Studies on the Michael addition of naphthoquinones to sugar nitro olefins: First synthesis of polyhydroxylated hexahydro-11H-benzo[a]carbazole-5,6-diones and hexahydro-11bH-benzo[b]carbazole-6,11-diones

Article abstract of DOI:10.1016/j.tet.2011.11.072

A strategy for the synthesis of the novel (6bR,7R,8S,9S,10S,10aR)-8- (benzyloxy)-7,9,10-trihydroxy-6b,7,8,9,10,10a-hexahydro-11H-benzo[a]carbazole-5, 6-dione is reported. The key steps were the Michael addition of 2-hydroxy-1,4-naphthoquinone to 1-nitrocy

Full text of DOI:10.1016/j.tet.2011.11.072

Tetrahedron 68 (2012) 1612e1621
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies on the Michael addition of naphthoquinones to sugar nitro olefins: first
synthesis of polyhydroxylated hexahydro-11H-benzo[a]carbazole-5,6-diones and
hexahydro-11bH-benzo[b]carbazole-6,11-diones
a
,
b
,
a
,
b
c
c
a,b
*
ꢀ
ꢀ
ꢀ
Jose M. Otero
, Jose C. Barcia , Cristian O. Salas , Pablo Thomas , Juan C. Estevez
,
a,b,
*
ꢀ
ꢀ
Ramon J. Estevez
a
ꢀ
ꢀ
CIQUS (Centro Singular de Investigacion en Química Biologica y Materiales Moleculares), Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Departamento de Química Organica, Facultad de Química, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Departamento de Química Organica, Facultad de Química, Pontificia Universidad Catolica de Chile, 702843 Santiago de Chile, Chile
b
c
ꢀ
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2011
Received in revised form 8 November 2011
Accepted 24 November 2011
Available online 13 December 2011
A
strategy for the synthesis of the novel (6bR,7R,8S,9S,10S,10aR)-8-(benzyloxy)-7,9,10-trihydroxy-
6b,7,8,9,10,10a-hexahydro-11H-benzo[a]carbazole-5,6-dione is reported. The key steps were the Michael
addition of 2-hydroxy-1,4-naphthoquinone to 1-nitrocyclohexene or 3-O-benzyl-5,6-dideoxy-1,2-O-iso-
propylidene-6-nitro-
action of 3-O-benzyl-5,6-dideoxy-5-C-(30-hydroxy-10,40-naphthoquinon-20-yl)-1,2-O-isopropylidene-6-
nitro-
-glucofuranose to give the key (1S,2S,3S,4R,5R,6R)-3-(benzyloxy)-1,2,4-trihydroxy-5-(30-hy-
a-D-xylo-hex-5-enefuranose and the diastereoselective intramolecular Henry re-
a-D
Keywords:
Sugar
Quinones
Nitro compounds
Michael addition
Henry reaction
Indoles
droxy-10,40-naphthoquinon-20-yl)-6-nitrocyclohexane. When 2-hydroxy-1,4-naphthoquinone was re-
placed by (1,4-dimethoxynaphthalen-2-yl)lithium, the novel (1R,2S,3S,4R,4aS,11bS)-2-(benzyloxy)-1,3,4-
trihydroxy-1,2,3,4,4a,5-hexahydro-11bH-benzo[b]carbazole-6,11-dione was obtained.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
adjacent pairs of DNA bases and, therefore, interferes with DNA
replication and transcription.7 In addition, the quinone moiety
Quinones and naphthoquinones are of perennial chemical
interest due to the widespread occurrence of the quinone nu-
cleus in natural products that have important biological func-
tions, together with their industrial applications and the
biological activity shown by a number of quinone-containing
compounds.1 Specifically, 2-hydroxy-1,4-naphthoquinones are
of interest as pigments2 and because of their cytotoxic proper-
ties, which have been attributed to the presence of the quinone
moiety.1f,g,3,4 For example, parvaquone (I) is a hydroquinone that
has been used against Theileria parva, a microscopic parasite that
causes East Coast Fever (theileriosis).5 From a chemical point of
view, particular interest has been focussed on 3-phenyl-2-
hydroxynaphthoquinones because they have proven to be con-
venient precursors for the synthesis of polycyclic naph-
thoquinone derivatives, including 5H-benzo[b]carbazole-6,11-
diones (II),6 which display antineoplastic activity. This behavior
has been related to the presence in the structure of an embedded
2-phenylnaphthalene subunit (highlighted in blue in Fig. 1) in
a planar conformation. This unit facilitates intercalation between
present in the 5H-benzo[b]carbazole ring skeleton explains its
O
B
O
D
C
A
N
OH
H
O
II
O
I
parvaquone
5H-benzo[b]carbazole-6,11-diones
OH
R
2
R
1
HO
OH
OH
R
A
O
B
R
D
3
D
O
O
C
C
O
B
R
N
4
NH
H
O
IV: R , R , R , R =H, OH
OH
III
1
2
3
4
(+)-pancratistatin
hexahydro-11H-
benzo[b]carbazole-6,11-diones
ꢀ
* Corresponding authors. E-mail address: ramon.estevez@usc.es (R.J. Estevez).
Fig. 1. Polycyclic compounds of biological interest.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.072

J.M. Otero et al. / Tetrahedron 68 (2012) 1612e1621
1613
cytotoxic properties and facilitates the strength of intercalative
2. Results and discussion
binding to DNA through the formation of charge-transfer in-
teractions with the electron-rich DNA bases.8
Our preliminary studies on this project were aimed at the syn-
thesis of the D ring unsubstituted model target 1a. We started its
synthesis taking advantage of the nucleophilic properties conferred
to 2-hydroxy-1,4-naphthoquinones by their enol moiety.3,14,15 Thus,
the addition of commercially available 2-hydroxy-1,4-
naphthoquinone (3) to nitrocyclohexene 4a17 provided the trans-
2-naphthyl-1-nitrocyclohexane racemic mixture 2a only (the
thermodynamically more stable isomers) (Scheme 2),3,14 as a result
of a thermodynamically controlled Michael addition of the quinone
to the nitro olefin. The structure of compound 2a was easily
established from its spectroscopic and analytical data. In fact, in the
1H NMR spectrum a double triplet (J 11.6 and 4.0 Hz) was observed
(þ)-Pancratistatin (III) is an Amaryllidaceae alkaloid9 that
exhibits high levels of antitumor and antiviral activity as it
displays strong toxicity against human tumor cells and is able
to induce apoptosis in cancer cells by targeting their mito-
chrondria.10 From a structural point of view, this compound
consists of a phenanthridinone skeleton with a trans-fused BC
bicyclic subunit and a D ring bearing six contiguous stereogenic
centers.
Hexahydro-11bH-benzo[b]carbazole-6,11-diones (IV) are de
novo designed tetracyclic naphthoquinone derivatives that have an
ABCD ring system closely related to that of 5H-benzo[b]carbazole-
6,11-diones (II). In addition, their highly oxygenated members
(R1¼R2¼R3¼R4¼OH) include a structural subunit (highlited in red
in Fig. 1), that is, also embedded in (þ)-pancratistatin (III). These
unique structural features and potential pharmacological interest
make them particularly attractive targets for synthetic and bi-
ological studies.
at 3.71 ppm due to the proton in the position
together with a second double triplet at 5.40 ppm (J 11.6 and 4.0 Hz)
due to the proton in the position -to the nitro group. The multi-
a-to the quinone unit,
a
plicity of both signals and the values for the coupling constants are
consistent with an equatorial disposition of both the nitro and the
quinone substituents on the cyclohexane ring.
Nitrocompounds are very versatile in organic synthesis due to
their ready availability and ease of transformation into a wide va-
riety of functionalities.11 The chemistry of these compounds is
dominated by the electron-withdrawing character of the nitro
group. Thus the nitroaldol condensation (Henry reaction) is a clas-
sical method for carbonecarbon bond formation in which a car-
bonyl compound is coupled with a nitroalkane, a process that can
result in the formation of one or two chiral centers.11c,12 The
intramolecular modality makes this a powerful method for the
preparation of nitrocycloalkanes and this reaction is of appreciable
interest for the transformation of nitro sugars into cyclopentane
and cyclohexane derivatives.12c,13 Nitroalkenes can act as potent
Michael acceptors and, in fact, conjugate addition of nucleophiles
to nitroolefins is another important tool for the creation of
carbonecarbon bonds and carboneheteroatom bonds.12c,13 After
employing these two powerful methods for the construction of
cabonecarbon bonds, the nitro group can be transformed into
Catalytic hydrogenation of nitrocyclohexylnaphthoquinone 2a
afforded the expected aminocyclohexylnaphthoquinone 5a, prob-
ably via triol intermediate, which results from the simultaneous
reduction of the nitro group and the quinone moiety followed by
spontaneous oxidation under the work-up conditions.18 When
a solution of 5a in dioxane was heated under reflux for 5 h, a mix-
ture of the isomeric indolequinones 1a (20% yield) and 7a (25%
yield) resulted and these were clearly differentiated by their in-
frared spectra.18,19 The infrared spectrum of 1a contained, at
1681 cmꢀ1
naphthoquinones. On the other hand, isomer 7a showed the ex-
pected two bands for 1,2-naphthoquinones at 1670 and 1628 cmꢀ1
,
the only typical band described for 1,4-
.
Benzocarbazolediones 1a and 7a should result from the conju-
gate addition of the amino group to the quinone moiety of tauto-
mers 5a and 6a, respectively, followed by dehydration (Scheme 3).6d
The conjugate addition of the amino group of compound 5a to
the quinone moiety should give intermediate 8 and, upon de-
hydration, this should irreversibly provide the novel tetracyclic
quinone 1a. Alternatively, compound 5a could tautomerize to
compound 6a, via intermediates 9 and 10, and this could be fol-
lowed by the conjugate addition of the amino group of 6a to its
quinone subunit, a reaction that should result in the formation of
intermediate 11, from which quinone 7a should be irreversibly
formed by dehydration. The low yield achieved in these processes
may be related to the trans disposition of the quinone and the
amino substituents on the cyclohexane ring of 5a and 6a, a struc-
tural feature that precludes the planar conformation required for
efficient formation of the nitrogen ring.
a
variety of funcitionalitiesdincluding amino groups by
reduction.12c
In connection with our continued interest in nitro com-
pounds12c and quinones, including 5H-benzo[b]carbazole-6,11-
diones (II),6 a few years ago we envisaged that the then un-
explored3,14,15 Michael addition of 2-hydroxy-1,4-naphthoquinone
(3) to nitrocyclohexenes 4a should give the novel 2-(2-
nitrocyclohexyl)-3-hydroxynaphthalene-1,4-diones 2a. We also
reasoned that this quinone should provide access to the novel
1,2,3,4,4a,5-hexahydro-11bH-benzo[b]carbazole-6,11-diones 1a by
means of a heteroannulation process involving the reduction of
the nitro group to amino and the subsequent Michael addition of
the amino group to its quinone system (Scheme 1). We report
here a full account of studies that have been previously un-
reported or have been published as preliminary reports14,16 on the
synthesis of targets IV according to the synthetic plan outlined in
Scheme 1.
In the context of our continuous interest in novel synthetic
applications of nitro sugars,12c,13a,b,16,20 we decided to explore the
extension of this methodology to the highly polysubstituted
nitrocyclohexene 4b (Scheme 4), with the aim of preparing the
similar highly functionalized indoloquinones 1b and 7b (Scheme 6)
for chemical and biological studies.
Scheme 1. Retrosynthetic plan for the preparation of hexahydro-11bH-benzo[b]carbazole-6,11-dione (1a).

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J.M. Otero et al. / Tetrahedron 68 (2012) 1612e1621
Scheme 2. Reagents and conditions: (i) K2CO3, DMF, 90 ꢁC, 16 h, 95%; (ii) H2, Pd/C, MeOH, rt, 24 h, 80%; (iii) 1,4-dioxane, reflux, 5 h, 20% for 1a and 25% for 7a.
Scheme 3. Proposed mechanism to obtain benzocarbazoldiones 1a and 7a.
Nitrocyclohexene 4b was prepared from diacetone-
D
-glucose
allowed by their parallel alignment, provided nitrocyclohexane
14a-2 through attack of the nitronate anion to the Si-face of the C]
O group. On the other hand, the orthogonal orientation of C]O and
via its nitro sugar derivative 12, as depicted in Scheme 4.21 Removal
of the isopropylidene protecting group of 12,20b by treatment with
a trifluoroacetic acid/water mixture, was followed by treatment of
the resulting nitroglucofuranose 13 with sodium bicarbonate in
order to promote an intramolecular Henry reaction. This provided
a mixture of the expected epimeric nitrocyclohexanes 14a-1 and
14a-2, which were isolated in 22% yield and 52% yield, respectively,
after column chromatography. The structural assignment for 14a-1
and 14a-2 was carried out by 1D and 2D NMR studies. For 14a-1, the
proton chemical shift at 5.0 ppm (d, J 11.3 Hz), due to the proton in
C]N in transition state TS1 precludes the
p-orbital overlap and
disfavors this transition state, making the formation of nitro-
cyclohexane 14a-1 less favored.
According to our plan, when compound 14a-2 was subjected to
Ballini and Palestine’s conditions for the dehydration of
b-nitro
alkanols (Ac2O, DMAP),22 the desired polysubstituted nitro-
cyclohexene 4b was isolated in only 26% yield, probably due to
elimination of one acetoxy group from the tri-O-acetyl derivative
15a-2. In addition, when this protocol was applied to the mixture
14a-1þ14a-2, the nitro olefin 4b was also obtained in 35% yield,
probably via the mixture 15a-1þ15a-2. Continuing with our plan,
the Michael addition of 2-hydroxy-1,4-naphthoquinone (3) to this
nitrocyclohexene 4b led to the formation of an inseparable equi-
molar mixture of compounds 2b-1 and 2b-2. The mass spectrum of
this mixture confirmed the molecular weight expected for these
epimers and the 1:1 ratio was established from the 1H NMR spec-
trum, by comparison of the intensities of the signals due to the
acetyl substituents. A trans disposition for the naphthyl and nitro
substituents was tentatively proposed on the basis that the 1H NMR
spectrum of this mixture includes a doublet of doublets (J 11.8 and
2.6 Hz) at 5.86 ppm. This requires an equatorial disposition of both
the nitro and the quinone substituents. Unfortunately, the Michael
addition of 3 to 4b occurred without stereochemical control despite
the variety of substituents present in the cyclohexane ring. This
result is probably due to the fact that both faces of the C]C double
the position
axialeaxial coupling with the proton
group. The absence of coupling with the proton
a
-to the nitro group, provides evidence for an
-to the adjacent benzyloxy
-to the hydroxy
a
a
group is consistent with an axialeequatorial disposition. On the
other hand, compound 14a-2 shows a triplet at 4.84 ppm (J 10.5 Hz)
for the proton in the position a-to the nitro group. The coupling
constant values are in accordance with an axial disposition of this
proton and its neighboring protons.
The outcome of this reaction can be explained as depicted in
Scheme 4,13c assuming that abstraction of a proton
a-to the nitro
group of nitro sugar 13 results in the formation of a nitronate. This
compound undergoes an intramolecular Henry reaction via the six-
membered cyclic transition states TS1 and TS2, with the bulky
benzyloxy and nitro groups oriented equatorially and the hydroxy
groups in axial dispositions, with stabilization through intra-
molecular hydrogen bonds. The transition state TS2, which is sta-
bilized by the p-orbital overlap of C]O and C]N of the nitronate

J.M. Otero et al. / Tetrahedron 68 (2012) 1612e1621
1615
Scheme 4. Reagents and conditions: (i) TFA, H2O, rt, 17 h; (ii) NaHCO3, MeOH, H2O, rt, 14 h, 22% for 14a-1 and 52% for 14a-2; (iii) DMAP, Ac2O, Et2O, 0 ꢁC, 1 h, 26% from 14a-2 or 35%
from mixture 14a-1þ14a-2; (iv) 3, K2CO3, THF, rt, 16 h, 57%.
bond in compound 4b are equally hindered by the adjacent acetoxy
and benzyloxy groups.
The global low yield achieved for the transformation of the
mixture 14a-1þ14a-2 into nitrocyclohexene 4b, together with the
lack of stereoselectivity in the Michael addition of 3 to 4b and the
inseparable nature of the resulting mixture of aducts 2b-1þ2b-2,
led us to abandon this synthetic plan in favor of the alternative
synthesis outlined in Scheme 5. This approach involved the in-
troduction of the quinone unit prior to the Henry cyclization. This
novel plan started with the nitro olefin 16,23 reaction of which with
naphthoquinone 3 provided compound 17 with high diaster-
eoselectivity (96% de) and in excellent yield (98%). The spectro-
scopic properties of 17 did not allow assignment of the
configuration of the new stereogenic center at C-5, but this com-
pound could be crystallized and its structure was firmly established
by means of X-ray diffraction (Fig. 2).24
Fig. 2. ORTEP diagram of compound 17.
The stereoselectivity achieved in this reaction can be easily
explained in terms of the FelkineAnh model (Scheme 5).25 Thus,
it was assumed that the thermodynamically more stable con-
formation of nitro olefin 16 involves an orthogonal disposition of
its double bond with respect to the nearest electronegative
Scheme 5. Reagents and conditions: (i) K2CO3, THF, rt, 35 h, 96% de, 98% yield.
substituent (the ring oxygen), together with the nitro group

1616
J.M. Otero et al. / Tetrahedron 68 (2012) 1612e1621
Scheme 6. Reagents and conditions: (i) CH2Cl2, H2O, TFA, rt, 5 h; (ii) Na2CO3, MeOH, H2O, rt, 12 h, 90% from 17; (iii) a: H2 (1 atm), Ni-Raney, MeOH, rt, 5 h; b: 1,4-dioxane, reflux,
12 h, 32%.
directed toward the smaller substituent. The most favored attack
by the hydroxyquinone 3 corresponds to an approach to the
double bond by the opposite face to that containing the elec-
tronegative oxygen. This explains the high diastereoselectivity
achieved in this reaction.
As the final part of our plan, treatment of 17 with a trifluoro-
acetic acid/water mixture at rt gave the desired compound 18
(Scheme 6) by removal of the isopropylidene protecting group.
When 18 was directly reacted with sodium carbonate, naphthyl-
muco-inositol 2c was the only product, which resulted from an
intramolecular Henry reaction of the nitronate of compound 19
(the open form of compound 18).
Compound 2c was easily characterized from its spectroscopic
properties. The absence from the 13C NMR spectrum of any signal
due to the CH2eNO2 group confirmed that the desired nitroaldol
cyclization had occurred. On the other hand, the 1H NMR spectrum
showed a triplet at 6.03 ppm (J 11.0 Hz) and this was assigned to the
(32%) was significantly lower than for 1aþ7a (45%). This was at-
tributed to the presence of substituents on the cyclohexane ring of
tautomers 5b and 6b, since no debenzylated or other side-products
were observed in the crude mixture. This structural factor that
probably makes the transformation of 6b into 7b more difficult and
impedes the transformation of 5b into 1b.
Compound 1c (Scheme 8), a diastereoisomer of compound
1b, could be prepared when a slight modification was introduced
in this synthetic sequence. Reaction of 2-bromo-1,4-
dimethoxynaphthalene26 with tert-butyllithium in tetrahydrofu-
ran produced (1,4-dimethoxynaphthalen-2-yl)lithium (20), which
was reacted with sugar nitro olefin 16 to give an epimeric mixture
of the expected Michael adducts 21a-1þ21a-2 (65% de) due to at-
tack of the organolithium derivative on both faces of the double
bond of 16 (Scheme 7).
highly deshielded proton a-to the nitro group. The coupling con-
stant clearly indicates a double axial coupling of this proton with its
neighboring protons, which in turn allowed us to establish the axial
disposition of all these protons and therefore the equatorial dis-
position of the hydroxynaphthoquinonyl, nitro, and hydroxyl
groups. The diastereoselectivity observed in this cyclization was
explained assuming that the two six-membered cyclic transition
states TS3 and TS4 are possible, both of which have an equatorial
disposition of their bulky hydroxynaphthoquinonyl and nitro
groups. Transition state TS3 is probably strongly stabilized because
a parallel alignment of C]N and C]O groups of the nitronate of 19
could allow efficient p-orbital overlap. This might explain the for-
mation of compound 2c only.
Finally, proceeding as for compound 2a, catalytic hydrogenation
of nitroinositolquinone 2c should result in a mixture of tautomers
5b and 6b, and conjugate addition of the amino functionality to
their respective quinone moieties followed by dehydration should
provide a mixture of indoloquinones 1b (as the minor component)
and 7b (as the major component), respectively. However, surpris-
ingly only one product was obtained and this had the molecular
formula C23H21NO6, as expected for both indoloquinones 1b and 7b
(Scheme 6). This compound was tentatively characterized as isomer
7b, on the basis of the similarities of its infrared spectrum and the
infrared spectrum of compound 7a. The global yield now achieved
Scheme 7. Reagents and conditions: (i) THF, ꢀ78 ꢁC, 4 h, 65% de, 77% yield of 21a-
1þ21a-2, 54% of 21a-2 after crystallization.
The moderate stereoselectivity achieved, which was opposite to
that produced by the Michael addition of 2-hydroxy-1,4-
naphthoquinone 3 to compound 16, should be due to chelation of
the lithium atom with the furanose ring oxygen favoring the attack
of the lithium salt on the most hindered face of the double bond.27
The mixture of 21a-1 and 21a-2 could not be separated by column
chromatography, but the main epimer 21a-2 was isolated in 54%

J.M. Otero et al. / Tetrahedron 68 (2012) 1612e1621
1617
Scheme 8. Reagents and conditions: (i) 1,4-dioxane, H2O, TFA, 50 ꢁC, 16 h; (ii) NaHCO3, MeOH, H2O, rt, 24 h, 87% from 21a-2; (iii) H2 (1 atm), Ni-Raney, MeOH, rt, 3 h, 95%; (iv) CAN,
CH3CN, H2O, 0 ꢁC, 1 h, 92%; (v) THF, 60 ꢁC, 24 h, 20%.
yield by crystallization. Moreover, the minor epimer 21a-1 was
isolated as a sticky oil containing small amounts of 21a-2. The
24 results in its efficient transformation into the corresponding
aminocyclohexane 25. Finally, treatment of this compound with
cerium ammonium nitrate gave aminocyclohexanenaphthoquinone
26, which, on heating in tetrahydrofuran, provided a low yield of
a dark purple compound. 1H and 13C NMR spectroscopy allow us
identify this product as hexahydro-11bH-benzo[b]carbazole-6,11-
dione 1c, which also showed the expected molecular formula of
C23H21NO6 in its HRMS. The infrared spectrum included at 1661 cmꢀ1
the only typical band reported for 1,4-naphthoquinones. The for-
mation of this compound might occur by conjugate addition of the
amino group to the quinone moiety of compound 26 followed by
spontaneous oxidation of the resulting naphthol. The trans disposi-
tion of the amino and quinone substituents on the cyclohexane ring
disfavors theformationof thepentacyclic nitrogen ringof1c, andthis
would explain the low efficiency of this intramolecular addition.
In conclusion, we have developed novel chemical applications of
nitro compounds and these have allowed the first reported synthesis
of (6bR,7R,8S,9S,10S,10aR)-8-(benzyloxy)-7,9,10-trihydroxy-6b,7,8,9,-
10,10a-hexahydro-11H-benzo[a]carbazole-5,6-dione 7b and (1R,2S,3-
S,4R,4aS,11bS)-2-(benzyloxy)-1,3,4-trihydroxy-1,2,3,4,4a,5-hexahyd-
ro-11bH-benzo[b]carbazole-6,11-dione 1c, two novel benzocarba-
zoldiones, the two first examples of two novel families of compounds
of probable biological interest, on account of their structural re-
lationship with benzo[b]carbazoldiones II and (þ)-pancratistatin (III).
The routes involved in the preparation of benzocarbazolediones
1a, 1c, 7a, and 7b include novel chemistry. It consists of the first
reported example on the addition of quinones to nitro olefins,14
which allowed to prepare compounds 2b and 2c, the two first ex-
amples of naphthoquinones bearing a highly functionalized cy-
clohexane ring linked to their C-2 position. They can then be
considered as novel derivatives of parvaquone (2-cyclohexyl-3-
hydroxy-1,4-naphthoquinones I), a hydroxyquinone that displays
interesting biological properties.
L-
idofuranose configuration of 21a-2 was firmly established by X-ray
diffraction (Fig. 3).24 Removal of the acetonide protecting group of
21a-2 with trifluoroacetic acid (Scheme 8), followed by treatment
of the resulting furanose 22 with sodium bicarbonate, allowed us to
obtain 87% yield of naphthylcyclohexane 24. Alternative cyclization
subproducts were not detected by TLC or by 1H NMR spectroscopy.
The configuration of compound 24 was easily established from the
1H NMR spectrum, which included at 5.15 ppm a doublet of dou-
blets (J 10.3 and 10.7 Hz) corresponding to the highly deshielded
hydrogen a-to the nitro group. This signal can be explained in terms
of double axial coupling between this proton and its neighboring
protons. This result requires an equatorial disposition for the
dimethoxynaphthalenyl, nitro and hydroxy substituents.
The high diastereoselectivity observed in this process was again
explained by assuming the presence of stabilized six-membered
cyclic transition states with the bulkiest substituents in equatorial
disposition. The parallel alignment of C]O and C]N present in the
transition state TS6 allows a high level of stabilization by p-orbital
overlap, which in turn prevents the formation of less stabilized
transition state TS7 and explains the exclusive formation of the di-
astereomer 24. Catalytic hydrogenationof naphthylnitrocyclohexane
Work is now in progress aimed at the optimization of the syn-
thetic routes here reported, as a preliminary step for the preparation
of libraries of type 1, 2, 7, and 26 naphthoquinone derivatives from
the plethora of hexoses for future chemical and biological studies.
3. Experimental section
3.1. General
Melting points were determined on a Kofler Thermogerate ap-
paratus and are uncorrected. Infrared spectra were recorded on
a JASCO FT/IR-400 spectrophotometer. Nuclear magnetic resonance
spectra were recorded, unless otherwise specified, on a Bruker
DPX-250 apparatus using deuterochloroform solutions containing
Fig. 3. ORTEP diagram of compound 21a-2.

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J.M. Otero et al. / Tetrahedron 68 (2012) 1612e1621
tetramethylsilane as internal standard. 1H NMR splitting patterns
are designated as singlet (s), doublet (d), triplet (t), quartet (q) or
quintuplet (p). All first-order splitting patterns were assigned on
the basis of the appearance of the multiplet. Splitting patterns that
could not be easily interpreted are designated as multiplet (m) or
broad (br). Mass spectra were obtained on an HP 5988A mass
spectrometer, using the electron impact (EI) or the chemical ioni-
zation (CI) techniques. Elemental analyses were performed on EA
1108 CHNS Fisons. Thin layer chromatography (TLC) was performed
using Merck GF-254 type 60 silica gel and dichloromethane/
methanol or ethyl acetate/hexane mixtures as eluants; the TLC
spots were visualized with ultraviolet light or iodine vapor. Column
chromatography was carried out using Merck type 9385 silica gel.
Solvents were purified as per Ref. 28. Solutions of extracts in or-
ganic solvents were dried with anhydrous sodium sulfate.
1H, CH), 7.57e7.94 (m, 4H, 4ꢃ AreH), 9.21 (br s, 1H, NH); 13C NMR
(d, ppm, DMSO-d6): 24.3, 25.3, 28.4, 30.0, 47.5, 67.7, 115.7, 124.2,
127.4, 127.7, 131.5, 131.6, 133.9, 161.1, 171.2, 183.6; MS (FAB) (m/z, %):
253 [M]þ (63), 195 (100). HRMS calcd for C16H15NO2 [M]þ
253.110279; found 253.109090.
3.1.3.2. (ꢂ)-(6bS,10aR)-6b,7,8,9,10,10a-Hexahydro-11H-benzo[a]car-
bazole-5,6-dione (ꢂ-7a). Orange solid (25% yield); IR (
n ,
, cmꢀ1
NaCl): 2931, 1670, 1628; 1H NMR (
d, ppm, CD3COCD3): 1.28e1.92
(m, 6H, 3ꢃ CH2), 2.20e2.31 (m, 1H, CH), 2.56e2.74 (m, 2H, CH2),
3.19e3.33 (m, 1H, CH), 6.65 (br s, 1H, NH), 7.68 (td, 1H, J¼7.5, 1.6 Hz,
AreH), 7.76 (td, 1H, J¼7.5, 1.6 Hz, AreH), 7.91e7.99 (m, 2H, 2ꢃ
AreH); 13C NMR (
d, ppm, CD3COCD3): 26.3, 27.6, 30.6, 32.7, 50.7,
70.3, 124.5, 127.0, 127.1, 133.6, 135.8, 135.9, 136.2, 156.4, 181.5, 182.0;
MS (FAB, m/z, %): 253 [M]þ (91), 224 (100); HRMS calcd for
C16H15NO2 [M]þ 253.110279; found 253.109088.
3.1.1. (ꢂ)-2-Hydroxy-3-((1S,2R)-2-nitrocyclohexyl)naphthalene-1,4-
dione (ꢂ-2a). An oven-dried round-bottomed flask was charged
with 2-hydroxynaphthalene-1,4-dione (3) (0.400 g, 2.30 mmol), 1-
nitrocyclohexene (4a) (0.350 g, 2.76 mmol), anhydrous potassium
carbonate (0.635 g, 4.60 mmol), and dry tetrahydrofuran (16 mL).
The mixture was heated at 50 ꢁC during 20 h under a nitrogen at-
mosphere and the reaction was quenched with water (30 mL) and
acidified with several drops of 1.0 M hydrochloric acid. The reaction
mixture was extracted with dichloromethane (3ꢃ15 mL) and the
combined organic extracts were dried with anhydrous sodium
sulfate. After filtration and evaporation of the solvent under vac-
uum, column chromatography of the crude product on silica gel (5%
methanol in dichloromethane) afforded ( )-2a (0.614 g, 89% yield).
3.1.4. 1L-3,5-Di-O-benzyl-6-deoxy-6-nitro-muco-inositol
and 1L-2,6-di-O-benzyl-3-deoxy-3-nitro-chiro-inositol (14a-2). A
solution of 3,5-di-O-benzyl-6-deoxy-1,2-O-isopropylidene-6-nitro-
(14a-1)
a-D-glucofuranose (12) (0.103 g, 0.241 mmol) in water (6 mL) and
trifluoroacetic acid (6 mL) was stirred at rt during 17 h. The solvent
was evaporated under vacuum and the residue was coevaporated
with toluene (3ꢃ6 mL). The unstable yellow oil obtained was dis-
solved in methanol (7 mL), 2% sodium bicarbonate aqueous solution
(2.5 mL) was added, and the mixture was stirred at rt during 14 h. The
reaction mixture was quenched by acidification with acid resin, the
solids were filtered off, the solvent was removed under vacuum, and
the residue was purified by column chromatography (AcOEt/hexane,
2:3) to give the muco-inositol 14a-1 and the chiro-inositol 14a-2.
Orange solid; mp 181e183 ꢁC; IR (
n
, cmꢀ1, NaCl)
n
¼1673,1644,1540,
1367; 1H NMR (
d
, ppm, CDCl3): 1.38e1.64 (m, 2H, CH2), 1.73e2.08
(m, 5H, 2ꢃ CH2þCHH), 2.33e2.51 (m, 1H, CHH), 3.71 (td, 1H, J¼11.6,
4.0 Hz, CH), 5.40 (td, 1H, J¼11.6, 4.0 Hz, CHeNO2), 7.67 (td, 1H, J¼7.6,
1.5 Hz, AreH); 7.76 (td, 1H, J¼7.6, 1.5 Hz, AreH), 8.05 (dd, 1H, J¼7.6,
3.1.4.1. 1L-3,5-Di-O-benzyl-6-deoxy-6-nitro-muco-inositol
(14a-
1). Yellow oil (22% yield); IR ( d,
n
, cmꢀ1): 3410; 1559; 1376; 1H NMR (
ppm, CDCl3): 2.68 (br s, 3H, 3ꢃ OH); 3.47e3.50 (m,1H, H-1); 3.54 (d,
1H, J¼2.3 Hz, H-5); 3.62 (dd, 1H, J¼2.4 Hz, H-1); 4.43e4.55 (m, 3H,
eOCH2Ph, H-6); 4.73e4.79 (m, 2H, eOCHPh, H-4); 5.00 (d, 1H,
1.5 Hz, AreH), 8.11 (dd, 1H, J¼7.6, 1.5 Hz, AreH); 13C NMR (
d, ppm,
CDCl3):
d¼24.2, 25.0, 28.4, 32.1, 38.5, 85.9, 121.6, 126.2, 127.0, 129.0,
132.7, 133.1, 135.2, 153.4, 181.0, 183.7; MS (FAB) (m/z, %): 302
[MþH]þ (12), 137 (100). Anal. Calcd for C16H15NO5: C, 63.78; H,
5.02; N, 4.65. Found C, 63.54; H, 5.28; N, 4.78.
J¼11.3 Hz, H-3); 7.19e7.37 (m, 10H, 10ꢃ AreH); 13C NMR (
d, ppm,
CDCl3): 69.6, 72.6, 74.6, 75.3, 75.9, 78.0, 79.8, 86.7, 128.0e128.7,
137.3, 138.1; MS (CI, m/z, %): 390 [MH]þ (1); 341 (2); 298 (2), 91
[PhCH2]þ (100).
3.1.2. (ꢂ)-2-((1S,2R)-2-Aminocyclohexyl)-3-hydroxynaphthalene-
1,4-dione (ꢂ-5a). A suspension of compound (ꢂ)-2a (0.100 g,
0.33 mmol) and 10% palladium on activated charcoal (0.100 g) in
methanol (20 mL) was degassed under a nitrogen atmosphere. This
mixture was stirred at rt during 24 h under a hydrogen atmosphere
and the catalystwasfilteredoff. Removalofthesolventunder vacuum
produced a crude red solid of (ꢂ)-2-((1S,2R)-2-aminocyclohexyl)-3-
hydroxynaphthalene-1,4-dione (ꢂ-5a) (0.090 g, 100%), which was
used in the next reaction without further purification.
3.1.4.2. 1L-2,6-Di-O-benzyl-3-deoxy-3-nitro-chiro-inositol
(14a-
2). Yellow oil (52% yield); IR ( d,
n
, cmꢀ1): 3410; 1559; 1376; 1H NMR (
ppm, CDCl3): 3.28 (br s, 3H, 3ꢃ OH); 3.90 (t,1H, J¼2.9 Hz, H-3); 4.06 (br s,
2H, H-2þH-4); 4.22e4.30 (m, 2H, H-1þH-5); 4.40e4.58 (m, 4H, 2ꢃ
OCH2Ph); 4.84 (t, 1H, J¼10.5 Hz, H-6); 7.23e7.40 (m, 10H, 10ꢃ AreH);
13C NMR (
d, ppm, CDCl3): 69.1, 70.4, 71.2, 72.8, 72.9, 72.9, 76.0, 76.2, 88.7,
127.7e128.7, 136.7, 137.2; MS (CI, m/z, %): 388 [MꢀH]þ, (2); 370 (2);
298 (4); 181 (25); 91 [PhCH2]þ (100).
3.1.3. (ꢂ)-(4aR,11bS)-1,2,3,4,4a,5-Hexahydro-11bH-benzo[b]carba-
zole-6,11-dione (ꢂ-1a) and (ꢂ)-(6bS,10aR)-6b,7,8,9,10,10a-hexahy-
dro-11H-benzo[a]carbazole-5,6-dione (ꢂ-7a). A round-bottomed
flask was charged with crude amino derivative (ꢂ)-5a (0.090 g,
0.33 mmol) and 1,4-dioxane (20 mL) and the mixture was heated
under reflux for 5 h. The mixture was cooled to rt and benzo[b]
carbazole-6,11-dione derivative (ꢂ)-1a (0.018 g) was isolated by
filtration. The mother liquors were concentrated to dryness under
vacuum and the crude residue was submitted to column chroma-
tography on silica gel (5% methanol in dichloromethane) to afford
benzo[a]carbazole-5,6-dione derivative (ꢂ)-7a (0.022 g).
3.1.5. (1R,2R,3S,6R)-2,6-Bis(benzyloxy)-5-nitrocyclohex-4-ene-1,3-
diyl diacetate (4b). A mixture of inositols 14a-1 and 14a-2 (113 mg,
0.29 mmol) in Et2O (11 mL) was cooled to 0 ꢁC under a nitrogen
atmosphere and a catalytic amount of 4-(dimethylamino)pyridine
and acetic anhydride (1.30 mL) were added. The reaction mixture
was stirred until complete conversion (TLC analysis), then acidified
to pH 6 with 10% hydrochloric acid and the stirring was continued
for 1 h. The mixture was diluted with water (10 mL), extracted with
ethyl acetate (3ꢃ10 mL), and the combined organic extracts were
dried over anhydrous sodium sulfate and concentrated to dryness
under vacuum. The residue was purified by column chromatogra-
phy (ethyl acetate/hexane 1:5) to give nitrocyclohexene 4b
3.1.3.1. (ꢂ)-(4aR,11bS)-1,2,3,4,4a,5-Hexahydro-11bH-benzo[b]carba-
zole-6,11-dione (ꢂ-1a). Violet solid (20% yield); mp higher than
(46.2 mg, 35% yield). Yellow oil; ½a D20
ꢄ
þ0.07 (c 0.6, CHCl3). IR (
n,
cmꢀ1, NaCl): 1530; 1365; 1745; 1H NMR (
d
, ppm, CDCl3):
d
¼1.95 (s,
300 ꢁC, IR (
n
, cmꢀ1, NaCl): 2935, 1681; 1H NMR (
d, ppm, DMSO-d6):
3H, OCH3); 1.98 (s, 3H, OCH3); 4.19 (dd, 1H, J¼7.8, 9.9 Hz, H-2);
4.59e4.76 (m, 4H, 2ꢃ CH2Ph); 4.98e5.04 (m, 2H, H-1þH-6); 5.52
1.16e2.27 (m, 8H, 4ꢃ CH2), 2.50e2.65 (m, 1H, CH), 3.43e3.59 (m,

J.M. Otero et al. / Tetrahedron 68 (2012) 1612e1621
1619
(dd, 1H, J¼2.6, 7.8 Hz, H-3); 7.06 (d, 1H, J¼2.7 Hz, H-4); 7.21e7.32
glucofuranose derivative 17 (0.250 g, 0.51 mmol) in dichloro-
methane (1 mL), water (3 mL), and trifluoroacetic acid (6 mL) was
stirred at rt during 5 h. The solvent was evaporated and the residue
was coevaporated with toluene (3ꢃ5 mL) to yield the 3-O-benzyl-
5,6-dideoxy-5-C-(30-hydroxy-10,40-naphthoquinon-20-yl)-6-nitro-
(m, 10H, 10ꢃ AreH); 13C NMR (
d, ppm, CDCl3): 20.6, 20.7, 70.8, 71.2,
72.3, 74.9, 75.0, 75.8, 127.8, 127.9, 128.1, 128.2, 128.5, 132.3, 137.3,
137.7, 148.1, 169.8, 169.9 ppm. MS (m/z, %): 456 [MH]þ (8); 91
[PhCH2]þ (90). Anal. Calcd for C24H25NO8: C, 63.29; H, 5.53; N, 3.08.
Found C, 63.58; H, 5.79; N, 2.90.
D-glucose 18 as an unstable yellow oil, which was dissolved in
methanol (12 mL) and 2% sodium carbonate aqueous solution
(4 mL). After stirring the mixture at rt during 12 h, the reaction was
quenched by acidification with acid resin, filtered, and the solvent
was evaporated under vacuum. The resulting residue was subjected
to chromatography on silica gel (dichloromethane/methanol/acetic
acid 10:0.5:0.2) affording nitrocyclohexane 2c (0.213 g, 0.46 mmol).
3.1.6. (1S,2R,3R,4R,5R,6R)-þ(1S,2R,3R,4R,5S,6S)-2,6-Di-O-benzyloxy-
4-(30-hydroxy-10,40-naphthoquinon-20-yl)-5-nitrocyclohexan-1,3-dyil
diacetate (2b-1þ2b-2). To
a solution of nitrocyclohexene 4b
(25.7 mg, 0.056 mmol) in dry tetrahydrofuran (1.0 mL), 2-hydroxy-
1,4-naphthoquinone (3) (15.6 mg, 0.113 mmol), and anhydrous
potassium carbonate (31.6 mg, 0.226 mmol) were added and the
suspension was stirred under a nitrogen atmosphere at rt for 16 h.
The mixture was acidified with 10% hydrochloric acid, the tetra-
hydrofuran was removed under vacuum and the aqueous phase
was extracted with dichloromethane (3ꢃ5 mL). The combined or-
ganic extracts were dried over anhydrous sodium sulfate, filtered,
and concentrated to dryness under vacuum. The residue was pu-
rified by column chromatography (ethyl acetate/hexane 1:1) to
yield an inseparable mixture of nitrocyclohexanes 2b-1 and 2b-2
Amorphous orange solid (90% yield); ½a D20
ꢄ
þ60.8 (c 4.5, CH3COCH3).
IR (n d, ppm,
, cmꢀ1, NaCl): 3393, 1672, 1647, 1552, 1371; 1H NMR (
CD3COCD3): 3.98 (t, 1H, J¼3.2 Hz, H-3), 4.24e4.29 (m, 2H, H-2þH-
4), 4.39 (dd, 1H, J¼3.0, 11.0 Hz, H-1), 4.46 (d, 1H, J¼11.0 Hz, H-5),
4.72 (d, 1H, J¼11.8 Hz, CH2ePh), 4.82 (d, 1H, J¼11.8 Hz, CH2ePh),
6.03 (t, 1H, J¼11.0 Hz, H-6), 7.29e7.56 (m, 5H, 5ꢃ HeAr), 7.76e7.89
(m, 2H, H-60þH-70), 8.04e8.11 (m, 2H, H-50þH-80); 13C NMR (
d,
ppm, CD3COCD3): 40.8, 73.2, 73.5, 73.8, 74.5, 78.5, 87.3, 119.1, 127.5,
128.0, 129.5, 130.0, 131.3, 133.9, 134.9, 136.6, 139.7, 159.2, 182.7,
185.4; MS (CI, m/z, %): 349 [MHꢀBnO]þ (20), 281 [MꢀC10H6O3]þ
(14), 91 [Bn]þ (100). Anal. Calcd for C23H21NO9: C, 60.66; H, 4.65; N,
3.08. Found: C, 60.73; H, 4.98; N, 2.65.
(20.4 mg, 57% yield). Orange oil; IR (
n
, cmꢀ1, NaCl): 3326; 1671;
1649; 1555; 1367; 1H NMR (
d, ppm, CDCl3): 1.74 (s, 3H, CH3); 1.78 (s,
3H, CH3); 1.92 (s, 3H, CH3); 1.94 (s, 3H, CH3); 4.16e4.38 (m, 3H);
4.58e4.76 (m, 11H); 5.03e5.17 (m, 2H); 5.47e5.67 (m, 3H); 5.86
(dd, 1H, J¼2.6, 11.8 Hz); 7.22e7.42 (m, 20H, 20ꢃ AreH); 7.63e7.80
3.1.9. (6bR,7R,8S,9S,10S,10aR)-8-(Benzyloxy)-7,9,10-trihydroxy-
6b,7,8,9,10,10a-hexahydro-11H-benzo[a]carbazole-5,6-dione (7b). A
degassed suspension of nitrocyclohexane derivative 2c (0.052 g,
0.11 mmol) and Raney-nickel (0.100 g) in methanol (5 mL) was
stirred under a hydrogen atmosphere at rt during 5 h. The catalyst
was filtered off and the solvent evaporated, providing the amino
intermediate 6b as a yellow oil, which was directly dissolved in 1,4-
dioxane (5 mL) and heated under reflux during 12 h. The solvent
was evaporated and the crude solid was subjected to column
chromatography on silica gel (10% methanol in dichloromethane)
to afford benzo[a]carbazoledione 7b (0.016 g, 0.04 mmol). Red solid
(m, 4H, 4ꢃ AreH); 7.94e8.20 (m, 4H, 4ꢃ AreH); 13C NMR (
d, ppm,
CDCl3): 20.4, 20.5, 20.7, 34.1, 37.0, 70.7, 72.6, 73.5, 73.6, 75.1, 75.3,
75.7, 77.4, 77.5, 77.9, 78.0, 82.1, 82.9, 126.4e128.5, 128.9, 129.2,
132.8,133.1,133.2,135.2,135.6,136.9,137.0,138.0,138.1,155.7,169.8,
169.9, 180.6, 182.7, 184.4; MS (CI, m/z, %): 630 [MH]þ (5); 91,
[CH2Phþ] (100).
3.1.7. 3-O-Benzyl-5,6-dideoxy-5-C-(30-hydroxy-10,40-naphthoquinon-
20-yl)-1,2-O-isopropylidene-6-nitro-
a
-
D
-glucofuranose (17). An oven-
dried round-bottomed flask was charged with 3-O-benzyl-5,6-
dideoxy-1,2-O-isopropylidene-6-nitro- -xylo-hex-5-enefuranose
a-D
(32% yield); mp 193e194 ꢁC (methanol); ½a 2D0
ꢄ
ꢀ112.3 (c 0.34,
(16) (0.590 g, 1.83 mmol), 2-hydroxy-1,4-naphthoquinone (3)
(0.312 g, 2.12 mmol), anhydrous potassium carbonate (0.510 g,
3.65 mmol), and dry tetrahydrofuran (17 mL). The suspension was
stirred at rt under a nitrogen atmosphere during 35 h, the reaction
was quenched with water (30 mL) and acidified with several drops
of 1.0 M hydrochloric acid. The resulting mixture was extracted with
dichloromethane (3ꢃ15 mL) and the combined organic extracts
were dried with anhydrous sodium sulfate. After filtration and
evaporation of the solvent under vacuum, column chromatography
of the crude product on silica gel (methanol in dichloromethane
1:60 to 1:30 gradient) afforded compound 17 (0.892 g,1.79 mmol) as
a solid, which was crystallized from dichloromethane/heptane.
CH3OH); IR (n d, ppm,
, cmꢀ1, NaCl): 3341, 1671, 1623; 1H NMR (
CD3OD): 3.37e3.57 (m, 2H, H-7þH-8), 3.77 (t, 1H, J¼2.7 Hz, H-9),
3.85 (dd, 1H, J¼3.4, 10.4 Hz, H-6b), 3.97e4.09 (m, 2H, H-10þH-10a),
4.53 (d, 1H, J¼12.0 Hz, CH2ePh), 4.60 (d, 1H, J¼12.0 Hz, CH2ePh),
7.16e7.29 (m, 5H, 5ꢃ HeAr), 7.51e7.67 (m, 2H, H-2þH-3), 7.86e7.91
(m, 2H, H-1þH-4); 13C NMR (
d, ppm, CDCl3): 48.6, 62.1, 68.9, 73.4,
74.0, 74.5, 81.8, 120.7, 126.5, 126.8, 128.9, 129.0, 129.5, 133.2, 135.3,
135.7, 139.6, 157.3, 180.6, 182.4; MS (CI, m/z, %): 409 [MH2]þ (42),
408 [MH]þ (37), 358 (17), 185 (100). HRMS calcd for C23H21NO6
[M]þ 407.136890; found 407.136881.
3.1.10. 3-O-Benzyl-5,6-dideoxy-5-C-(10,40-dimethoxynaphthalen-20-
yl)-1,2-O-isopropyliden-6-nitro-b-L-idofuranose (21a-2). A 2.1 M
Yellow solid (98% yield), mp 130e131 ꢁC; ½a D20
ꢄ
þ45.6 (c 1.1, CHCl3);
IR (n
, cmꢀ1, NaCl): 3359, 1669, 1648, 1552, 1380; 1H NMR (
d
, ppm,
solution in hexanes of tert-butyllithium (1.9 mL, 4.04 mmol,
2.5 equiv) was added dropwise to a solution of 2-bromo-1,4-
dimethoxynaphthalene (540 mg, 2.02 mmol, 1.2 equiv) in dry tet-
rahydrofuran (4 mL) at ꢀ78 ꢁC under nitrogen atmosphere. After
15 min a solution of nitro olefin 16 (520 mg, 1.61 mmol) in dry
tetrahydrofuran (4 mL) was added to the mixture and after 4 h at
ꢀ78 ꢁC, the reaction was quenched with saturated aqueous am-
monium chloride solution (10 mL). The aqueous layer was extracted
with dichloromethane (3ꢃ20 mL) and the pooled organic layers
were dried over anhydrous sodium sulfate, filtered, and concen-
trated to dryness under reduced pressure. The residue was purified
by column chromatography (ethyl acetate/hexane, 1:6) providing
a mixture of 21a-1 and 21a-2 (640 mg, 77% yield) as a yellow solid
(diastereoisomeric ratio¼50:1 determined by 1H NMR). Major di-
astereoisomer (21a-2) was isolated from this mixture in 54% yield
by crystallization from hexane. Colorless solid: mp 145e147 ꢁC;
CDCl3): 1.33 (s, 3H, CH3), 1.54 (s, 3H, CH3), 1.61 (br s, 1H, OH), 3.73 (d,
1H, J¼3.0 Hz, H-3), 4.24 (d, 1H, J¼11.6 Hz, CH2Ph), 4.38 (ddd, 1H,
J¼4.6, 9.7 Hz, J¼10.1 Hz, H-5), 4.51 (d, 1H, J¼11.6 Hz, CH2Ph), 4.61 (d,
1H, J¼4.0 Hz, H-2), 4.90 (dd, 1H, J¼3.0, 9.7 Hz, H-4), 4.90 (dd, 1H,
J¼4.6, 12.2 Hz, H-6), 5.00 (dd, 1H, J¼10.1, 12.2 Hz, H-6), 5.98 (d, 1H,
J¼4.0 Hz, H-1), 7.07e7.15 (m, 5H, 5ꢃ HeAr), 7.69e7.83 (m, 2H, H-
60þH-70), 8.04e8.09 (m, 2H, H-50þH-80); 13C NMR (
d, ppm, CDCl3):
26.1, 26.6, 35.1, 71.4, 75.9, 78.1, 80.7, 81.5, 104.7, 111.8, 117.7, 126.1,
126.9, 127.7, 128.1, 129.0, 132.3, 133.0, 135.1, 136.2, 154.7, 180.4, 183.2;
MS (CI, m/z, %): 496 [MH]þ (1), 480 [MꢀCH3]þ (2), 438 [MꢀC3H6O]þ
(11), 91 [PhCH2]þ (100). Anal. Calcd for C26H25NO9: C, 63.03; H, 5.09;
N, 2.83. Found: C, 62.74; H, 5.15; N 2.81.
3.1.8. 2-((1R,2R,3S,4S,5S,6R)-3-(Benzyloxy)-2,4,5-trihydroxy-6-
nitrocyclohexyl)-3-hydroxynaphthalene-1,4-dione (2c). A solution of

1620
J.M. Otero et al. / Tetrahedron 68 (2012) 1612e1621
½
a 2D0
ꢄ
ꢀ86.4 (c 1.5, CHCl3); IR (
n
, cmꢀ1, NaCl): 1558; 1367; 1H NMR (
d
,
acetone (1 mL). The solids were filtered off and the filtrate was
concentrated to dryness under vacuum to give compound 26
(45 mg, 92% yield) as a yellow oil, which was used without further
purification.
ppm, CDCl3): 1.29 (s, 3H, CH3); 1.47 (s, 3H, CH3); 3.79 (s, 3H, OCH3);
3.83 (d, 1H, J¼2.8 Hz, H-3); 3.93 (s, 3H, OCH3); 4.50 (d, 1H,
J¼12.0 Hz, CH2Ph); 4.60 (dd, 1H, J¼8.0, 2.8 Hz, H-4); 4.63 (d, 1H,
J¼3.7 Hz, H-2); 4.70e4.74 (m, 1H, H-5); 4.75 (d, 1H, J¼12.0 Hz,
CH2Ph); 4.80 (dd, 1H, J¼12.9, 4.3 Hz, H-6); 5.01 (dd, 1H, J¼12.9,
9.6 Hz, H-6); 5.92 (d, 1H, J¼3.7 Hz, H-1); 6.62 (s, 1H, H-30);
7.33e7.42 (m, 5H, 5ꢃ HePh); 7.46 (dd, 1H, J¼8.3, 7.1 Hz, H-60); 7.52
(dd, 1H, J¼8.3, 7.1 Hz, H-70); 8.01 (d, 1H, J¼8.3 Hz, H-80); 8.19 (d, 1H,
3.1.15. (1R,2S,3S,4R,4aS,11bS)-2-(Benzyloxy)-1,3,4-trihydroxy-
1,2,3,4,4a,5-hexahydro-11bH-benzo[b]carbazole-6,11-dione (1c). A
solution of compound 26 (45 mg, 0.11 mmol) in dry tetrahydrofu-
ran (3 mL) was stirred and heated at 60 ꢁC during 24 h. The solvent
was removed under vacuum and the residue purified by pre-
parative TLC (dichloromethane/methanol, 9:1) providing the benzo
[b]carbazoledione 1c (9.0 mg, 20% yield). Violet solid: mp higher
J¼8.3 Hz, H-50); 13C NMR (
d, ppm, CD3OD): 26.1, 26.6, 37.7, 55.5,
62.5, 71.4, 75.7, 79.7, 81.2, 82.0, 102.0, 104.5, 111.7, 122.2, 122.3, 124.1,
125.6, 126.3, 126.7, 127.2, 128.2, 128.4, 128.7, 136.9, 148.2, 152.2; MS
(CI, m/z, %): 509 (4, Mþ); 91 (25, [PhCH2]þ); 29 (100). Anal. Calcd for
C28H31NO8: C, 66.00; H, 6.13; N, 2.75. Found: C, 66.08, H, 6.33; N,
2.45.
than 260 ꢁC; ½a 2D0
ꢄ
þ26.0 (c 0.10, CH3COCH3); IR (
n
, cmꢀ1, NaCl): 3434
d, ppm, CD3COCD3,): 2.80 (s,
(b, OHþNH); 1661 (m, CO); 1H NMR (
1H, OH); 3.57 (dd, 1H, J¼7.3, 9.9 Hz, H-11b); 3.73 (ddd, 1H, J¼3.1, 7.5,
9.9 Hz, H-4a); 4.36 (d, 1H, J¼3.4 Hz, OH); 4.63e4.69 (m, 1H, H-2);
4.87 (d, 1H, J¼11.7 Hz, CH2Ph); 4.87e4.91 (m, 2H, H-1þH-4); 5.11 (d,
1H, J¼11.7 Hz, CH2Ph); 5.17 (d, 1H, J¼1.3 Hz, H-3); 7.26e7.51 (m, 6H,
5ꢃ HeArþH-7); 7.68 (td, 1H, J¼1.3, 7.5 Hz, H-10); 7.94e8.03 (m, 2H,
3.1.11. 3-O-Benzyl-5,6-dideoxy-5-C-(10,40-dimethoxynaphthalen-20-
yl)-6-nitro-b-L-idofuranose (22). A solution of idofuranose 21a-2
(0.390 g, 0.76 mmol) in 1,4-dioxane (6 mL), water (2 mL), and tri-
fluoroacetic acid (4 mL) was stirred at 50 ꢁC during 16 h. The solvent
was evaporated and the residue was coevaporated with toluene
(3ꢃ5 mL) to give the 3-O-benzyl-5,6-dideoxy-5-C-(30-hydroxy-
H-8þH-9), 11.42 (br s, 1H, NH); 13C NMR (
d, ppm, CD3COCD3): 42.0,
67.2, 70.6, 71.3, 76.3, 78.4, 85.9, 124.2, 127.3, 129.1, 129.8, 130.0,
130.8, 131.5, 131.9, 134.1, 137.2, 141.5, 157.7, 177.2, 182.9; MS (FABþ,
m/z, %): 407 (1, Mþ); 390 (5, [MꢀOH]þ); 91 (100, [PhCH2]þ); HRMS
calcd for C23H21NO6 [M]þ 407.136890; found 407.136897.
10,40-naphthoquinon-20-yl)-6-nitro-
b-L-idofuranose (22) as a color-
less oil, which was used in the next reaction without further
purification.
Acknowledgements
3.1.12. (1R,2S,3S,4R,5S,6S)-3-(Benzyloxy)-5-(10,40-dimethoxynaph-
thalen-20-yl)-6-nitrocyclohexane-1,2,4-triol (24). A 2% aqueous so-
lution of sodium bicarbonate (4 mL) was added to a solution of 22
(390 mg, 0.76 mmol) in methanol (12 mL) and the mixture was
stirred at rt for 24 h. The reaction mixture was acidified with acid
resin, filtered, and the solvents were evaporated under vacuum.
The residue was purified by column chromatography (dichloro-
methane/methanol/acetic acid, 10:0.5:0.2) to obtain nitro-
cyclohexanetriol 24 (310 mg, 87% yield from 21a-2). White
We thank the Spanish Ministry of Science And Innovation for
financial support (CTQ2009-08490) and for an FPU to Jose M. Otero.
We also thank the Xunta de Galicia for grants to Jose C. Barcia and
Pablo Thomas and the University of Santiago de Compostela for
a visiting professorship to Cristian O. Salas.
ꢀ
ꢀ
References and notes
amorphous solid. ½a D20
ꢄ
þ15.7 (c 2.00, CHCl3); IR (
n
, cmꢀ1, NaCl):
1. (a) The Chemistry of Functional Groups: The Chemistry of the Quinonoid Com-
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nones Chapman and Hall: London/New York, NY, 1997; (d) Duke, J. A. CRC Hand-
book of Medicinal Herbs; CRC: Boca Raton, 1985; p 470; (e) Spyroudis, S. Molecules
3434; 1557; 1371; 1H NMR (
d
, ppm, CD3COCD3): 3.61 (t, 1H,
J¼8.8 Hz, H-3); 3.75 (ddd, 1H, J¼4.3, 8.8, 9.1 Hz, H-2); 3.91 (s, 3H,
OCH3); 3.96e4.06 (m, 1H, H-5); 4.02 (s, 3H, OCH3); 4.09e4.15 (m,
1H, H-4); 4.21 (ddd, 1H, J¼4.6, 9.1, 10.3 Hz, H-1); 4.45 (d, 1H,
J¼4.3 Hz, OH-2); 4.75 (d, 1H, J¼4.6 Hz, OH-1); 4.95e5.01 (m, 3H,
OH-4þCH2Ph); 5.15 (t, 1H, J¼10.3 Hz, H-6); 7.21 (s, 1H, H-30);
7.24e7.35 (m, 3H, 3ꢃ HeAr); 7.40e7.58 (m, 4H, 2ꢃ HePhþH-60þH-
ꢀ
ꢀ
ꢀ
2000, 5, 1291; (f) Ravelo, A.; Estevez-Braun, A.; Chavez-Orellana, H.; Perez-
Sacau, E.; Mesa-Silverio, D. Curr. Top. Med. Chem. 2004, 4, 241; (g) Solorio-Al-
~
ꢀ
ꢀ
varado, C. R.; Pena-Cabrera, E.; García-Solto, J.; Lopez-Godínez, J.; Gonzalez, F. J.;
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d, ppm, CD3COCD3):
Tetrahedron Lett. 2009, 50, 5116 and references cited therein.
45.4, 57.1, 64.0, 75.0, 76.0, 76.3, 76.5, 86.9, 92.7, 103.8, 123.8, 124.0,
126.7, 127.2, 127.8, 128.3, 128.9, 129.4, 129.7, 130.2, 141.4, 150.8,
153.8; MS (CI, m/z, %): 469 (5, Mþ); 133 (100); 91 (25, [PhCH2]þ).
Anal. Calcd for C25H27NO8: C, 63.96; H, 5.80; N, 2.98. Found: C,
63.71; H, 5.59; N 3.29.
ꢀ
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the amino derivative 25 (53 mg, 95% yield) as a colorless oil, which
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