79–
7.74 (2 H, m, H-5,8), 6.31 (1 H, dd, J = 17.5, 10.9 Hz, H-1¢), 5.75
(1 H, dd, J = 5.0, 3.6 Hz, H-3), 5.22 (1 H, d, J = 17.6 Hz, H-2¢), 4.97
(1 H, d, J = 10.9 Hz, H-2¢), 3.56 (1 H, dd, J = 19.9, 2.5 Hz, H-1),
3.10 (1 H, m, H-9a), 3.04 (1 H, d, J = 4.5 Hz, Hb-4), 3.03 (3 H, s,
OCH3), 2.98 (2 H, t, J = 6.5 Hz, H-2¢¢), 2.05 (1 H, dd, J = 19.9, 5.4
Hz, Ha-4), 1.36–1.30 (2 H, m, H-1¢¢), 1.31 (3 H, s, CH3).
13C NMR (125 MHz, CDCl3): d = 200.8 (C-9), 198.9 (C-10), 139.9
(C-4b/8a), 138.1 (C-1¢), 134.8 (C-4b/8a), 134.6 (C-5/6/7/8), 134.1
(C-5/6/7/8), 133.9 (C-2), 127.5 (C-5/6/7/8), 126.7 (C-5/6/7/8),
126.4 (C-3), 111.5 (C-2¢), 70.6 (C-2¢¢), 58.9 (C-9a), 58.1 (OCH3),
46.2 (C-4a), 34.6 (C-1), 31.6 (C-4), 31.5 (C-1¢¢), 30.9 (CH3).
Procedure 2: 2-Methylnaphthoquinone (21; 100 mg, 0.58 mmol, 1
equiv) and a solution of triene 15 (323 mg, 1.45 mmol, 2.5 equiv) in
CH2Cl2 (3 mL, 0.2 M) were added to a sealed glass tube. The mix-
ture was then cooled to 0 °C and BF3·OEt2 (681 mg, 0.36 mL, 2.9
mmol, 5 equiv) was added very slowly. The reaction mixture was
left to stir at this temperature for 36 h, then quenched with ice water
(15 mL), and the organic and aqueous phases were separated. The
latter was extracted with CH2Cl2 (3 × 10 mL). The combined organ-
ic phases were washed with H2O (10 mL) and brine (10 mL), dried
(MgSO4), and concentrated under reduced pressure. The crude mix-
MS (EI): m/z (%) = 311.20 (MH+, 70), 279.35 (M+ – 32, 100).
HRMS: m/z calcd for C20H22O3 + H: 311.1647; found: 311.1649 [M
+ H]+.
Anal. Calcd for C20H22O3: C, 77.39; H, 7.14. Found: C, 77.43; H,
7.22.
Synthesis 2011, No. 14, 2321–2333 © Thieme Stuttgart · New York

2330
Y. Bendiabdellah et al.
PAPER
ture was purified by flash column chromatography on silica gel us-
ing n-hexane and Et2O (8:2) to afford 32 (57 mg, 25%) and 33 (31
mg, 19%) and the starting material 21 (25%) as yellow oils (98%
purity assessed by NMR and LC-MS analysis).
with H2O (5 mL) and brine (5 mL), dried (MgSO4), and concentrat-
ed under reduced pressure.
(3aSR,6aRS)-6a-Methyl-4-vinyl-3,3a,6,6a-tetrahydro-2H-an-
thra[9,1-bc]pyran-7-one (23)
32
The crude mixture was purified by flash column chromatography on
silica gel using n-hexane and Et2O (95:5) to afford 23 (yield as in-
dicated in Table 1) as a yellow solid (98% purity assessed by NMR
and LC-MS analysis); mp 118.9 °C; Rf = 0.54 (CH2Cl2).
Rf = 0.24 (Et2O–n-hexane, 1:1).
IR (neat): 3379, 2971, 1684, 1509, 1247 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.10 (2 H, dtd, J = 6.1, 3.4, 2.5 Hz,
H-9,11), 7.74–7.81 (2 H, m, H-8,10), 6.33 (1 H, dd, J = 17.6, 11.0
Hz, H-1¢), 5.78 (1 H, dd, J = 5.1, 3.5 Hz, H-5), 5.15 (1 H, d, J = 17.5
Hz, H-2¢ trans), 5.00 (1 H, d, J = 10.9 Hz, H-2¢ cis), 4.15 (1 H, s,
NH), 3.54 (1 H, d, J = 20.2 Hz, Hb-6), 3.06 (1 H, d, J = 4.4 Hz, H-
12a), 2.98 (1 H, dd, J = 12.8, 5.4 Hz, H-3), 2.79 (2 H, q, J = 6.8 Hz,
H-1), 2.06 (1 H, dd, J = 19.8, 5.5 Hz, Ha-6), 1.33 [9 H, s, C(CH3)3],
1.32 (3 H, s, CH3), 1.33–1.19 (2 H, m, H-2).
13C NMR (100 MHz, CDCl3): d = 200.3 (C-7/12), 198.9 (C-7/12),
155.4 (COO), 139.4 (C-7a/11a), 137.9 (C-1¢), 134.7 (C-8/10), 134.6
(C-8/10), 133.8 (C-7a/11a), 132.3 (C-4), 127.7 (C-9/11), 127.6 (C-
9/11), 126.4 (C-5), 111.6 (C-2¢), 79.5 [C(CH3)3], 58.6 (C-12a), 46.2
(C-6a), 39.4 (C-1), 35.5 (C-3), 31.7 (C-6), 28.4 (C-2), 28.3 (CH3),
28.2 [C(CH3)3].
IR (neat): 2914, 2323, 1648, 1300 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.09 (1 H, dd, J = 7.8, 1.3 Hz, H-
8/11), 7.75 (1 H, dd, J = 7.9, 0.9 Hz, H-8/11), 7.63 (1 H, td, J = 7.6,
1.4 Hz, H-9/10), 7.38 (1 H, td, J = 7.5, 1.1 Hz, H-9/10), 6.30 (1 H,
dd, J = 17.7, 11.0 Hz, H-1¢), 5.84 (1 H, d, J = 6.2 Hz, H-5), 5.18 (1
H, d, J = 17.7 Hz, H-2¢ trans), 5.08 (1 H, d, J = 11.1 Hz, H-2¢ cis),
4.46 (1H, ddd, J = 10.8, 3.7, 2.5 Hz, Hb-2), 4.17 (1 H, ddd, J = 12.7,
10.8, 1.9 Hz, Ha-2), 3.38 (1 H, m, H-3a), 2.53 (1 H, ddt, J = 13.7,
5.6, 2.2 Hz, Hb-3), 2.46 (1 H, dd, J = 17.9, 6.2 Hz, Hb-6), 2.20 (1
H, d, J = 18.0 Hz, Ha-6), 1.64 (1 H, dddd, J = 13.6, 12.7, 11.5, 3.7
Hz, Ha-3), 1.33 (3 H, s, CH3).
13C NMR (100 MHz, CDCl3): d = 200.4 (C-7), 140.1 (C-11a), 137.8
(C-4), 137.1 (C-1), 135.9 (C-7a/11a), 134.5 (C-8/11), 127.9 (C-7a/
11a), 127.6 (C-9/10), 127.0 (C-8/11), 125.1 (C-5), 122.1 (C-9/10),
115.8 (C-11b), 112.5 (C-2¢), 65.7 (C-2), 44.7 (C-6a), 37.1 (C-6),
31.8 (C-3a), 28.5 (C-3), 32.6 (CH3).
MS (EI): m/z (%) = 396.27 (MH+, 45), 340.20 (M+ – 56, 45), 296.33
(M+ – 99, 100).
HRMS: m/z calcd for C24H29NO4 + H: 396.2175; found: 396.2174
MS (EI): m/z (%) = 278.91 (M+, 100), 250.81 (M+ – 28, 10), 301.00
[M + H]+.
(M + Na+, 10).
33
HRMS: m/z calcd for C19H18O2 + H: 279.1385; found: 279.1391 [M
Rf = 0.05 (Et2O–n-hexane, 1:1).
+ H]+.
IR (neat): 3364, 2922, 2362, 1690, 1592, 1246 cm–1.
Anal. Calcd for C19H18O2: C, 81.99; H, 6.52. Found: C, 81.89; H,
6.41.
1H NMR (400 MHz, CDCl3): d = 8.21 (1 H, m, H-2/11), 8.05–8.02
(2 H, m, H-4,13), 7.99 (1 H, m, H-2/11), 7.77–7.74 (2 H, m, H-
10,12), 7.73–7.68 (2 H, m, H-1,3), 5.68 (1 H, d, J = 4.7 Hz, H-7),
3.25 (1 H, d, J = 7.1 Hz, H-5b), 3.16 (1 H, dd, J = 18.2, 5.5 Hz, Hb-
6), 2.95 (1 H, d, J = 6.0 Hz, H-8a), 2.87–2.67 (5 H, m, H-2¢,8,15a),
1.90 (1 H, dd, J = 12.4, 3.4 Hz, Ha-6), 1.88 (1 H, dt, J = 18.1, 1.8
Hz, Hb-15), 1.39 [9 H, s, C(CH3)3], 1.31 (3 H, s, CH3), 1.26 (3 H, s,
CH3), 0.86–0.82 (2 H, m, H-2¢), 0.54 (1 H, t, J = 12.9 Hz, Ha-15).
13C NMR (100 MHz, CDCl3): d = 201.2 (C=O), 200.6 (C=O), 199.6
(C=O), 199.1 (C=O), 155.3 (COO), 135.5 (C-7a), 134.7 (C-4a,13a),
134.6 (C-2), 134.5 (C-4), 134.2 (C-11), 134.1 (C-13), 134.1 (C-9a),
133.1 (C-16a), 127.3 (C-3/12), 127.2 (C-3/12), 126.4 (C-1/10),
126.30 (C-1/10), 121.5 (C-7), 80.0 [C(CH3)3], 61.6 (C-8a), 57.2 (C-
15b), 48.2 (C-5a/14a), 46.3 (C-5a/14a), 46.1 (C-2¢), 44.5 (C-8),
38.7 (C-15), 34.2 (C-15a), 32.2 (C-1¢), 31.0 (C-6), 29.0 (CH3), 28.9
(CH3), 28.4 [C(CH3)3].
(5aS,8R,8aR,14aS,15aR,15bR)-8-(2-Hydroxyethyl)-8a,15b-di-
methyl-5a,6,8,8a,15,15a-hexahydrohexaphene-
5,9,14,16(14aH,15bH)-tetraone (24)
The crude mixture was purified by flash column chromatography on
silica gel using n-hexane and Et2O (95:5) to afford 24 (Figure 1) as
pale yellow oil (11 mg, 40% yield; 98% purity assessed by NMR
and LC-MS analysis); Rf = 0.15 (n-hexane–EtOAc, 3:1).
OH
O
H
O
H
H
O
MS (EI): m/z (%) = 468.37 (M+ – Boc, 70), 296.25 (M+ – 172, 25).
O
( )-24
HRMS: m/z calcd for C35H37NO6 + Na: 590.2518; found: 590.2510
[M + Na]+.
Figure 1 Structure of 24
Synthesis of the Tetracyclic Scaffolds
Lewis Acid Promoted Synthesis of Tetracyclic Scaffolds; Gen-
eral Procedure
IR (neat): 2819, 2523, 1748, 1400 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.25 (1 H, m, ArH), 8.10 (1 H, m,
ArH), 8.01–7.92 (2 H, m, ArH), 7.80–7.65 (4 H, m, ArH), 5.72 (1
H, d, J = 5.1 Hz, H-7), 3.38 (1 H, m, Ha-2¢), 3.28 (1 H, m, Hb-2¢),
3.16 (1 H, d, J = 6.1 Hz, H-5a), 3.11 (1 H, dd, J = 18.3, 5.3 Hz, Ha-
6), 2.71 (1 H, dd, J = 5.2, 1.8 Hz, H-14a), 2.50–2.42 (2 H, m, H-
8,15a), 2.22 (1 H, ddt, J = 10.8, 6.2, 2.1 Hz, Hb-6), 1.98 (1 H, ddd,
J = 12.8, 3.9, 1.9 Hz, Ha-15), 1.60 (1 H, s, OH), 1.54 (3 H, s, CH3),
1.39 (3 H, s, CH3), 1.34 (1 H, m, Ha-1¢), 1.16 (1 H, ddd, J = 18.2,
11.4, 4.6 Hz, Hb-15), 1.04 (1 H, tdd, J = 13.3, 7.6, 3.59 Hz, Hb-1¢).
Naphthoquinone (0.12 mmol, 1 equiv) and triene (equiv as indicat-
ed in Tables 1– 5) in CH2Cl2 (0.5 mL, 0.24 M for alcohols 17–18; 1
mL, 0.12 M for amines 19–20) were added to a sealed glass tube.
The mixture was cooled to the indicated temperature and then the
Lewis acid (equiv as indicated in Tables 1– 5) was added dropwise,
if in liquid form, and at once, if a solid. The reaction mixture was
left to stir at the indicated temperature for the indicated time, and
then quenched with ice water (5 mL), and the organic and aqueous
phases were separated. The aqueous solution was extracted with
CH2Cl2 (3 × 5 mL). The combined organic phases were washed
13C NMR (100 MHz, CDCl3): d = 200.5 (C=O), 200.0 (C=O), 197.8
(C=O), 196.7 (C=O), 136.4 (C, Ar), 135.9 (C, Ar), 135.2 (C, Ar),
Synthesis 2011, No. 14, 2321–2333 © Thieme Stuttgart · New York

PAPER
Fused-Tetracyclic Scaffolds from Naphthoquinones
2331
135.2 (C, Ar), 134.2 (CH, Ar), 134.1 (2 × CH, Ar), 134.0 (C-7a),
127.3 (CH, Ar), 127.1 (CH, Ar), 126.2 (CH, Ar), 125.9 (2 × CH,
Ar), 122.1 (C-7), 60.7 (C-2¢), 52.8 (C-8a), 52.4 (C-8), 51.6 (C-14a),
50.5 (C-15b), 50.2 (C-5a), 38.3 (C-15a), 32.5 (C-1¢), 26.6 (C-15),
24.5 (CH3), 23.8 (CH3), 20.6 (C-6).
Anal. Calcd for C19H18O3: C, 77.53; H, 6.56. Found: C, 77.46; H,
6.66.
(2aSR,5aRS)-5a-Methyl-3-vinyl-5,5a-dihydro-2H-anthra[9,1-
bc]furan-6(2aH)-one (27)
The crude mixture was purified by flash column chromatography on
silica gel using n-hexane and Et2O (95:5) to afford 27 (yield as in-
dicated in Table 2) as yellow solid (98% purity assessed by NMR
and LC-MS analysis); mp 130.9 °C; Rf = 0.53 (CH2Cl2).
MS (EI): m/z = 469.18.
HRMS: m/z calcd for C30H28O5 + H: 469.2015; found: 469.2015 [M
+ H]+.
IR (neat): 2361, 1683, 1596, 1265, 769 cm–1.
(3aSR,6aRS)-6a-Methyl-3,3a,6,6a-tetrahydro-2H-anthra[9,1-
bc]pyran-7-one (25)
1H NMR (500 MHz, CDCl3): d = 7.61 (1 H, td, J = 7.5, 1.3 Hz, H-
7/10), 7.41 (1 H, dt, J = 7.7, 0.6 Hz, H-7/10), 7.37 (2 H, td, J = 7.6,
1.2 Hz, H-8,9), 6.33 (1 H, dd, J = 17.7, 10.8 Hz, H-1¢), 5.74 (1 H,
m, J = 6.2 Hz, H-4), 5.09 (1 H, dd, J = 9.8, 8.6 Hz, Hb-2), 5.07 (1
H, d, J = 10.3 Hz, H-2¢ cis), 4.94 (1 H, d, J = 17.6 Hz, H-2¢ trans),
4.15 (1 H, dd, J = 10.1, 8.6 Hz, Ha-2), 4.04 (1 H, t, J = 11.0 Hz, H-
2a), 2.51 (1 H, dd, J = 18.2, 5.4 Hz, Hb-5), 2.34 (1 H, d, J = 21.3 Hz,
Ha-5), 1.35 (3 H, s, CH3).
13C NMR (100 MHz, CDCl3): d = 202.7 (C-6), 144.3 (C-10a/6a),
139.0 (C-3), 137.6 (C-1¢), 134.4 (C-7/10), 131.8 (C-6a/10a), 129.4
(C-1), 128.3 (C-7/10), 127.8 (C-4), 127.6 (C-8/9), 121.4 (C-8/9),
117.8 (C-10b), 112.6 (C-2¢), 76.7 (C-2), 43.8 (C-5a), 39.9 (C-2a),
38.1 (C-4), 20.9 (CH3).
Diene 17a was prepared according to the procedure of DeBoef.18
The crude mixture was purified by flash column chromatography on
silica gel using n-hexane and Et2O (95:5) to afford 25 (yield: 50%)
as a yellow solid (98% purity assessed by NMR and LC-MS analy-
sis); mp 82.4 °C; Rf = 0.35 (CHCl3).
IR (neat): 2971, 2927, 2863, 1675, 1648, 1595, 1288, 1098 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.09 (1 H, dd, J = 7.8, 1.4 Hz, H-
8), 7.72 (1 H, dt, J = 7.9, 0.6 Hz, H-11), 7.62 (1 H, tdd, J = 7.6, 1.4,
0.4 Hz, H-9), 7.37 (1 H, td, J = 7.5, 1.2 Hz, H-10), 5.72 (1 H, ddt,
J = 9.6, 4.7, 2.3 Hz, H-4), 5.67 (1 H, dt, J = 10.0, 2.2 Hz, H-5), 4.43
(1 H, ddd, J = 10.7, 3.6, 2.7 Hz, Hb-2), 4.09 (1 H, ddd, J = 12.4,
10.6, 1.9, Ha-2), 3.14 (1 H, ddtt, J = 9.0, 6.4, 2.3, 2.0 Hz, H-3a),
2.39 (1 H, ddd, J = 17.6, 4.8, 1.4 Hz, Hb-6), 2.17 (1 H, dq, J = 6.2,
2.2 Hz, Ha-6), 2.13 (1 H, m, Hb-3), 1.73 (1 H, dtd, J = 13.2, 12.0,
3.6 Hz, Ha-3), 1.41 (3 H, s, CH3).
13C NMR (101 MHz, CDCl3): d = 202.7 (C-7), 139.7 (C-11b), 135.8
(C-7a), 134.4 (C-9), 128.5 (C-5), 127.9 (C-11a), 127.5 (C-10),
127.0 (C-8), 124.1 (C-4), 121.9 (C-11), 116.2 (C-11c), 65.4 (C-2),
45.0 (C-6a), 36.9 (C-6), 31.2 (C-3a), 29.4 (C-3), 23.6 (CH3).
MS (EI): m/z (%) = 264.92 (M+, 15), 281.89 (M+ + 17, 100).
HRMS: m/z calcd for C18H16O2 + H: 265.1229; found: 265.1231 [M
+ H]+.
Anal. Calcd for C18H16O2: C, 81.71; H, 6.10. Found: C, 81.97; H,
6.15.
(3aSR,11cSR,6aRS)-11c-Methyl-4-vinyl-2,3,3a,6,6a,11c-
hexahydroanthra[9,1-bc]pyridine-7-one (30)
MS (EI): m/z (%) = 253.29 (MH+, 100), 235.55 (M+ – 18, 55).
Procedure 1, according to the General Procedure for the Lewis
acid promoted synthesis of tetracyclic scaffolds: The crude mixture
was purified by flash column chromatography on silica gel with n-
hexane and Et2O (1:1) to afford 30 (yield as indicated in Table 3) as
a yellow oil (98% purity assessed by NMR and LC-MS analysis).
HRMS: m/z calcd for C17H16O2: 253.1384; found: 253.1223 [M +
H]+.
Anal. Calcd for C17H16O2: C, 80.28; H, 7.13. Found: C, 80.21; H,
7.11.
Procedure 2: 2-Methylnaphthoquinone (21; 24 mg, 0.14 mmol, 1
equiv) was diluted with aq 5 M HCl (0.07 mL, 2.5 equiv) and the
solution was added at 0 °C to a solution of triene 19 (51 mg, 0.42
mmol, 3 equiv) in H2O (0.12 mL, 3.5 M). The reaction mixture was
vigorously stirred at 50 °C for 2.5 h, then diluted with CH2Cl2 (15
mL) and washed with sat. aq NaHCO3 (15 mL). The two phases
were separated and the aqueous phase was extracted with CH2Cl2
(5 × 5 mL). The combined organic extracts were washed with H2O
(5 mL) and brine (5 mL), dried (MgSO4), and concentrated under
reduced pressure. The crude mixture was purified by flash column
chromatography on silica gel with n-hexane and Et2O (1:1) to afford
30 (22 mg, 57%) as a yellow oil; Rf = 0.18 (n-hexane–Et2O, 1:1).
(3aSR,6aRS)-11-Hydroxy-6a-methyl-4-vinyl-3,3a,6,6a-tetrahy-
dro-2H-anthra[9,1-bc]pyran-7-one (26)
The crude mixture was purified by flash column chromatography on
silica gel using n-hexane and Et2O (95:5) to afford 26 (yield: 75%)
as a yellow solid (98% purity assessed by NMR and LC-MS analy-
sis); mp 112.5 °C; Rf = 0.5 (CH2Cl2).
IR (neat): 3390, 2924, 2847, 2361, 1690, 1646, 1455, 1263, 1033
cm–1.
1H NMR (400 MHz, CDCl3): d = 9.25 (1 H, s, OH), 7.68 (1 H, dt,
J = 7.7, 1.1 Hz, H-8), 7.28 (1 H, t, J = 7.9 Hz, H-9), 7.13 (1 H, dt,
J = 8.1, 1.1 Hz, H-10), 6.29 (1 H, dd, J = 17.8, 11.1 Hz, H-1¢), 5.85
(1 H, d, J = 6.2 Hz, H-5), 5.17 (1 H, d, J = 17.7 Hz, H-2¢ trans), 5.10
(1 H, d, J = 11.1 Hz, H-2¢ cis), 4.53 (1 H, ddd, J = 10.6, 3.7, 2.6 Hz,
Hb-2), 4.25 (1 H, ddd, J = 12.6, 10.6, 2.0 Hz, Ha-2), 3.37 (1 H, m,
H-3a), 2.56 (1 H, ddt, J = 13.9, 5.5, 2.4 Hz, Hb-3), 2.45 (1 H, dd,
J = 18.0, 6.2 Hz, Hb-6), 2.21 (1 H, d, J = 17.0 Hz, Ha-6), 1.71 (1 H,
m, Ha-3), 1.32 (3 H, s, CH3).
13C NMR (100 MHz, CDCl3): d = 201.6 (C-7), 154.3 (C-11), 141.7
(C-11a), 137.4 (C-4), 136.8 (C-1¢), 129.4 (C-7a), 129.3 (C-9), 125.2
(C-5), 123.6 (C-10), 119.4 (C-8), 119.2 (C-11b), 115.3 (C-11c),
112.7 (C-2¢), 66.4 (C-2), 44.4 (C-6a), 37.0 (C-6), 31.4 (C-3a), 27.9
(C-3), 22.6 (CH3).
IR (neat): 2950, 2918, 2852, 2361, 1633, 1455, 1279 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.01 (1 H, ddd, J = 7.8, 1.4, 0.5
Hz, H-8/11), 7.89 (1 H, dd, J = 7.8, 1.0 Hz, H-8/11), 7.64 (1 H, td,
J = 7.5, 1.4 Hz, H-9/10), 7.50 (1 H, td, J = 7.6, 1.3 Hz, Hz, H-9/10),
6.30 (1 H, dd, J = 17.7, 11.0 Hz, H-1¢), 5.86 (1 H, d, J = 5.2, 2.6 Hz,
H-5), 5.14 (1 H, d, J = 17.7 Hz, H-2¢ trans), 5.03 (1 H, d, J = 10.9
Hz, H-2¢ cis), 4.18 (1 H, ddd, J = 17.2, 3.8, 1.7 Hz, Hb-2), 3.66 (1
H, ddd, J = 10.8, 3.7, 2.5 Hz, Ha-2), 3.01 (1 H, ddd, J = 12.7, 10.8,
1.9 Hz, H-6a), 2.74 (1 H, dt, J = 19.8, 5.7 Hz, Hb-6), 2.47 (1 H, dd,
J = 12.7, 1.8 Hz, H-3a), 2.40 (1 H, m, Ha-6), 2.20 (1 H, m, Hb-3),
1.43 (1 H, m, Ha-3), 1.05 (3 H, s, CH3).
MS (EI): m/z (%) = 294.81 (M+, 35), 213.74 (M+ – 80, 100).
13C NMR (100 MHz, CDCl3): d = 198.3 (C-7), 170.4 (C-11b), 139.9
(C-4), 138.4 (C-1¢), 136.1 (C-7a/11a), 134.3 (C-9/10), 132.2 (C-7a/
11a), 130.0 (C-9/10), 126.3 (C-8/11), 126.0 (C-5), 125.9 (C-8/11),
HRMS: m/z calcd for C19H18O3 + H: 295.1334; found: 295.1325 [M
+ H]+; m/z calcd for C19H17O3 + Na: 317.1154; found: 317. 1156 [M
+ Na]+.
Synthesis 2011, No. 14, 2321–2333 © Thieme Stuttgart · New York

2332
Y. Bendiabdellah et al.
PAPER
111.2 (C-2¢), 50.8 (C-2), 47.7 (C-6a), 41.6 (C-3a1), 41.3 (C-3a),
26.9 (C-3), 22.9 (C-6), 20.7 (CH3).
Anal. Calcd for C19H19NO2: C, 77.79; H, 6.53; N,4.77. Found: C,
77.88; H, 6.39; N, 4.75.
MS (EI): m/z (%) = 277.97 (M+, 100), 296.60 (M+ + 18, 15).
(2aRS,10bSR,5aRS)-5a-Methyl-3-vinyl-2,2a,5,5a-tetrahydro-
2H-anthra[9,1-bc]pyrrole-6-one (34)
The crude mixture was purified by flash column chromatography on
silica gel using CH2Cl2 and Et2O (1:1) to afford 34 (yield as indicat-
ed in Table 5) as a yellow oil (purity assessed by NMR and LC-MS
analysis); Rf = 0.23 (n-hexane–Et2O, 1:1).
HRMS: m/z calcd for C19H19NO + H: 278.1545; found: 278.1539
[M + H]+.
Anal. Calcd for C19H19NO: C, 82.28; H, 6.90, N, 5.05. Found: C,
82.28; H, 6.61; N, 4.98.
IR (neat): 2924, 2852, 2359, 2330, 1684, 159, 1260, 730 cm–1.
(3aSR,11cSR,6aRS)-8-Hydroxy-11c-methyl-4-vinyl-
2,3,3a,6,6a,11c-hexahydroanthra[9,1-bc]pyridine-7-one (31a)
and (3aSR,11cSR,6aSR)-8-Hydroxy-11c-methyl-4-vinyl-
2,3,3a,6,6a,11c-hexahydroanthra[9,1-bc]pyridine-7-one (31b)
The crude mixture was purified by flash column chromatography on
silica gel with n-hexane and Et2O (1:1) to afford 31a (10 mg, 29%)
and 31b (23 mg, 65%) as colorless oils (98% purity assessed by
NMR and LC-MS analysis).
1H NMR (400 MHz, CDCl3): d = 8.04 (1 H, t, J = 8.1 Hz, H-7/10),
7.72 (1 H, t, J = 8.6 Hz, H-7/10), 7.65 (2 H, t, J = 7.5 Hz, H-8,9),
6.29 (1 H, dd, J = 17.7, 11.1 Hz, H-1¢), 5.75 (1 H, dt, J = 7.2, 0.9 Hz,
H-4), 5.11 (1 H, d, J = 17.8 Hz, H-2¢), 5.08 (1 H, d, J = 10.8 Hz, H-
2¢), 4.24 (2 H, t, J = 2.8 Hz, H-2), 3.44 (1 H, m, H-2a), 3.33 (1 H,
td, J = 7.1, 3.3 Hz, H-10c), 2.28 (2 H, d, J = 18.5 Hz, Hb-5), 1.92 (1
H, dd, J = 18.2, 6.5 Hz, Ha-5), 1.34 (3 H, s, CH3).
31a
13C NMR (100 MHz, CDCl3): d = 196.5 (C-6), 168.9 (C-10b), 137.8
(C-3), 136.5 (C-1¢), 133.2 (C-8/9), 133.1 (C-6a/10a), 132.8 (C-6a/
10a), 130.6 (C-8/9), 128.1 (C-7/10), 126.2 (C-4), 125.3 (C-7/10),
110.7 (C-2¢), 66.8 (C-2), 54.2 (C-10c), 45.4 (C-5a), 34.1 (C-2a),
29.7 (C-5), 20.4 (CH3).
Rf = 0.38 (Et2O–n-hexane, 2:1).
IR (neat): 2972, 2918, 2847, 2361, 1641, 1452, 1249, 820 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.01 (1 H, s, OH), 7.52 (1 H, t,
J = 7.9 Hz, H-10), 7.47 (1 H, dd, J = 7.7, 1.4 Hz, H-11), 7.04 (1 H,
dd, J = 8.1, 1.4 Hz, H-9), 6.24 (1 H, dd, J = 17.7, 11.1 Hz, H-1¢),
5.98 (1 H, m, H-5), 5.19 (1 H, d, J = 17.7 Hz, H-2¢), 5.08 (1 H, d,
J = 11.1 Hz, H-2¢), 3.84 (1 H, ddt, J = 18.7, 4.4, 1.3 Hz, Hb-2), 3.52
(1 H, ddd, J = 18.6, 12.5, 4.2 Hz, Ha-2), 2.65 (1 H, m, H-3a), 2.63
(1 H, dd, J = 11.9, 4.9 Hz, H-6a), 2.32 (1 H, m, Hb-6), 2.19 (1 H, m,
Ha-6), 2.13 (1 H, dddt, J = 12.4, 5.8, 3.0, 1.5 Hz, Hb-3), 1.90 (1 H,
ddt, J = 13.6, 12.7, 4.3 Hz, Ha-3), 1.39 (3 H, s, CH3).
13C NMR (101 MHz, CDCl3): d = 206.7 (C-7), 165.5 (C-11b), 161.9
(C-8), 138.8 (C-11a), 137.1 (C-1¢), 137.0 (C-4), 136.8 (C-10), 127.2
(C-5), 119.6 (C-9), 117.4 (C-11), 113.8 (C-7a), 113.2 (C-2¢), 53.7
(C-6a), 46.5 (C-2), 41.0 (C-11c), 38.4 (C-3a), 28.2 (C-6), 26.4
(CH3), 21.2 (C-3).
MS (EI): m/z (%) = 264.54 (MH+, 100), 214.50 (M+ – 50, 25).
HRMS: m/z calcd for C18H17NO + H: 264.1388; found: 264.1384
[M + H]+.
Anal. Calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32. Found: C,
82.13; H, 6.48; N, 5.32.
Synthesis of Polycyclic Derivatives for the Synthesis of the Poly-
cyclic Scaffolds; General Procedure
Anthraquinolic diene (0.064 mmol, 1 equiv) in toluene (1 mL, 0.06
M) and maleimide (0.322 mmol, 5 equiv) were added to a sealed
glass tube. The reaction mixture was stirred at 70 °C for 28 to 48 h.
Removal of the solvent under reduced pressure followed by flash
column chromatography on silica gel using Et2O afforded the poly-
cyclic compound (98% purity assessed by NMR and LC-MS anal-
ysis).
MS (EI): m/z (%) = 294.50 (MH+, 100), 295.50 (M+ + 2, 50).
HRMS: m/z calcd for C19H19NO2: 294.1494; found: 294.1505 [M +
H]+.
(3aSR,6SR,12aRS,13bRS,13aSR)-12a-Methyl-1¢,3a,4,6,12a,13-
hexahydro-2H-naphtho[3¢,2¢,1¢:8,1]isochromeno[6,5-e]isoin-
dole-1,3,12(7H,8aH,8bH)-trione (36a)
Anal. Calcd for C19H19NO2: C, 77.79; H, 6.53; N, 4.77. Found: C,
77.75; H, 6.55; N, 4.80.
The reaction time was 24 h to afford 36a as a white solid; yield: 23
mg (95%); Rf = 0.34 (Et2O); mp 246.5 °C.
IR (neat): 1740, 1697, 1648, 1593, 1364 cm–1.
31b
Rf = 0.27 (Et2O–n-hexane, 2:1).
IR (neat): 2951, 2919, 2853, 2362, 1633, 1455, 1279, 820 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.15 (1 H, ddd, J = 7.8, 1.4,
0.6 Hz, H-11/8), 6.93 (1 H, ddd, J = 7.9, 7.2, 1.4 Hz, H-9/10), 6.84
(1 H, dd, J = 7.7, 0.6 Hz, H-8/11), 6.66 (1 H, td, J = 7.5, 1.1 Hz H-
9/10), 5.00 (1 H, dd, J = 5.5, 2.8 Hz, H-5), 3.49 (1 H, dt, J = 10.7,
3.5 Hz, Hb-2¢), 3.28 (1 H, td, J = 11.1, 1.9 Hz, Ha-2¢), 2.58 (1 H, s,
H-6), 2.31 (1 H, td, J = 9.1, 1.6 Hz, H-13b), 2.29 (1 H, q, J = 6.1 Hz,
H-3a), 2.01 (1 H, m, H-13a), 1.67 (1 H, dd, J = 15.7, 6.3 Hz, Hb-4),
1.46–1.34 (2 H, m, Hb-1¢, Ha-4), 1.27 (1 H, t, J = 12.2 Hz, Hb-13),
1.21 (1 H, dd, J = 13.0, 7.2 Hz, Ha-13), 0.90 (1 H, tdt, J = 13.5,
10.7, 2.8 Hz, Ha-1¢), 0.45 (3 H, s, CH3).
1H NMR (400 MHz, CDCl3): d = 12.13 (1 H, s, OH), 7.53 (1 H, dd,
J = 8.3, 7.6 Hz, H-10), 7.34 (1 H, dd, J = 7.6, 1.1 Hz, H-11), 7.01 (1
H, dd, J = 8.4, 1.1 Hz, H-9), 6.30 (1 H, dd, J = 17.7, 11.0 Hz, H-1¢),
5.85 (1 H, dd, J = 5.3, 2.5 Hz, H-5), 5.15 (1 H, d, J = 17.8 Hz, H-
2¢), 5.05 (1 H, d, J = 11.0 Hz, H-2¢), 4.16 (1 H, ddd, J = 17.2, 3.8,
1.7 Hz, Hb-2), 3.63 (1 H, ddd, J = 17.2, 12.1, 3.6 Hz, Ha-2), 3.07 (1
H, dd, J = 10.9, 6.1 Hz, H-6a), 2.76 (1 H, dt, J = 19.7, 5.7 Hz, Hb-
6), 2.47 (1 H, d, J = 12.6 Hz, Hb-3), 2.37 (1 H, dd, J = 19.4, 10.6
Hz, Ha-6), 2.20 (1 H, dtd, J = 13.9, 3.3, 1.7 Hz, H-3a), 1.40 (1 H,
ddd, J = 12.5, 3.9, 1.3 Hz, Ha-3), 1.08 (3 H, s, CH3).
13C NMR (100 MHz, DMSO-d6): d = 201.3 (C-12), 180.9 (C-3),
180.0 (C-1), 141.0 (C-7), 138.7 (C-6a), 135.0 (C-7a/11a), 134.7 (C-
9/10), 127.8 (C-9/10), 127.2 (C-7a/11a), 126.5 (C-8/11), 121.6 (C-
8/11), 119.9 (C-5), 117.4 (C-5a), 64.8 (C-2¢), 46.2 (C-12a), 43.5 (C-
13b), 40.0 (C-3a), 35.7 (C-13), 33.5 (C-6), 31.6 (C-13a), 28.9 (C-
1¢), 23.3 (C-4), 21.5 (CH3).
13C NMR (101 MHz, CDCl3): d = 204.9 (C-7), 169.8 (C-11b), 161.4
(C-8), 140.5 (C-11a), 138.2 (C-1¢), 137.0 (C-10), 136.3 (C-4), 125.8
(C-5), 119.1 (C-9), 117.0 (C-11), 116.2 (C-7a), 111.5 (C-2¢), 50.8
(C-6a), 47.6 (C-2), 41.3 (C-11c), 41.1 (C-3a), 26.9 (C-6), 22.5 (C-
3), 20.4 (CH3).
MS (EI): m/z (%) = 294.52 (MH+, 100), 295.55 (M+ + 2, 45).
MS (EI): m/z = 376.52 (MH+, 100%).
HRMS: m/z calcd for C19H19NO2 + H: 294.1494; found: 294.1505
[M + H]+.
HRMS: m/z calcd for C23H21NO4 + H: 376.1549; found: 376.1536
[M + H]+.
Synthesis 2011, No. 14, 2321–2333 © Thieme Stuttgart · New York

PAPER
Fused-Tetracyclic Scaffolds from Naphthoquinones
2333
Anal. Calcd for C23H21NO4: C, 73.58; H, 5.64: N, 3.73. Found: C,
73.55; H, 5.66; N, 3.70.
G.; Thurston, D. E. Proceedings of the 100th Annual
Meeting of the American Association for Cancer Research,
San Diego, April 18-22, 2009; AACR: Philadelphia, 2009,
4646.
3¢-[(3aSR,6SR,12aRS,13bRS,13aSR)-12a-Methyl-1,3,12-trioxo-
1,3,3a,5a,6,12a,13,13a,13b-decahydro-2H-naph-
tho[3¢,2¢,1¢:8,1]isochromeno[6,5-e]isoindol-2(5H)-yl]propanoic
Acid (36b)
The reaction time was 48 h to afford 36b as a white solid; yield: 26
mg (90%); mp 207.6 °C; Rf = 0.29 (EtOAc–AcOH, 99:1).
(3) Park, E. J.; Kong, D.; Fisher, R.; Cardellina, J.; Shoemaker,
R. H.; Melillo, G. Cell Cycle 2006, 5, 1847.
(4) (a) Ward, D. E.; Abaee, M. S. Org. Lett. 2000, 2, 3937.
(b) Ward, D. E.; Souweha, M. S. Org. Lett. 2005, 7, 3533.
(c) Souweha, M. S.; Arab, A.; ApSimon, M.; Fallis, A. G.
Org. Lett. 2007, 9, 615. (d) Souweha, M. S.; Enright, G. D.;
Fallis, A. G. Org. Lett. 2007, 9, 5163.
IR (neat): 2928, 1738, 1694, 1399 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.85 (1 H, dt, J = 7.7, 0.6 Hz, H-
11/8), 7.55 (1 H, td, J = 7.3, 1.3 Hz, H-9,10), 7.52 (1 H, dd, J = 7.8,
1.6 Hz, H-8/11), 7.33 (1 H, ddd, J = 7.6, 6.9, 1.7 Hz, H-9/10), 5.49
(1 H, dd, J = 7.0, 2.8 Hz, H-5), 4.10 (1 H, ddd, J = 10.3, 6.4, 3.6 Hz,
Hb-2¢), 4.03 (1 H, ddd, J = 10.8, 8.2, 2.8 Hz, Ha-2¢), 3.76 (2 H, t,
J = 7.3 Hz, H-3¢), 3.16 (1 H, dd, J = 8.8, 6.0 Hz, H-13b), 3.09 (1 H,
td, J = 8.1, 1.2 Hz, H-3a), 3.02 (1 H, m, H-13a), 2.99 (1 H, dd,
J = 14.1, 4.3 Hz, Hb-13), 2.71 (1 H, dd, J = 15.0, 7.2 Hz, H-4), 2.61
(2 H, t, J = 7.1 Hz, H-4¢), 2.29 , q, J = 13.0 Hz, Ha-13), 2.22 (1 H,
m, H-6), 2.21 (1 H, m, Hb-1¢), 2.12 (1 H, m, H-4), 2.01 (1 H, m, Ha-
1¢), 1.37 (3 H, s, CH3).
13C NMR (100 MHz, CDCl3): d = 203.8 (C-12), 179.5 (C-3), 177.6
(C-1), 175.0 (CO2H), 143.5 (C-7), 143.2 (C-6a), 135.0 (C-7a/11a),
133.8 (C-8/11), 129.0 (C-7a/11a), 127.9 (C-9/10), 126.7 (C-9/10),
121.6 (C-8/11), 117.8 (C-5a), 116.0 (C-5), 63.4 (C-2¢), 49.0 (C-
12a), 43.3 (C-13b), 39.8 (C-3a), 34.7 (C-6), 34.3 (C-3¢), 31.8 (C-4¢),
31.7 (C-13a), 29.3 (C-13), 29.2 (CH3), 25.0 (C-1¢), 24.5 (C-4).
(5) Nicolaou, K. C.; Lim, Y. H.; Becker, J. Angew. Chem. Int.
Ed. 2009, 48, 3444.
(6) Grieco, P. A.; Galatsis, P.; Spohn, R. F. Tetrahedron 1986,
42, 2847.
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(8) The reactions were monitored by LC-MS and TLC on silica
gel.
(9) The structures and relative stereochemistries were
unambiguously assigned by 1D and 2D NMR experiments
(including NOESY). Full characterization of the novel
skeletons with their NMR data and spectra are included in
the Supporting Information.
(10) (a) Grieco, P. A.; Nunes, J. J.; Gaul, M. D. J. Am. Chem. Soc.
1990, 112, 4595. (b) Heydari, A. Tetrahedron 2002, 58,
6777.
(11) (a) Stojanac, Z.; Dickinson, R. A.; Stojanac, N.; Woznow, R.
J.; Valenta, Z. Can. J. Chem. 1975, 53, 616. (b) Kelly, T.
R.; Gillard, J. W.; Goerner, R. N. Jr.; Lyding, J. M. J. Am.
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Vladuchick, W. C. J. Am. Chem. Soc. 1977, 99, 8116.
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Chem. Soc. 1978, 100, 7098. (e) Motoyoshiya, J.; Kameda,
T.; Asari, M.; Miyamoto, M.; Narita, S.; Aoyama, H.;
Hayashi, S. J. Chem. Soc., Perkin Trans. 2 1997, 1845.
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A.; Takayanagi, H.; Yokozawa, T. Angew. Chem. Int. Ed.
2004, 43, 1360.
MS (EI): m/z = 448.56 (MH+, 100%).
HRMS: m/z calcd for C26H25NO6 + H: 447.1682; found: 447.1584
[M + H]+.
Anal. Calcd for C26H25NO6: C, 69.79; H, 5.63; N, 3.13. Found: C,
69.77; H, 5.60; N, 3.11.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
(13) Ito, M.; Koo, L. W.; Himizu, A.; Kobayashi, C.; Sakaguchi,
A.; Ikariya, T. Angew. Chem. Int. Ed. 2009, 48, 1324.
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L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2008,
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359.
Acknowledgment
Cancer Research UK is acknowledged for financial support of this
work (C180/A8004 to DET), and the British Commonwealth Fund
and the Algerian Government are thanked for studentships to
M.H.R. and Y.B., respectively.
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References
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Synthesis 2011, No. 14, 2321–2333 © Thieme Stuttgart · New York