Asymmetric synthesis of rubiginones A2 and C2 and their 11-methoxy regioisomers

Article abstract of DOI:10.1002/chem.200600809

Convergent enantioselective syntheses of angucyclinone-type natural products rubiginones A₂ (2) and C₂ (1) and their 11-methoxy regioisomers 3a and 3b have been achieved by using two domino processes from a common enantiomerically pu

Full text of DOI:10.1002/chem.200600809

FULL PAPER
DOI: 10.1002/chem.200600809
Asymmetric Synthesis of Rubiginones A2 andC andTheir 11-Methoxy
2
Regioisomers
M. Carmen CarreÇo,* lvaro Somoza, María Ribagorda, and Antonio Urbano*[a]
Abstract: Convergent enantioselective
syntheses of angucyclinone-type natu-
ral products rubiginones A2 (2) and C2
(1) and their 11-methoxy regioisomers
3a and 3b have been achieved by using
two domino processes from a common
enantiomerically pure 1-vinylcyclohex-
ene 4. Key steps in the synthesis of this
diene were the stereoselective conju-
gate addition of AlMe3 on (SS)-[(p-tol-
ylsulfinyl)methyl]-p-quinol (9) and the
elimination of the b-hydroxy sulfoxide
fragment, after oxidation to sulfone, to
recover a carbonyl group. The first
domino sequence comprised Diels–
Alder reaction with a sulfinyl naphtho-
quinone followed by sulfoxide elimina-
tion. An efficient opposite regioselec-
tion in the cycloaddition step was ach-
ieved in the convergent construction of
the tetracyclic skeleton using a sulfox-
ide at C-2 or C-3 of the dienophiles 5
or 6, derived from 5-methoxy-1,4-naph-
thoquinone. The second domino pro-
cess, triggered by oxygen and sunlight,
allowed the transformation of the ini-
tial tetracyclic adducts into the final
products after B ring aromatization,
silyl deprotection and C-1 oxidation.
Keywords: antibiotics · asymmetric
synthesis · cycloaddition · natural
products
Introduction
myces griseorubiginosus.[6] They show the common structural
features of all angucyclinones and, in the case of rubiginones
A and C, an extra stereogenic oxygenated group at C-4
(Figure 1). They have shown potency of vincristine-induced
cytotoxicity against multi-drug-resistant tumor cells.[6] In ad-
dition, rubiginone A2, also named fujianmycin B[7] or SNA-
8073-B,[8] was claimed to be useful in the treatment of AIDS
and Alzheimerꢀs disease.[9] The absolute stereochemistry of
all rubiginones, shown in Figure 1, has been determined by
the O-methyl mandelate method.[10]
Angucyclines and their aglycones, the angucyclinones, are a
large group of naturally occurring quinones isolated from
the culture broths of different microorganims.[1] All mem-
bers of the family share a benz[a]anthracenequinone frame-
work of decaketide origin,[2] bearing an alkyl (methyl or
ethyl) group at C-3 and oxygen functionalities at C-1 and C-
8. Most of them show a broad range of biological properties
including anticancer, antibacterial and antiviral activity, or
enzyme and platelet aggregation inhibition. Their challeng-
ing structure and biological interest have stimulated many
synthetic studies on both racemic[3,4] and enantioselective[3,5]
forms. In spite of the important advances reached, efficient
syntheses of these products are still necessary due to the low
yields obtained from microorganisms. New chemical synthe-
ses also allow the access to modified analogues with im-
proved biological properties.
Rubiginones are a family of these natural products that
have been isolated from the fermentation broth of Strepto-
[a] Prof. Dr. M. C. CarreÇo, Dr. . Somoza, Dr. M. Ribagorda,
Dr. A. Urbano
Departamento de Química Orgµnica (C-I)
Universidad Autónoma. Cantoblanco, 28049 Madrid (Spain)
Fax : (+34)914-973-966
E-mail: carmen.carrenno@uam.es
antonio.urbano@uam.es
Figure 1. Structures of rubiginones A–C.
Chem. Eur. J. 2007, 13, 879 – 890
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879

The main problems emerging when planning the synthesis
of the angucyclinones are the regioselective construction of
the angularly fused tetracyclic skeleton and the stereoselec-
tive introduction of the different stereogenic centers. Both
have been addressed by several methods which are summar-
ized in different review articles.[3] Among them, the Diels–
Alder reaction between a juglone derivative (5-hydroxy-1,4-
naphthoquinone) and a vinyl cyclohexene, appears to be the
most widely used strategy for the synthesis of the angucycli-
none-type structures. In this case, the regioselective forma-
tion of the angular skeleton is highly reliant on the substitu-
ents present in the naphthoquinone dienophiles. The asym-
metric version of these cycloadditions also allowed the
access to enantiopure derivatives.[11]
Based on this Diels–Alder strategy, we also achieved the
enantioselective total synthesis of rubiginones A2 (1) and C2
(2),[18] bearing the additional C-4 oxygenated function
(Scheme 1), using an enantiopure vinyl cyclohexene deriva-
In 1999, we reported the asymmetric total synthesis of
(+)-rubiginone B2 and (+)-ochromycinone,[12] through the
[4+2] cycloaddition of enantiomerically pure sulfinyl naph-
thoquinones, as chiral dienophiles, and racemic chiral vinyl
cyclohexenes, as dienes. The strategy used was based on the
ability of the sulfoxide to control the p-facial diastereoselec-
tivity of endo cycloadditions of sulfinylquinones.[13] More-
over, the sulfinyl group triggered an efficient domino[14] pro-
cess where the Diels–Alder reaction was followed by the
elimination of the sulfoxide, that allowed to recover the qui-
none moiety in the resulting adduct. When the Diels–Alder
reaction was run with a chiral racemic diene,[15] the enantio-
pure (SS)-2-(p-tolylsulfinyl)-1,4-naphthoquinone promoted a
double asymmetric induction process leading to the efficient
kinetic resolution of the diene. As a result, using adequately
substituted dienes, a one-pot enantioselective formation of
the angucyclinone framework[16] occurred. The process was
shown to be applicable to a wide range of 1-vinylcyclohex-
ene derivatives.[17]
Scheme 1. Retrosynthesis of rubiginones A2 (1) and C2 (2) and their 11-
methoxy regiosomers 3a and 3b.
tive as the source of chirality. Since the absolute configura-
tion at C-1, C-3 and C-4 stereogenic centers[19] was already
in the diene moiety, the regioselective construction of the
characteristic angular four-ring framework was later ach-
ieved by Diels–Alder reaction with racemic 5-methoxy-2-(p-
tolylsulfinyl)-1,4-naphthoquinone (5) as dienophile. The re-
giocontrol of the cycloaddition was warranted by the sulfox-
ide 5, which also facilitated the formation of the quinonic
À
C6a C12a double bond by spontaneous elimination, once the
tetracyclic skeleton was generated.
With the aim of validating the role of the sulfoxide as a
regiochemical controller, we decided to investigate the ap-
plication of this strategy to the synthesis of the 11-methoxy
regioisomers of rubiginones A2 and C2, compounds 3a and
3b (Scheme 1). In this paper we report the synthesis of
these analogues, taking advantage of the regiocontrolled
Diels–Alder reaction occurring when 5-methoxy-3-(p-tolyl-
sulfinyl)-1,4-naphthoquinone (6) was used as the dienophile.
Our previous work, leading to the synthesis of natural rubi-
ginones A2 and C2, is also discussed in full detail, including
results not described in our earlier communication.
Abstract in Spanish: La síntesis enantioselectiva convergente
de los productos naturales de tipo anguciclinona, rubiginonas
A2 (1) y C2 (2), así como de sus regioisómeros C-11 metoxi
sustituidos, 3a y 3b, se ha descrito aplicando dos procesos
dominó a partir del 1-vinilciclohexeno enantiomØricamente
puro 4. Las etapas clave en la síntesis de este dieno han cor-
A
sobre el (SS)-[p-(tolilsulfinil)metil]-p-quinol (9) y a la elimi-
nación del fragmento de b-hidroxi sulfóxido, despuØs de oxi-
darlo a sulfona, para recuperar un grupo carbonilo. La pri-
mera secuencia dominó tuvo lugar mediante una reacción de
Diels–Alder con una sulfinil naftoquinona seguida de la eli-
minación del sulfóxido. La regioselectividad en la etapa de ci-
cloadición que conduce al esqueleto tetracíclico se ha contro-
lado de forma muy efectiva por el sulfóxido existente en las
posiciones 2 o 3 de los filodienos 5 y 6, derivados de la 5-
metoxi-1,4-naftoquinona. El segundo proceso dominó, pro-
movido por el oxígeno y la luz solar, permitió la transforma-
ción de los aductos tetracíclicos iniciales en los correspon-
dientes productos finales tras la aromatización del anillo B,
desprotección del grupo sililo y oxidación del carbono 1.
Synthetic plan: The retrosynthesis for compounds 3a and
3b, the C-11-methoxy regioisomer of rubiginones A2 and C2
(Scheme 1), anticipated the use of a Diels–Alder reaction
between 5-methoxy-3-(p-tolylsulfinyl)-1,4-naphthoquinone
[(Æ)-6] and chiral vinyl cyclohexene 4. The regioselective
construction of the tetracyclic skeleton will be reliant on the
ability of the sulfoxide to exert an efficient regiocontrol in
the cycloaddition step. The key diene 4, bringing the final
stereogenic centers, is a common intermediate which also al-
lowed the synthesis of natural rubiginones A2 (1) and C2 (2)
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Rubiginones and Isomers
FULL PAPER
using regioisomeric 5-methoxy-2-(p-tolylsulfinyl)-1,4-naph-
thoquinone [(Æ)-5], as the dienophilic partner.
The synthesis of diene 4 was inspired by two pivotal ob-
servations dealing with the reactivity of (SR)-[(p-tolylsulfi-
nyl)methyl]-p-quinols. First, the efficient and highly diaste-
reoselective conjugated addition of organoaluminum re-
agents to the prochiral dienone moiety of (SR)-[(p-tolylsulfi-
nyl)methyl]-p-quinols,[20,21] allowed to envisage this process
for the introduction of the C-3 methyl substituent of 4.[19]
Starting from (SR)-p-quinols, aluminum reagents gave rise
to conjugate addition products resulting in the exclusive for-
mation of a new b-alkyl substituted stereogenic center with
the (S) absolute configuration. We had also shown that the
b-hydroxy sulfoxide moiety present at C-4 in the resulting
(5S,SR)-5-alkyl-4-hydroxy-4-[(p-tolylsulfinyl)methyl]-2-cy-
clohexenones was masking a carbonyl group, which could be
liberated upon simple oxidation to sulfone and retroaddition
in basic medium.[22] All these features suggested the retro-
synthesis shown in Scheme 1 for the preparation of the vinyl
cyclohexene 4. The vinyl group could proceed from a Pd-
catalyzed coupling on bromocyclohexenone 7, whereas the
OR substituent at C-4[19] could be derived from a stereose-
lective reduction of the precursor 7, in turn available from
8, after elimination of the b-hydroxy sulfone in a retroaddi-
tion process. Taking into account the known stereochemical
pathway of AlR3 conjugate additions on our [(p-tolylsulfi-
nyl)methyl]-p-quinols,[20,22] the required final (3R) absolute
configuration of the methyl-bearing chiral center of 8,
would be available from [(p-tolylsulfinyl)methyl]-p-quinol 9
with the (S) absolute configuration at sulfur.
Scheme 2. Synthesis of b-hydroxy sulfone 15 from p-benzoquinone di-
methyl bisketal 10.
Table 1. Addition of Me3Al to dienone 9 under different experimental
conditions.
Entry
Solvent
T [8C]
(4R,5R,SS)-13
(4S,5S,SS)-13
14
1
2
3
toluene
toluene
heptane
À78
À100
À78
64
64
4
2
0
32
28
0
100 (65% yield)
uct (4R,5R,SS)-13 was observed, being only a 2% of the
(4S,5S,SS)-13 diastereomer formed, together with a 28% of
the double addition product 14 (entry 2). The best results
were achieved after a laborious investigation, which allowed
to establish that the temperature and the solvent of the
commercially available AlMe3 were the most critical factors
to the success of this reaction. Thus, performing the reaction
by adding a CH2Cl2 solution of the (SS)-p-quinol 9 at
À788C over a heptane solution of AlMe3 (4 equiv), the dia-
stereomer (4R,5R,SS)-13 was exclusively detected and was
isolated pure in 65% yield (entry 3).
The highly chemoselective and p-facial diastereoselective
formation of compound (4R,5R,SS)-13 could be explained
according with the model already proposed for the analogue
reaction on the (SR) enantiomer of p-quinol 9.[20b] Thus, the
first equivalent of AlMe3 must react with the quinol 9 to
form an aluminum alkoxide bearing the spirane-like struc-
ture shown in the intermediate I (Scheme 2). In such a
structure, the aluminum atom of the alkoxide must be asso-
ciated with the sulfinyl oxygen giving a species which adopts
a frozen chair-like conformation due to the presence of the
bulky p-tolyl group, situated in the equatorial position. In
this arrangement, the axial methyl group linked to the alu-
minum atom is hindering the pro-S double bond to the nu-
cleophile approach from the face containing the alkoxide
group, rendering only the pro-R conjugate position accessi-
ble. A second AlMe3 equivalent must be associated to the
carbonyl group thus increasing the electrophilicity of the
whole dienone system. The high reactivity observed for the
AlMe3 conjugate addition, can be due to the intramolecular
Results andDiscussion
The synthesis of enantiopure diene 4 began with 3,3,6,6-tet-
ramethoxy-1,4-cyclohexadiene (10),[23] which was subjected
to a controlled monohydrolysis with a mixture of acetone/
water 10:1 affording the dimethyl monoketal of p-benzoqui-
none (11)[24] in 88% yield (Scheme 2). (SS)-[(p-Tolylsulfi-
nyl)methyl]-p-quinol (9) was synthesized following the pro-
cedure reported for the (SR)-enantiomer,[25] by reaction of
4,4-dimethoxy-2,5-cyclohexadienone (11) with the lithium
anion derived from (SS)-methyl-p-tolylsulfoxide 12,[26] fol-
lowed by ketal hydrolysis with aqueous oxalic acid, in 76%
overall yield. The stereoselective conjugated addition of
AlMe3 on 9 was conducted successfully after an optimization
study (Scheme 2, Table 1). When a CH2Cl2 solution of (SS)-
9 was added over a commercially available toluene solution
of AlMe3 (4 equiv) at À788C,
a 64:4:32 mixture of
(4R,5R,SS)-13, ( S4,5S,SS)-13, and (3R,4S,5S,SS)-14 was
formed (entry 1). Diastereoisomers (4R,5R,SS)-13 and
(4S,5S,SS)-13 resulted, respectively, from attack of AlMe3 to
the pro-R and pro-S conjugate positions of 9, whereas deriv-
ative (3R,4S,5S,SS)-14 was obtained after a double conjugate
addition of AlMe3 on both dienone moieties of 9. Working
at lower temperatures (À1008C), a slight increase of the dia-
stereoselectivity in favor of the desired mono-addition prod-
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881

M. C. CarreÇo, A. Urbano et al.
transfer assisted by the alkoxide of a third equivalent, as
shown in Scheme 2 for intermediate I.[27] The use of an
excess of AlMe3 reagent warrants the quick completion of
the reaction with this reagent, which otherwise is a poor re-
active for 1,4-conjugate additions.[20]
En route to the vinyl cyclohexene 4, we next transformed
the sulfoxide group of (4R,5R,SS)-13 into the sulfone 15 by
oxidation with m-chloroperoxybenzoic acid (m-CPBA) in
96% yield (Scheme 2).
The stereoselective reduction of the carbonyl group of cy-
clohexenone 15, was accomplished with DIBALH, which af-
forded carbinol (4S)-16 in almost quantitative yield
(Scheme 3). The S absolute configuration of the new stereo-
of the a-position at C-6 of 17, rendering 18. This undesired
product was formed as a unique diastereoisomer in an
almost quantitative conversion (Scheme 3).[30]
In accordance with the stereochemistry of the final natu-
ral products, the stereochemical course of the reduction of
the carbonyl group of bromoenone 7 had to be controlled in
order to generate alcohol (1S)-19 with the correct absolute
configuration in a highly diastereoselective way. The most
stable conformer of 7 must situate both Me and OTBDMS
substituents in the pseudoequatorial disposition (Scheme 4).
Scheme 4. Stereoselective reduction of bromocyclohexenone 7 and syn-
thesis of enantiopure vinylcyclohexene 4.
A small hydride, favoring the axial approach to the carbonyl
group,[29] would be adequate. We therefore checked different
reagents such as LiAlH4, DIBALH and AlH3. In all cases,
the reduction of 7 was highly diastereoselective giving rise
to the expected carbinol (1S)-19, which resulted from the
axial attack of the hydride, together with some amount of
the corresponding epimer (1R)-19 (Table 2). The tempera-
Scheme 3. Synthesis of bromocyclohexenone 7 from b-hydroxy sulfone
15.
Table 2. Reduction of ketone 7 under different experimental conditions.
Entry
Hydride
T [8C]
Addition[a]
(1S)-19
(1R)-19
genic center as well the optical purity of 16 was confirmed
by further conversion into the corresponding Mosherꢀs
esters.[28] The high stereoselectivity observed in this reduc-
tion could be a consequence of the rigid half-chair confor-
mation of 15, shown in Scheme 3, where both, the (p-tolyl-
sulfonyl)methyl substituent and the C-5 methyl group, are
situated in the most favored equatorial dispositions. In such
a conformation, the axial attack of the small hydride
DIBALH is favored both from steric and stereoelectronic
points of view.[29]
Protection of the resulting carbinol 16 as the TBDMS
ether 8 (TBDMSOTf, 2,6-lutidine, 93%), was necessary
since all trials to eliminate the b-hydroxysulfone in 16 were
unsuccessful. The next step was the transformation of the b-
hydroxysulfone moiety of 8 into a carbonyl group by a ret-
roaddition process to eliminate methyl p-tolylsulfone. This
reaction was carried out by treatment of 8 with Cs2CO3 in
acetonitrile at room temperature. Under these conditions,
enantiopure cyclohexenone 17 was isolated in 89% yield.
Slow addition of a CCl4 solution of bromine at 08C over 17,
followed by subsequent treatment with Et3N, led to a-bro-
moenone 7 in 80% yield. This transformation must occur
through the intermediate formation of a non-isolated dibro-
mide suffering the elimination of HBr promoted by Et3N.
The amount of Br2 added to 17 should be stoichiometric
since an excess of Br2 produced the additional bromination
1
2
3
4
5
6
LiAlH4
LiAlH4
LiAlH4
AlH3
AlH3
DIBALH
À78
À100
À100
À78
À78
À78
direct
direct
inverse
direct
inverse
inverse
88
93
90
86
88
80
12
7
10
14
12
20
[a] Direct: addition of the hydride to a solution of 7 in THF. Inverse: ad-
dition of a solution of 7 in THF to the hydride.
ture and the order of addition of the reagents were shown
to influence slightly the stereoselectivity of the process. The
best result was achieved by addition of LiAlH4 to a THF so-
lution of ketone 7 at À1008C, which gave, in quantitative
yield, a 93:7 mixture of (1S)-19 and (1R)-19, which was used
without further purification in the next step. Neither AlH3
nor DIBALH were able to increase the diastereoselectivity
of this reduction. Other reagents which were checked in
order to explore the possibility of forming the epimer (1R)-
19 as a major component were fruitless. Bulky hydrides,
such as L-Selectride or LiBHEt3, as well as Luche reagent,
afforded different mixtures of 1,2- and 1,4-hydride addition
products being always (1S)-19 the major component of the
final mixtures. The (S) absolute configuration at C-1 of 19
as well as its enantiomeric excess (ee >97%) were deter-
mined after formation of the corresponding Mosherꢀs
esters.[28] Finally, protection of 19 as the isobutyrate ester 20
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Rubiginones and Isomers
FULL PAPER
(79% yield for the two last steps) and Stille coupling reac-
tion with tributylvinylstannane (78% yield) gave rise to vi-
nylcyclohexene 4 bearing the three stereogenic centers pres-
ent in the natural angucyclinones, with the appropriate abso-
lute configuration (Scheme 4).
spontaneous elimination of p-tolylsulfenic acid, which regen-
erated the quinonic double bond (Scheme 7).
With the enantiopure diene in hand, the completion of
the angucyclinones syntheses required the preparation of
the dienophiles (Æ)-5 and (Æ)-6. Racemic 5-methoxy-2-(p-
tolylsulfinyl)-1,4-naphthoquinone (5)[31] was prepared
(Scheme 5) from 2-bromo-1,4,5-trimethoxy naphthalene
Scheme 7. Diels–Alder reaction between diene 4 and (Æ)-5-methoxy-2-
(p-tolylsulfinyl)-1,4-naphthoquinone (5).
Scheme 5. Synthesis of (Æ)-5-methoxy-2-(p-tolylsulfinyl)-1,4-naphthoqui-
none (5): a) nBuLi, THF, À788C; then MeOSOpTol, À788C, 2 h, 65%;
b) CAN, MeCN, H2O, RT, 1 h, 79%.
Under similar conditions, (Æ)-5-methoxy-3-(p-tolylsulfin-
yl)-1,4-naphthoquinone (6) reacted with 4 leading to the ex-
clusive formation of tetracyclic quinone (+)-26 in 76% yield
(Scheme 8). Compound 26 also resulted from the spontane-
(21),[32] by lithium–bromine exchange followed by treatment
with methyl p-toluene sulfinate.[33] Oxidation of the diaro-
matic sulfoxide 22 with cerium ammonium nitrate (CAN)
occurred selectively at the more electron-rich dimethoxy
substituted aromatic ring, giving rise to 2-(p-tolylsulfinyl) ju-
glone methyl ether (5) in 79% yield (Scheme 5).
For the synthesis of racemic 3-(p-tolylsulfinyl)-substituted
methyl juglone (6), we started from commercially available
juglone which was known to react regioselectively with p-
tolylthiophenol affording 3-(p-tolylthio)-1,4,5-trihydroxy-
naphthalene.[34] The product initially formed suffered a
spontaneous air oxidation in the reaction medium, rendering
3-(p-tolylthio)juglone (23) in 67% yield. Quantitative for-
mation of the methyl ether with methyl iodide in the pres-
ence of silver oxide[35] followed by thio ether controlled oxi-
dation using m-CPBA at À788C, afforded 3-(p-tolylsulfinyl)-
1,4-naphthoquinone (6) in 70% isolated yield (Scheme 6).
Scheme 8. Diels–Alder reaction between diene 4 and (Æ)-5-methoxy-3-
(p-tolylsulfinyl)-1,4-naphthoquinone (6).
ous elimination of the sulfoxide in the initially formed cyclo-
adduct 27 (see Scheme 8), which was formed in a completely
region- and diastereoselective way. The regiochemistry of
the initial Diels–Alder adduct 27, resulting from juglone
methyl ether 6 bearing the sulfoxide at C-3, must be the op-
posite to that of adduct 25 formed from juglone derivative 5
with the sulfoxide at C-2.
Scheme 6. Synthesis of (Æ)-5-methoxy-3-(p-tolylsulfinyl)-1,4-naphthoqui-
none (6): a) pTolSH, EtOH, 08C, 4 d, 67 %; b) i) Ag2O, MeI, CH2Cl2, RT,
2 d, 99%; ii) m-CPBA, CH2Cl2, À788C, 4 h, 70%.
Regio- andstereochemistry : The regiochemistry of Diels–
Alder reactions with juglone derivatives and other substitut-
ed naphthoquinones is well known.[36] As shown in Figure 2,
the presence of the intramolecularly associated OH in ju-
glone increases the electron withdrawing character of the C-
4 carbonyl polarizing the C2=C3 quinonic double bond. In
Diels–Alder reactions with juglone methyl ether 28, the
main factor in the regiocontrol of cycloadditions with elec-
tron-rich dienes, is the electron donating effect of the 5-
OMe substituent (Figure 2), which makes the C-4 carbonyl
the less electron-withdrawing substituent on C2=C3 double
We then proceeded to the construction of the tetracyclic
skeleton of derivatives 1--3 through the Diels–Alder reac-
tion with enantiomerically pure vinyl cyclohexene 4. After
refluxing two equivalents of (Æ)-2-(p-tolylsulfinyl)-juglone
methyl ether (5) with diene 4 in CH2Cl2 for 24 h, the tetra-
cyclic quinone (+)-24 was obtained as a sole regioisomer
and pure diastereomer, in 52% yield. Compound 24 resulted
from a regioselective Diels–Alder reaction, followed by the
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883

M. C. CarreÇo, A. Urbano et al.
chemical course of Diels–Alder reactions with chiral vinyl-
cyclohexenes bearing an allylic oxygenated substituent at C-
3 was governed also by steric factors involving the size of
the allylic substituents. As shown in Figure 3 (A[38] and B[39]
)
Figure 2. Expected polarization of differently substituted juglone deriva-
tives.
bond. As a result, the value of the coefficient of the LUMO
of the C-1 carbonyl remote from the OMe group become
larger and the dienophilic double bond of 28 is polarized as
shown.[36e] The presence of a sulfoxide at C-2 in juglone
methyl ether derivative 5, reinforces the polarization effect
of the OCH3 group and cooperates in the regiochemical
control of Diels–Alder reactions.[12,17] Up to date, the effect
of the sulfoxide at C-3 in juglone derivative 6, was unknown.
The structure of tetracyclic compound 24, resulting from the
reaction between diene 4 and sulfinyl quinone 5, was a con-
sequence of the initial formation of the not isolated ortho-
adduct 25 (Scheme 7); its regiochemistry was as expected
taking into account the 1,2-disubstitution of the butadiene
derivative 4[5e,f] and the above considerations on dienophile
5. This is in sharp contrast to the moderate regioselectivitity
reported for cycloadditions of 2-p-tolylsulfinyl juglone aceta-
te.[36a]
Even more interesting was the opposite regiochemical
control of the cycloaddition between 3-(p-tolyl)sulfinyl ju-
glone methyl ether (6) and diene 4 which is exclusively dic-
tated by the sulfoxide. This result showed that the effect of
the sulfoxide in the regiochemical control is more powerful
than that of the C-5 OMe substituent in the unsubstituted
system 28, giving rise to the formation of the regioisomeric
Figure 3. Favored approaches of chiral semicyclic dienes in Diels–Alder
reactions with different dienophiles.
the models proposed by these authors to justify the major or
exclusive formation of the anti cycloadducts, corresponded
to the preferred endo approach of the dienophile from the
face of the diene anti to the oxygenated function.
With respect to the p-diastereofacial selectivity of Diels–
Alder reactions of enantiopure 2-(p-tolylsulfinyl)quinones
with simple dienes, our previous results had suggested that
the most favored endo approach of the diene normally oc-
curred from the face of the sulfinyl quinone containing the
less sterically demanding lone electron pair of the sulfoxide
on the reactive s-cis conformation.[13] When the diene part-
ner was a chiral C-3 oxygenated vinylcyclohexene (C in
Figure 3), the stereochemical course of the cycloaddition
with enantiopure (SS)-2-(p-tolylsulfinyl)-1,4-naphthoqui-
none was a consequence of the preference for the anti ap-
proach of the diene, to the less hindered upper face of the s-
cis conformation of the quinone.[15]
ortho-adduct 27 upon reaction with chiral diene
(Scheme 8).
4
On the basis of the above-mentioned model of approach
and the experimental data, we propose that diastereomers
24 and 26, resulting from reaction between enantiopure
diene 4 and racemic 5 or 6, must arise from transition state
endo-anti-TSI, shown in Figure 4. A double asymmetric in-
duction process, where the matched pair in the cycloaddition
corresponded to the (R) enantiomer of the sulfinyl-dieno-
phile 5 or 6 reacting with the enantiopure diene (3S,5R,4S)-
4 (TSI, Figure 4). This was supported by the need of double
molar amount of quinones 5 or 6 versus 4, to achieve com-
pletion of the reaction in 24 h (see Experimental Section).
The OTBDMS group at C-3 must be the responsible of the
facial diastereoselectivity observed, directing the diene ap-
proach anti to the bulkier allylic C-3 OTBDMS substituent
leading to the C-12b (R) absolute configuration. As can be
seen in TSI, the C-3 allylic group is proximal to the sulfox-
ide in this endo approach. Thus, more severe interactions
would appear between the bulky OTBDMS substituent and
the sulfoxide group if the syn-endo attack would take place.
The absolute configurations of the new stereogenic cen-
ters created at C-12b in the domino Diels–Alder reaction/
sulfoxide elimination process leading to 24 and 26 were es-
tablished on the base of the known configurations of the ste-
1
reogenic centers at the A ring as well as their H NMR data.
Double resonance experiments on 24 disclosed the existence
of a doublet at d 3.38 ppm showing a coupling constant of
J
1,12b =9.4 Hz, which was assigned to H12b situated in a trans-
diaxial disposition with respect to H-1.[37] We thus assigned
the (R) absolute configuration to C-12b. This is in accord-
ance with a process corresponding to the formation of the
ortho-adduct in an endo fashion, anti with respect to the
OTBDMS substituent of the vinyl cyclohexene.
The p-facial approach on both diene and dienophile was
dictating the stereochemistry at C-12b, which must result
from a double asymmetric induction process. Precedent
work by Frank[38] and Larsen[39] had shown that the stereo-
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Rubiginones and Isomers
FULL PAPER
Figure 4. Favored approach of enantiopure vinylcyclohexene 4 in Diels–
Alder reactions with sulfinyl naphthoquinones 5 or 6.
Scheme 9. Synthesis of rubiginones C2 (2) and A2 (1) from tetracyclic pre-
cursor 24.
Due to this closer disposition, the stereochemical course
with dienophiles 5 or 6 must be identical, independently of
the location of the OMe group on the naphthyl moiety.
An interesting aspect of the stereochemical model label-
led endo-anti-TSI that should be mentioned, is the proposed
chair-like conformation of the reacting vinylcyclohexene 4.
Two possible conformations could result from the anti ap-
proach represented as TSI and TSII in Figure 4. Both would
evolve into 25 or 27 initial adducts, but according to Houkꢀs
work,[40] allylic substituents on the diene moiety must be
staggered with respect to the forming bonds in the transition
state to avoid torsional strain. The torsional interaction exis-
ral rubiginone C2 (2)—that was isolated pure in 40% yield
(Scheme 10). Methanolysis of the isobutyric ester at C-4
with K2CO3/MeOH/THF afforded carbinol 3a {[a]2D0 =+61
(c=0.3 in CHCl3)}, which is a regioisomer of natural rubigi-
none A2 (1), in 90% yield.
À
tent in TSII between the partially formed C C bond and
the pseudoaxial C3-H allylic is highly destabilizing. The tran-
sition state TSI would eventually alleviate this torsional
strain leading to a more stable situation.
Next step in the transformation of 24 and 26 towards rubi-
ginones 1 and 2 and their regioisomers 3a and 3b was the
controlled aromatization of the B ring. All the experiments
carried out under the standard aromatization conditions
(DBU, DDQ or K2CO3), gave complex reaction mixtures
where the desired products were even not detected. In sev-
eral experiments, we observed that adducts 24 and 26 were
extremely sensitive to light and evolved, in the presence of
air, into different mixtures of products, where final rubigi-
nones could be detected. Finally, we could establish that
upon exposure of 24 to sunlight in the presence of air under
solvent-free conditions,[41] a slow evolution occurred to give
rubiginone C2 (2) which was isolated pure by column chro-
matography in 35% yield (Scheme 9). Synthetic 2 was iden-
tical in all physical and spectroscopic data to natural (À)-ru-
biginone C2 (2).[6] The other natural product, (+)-rubiginone
A2 (1), was obtained by methanolysis of (À)-2 with K2CO3/
MeOH/THF, affording, in 91% yield, compound 1 {[a]2D0 =
+78 (c=0.2 in CHCl3)}, identical in all aspects to natural
(+)-rubiginone A2.[42]
Scheme 10. Synthesis of regioisomeric angucyclinones 3a and 3b from
tetracyclic precursor 26.
This unprecedented photoinduced one-pot transformation
implied a domino sequence of three reactions on 24 and 26
in a very efficient way: aromatization of the B ring, depro-
tection of the silyl ether and oxidation of the C-1 position
into a carbonyl group. Although the relative order of these
reactions has not been unequivocally established, according
to previous observations of photoinduced oxidations of an-
gucyclinone systems,[10] we propose the mechanism depicted
in Scheme 11 for this domino process.
We assume that the aromatization of the B ring of 24 or
26 had to occur first to facilitate further transformations.
The photo-aromatization may take place through the inter-
mediate formation of an excited state oxygen centered bir-
adical I,[43] from the naphthoquinone moiety of 24 or 26, fol-
Regioisomeric derivative 26 showed a similar behavior,
and, upon sunlight irradiation in the presence of air under
solvent-free conditions evolved into tetracyclic quinone 3b
{[a]2D0 =À74 (c=0.2 in CHCl3)}—a regioisomer of the natu-
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885

M. C. CarreÇo, A. Urbano et al.
Conclusion
In summary, we have reported the total enantioselective
synthesis of the C-4 oxygenated angucyclinones rubiginones
A2 (1), C2 (2) and their C-11 methoxy regioisomers 3a and
3b, based on the asymmetric Diels–Alder reaction between
the enantiopure vinyl cyclohexene (+)-4 and the racemic
methoxy substituted sulfinylnaphthoquinones 5 and 6. The
successful route presented employed the chemo- and stereo-
selective addition of Me3Al to (SS)-[(p-tolylsulfinyl)methyl]-
p-quinol (9) and the elimination of the chiral sulfoxide as
methyl p-tolylsulfone in the intermediate b-hydroxy sulfone
8, as the key steps for the synthesis of enantiopure diene 4.
Compound 4 was thus obtained in nine steps and 26% over-
all yield from 9. The regioselective construction of the tetra-
cyclic skeleton of natural angucyclinones (+)-1, (À)-2 and
the
C-11
methoxy
regioisomers
(À)-3a
and
(À)-3b was achieved in a stereocontrolled Diels–Alder reac-
tion between 4 and the C-2 or C-3 sulfoxide-bearing juglone
derivatives 5 and 6, after a domino cycloaddition/sulfoxide
elimination process. The inversion of the regioselectivity ob-
served in the cycloadditions of 5 and 6, showed the efficien-
cy of the sulfoxide in the regiochemical control, being re-
markable in the case of 6, where the regiochemistry was the
opposite to that expected with 5-methoxy-1,4-naphthoqui-
none lacking the sulfoxide. Another noteworthy feature of
our synthesis was the practical domino light-induced se-
quence involving B ring aromatization, OTBDMS deprotec-
tion and oxidation at C-1 of derivatives 24 and 26 allowing
the total enantioselective synthesis to occur in 11 steps from
p-quinol 9 with >98% ee and 4.4, 4.8, 6.5 and 7.2% overall
yield, for rubiginones A2 (1), C2 (2) and their regioisomers
3a and 3b, respectively.
Scheme 11. Proposed mechanism for the sunlight-mediated transforma-
tion of 24 or 26 into angucyclinones 2 and 3b.
lowed by elimination of a hydrogen radical from the angular
C-12b benzylic carbon, leading to II. A second hydrogen
radical elimination from II could occur to give the angularly
fused anthraquinone system III. As proposed by Krohn[44] in
analoguous systems, an intramolecular hydrogen transfer
from the C-1 situated in the g-position with respect to the
C-12 carbonyl in III in a Norrish type II process would pro-
duce a new 1,4-biradical IV. This process must be easy due
Experimental Section
À
to the adequate geometric disposition of both the C H
General: Melting points were obtained in open capillary tubes and are
uncorrected. 1H and 13C NMR spectra were recorded in CDCl3 at 300
and 75 MHz, respectively. Diastereoisomeric ratios were established by
integration of well-separated signals of both diastereomers in the crude
reactions mixtures. All reactions were monitored by thin-layer chroma-
tography that was performed on precoated sheets of silica gel 60, and
flash column chromatography was done with silica gel 60 (230–400 mesh)
of Merck. Eluting solvents are indicated below. The apparatus for inert
atmosphere experiments was flame-dried under a stream of dry argon.
THF and CH2Cl2 were dried over 4 Š molecular sieves. Diisopropyl-
bond at C-1 and the carbonyl group at C-12.[45] The subse-
quent reaction of IV with singlet oxygen must take place
through the intermediate formation of a peroxy radical,[46]
to give the cyclic peroxide V. Although some cyclic peroxide
hemiketals are stable compounds[47] we did not detect com-
pound V, which evolved directly into the rubiginone C2 (2)
or the regioisomer 3b. The driving force of the rapid trans-
formation of V into VI, must be the formation of the highly
stable conjugate quinone system. Photochemical cleavage of
silanes and polysilanes has been reported to occur when
close oxygen functionalities can assist the reaction.[48] In our
case, the deprotection of the silyloxy hydroperoxy group in
VI, can take place easily with assistance of the hydroperoxy
moiety whose instability as a hydroperoxy silyl hemiketal
must favor a rapid reaction leading to the conjugate ketone
of the final products 2 and 3a.
A
used without purification. For routine workup, hydrolysis was carried out
with water, extractions with CH2Cl2, and solvent drying with MgSO4.
(SS)-4-Hydroxy-4-[(p-tolylsulfinyl)methyl]-cyclohexa-2,5-dienone
nBuLi 2.4m in hexanes (56 mL, 135.5 mmol) was added under argon at
À788C to solution of freshly distilled diisopropylamine (20.7 mL,
(9):
a
147.8 mmol) in THF (250 mL). After stirring for 30 min, a solution of
(SS)-methyl-p-tolylsulfoxide (12)[26] (19.0 g, 123.2 mmol) in THF
(200 mL) was added at À788C. After 30 min, a solution of 4,4-dime-
thoxy-2,5-cyclohexadienone (11)[24] (19.9 g, 129.4 mmol) in THF (430 mL)
was slowly added and the mixture was stirred for 2 h at À788C. The mix-
ture was hydrolyzed with an aqueous saturated solution of ammonium
chloride (40 mL) and the organic layer was extracted with EtOAc. After
workup, the crude product was dissolved in THF (80 mL) and a solution
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Rubiginones and Isomers
FULL PAPER
of oxalic acid (1.16 g, 12.9 mmol) in water (20 mL) was added. After stir-
ring for 2 h, hydrolysis with saturated solution of NaHCO3, extraction
with EtOAc and workup, the residue was recrystallized from EtOAc/
hexane giving compound 9 as a white solid (24.5 g, 76%). M.p. 142–
1448C; [a]2D0 =À177 (c=1 in CHCl3); 1H NMR: d=7.54, 7.36 (AA’BB’
system, 4H), 7.25 (dd, J=10.2, 3.2 Hz, 1H), 7.00 (dd, J=10.2, 3.2 Hz,
1H), 6.30 (dd, J=10.2, 1.8 Hz, 1H), 6.18 (dd, J=10.1, 1.9 Hz, 1H), 4.93
(s, 1H), 3.16, 2.85 (AB system, J=13.3 Hz, 2H), 2.43 (s, 3H); 13C NMR:
d = 184.9, 149.2, 149.1, 142.2, 139.6, 130.1 (2C), 128.1, 127.6, 123.9 (2C),
68.0, 67.1, 21.3; elemental analysis calcd (%) for C14H14O3S (262.3): C
64.10, H 5.38, S 12.22; found C 63.91, H 5.48, S 12.47.
without further purification. An analytical sample was obtained after
flash chromatography (EtOAc/hexane 1:3) and recrystallization in ethyl
ether/hexane, giving 8 as a white solid (200 mg). M.p. 107–1088C; [a]D20
=
+41 (c=1 in acetone); 1H NMR: d=7.78, 7.36 (AA’BB’ system, 4H),
6.04 (dd, J=10.1, 2.0 Hz, 1H), 5.76 (dt, J=10.1, 2.0 Hz, 1H), 4.23 (m,
1H), 3.44, 3.29 (AB system, J=14.2 Hz, 2H), 2.59 (s, 1H), 2.45 (s, 3H),
1.91 (m, 1H), 1.74–1.53 (m, 2H), 1.01 (d, J=6.9 Hz, 3H), 0.89 (s, 9H),
0.08, 0.07 (2s, 6H); 13C NMR: d= 144.8, 138.1, 135.9, 129.9 (2C), 129.8,
127.7 (2C), 70.3, 67.7, 63.2, 36.4, 35.7, 25.8 (3C), 21.6, 18.1, 15.0, À3.6,
À3.7; FAB MS: m/z: calcd for C21H34OSSi: 411.1947, found 411.2026
[M+H]+; FAB MS: m/z (%): 411 (7) [M+H]+, 393 (100), 371 (46).
A
G
(17): Cs2CO3 (3.9 g, 12 mmol) was added to a solution of 8 in CH3CN
(60 mL). After stirring for 17 h, the reaction mixture was hydrolyzed with
water and extracted with EtOAc. The organic layer was washed with
brine and dried over MgSO4. After workup and purification by flash
chromatography (EtOAc/hexane 1:12), compound 17 was obtained as a
colorless oil (1.25 g, 87%) for the final two steps. [a]2D0 =À76 (c=1 in ace-
tone); 1H NMR: d=6.77 (dt, J=10.1, 2.0 Hz, 1H), 5.91 (dd, J=10.1,
2.4 Hz, 1H), 4.59 (m, 1H), 2.38 (m, 1H), 2.20 (m, 1H), 1.77 (ddd, J=
13.9, 12.5, 10.3 Hz, 1H), 1.14 (d, J=6.5 Hz, 3H), 0.91 (s, 9H), 0.12 (s,
6H); 13C NMR: d= 201.0, 154.0, 128.2, 68.0, 41.9, 40.1, 25.7 (3C), 18.0,
15.0, À3.5, À3.7; EI MS: m/z: calcd for C9H15O2Si: 183.0841; found:
183.0846 [MÀC4H9]+; EI MS: m/z (%): 183 (100) [MÀC4H9]+, 139 (10),
113 (15).
1-one (13): A solution of 9 (500 mg, 1.9 mmol) in CH2Cl2 (10 mL) was
added under argon at À788C to a solution of Me3Al 2m in heptane
(3.8 mL, 7.6 mmol) in CH2Cl2 (10 mL). After 4 h at the same tempera-
ture, the excess of Me3Al was destroyed with methanol, and the mixture
was poured into an Erlenmeyer containing EtOAc and a saturated solu-
tion of sodium potassium tartrate and stirred vigorously for 30 min. The
organic layer was washed with brine and dried over MgSO4. After
workup and flash chromatography (EtOAc/hexane 1:1), compound 13
was obtained as a white solid (345 mg, 65%). M.p. 120–1218C (EtOAc/
hexane); [a]2D0 =À245 (c=1 in CHCl3); 1H NMR: d=7.56, 7.37 (AA’BB’
system, 4H), 7.25 (d, J=10.2 Hz, 1H), 6.10 (dd, J=10.2 Hz, 1H), 4.85 (s,
1H), 3.22, 2.92 (AB system, J=12.2 Hz, 2H), 2.62–2.22 (m, 3H), 2.44 (s,
3H), 1.10 (d, J=7.0 Hz, 3H); 13C NMR: d = 198.3, 149.7, 142.4, 139.7,
130.3 (2C), 129.0, 123.8 (2C), 71.6, 64.9, 41.7, 38.8, 21.3, 14.2; elemental
analysis calcd (%) for C15H18O3S (278.4): C 64.72, H 6.52, S 11.52; found
C 64.69, H 6.85, S 11.89.
A
1-one (7): A solution of bromine (15 mL, 0.30 mmol) in CCl4 (3 mL) was
added dropwise at 08C to a solution of 17 (72 mg, 0.30 mmol) in CCl4
(3 mL). When no starting material was observed, triethylamine (0.15 mL,
1.1 mmol) was added and the mixture was stirred at RT for 32 h. The re-
action mixture was quenched with aqueous saturated solution of Na2SO3
and extracted with CH2Cl2. After workup and flash chromatography
A
one (15): A solution of m-CPBA (6.2 g, 17.9 mmol) in CH2Cl2 (60 mL)
was added dropwise at 08C to a solution of 13 (3.8 g, 13.8 mmol) in
CH2Cl2 (45 mL). After stirring at 08C for 30 min, the mixture was hydro-
lyzed with an aqueous saturated solution of Na2SO3, extracted with
CH2Cl2, and the organic layer washed with an aqueous saturated solution
of NaHCO3. After workup and recrystallization (EtOAc/hexane), com-
pound 15 was obtained as a white solid (3.9 g, 96%). M.p. 145–1468C;
[a]2D0 =À65 (c=1 in acetone); 1H NMR: d=7.80, 7.39 (AA’BB’ system,
4H), 7.05 (dd, J=10.2, 0.9 Hz, 1H), 5.95 (d, J=10.2 Hz, 1H), 4.08 (brs,
1H), 3.50, 3.45 (AB system, J=14.2 Hz, 2H), 2.62–2.37 (m, 3H), 2.47 (s,
3H), 1.09 (d, J=6.6 Hz, 3H); 13C NMR: d = 198.3, 149.7, 142.4, 139.9,
130.2 (2C), 129.1, 123.8 (2C), 71.7, 64.9, 41.7, 38.9, 21.4, 14.3; elemental
analysis calcd (%) for C15H18O4S (294.4): C 61.20, H 6.16, S 10.89; found
C 61.12, H 6.19, S 11.24.
(EtOAc/hexane 1:120), compound
7 was obtained as a white solid
(77 mg, 80%). M.p. 40–418C; [a]2D0 =À38 (c=1 in acetone); 1H NMR:
d=7.22 (m, 1H), 4.59 (m, 1H), 2.46 (m, 1H), 2.25 (m, 1H), 1.87 (m,
1H), 1.21 (d, J=6.7 Hz, 3H), 0.91 (s, 9H), 0.13, 0.12 (2s, 6H); 13C NMR:
d=193.1, 154.3, 123.4, 69.0, 41.6, 40.0, 25.7 (3C), 18.0, 15.6, À3.4, À3.6;
elemental analysis calcd (%) for C13H23BrO2Si (319.3): C 48.90, H 7.26;
found C 48.88, H 7.56.
A
hexen-1-one (18): When the above mentioned reaction was performed
with an excess of bromine, compound 18 was obtained as a yellow oil.
[a]2D0 =À29 (c=1.9 in acetone); 1H NMR: d=7.16 (dd, J=2.3, 2.2 Hz,
1H), 4.64 (ddd, J=7.2, 5.0, 2.2 Hz, 1H), 2.56 (ddd, J=14.4, 5.0, 2.1 Hz,
1H), 2.07 (dd, J=14.4, 9.1 Hz, 1H), 1.88 (s, 3H), 0.85 (s, 9H), 0.09 (s,
3H), 0.08 (s, 3H); 13C NMR: d = 184.6, 153.9, 120.0, 68.4, 58.2, 48.9,
28.5, 25.7, 18.0, À3.4, À3.5; EI MS: m/z: calcd for C13H22Br2O2Si:
395.9756; found: 395.9754 [M]+.
A
(16): A solution of 15 (3.9 g, 13.3 mmol) in THF (45 mL) was added
dropwise under argon at À788C to a solution of DIBALH 1m in hexanes
(39.8 mL, 39.8 mmol) in THF (130 mL). After 30 min at the same tem-
perature, the excess of DIBALH was destroyed with methanol, and the
mixture was poured into an Erlenmeyer containing ethyl acetate and a
saturated solution of sodium potassium tartrate and stirred vigorously for
30 min. The organic layer was washed with brine and dried over MgSO4.
After workup, compound 16 was obtained as a white solid (3.7 g, 99%),
which could be used in the next step without further purification. M.p.
96–978C (EtOAc/hexane); [a]2D0 =À56 (c=1 in acetone); 1H NMR: d=
7.79, 7.36 (AA’BB’ system, 4H), 6.17 (dd, J=10.1, 2.0 Hz, 1H), 5.85 (dt,
J=10.1, 1.8 Hz, 1H), 4.5 (s, 1H), 4.23 (m, 1H), 3.46, 3.25 (AB system,
J=14.3 Hz, 2H), 2.46 (s, 3H), 1.85 (m, 2H), 1.68–1.51 (m, 2H), 1.01 (d,
J=6.7 Hz, 3H); 13C NMR: d= 144.9, 138.2, 134.6, 130.0, 129.9 (2C),
127.7 (2C), 70.3, 67.2, 63.3, 36.1 (2C), 21.6, 14.9; elemental analysis calcd
(%) for C15H20O4S (296.1): C 60.79, H 6.80, S 10.82; found C 60.46, H
7.14, S 10.56.
A
en-1-ol (19): A solution of LiAlH4 (31 mg, 0.76 mmol) in THF (25 mL)
was added under argon to a solution of 7 (163 mg, 0.51 mmol) in THF
(17 mL) at À1008C. After 30 min at the same temperature, the reaction
was hydrolyzed with methanol, and the mixture was poured into an Er-
lenmeyer flask containing ethyl acetate and a saturated solution of
sodium potassium tartrate and stirred vigorously for 30 min. The organic
layer was washed with brine and dried over MgSO4. After workup, com-
pound 19 was isolated, in quantitative yield, as a 93:7 diastereoisomeric
mixture, which was used without further purification in the next step. An
analytical sample of 19 could be isolated pure by HPTLC as a white
solid. M.p. 88–898C; [a]D20 =À67 (c=1 in CHCl3); 1H NMR: d=6.05 (d,
J=1.6 Hz, 1H), 4.29 (m, 1H), 3.82 (m, 1H), 2.24 (d, J=3.6 Hz, 1H), 1.90
(m, 1H), 1.78 (m, 1H), 1.45 (m, 1H), 1.15 (d, J=6.5 Hz, 3H), 0.89 (s,
9H), 0.08, 0.07 (2s, 6H); 13C NMR: d=136.4, 128.4, 75.8, 68.9, 39.9, 36.3,
25.8 (3C), 19.0, 18.1, À3.5, À3.6; elemental analysis calcd (%) for
C13H25BrO2Si (321.33): C 48.59, H 7.84; found C 48.33, H 7.54.
A
nyl)methyl]-2-cyclohexen-1-ol (8): 2,6-Lutidine (1.8 mL, 14.9 mmol) and
TBDMSOTf (1.8 mL, 25.3 mmol) were added at 08C under argon to a
solution of 16 (1.8 g, 6.0 mmol) in dry CH2Cl2 (20 mL). After 2 h, the
mixture was hydrolyzed with 10% HCl, extracted with CH2Cl2 and the
organic layer washed with brine. After workup, compound 8 was ob-
tained as a yellowish oil (2.2 g, 93%), which could be use in the next step
A
en-1-yl isobutyrate (20): Isobutyryl chloride (76 mL, 0.71 mmol) and 4-di-
methylaminopyridine (135 mg, 1.1 mmol) were added to a solution of the
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887

M. C. CarreÇo, A. Urbano et al.
above obtained mixture containing 19 dissolved in CH2Cl2 (1 mL). The
reaction mixture was stirred for 1 h, hydrolyzed with water and extracted
with CH2Cl2. After workup and flash chromatography (EtOAc/hexane
1:50), isobutyrate ester 20 was obtained as a colorless oil (158 mg, 79%
yield over two steps). 1H NMR: d=6.14 (dd, J=3.6, 1.6 Hz, 1H), 5.32
(m, 1H), 4.32 (m, 1H), 2.61 (sept, J=7.1 Hz, 1H), 1.92 (m, 2H), 1.52 (m,
1H), 1.21 (d, J=6.9 Hz, 3H), 1.20 (d, J=7.1 Hz, 3H), 0.99 (d, J=6.5 Hz,
3H), 0.88 (s, 9H), 0.07, 0.06 (2s, 6H); 13C NMR: d=176.4, 138.1, 122.9,
75.6, 68.5, 39.5, 34.9, 34.2, 25.7 (3C), 19.1, 19.0, 18.5, 18.0, À3.5, À3.6; EI
MS: m/z: calcd for C9H13BrO3Si: 333.0522; found: 333.0519 [MÀC4H9]+;
EI MS: m/z (%): 333 (35) [MÀC4H9]+, 311 (71), 289 (14), 259 (9), 241
(100), 223 (15).
1.2 Hz, 3H), 1.23 (d, J=1.2 Hz, 3H), 1.01 (d, J=5.9 Hz, 3H), 0.73 (s,
9H), À0.12, À0.37 (2s, 6H); 13C NMR: d=183.7, 183.6, 176.1, 159.3,
142.9, 141.6, 135.2, 135.1, 134.5, 119.5, 116.9, 113.2, 77.3, 76.4, 56.4, 43.0,
42.9, 37.5, 34.3, 25.6 (3C), 25.1, 19.2, 19.1, 18.5, 17.8, À3.2, À3.3; EI MS:
m/z: calcd for C30H40O6Si: 524.2594; found: 524.2573 [M]+; EI MS: m/z
(%): 526 (62) [M+2]+, 524 (54) [M]+, 509 (57), 499 (41), 483 (100), 483
(100), 481 (71).
(1S,3R,4S,12bS)-1-[(tert-Butyldimethylsilyl)oxy)-11-methoxy-3-methyl-
7,12-dioxo-1,2,3,4,6,7,12,12b-hexahydrobenz[a]anthracen-4-yl isobutyrate
(26): A solution of 5-methoxy-3-(p-tolylsulfiny)-1,4-naphthoquinone (6)
(89 mg, 0.29 mmol) and diene 4 (39 mg, 0.11 mmol) in dry CH2Cl2 (1 mL)
was refluxed for 24 h, under argon. After elimination of the solvent and
flash chromatography (EtOAc/hexane 1:9), compound 26 was obtained
as a yellowish solid (44 mg, 76%). M.p. 102–1038C; [a]2D0 =À149 (c=1 in
CHCl3); 1H NMR: d=7.71 (dd, J=7.7, 1.2 Hz, 1H), 7.61 (dd, J=8.3,
7.7 Hz, 1H), 7.23 (dd, J=8.3, 1.2 Hz, 1H), 5.61–5.57 (m, 1H), 4.90 (dd,
J=10.1, 1.6 Hz, 1H), 3.95–3.88 (m, 4H), 3.50–3.35 (m, 2H), 3.10–2.96 (m,
1H), 2.68 (sept, J=6.9 Hz, 1H), 2.0–1.93 (m, 1H), 1.76–1.57 (m, 2H),
1.26 (d, J=1.8 Hz, 3H), 1.23 (d, J=1.6 Hz, 3H), 1.01 (d, J=6.1 Hz, 3H),
0.71 (s, 9H), À0.14 (s, 3H), À0.33 (s, 3H); 13C NMR: d=184.4, 182.7,
176.1, 158.9, 145.7, 138.5, 135.5, 134.1, 133.9, 120.8, 118.6, 117.2, 112.7,
77.2, 76.5, 55.9, 43.0, 42.9, 37.5, 34.2, 31.7, 29.2, 25.6 (3C), 24.6, 19.2, 19.1,
18.5, 17.8, À3.1, À3.3; EI MS: m/z: calcd for C30H40O6Si: 524.2594; found
524.2572 [M]+.
A
en-1-yl isobutyrate (4): A mixture of compound 20 (583 mg, 1.5 mmol),
tetrakistriphenylphosphine palladium (0) (207 mg, 0.18 mmol) and tribu-
tylvinylstannane (0.58 mL, 0.18 mmol) in toluene (7.5 mL) was heated at
908C for 24 h. The reaction was hydrolyzed with water and extracted
with CH2Cl2. After workup and flash chromatography (EtOAc/hexane
1:60), compound
2 was obtained as a colorless oil (393 mg, 78%).
1H NMR: d=6.13 (dd, J=17.8, 10.9 Hz, 1H), 5.84 (m, 1H), 5.46 (m,
1H), 5.13 (d, J=17.8 Hz, 1H), 4.99 (d, J=10.9 Hz, 1H), 4.45 (m, 1H),
2.51 (sept, J=6.9 Hz, 1H), 1.90 (m, 2H), 1.45 (m, 1H), 1.14 (d, J=
6.9 Hz, 3H), 1.12 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H), 0.89 (s,
9H), 0.08, 0.07 (s, 3H); 13C NMR: d=177.0, 135.8, 135.7, 135.0, 114.2,
72.7, 66.9, 38.3, 34.2, 33.7, 25.8, 19.0, 18.9, 18.4, 18.1, À3.5, À3.6; FAB
MS: m/z: calcd for C15H27OSi: 251.1831; found: 251.1829 [MÀC4H7O2]+;
FAB MS : m/z (%): 265 (9) [MÀC3H5O2]+, 251 (100) [M-C4H7O2]+, 235
(52), 227 (10), 219 (37), 207 (22).
A
cen-4-yl isobutyrate (2), rubiginone C2: Compound 24 (42 mg,
0.08 mmol) was exposed, under solvent-free conditions, to the sunlight
for 16 h. After flash chromatography (EtOAc/hexane 1:3) and recrystalli-
zation (EtOAc), compound 2 (rubiginone C2) was obtained as a yellowish
solid (11.5 mg, 35%). M.p. 218–2198C; [a]2D0 =À57 (c=0.5 in CHCl3);
1H NMR: d=8.35 (d, J=8.3 Hz, 1H), 7.78 (dd, J=7.7, 1.4 Hz, 1H), 7.72
(t, J=7.9 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.31 (dd, J=8.1, 1.2 Hz, 1H),
5.84 (d, J=7.1 Hz, 1H), 4.04, (s, 3H), 3.17 (m, 1H), 2.75–2.56 (m, 3H),
1.24 (d, J=5.5 Hz, 3H), 1.22 (d, J=5.5 Hz, 3H), 1.12 (d, J=6.5 Hz, 3H);
13C NMR: d=196.6, 184.0, 181.2, 176.4, 159.9, 145.9, 137.5, 136.1, 135.5,
134.8, 134.6, 131.5, 130.1, 120.6, 119.7, 117.3, 73.3, 56.5, 43.8, 35.1, 34.1,
19.0, 18.9, 18.0; EI MS: m/z: calcd for C24H22O6: 406.1416; found:
406.1421 [M]+; EI MS: m/z (%): 406 (61) [M]+, 336 (68), 318 (100), 294
(90), 151 (25), 71 (92).
5-Hydroxy-3-(p-tolylthio)-1,4-naphthoquinone (23): A solution of p-tol-
ylthiophenol (766 mg, 6.17 mmol) in EtOH (40 mL) was added dropwise
to a solution of commercially available juglone (1.08 g, 6.17 mmol) in
EtOH (40 mL) at 08C. After 4 d, the precipitate was filtered and washed
with cold EtOH, giving pure 23 as a red solid (1.23 mg, 67%). M.p. 168–
1698C (lit.:[34] m.p. 1718C); 1H NMR: d=11.73 (s, 1H), 7.67–7.20 (m,
7H), 6.07 (s, 1H), 2.43 (s, 3H); 13C NMR: d=187.2, 181.2, 161.8, 156.7,
141.2, 137.0, 135.6 (2C), 132.2, 131.3, 131.2 (2C), 128.8, 123.7, 123.2,
119.3, 21.4.
5-Methoxy-3-(p-tolylsulfinyl)-1,4-naphthoquinone (6): Ag2O (1.06 g,
4.57 mmol) and MeI (0.57 mL, 9.13 mmol) were added to a solution of 23
(1.23 g, 4.15 mmol) in CH2Cl2 (50 mL) in absence of light. After 2 d, the
reaction mixture was filtered over Celite and the solvent removed under
reduce pressure, to give 5-methoxy-3-(p-tolylthio)-1,4-naphthoquinone as
a red solid (1.27 mg, 99%). M.p. 154–1558C; (lit.:[49] m.p. 154–1558C);
1H NMR: d=7.66–7.57 (m, 2H), 7.40–7.35 (m, 2H), 7.28–7.23 (m,
3H),6.00 (s, 1H), 3.99 (s, 3H), 2.39 (s, 3H); 13C NMR: d=181.9, 181.1,
160.1, 159.6, 140.7, 135.5 (2C), 135.4, 134.5, 131.0 (2C), 126.2, 124.3,
119.3, 119.2, 117.2, 56.4, 21.3.
A
1,7,12(2H)-trione (1), rubiginone A2: K2CO3 (10 mg, 72 mmol) was added
to a solution of 2 (4 mg, 9.8 mmol) in methanol (0.5 mL) and THF
(0.5 mL). After stirring for 90 min, the mixture was filtered through silica
gel, and the solvent evaporated to give 1 (rubiginone A2) as a yellowish
solid (3.0 mg, 91%). M.p. (decomp) >2158C (EtOAc); [a]2D0 =+78 (c=
0.2 in CHCl3); 1H NMR: d = 8.39, (d, J=8.3 Hz, 1H), 8.02 (dd, J=8.3,
1.0 Hz), 7.78 (dd, J=7.7, 1.4 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.31 (dd,
J=8.3, 1.4 Hz, 1H), 4.52 (m, 1H), 4.05 (s, 3H), 3.11 (dd, J=16.6, 5.7 Hz,
1H), 2.58 (dd, J=16.6, 10.7 Hz, 1H), 2.38 (m, 1H), 2.19 (d, J=6.9 Hz,
3H); 13C NMR: d=197.2, 184.3, 181.5, 159.9, 150.4, 137.5, 135.6, 135.5,
134.4, 134.0, 130.4, 130.2, 120.6, 119.7, 117.3, 73.5, 56.5, 44.8, 38.3, 18.2;
EI MS: m/z: calcd for C20H17O5: 337.1076: found 337.1069 [M+H]+; EI
MS: m/z (%): 337 (13) [M+H]+, 307 (10).
A solution of m-CPBA (595 mg, 2.65 mmol) in CH2Cl2 (40 mL) was
added dropwise at À788C to a solution of 5-methoxy-3-(p-tolylthio)-1,4-
naphthoquinone (791 mg, 2.55 mmol) in CH2Cl2 (40 mL). After 4 h, the
reaction mixture was quenched with aqueous saturated solution of
NaHCO3 and extracted with CH2Cl2. After workup and recrystallization
(EtOAc) compound 6 was obtained as a yellow solid (587 mg, 70%).[31]
1H NMR: d = 7.76–7.64 (m, 4H), 7.55 (s, 1H), 7.29–7.22 (m, 3H), 7.34
(s, 3H), 2.34 (s, 3H); 13C NMR: d = 183.0, 180.7, 160.2, 159.0, 142.5,
139.5, 135.9, 134.3, 131.9, 130.1 (2C), 126.0 (2C), 119.7, 118.2, 56.5, 21.5.
A
thracen-4-yl isobutyrate (3b): Compound 26 (11.6 mg, 0.0221 mmol) was
exposed, under solvent-free conditions, to the sunlight for 4 h. After flash
chromatography (EtOAc/hexane 1:2) and recrystallization (EtOAc),
compound 3 was obtained as a yellowish solid (3.6 mg, 40%). M.p. 165–
1668C; [a]2D0 =À74 (c=0.2 in CHCl3); 1H NMR: d=8.28 (d, J=7.7 Hz,
1H), 7.82 (dt, J=7.7, 0.8 Hz, 1H), 7.68 (td, J=8.3, 0.6 Hz, 1H), 7.54 (d,
J=8.1 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 5.86 (d, J=7.5 Hz, 1H), 4.02 (s,
3H), 3.21–3.12 (m, 1H), 2.72–2.60 (m, 3H), 1.24 (d, J=5.5 Hz, 3H), 1.22
(d, J=5.5 Hz, 3H), 1.12 (d, J=6.5 Hz, 3H); 13C NMR: d=196.6, 183.8,
182.4, 176.4, 159.1, 146.6, 138.8, 135.0, 134.8, 134.4, 133.7, 130.5, 129.4,
123.9, 119.3, 118.1, 73.4, 56.7, 43.6, 35.1, 34.1, 19.0, 18.9, 18.0; elemental
analysis calcd (%) for C24H22O6: C 70.92, H 5.46, found C 70.48, H 5.42.
(1S,3R,4S,12bR)-1-[(tert-Butyldimethylsilyl)oxy)]-8-methoxy-3-methyl-
7,12-dioxo-1,2,3,4,6,12b-hexahydrobenz[a]anthracen-4-yl isobutyrate (24):
A
solution of 5-methoxy-2-(p-tolylsulfinyl)-1,4-naphthoquinone (5)[31]
(37 mg, 0.12 mmol) and diene 4 (16 mg, 0.048 mmol) in dry CH2Cl2
(1 mL) was heated under reflux for 24 h, under argon. After elimination
of the solvent and flash chromatography (EtOAc/hexane 1:9), compound
24 was obtained as a yellowish solid (13 mg, 52%). M.p. 88–898C; [a]D20
=
1
À85 (c=0.25 in CHCl3); H NMR: d=7.71 (dd, J=7.7, 1.4 Hz, 1H), 7.64
(t, J=7.9 Hz, 1H), 7.25 (dd, J=8.3, 1.4 Hz, 1H), 5.62–5.58 (m, 1H),
4.91–4.84 (m, 1H), 4.01 (s, 3H), 3.81 (m, 1H), 3.49 (ddt, J=24.7, 4.0,
2.2 Hz, 1H), 3.38 (m, 1H), 3.05 (ddt, J=24.5, 4.6, 2.2 Hz, 1H), 2.68 (sept,
J=6.9 Hz, 1H), 1.97 (dd, J=8.9, 3.8 Hz, 1H), 1.69 (m, 2H), 1.26 (d, J=
AHCTREUNG
888
www.chemeurj.org
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 879 – 890

Rubiginones and Isomers
FULL PAPER
of 3 (4 mg, 9.8 mmol) in methanol (0.5 mL) and THF (0.5 mL). After stir-
ring for 90 min, the mixture was filtered through silica gel, and the sol-
vent evaporated to give 3b as a yellowish solid (3.0 mg, 91%). M.p.
(decomp) >2158C (EtOAc); [a]2D0 =À62 (c=0.2 in CHCl3); 1H NMR:
d = 8.29, (d, J=8.2 Hz, 1H), 7.94 (d, J=8.2 Hz), 7.82 (d, J=8.7 Hz,
1H), 7.66 (t, J=8.8 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 4.54–4.49 (m, 1H),
4.02 (s, 3H), 3.09 (dd, J=16.4, 5.1 Hz, 1H), 2.62–2.52 (m, 1H), 2.39–2.37
(m, 1H), 2.18 (d, J=6.9 Hz, 3H); 13C NMR: d=197.1, 184.1, 182.6, 159.0,
151.2, 138.5, 134.8, 134.3, 134.2, 133.2, 129.5, 129.4, 124.0, 119.2, 118.1,
73.6, 56.7, 44.6, 38.3, 18.2; FAB MS: calcd for C20H17O5: 337.1084: found
337.1075 [M+H]+; FAB MS: m/z (%): 337 (97), 154 (100), 136 (69).
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Acknowledgements
We thank Dirección General de Investigación Científica and TØcnica
(Grant CTQ2005-02095/BQU) for financial support. M.R. thanks the
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Received: June 9, 2006
Published online: November 6, 2006
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