Synthesis of quinone/hydroquinone sesquiterpenes

Article abstract of DOI:10.1016/j.tet.2010.08.038

ent-Halimic acid has been used in the synthesis of the quinone/hydroquinone sesquiterpenes (-)-aureol, (-)-smenoqualone, (-)-neomamanuthaquinone and in the formal synthesis of (-)-cyclosmenospongine.

Full text of DOI:10.1016/j.tet.2010.08.038

Tetrahedron 66 (2010) 8280e8290
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of quinone/hydroquinone sesquiterpenes
*
I.S. Marcos , A. Conde, R.F. Moro, P. Basabe, D. Díez, J.G. Urones
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caidos 1-5, 37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2010
Received in revised form 10 August 2010
Accepted 13 August 2010
Available online 19 August 2010
ent-Halimic acid has been used in the synthesis of the quinone/hydroquinone sesquiterpenes (ꢀ)-aureol,
(ꢀ)-smenoqualone, (ꢀ)-neomamanuthaquinone and in the formal synthesis of (ꢀ)-cyclosmenospongine.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
ent-Halimanes
Sesquiterpene quinones
Aureol
Smenoqualone
Cyclosmenospongine
Neomamanuthaquinone
1. Introduction
isolated from marine sponges, although there are some structures,
which have been reported in brown algae and fungi.4,5,6
Quinone/hydroquinone sesquiterpenes with drimane or rear-
ranged drimane skeleton are a very wide and diverse group of
secondary metabolites of mixed biogenesis with the terpenic unit
associated to a quinone or quinol.1 Those compounds are very in-
teresting not only for their biological activities, but also for the
diverse structures that they present.2,3 Most of them have been
Within this group, the quinone/hydroquinone sesquiterpenes
with aureane skeleton (rearranged drimane) (Fig. 1) are the least
common in nature, but they present remarkable biological properties
suchasantiviralandcitotoxic7 againstthecellularlinesofhumanlung
cancer A5498 and against Ehrlich cancer cells of mice, haemolytic,9
antiinflamatory,10,11 antiproliferative11 and antimicrobiane.
OMe
17
OH
20
NH2
17
O
18
19
18
21
11
HO
19
19
18
OMe
19
O
20
17
O
21
16
16
15
11
O
O
3
16
16
15
20
17
O
21
21
15
15
11
12
11
12
O
O
O
1
9
6
12
10
5
10
10
10
12
5
5
5
3
H
H
H
14
14
13
14
14
13
13
13
(-)-aureol
(-)-smenoqualone (-)-cyclosmenospongine (-)-neomamanuthaquinone
1
4
2
3
Figure 1.
In the last few years several synthesis and different methodol-
ogies for the preparation of substituted or polioxygenated sesqui-
* Corresponding author. Tel.: þ34 923 294474; fax: þ34 923294574;
e-mail address: ismarcos@usal.es (I.S. Marcos).
terpene quinones12 have been published.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.038

I.S. Marcos et al. / Tetrahedron 66 (2010) 8280e8290
OH
8281
In this paper we describe the synthesis of enantiomers of the
natural (þ)-neomamanuthaquinone 2,10,13 (þ)-aureol 1,14 (þ)-sme-
noqualone 315 and the formal synthesis of (þ)-cyclosmenospongine
4,9,13 four quinone/hydroquinone sesquiterpenes with a rearranged
drimane skeleton (aureane skeleton, Fig. 1). In the tetracyclic com-
pounds the quinone/quinol unit is attached to the sesquiterpene
moiety through a dihydropyran ring with an oxygenated bridge,
beingcyclosmenosponginetheonlyonewithatransdecalinjunction.
ent-Halimic acid 5,16 is a natural diterpene that has been used as
starting material in the synthesis of a wide range of natural occurring
compounds such as: ent-halimanolides,17 antitumoural sesterterpe-
nolides,18 chettaphanin I and II,19 compounds of mixed biogenesis as
agelasine C20 and alkaloid diterpenes: thyersindol C.21 Its character-
istic functionalization and natural abundance turns ent-halimic acid
into an excellent starting material for the synthesis of the enantio-
mers of these bioactive compounds, that are interesting targets
due to their particular structures and varied biological activities.
a
b
H
H
H
COOMe
COOH
R
R
9
CH2OH
ent-halimic acid, 5
8
c
d
10 CHO
11 Me
R
R
e
R
j
h
H
R
R
R
15 CH2OAc
16 CH2OH
12 CHO
f
17 CHO
k
i
13 CH2OH
14 CH2OAc
6
COOH
g
2. Results and discussion
Scheme 2. Reagents and conditions: (a) Ref. 19; (b) LiAlH4, Et2O, rt, 35 min, 97%;
(c) TPAP, NMO, DCM, rt, 1 h, 97%; (d) NH2NH2$H2O, KOH, diethylene glycol, 175 ꢁC, 17 h,
230 ꢁC, 3 h 30 min, 11, 90%; (e) (1) m-CPBA, DCM, rt, 90 min, 98%, (2) H5IO6, THF,
H2O, 2 h, rt, 94%; (f) LiAlH4, Et2O, rt, 50 min, 99%; (g) Ac2O, Py, rt, 19 h, 99%; (h)
HI, C6H6, 85 ꢁC, 35 min, 97%; (i) K2CO3, MeOH, rt, 2 h, 98%; (j) PDC, DMF, rt, 7 h, 17: 52%,
6: 35%; (k) PDC, DMF, rt, 7 h, 17: 58%, 6: 38%.
The syntheses of those quinone/hydroquinone sesquiterpenes
from ent-halimic acid 5, were planned according to the following
retrosynthesis, Scheme 1, which is developed by the approach
AB/ABD/ABCD.
OH
OH
15
13
20
According to the procedure developed in a previous work19
,
16
11
compound 8 was obtained from ent-halimic acid, Scheme 2. Re-
duction of C-18 to methyl group was achieved in a three steps
sequence 9 to 11 in an excellent global yield. The synthesis of the
substrate 14, suitablefor the isomerisationof thedecalindoublebond
was carried out in four steps that include chemoselective epox-
ydation of the side chain double bond in 11, followed by oxidative
cleavage to afford 12, and finally reduction and acetylation of the
hydroxy group at 13. Reaction of 14 with HI followed by hydrolysis of
the acetoxy group afforded the rearranged compound 16 in a very
good yield for the two steps. Several conditions were tested for the
oxidation of 16 to acid 6, PDC in DMF23 being the best one to afford
a mixture of aldehyde 17 and acid 6, which were easily separated.
Aldehyde 17 was further oxidised with PDC obtaining in this manner
acid 6 in a good global yield. When the time of this reaction was ex-
tended only the decomposition of the final compound was achieved.
COOH
1
OH
17
10
5
8
H
19
COOH
18
ent-halimic acid 5
6
7
R
OH
O
O
HO
O
D
D
O
OMe
C
C
O
O
B
A
A
B
H
H
R
5β OMe (-)-smenoqualone 3
(-)-aureol 1
5α NH2 (-)-cyclosmenospongine 4 (-)-neomamanuthaquinone 2
Scheme 1.
The synthesis of compounds with a quinoid or hydroquinoid
moiety can be achieved through an intermediate with the ring D
incorporated, for example, compound 7 or an analogue, Scheme 1.
This intermediate could be obtained from the tetranorderivative 6,
which would be previously synthesized from ent-halimic acid, 5.
The key step, in this sequence is a Barton decarboxylation reaction
in presence of benzoquinone.22
2.2. Synthesis of intermediate 7
Once intermediate
6 had been obtained, the Barton de-
carboxylation reaction in the presence of benzoquinone was tested
on this substrate. The synthesis of the required photo labile tio-
hydroxamic ester 18 (Scheme 3) was achieved by reaction of 6 with
2-mercaptopyridine N-oxide in the presence of DCC. The reaction
was carried out in absence of light due to the photo sensibility of
compound 18.
Light induced decarboxylation (500 W) of 18, in the presence of
benzoquinone, produced quinone 19.24 An explanation for 19 for-
mation can be seen in Scheme 4. Reduction of 19 with Ni-Raney, in
EtOH/H2O, afforded 20 while the same reaction in EtOH permitted
to obtain hydroquinone 7 whose oxidation with MnO2 provided 21,
more stable than its precursor hydroquinone (Scheme 3).
The radical mechanism proposed for this reaction is shown
in Scheme 4. Derivative 18, by irradiation (500 W) experiment
a decarboxylation to afford radicals A and B. Radical A reacts with
p-benzoquinone forming radical C, that is, coupled with B, to pro-
vide intermediate D. It turns into the corresponding tautomerized
form, hydroquinone 20. The p-benzoquinone excess present in the
media acts as a redox system for the transformation of the hydro-
quinone 20 into quinone 19.
With 7 in hand, (ꢀ)-neomamanuthaquinone 2, Scheme 1, can be
obtained by addition of NaOMe to the quinone ring. This tricyclic
sesquiterpene quinone/hydroquinone, 2, would give access to
(ꢀ)-smenoqualone 3 and (ꢀ)-cyclosmenospongine 4. On the other
hand the ring cyclization of intermediate
7 would provide
(ꢀ)-aureol 1.
To begin with, we will comment the elaboration of the key in-
termediates 6 and 7, afterwards the synthesis of the target quinone/
hydroquinone sesquiterpenes from those intermediates will be
described.
2.1. Synthesis of intermediate 6
The synthesis of 6 from ent-halimic acid, 5 (Scheme 2) requires
reduction at C-18, side chain degradation and double bond isom-
erization in the bicyclic system.

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I.S. Marcos et al. / Tetrahedron 66 (2010) 8280e8290
OAc
O
S
OH
S
O
COOH
N
N
O
O
O
O
a
b
d)
c)
OH
a)
H
+
H
23
1
6
18
19
b)
d
c
OH
+
OH
OH
O
O
OH
OH
OAc
S
7
N
OH
O
O
e
H
22
H
24
7
21
20
Scheme 5. (a) BF3$Et2O, DCM, ꢀ50 ꢁC/ꢀ5 ꢁC, 2 h, 60%; (b) p-TsOH, C6H6, rt, 15 h,
reflux 2 h, 1: 67%, 22: 25%; (c) Ac2O, Py, rt, 15 h, 23: 50%, 24: 49%; (d) LiAlH4, Et2O, rt,
35 min, 100%.
Scheme 3. a) 2-mercaptopyridine N-oxide, DCC, DCM, rt, 16 h, darkness; (b) p-ben-
zoquinone, DCM, h
500 W, 0 ꢁC, 2 h, 65% from 6; (c) Ni-Raney, EtOH/H2O, rt, 5 min,
99%; (d) Ni-Raney, EtOH, rt, 5 min, 99%; (e) MnO2, Et2O, rt, 30 min, 90%.
n
2.3. Synthesis of (L)-aureol
which were easily separated by chromatography. The spec-
troscopical properties of 23 were identical with those reported for
the natural aureol acetate.14 Reduction of 23 with LiAlH4 yielded
Once obtained hydroquinone 7 the desired compound, 1, was
synthesized as follows (Scheme 5).
22
again 1, (ꢀ)-aureol, [
a
]
ꢀ25.8 (c 0.2, CHCl3). Other examples of
D
Treatment of 7 with BF3$Et2O at low temperature exclusively
provided 1 with complete stereoseletivity.25 The spectroscopical
properties of 1 were identical with those reported by Faulkner and
co-workers for natural (þ)-aureol, establishing the configuration at
C-5 in compound 1. The structure of (þ)-aureol described by
sesquiterpene quinones that present discrepancy between the
optical rotation values in the natural product and in the synthetic
one, have been reported.12b
Faulkner and co-workers [
by X-ray of a derivative. The only difference between these struc-
tures is the value of the optical rotation, [
a
]
22 þ65 (c 2.0, CCl4)14 was corroborated
D
2.4. Synthesis of polyoxygenated quinones
22
a]
ꢀ24.3 (c 0.4, CHCl3)
D
With the key intermediate 19 synthesized, we next conduced the
synthesis of, (ꢀ)-neomamanuthaquinone 2, (ꢀ)-smenoqualone 3
and (ꢀ)-cyclosmenosongine 4, as is shown in Scheme 6. The differ-
ent substituents in the quinone ring were introduced by successive
additions of NaOMe according to the procedure of Theodorakis and
co-workers for the synthesis of ilimaquinone.24
for 1, that is, the enantiomer of (þ)-aureol.
When the cyclization of 7 was performed using p-TsOH,26 in-
stead of BF3$Et2O, it was obtained a mixture of unstable compounds
1 and 22, epimers at C-5 in a 67/25 ratio (Scheme 5). Acetylation of
the reaction mixture provided the acetylderivatives 23 and 24,
O
O
O
S
O
O
LX
N
CO2
O
CO2Me
A
CO2Me
C
N
18
S
B
O
O
OH
O
O
O
S
S
N
S
OH
OH
N
N
OH
O
+
19
20
D
Scheme 4.

I.S. Marcos et al. / Tetrahedron 66 (2010) 8280e8290
8283
OH
OH
OH
O
O
S
S
OMe
19
S
21
18
OMe
N
N
N
OH
a)
19
ox
OH
O
O
O
MeO
20
21
S
21
OMe
19
S
21
19
20
18
18
OMe
16
16
N
N
17
O
17
15
O
25 / 26
H
30
e)
O
b)
O
O
OH
OH
OMe
MeO
OMe
19
18
19
ox.
d)
OMe
O
c)
25
29
28
27
Scheme 6. a) MeONa, THF, ꢀ20 ꢁC, 10 min, 25/26 2.5:1, 70%; (b) NaOMe, MeOH, ꢀ20 ꢁC/2 ꢁC, 3 h 25: 46%, 27: 27%; (c) Ni-Raney, EtOH, rt, 5 min, 95%; (d) NaBH4, THF, H2O, rt,
30 min, 97%; (e) BF3$Et2O, DCM, ꢀ50 ꢁC/ꢀ5 ꢁC, 5 h 30 min, 50%.
The first addition of NaOMe to 19 keeping reaction temperature
at ꢀ20 ꢁC provided a mixture of hydroquinones that were quickly
oxidised in contact with air to the corresponding quinones 25/26 in
a 2.5:1 ratio (Scheme 6). This mixture was not separable by column
chromatography.
The structure of compounds 25 and 26 was determined by se-
lective transformation of one of them. The mixture of 25/26 was
treated with NaOMe/MeOH at ꢀ20 ꢁC and the reaction was fol-
lowed by TLC analysis. It was observed that the minor component
of the mixture (Rf lower) was transformed progressively, into 27,
while the major component 25 remained unaltered (Scheme 6).
The spectroscopical properties of 27, were coincident with the ones
ratio observed by Theodorakis and co-workers in the same reaction
made over a similar compound, in the synthesis of ilimaquinone.24
It might be due to the different conformation of the decalin
fragment.
We made an attempt to invert the ratio of the mixture 25/26 by
irradiation of compound 18, with a 500 W lamp in presence of
methoxy-p-benzoquinone, Scheme 7. The result was similar to that
obtained by addition of NaOMe to compound 19, a mixture of 25/26
in a 3/1 ratio, Scheme 7.
O
reported for the compound obtained by methylation of the natural
S
S
R1
R2
22
O
compound (þ)-neomamanuthaquinone
[
a
]
D
þ14.6 (c 0.1,
N
22
CHCl3).10,27 The optical rotation of 27, [
a
]
ꢀ11.1 (c 0.2, CHCl3),
N
D
O
O
shows that this compound is the enantiomer of (þ)-neo-
a)
mamanuthaquinone methyl ether.
To determine unequivocally the structure of the major
component of the mixture, 25, the following transformations
were carried out, (Scheme 6). Reduction of 25 with Ni-Raney
afforded 28 that was quickly oxidised in contact with air
yielding the corresponding quinone 29. New reduction of 29
with NaBH4, provided hydroquinone 28, which was treated with
BF3$Et2O to produce the cyclization compound 30, 19-methox-
yaureol. The structure of 30 was perfectly established by NMR
bidimensional experiments HMBC and HMQC, that corroborate
the presence of a methoxy group at C-19 in compound 28 and
its precursor, 25.
The HMBC experiment locates the methoxy group at C-19, due
to the correlation of the methylene C-15 with one of the aromatic
hydrogens, H-21, and the correlation of the other aromatic hydro-
gen at C-18 with the quaternary carbon C-16.
It is important to underline that to our surprise the ratio of the
mixture obtained in the addition of NaOMe to 19 is opposite to the
O
O
OMe
R1- R2
18
25 OMe H
26 OMe
H
Scheme 7. (a) Methoxy-p-benzoquinone, DCM, hn
500 W, 0 ꢁC, 2 h, 25: 49%, 26: 17%.
2.4.1. Synthesis of the enantiomers of the natural products (þ)-neo-
mamanuthaquinone, (þ)-smenoqualone, (þ)-cyclosmenospongine.
(ꢀ)-Neomamanuthaquinone methyl ether 27 is the adequate in-
termediate for the synthesis of (ꢀ)-neomamanuthaquinone 2,
according to the synthetic route shown in Scheme 8.
Selective desmethylation of 27 would provide (ꢀ)-neo-
mamanuthaquinone 2. From this compound the synthesis of
(ꢀ)-smenoqualone 3 and (ꢀ)-cyclosmenospongine 4, could be
easily achieved by a cyclization reaction (Scheme 8).

8284
I.S. Marcos et al. / Tetrahedron 66 (2010) 8280e8290
OMe
O
O
NH2
O
O
O
O
MeO
HO
O
O
H
(-)-smenoqualone
OMe
OMe
b)
O
O
3
a)
OMe
H
(-)-cyclosmenospongine
O
27
2
4
c)
O
O
H
(+)-5-epi-smenoqualone
31
Scheme 8. (a) HClO4 60%, THF, rt, 4 h, 70%; (b) p-TsOH, C6H6, reflux, 30 min, 3: 24%, 31: 20%; (c) Ref. 13.
There are in the literature, numerous precedents of reactions
The transformation of 5-epi-smenoqualone, into cyclo-
smenospongine 4 has been described using NH3 in EtOH13 there-
fore the synthesis described in this work constitute a formal
synthesis of the enantiomer of sesquiterpene quinone/hydroqui-
none cyclosmenospongine.
with HClO4 or BCl312b,28 to deprotect the methoxy groups presents
in different quinone systems. For that reason compound 27
was treated with HClO424,28b,29 to afford 2 [
a
]
D
22 ꢀ9.1 (c 0.1, CHCl3),
in a 70% yield, Scheme 8. The spectroscopical properties of 2 were
coincident with those reported for the natural (þ)-neo-
mamanuthaquinone. In the literature can be found different optical
3. Conclusions
22
rotation values for the natural compound [
a
]
þ3.3 (c 0.14,
D
22
CHCl3),10
[
a]
þ11 (c 0.09, CHCl3).13 Nevertheless the optical rota-
ent-Halimic acid is an adequate starting material for the syn-
thesis of quinone/hydroquinone sesquiterpenes (ꢀ)-aureol,
(ꢀ)-smenoqualone, (ꢀ)-neomammanuthaquinone and (ꢀ)-cyclo-
smenospongine. The Barton decarboxylation in presence of ben-
zoquinone is the key transformation in these syntheses. The
cyclization to get the tetracyclic compound was achieved with
p-TsOH and in a stereoselective manner with F3B$Et2O.
D
tion obtained for 2 is in the same order of magnitude that the de-
scribed values for (þ)-neomamanuthaquinone and has opposite
sign, therefore it can be concluded that 2 is the enantiomer of the
natural compound.
The selectivity observed in the deprotection may be explained
by considering the relative stability of the tetrasubstituted enol A,
formed as a result of the conjugated addition of H2O at C-21, versus
the less substituted one, B, arising from the conjugated addition of
H2O at C-18 centre, as can be observed in Figure 2.
4. Experimental
4.1. General
Reaction of 2, with p-TsOH in benzene30 yielded a mixture from
22
22
which only components 3 [
a]
ꢀ63.5 (c 0.1, CHCl3), and 31 [
a]
D
D
þ69.3 (c 0.1, CHCl3) could be separated in pure form and low yield
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available and were used without fur-
ther purification. IR spectra were recorded on a BOMEM 100 FT-IR
or an AVATAR 370 FT-IR Thermo Nicolet spectrophotometers. 1H
and 13C NMR spectra were performed in CDCl3 and referenced to
(Scheme 8).
The spectroscopical properties of 3 were coincident with those
22
described natural (þ)-smenoqualone [
a
]
D
þ70 (c 1.25ꢂ10ꢀ3
,
CHCl3),15 and the sign of the optical rotation was the opposite, for
that reason it can be said that 3 is the enantiomer of natural
smenosqualone.
the residual peak of CHCl3 at
13C, respectively, using Varian 200 VX and Bruker DRX 400 in-
struments. Chemical shifts are reported in parts per million and
d 7.26 ppm and d
77.0 ppm, for 1H and
On the other hand the spectroscopical properties of 31, were
d
identical tothose described for (ꢀ)-5-epi-smenoqualone [
a
]
22 ꢀ75.6
coupling constants (J) are given in hertz. MS were performed at
a VG-TS 250 spectrometer at 70 eV ionising voltage. Mass spectra
are presented as m/z (% rel int.). HRMS were recorded on a VG
D
(c 0.16, CHCl3),27 the sign of the optical rotation value indicates that
both compounds are enantiomers.
O
OH
O
O
O
O
HO
MeO
MeO
HO
MeO
21
21
21
18
O
18
18
OMe
OMe
OH
OMe
OMe
OH
HClO4
27
A
B
2
Figure 2.

I.S. Marcos et al. / Tetrahedron 66 (2010) 8280e8290
8285
Platform (Fisons) spectrometer using chemical ionisation (ammo-
nia as gas) or Fast Atom Bombardment (FAB) technique. For some of
the samples, QSTAR XL spectrometer was employed for electro-
spray ionization (ESI). Optical rotations were determined on a Per-
kineElmer 241 polarimeter in 1 dm cells. Diethyl ether and THF
were distilled from sodium, and dichloromethane was distilled
from calcium hydride under argon atmosphere.
1130, 1030, 954, 849; 1H NMR (200 MHz)
d
: 5.30 (1H, m, H-1), 4.97
(1H, t, J¼6.8 Hz, H-12), 2.43 (1H, m, H-5), 2.06e1.83 (4H, m), 1.67
(3H, s, Me-14), 1.60 (3H, s, Me-16), 1.39e1.09 (7H, m), 0.87 (6H, s,
Me-19 and Me-20), 0.83 (3H, s, Me-18), 0.80 (3H, d, J¼6.0 Hz, Me-
17); 13C NMR (50 MHz)
d ppm: 142.3 (C-10), 131.9 (C-13), 122.0
(C-12),119.5 (C-1), 43.9 (C-9), 43.5 (C-5), 38.8 (C-8), 37.8 (C-11), 33.7
(C-3), 31.6 (C-4), 29.5 (C-7), 28.3 (C-19), 26.3 (C-14), 26.1 (C-18),
23.8 (C-6), 23.3 (C-2), 23.2 (C-20), 18.3 (C-16), 15.9 (C-17); EIHRMS:
calcd for C19H32 (MþNaþ): 283.2402; found: 283.2398.
4.2. Reaction of 8 with LAH to yield 9
A solution of compound 8 (5.74 g, 18.9 mmol) in Et2O (120 ml)
was reduced with LAH (718 mg, 18.9 mmol) at 0 ꢁC for 1 h. Then
aqueous Et2O was added and after filtration, the solvent was
evaporated to give a residue, which was purified by silica gel col-
umn chromatography (Hex/EtOAc 9/1) to yield 9 (5.05 g, 97%).
4.5. Reaction of 11 with m-CPBA and H5IO6 to yield 12
To an ice-cooled solution of 11 (0.21 g, 0.79 mmol) in dry
CH2Cl2 (7.7 mL) m-CPBA (0.15 g, 0.80 mmol) was added. After 1 h,
the reaction mixture was diluted with water and extracted with
Et2O. The organic layer was washed successively with aqueous
10%, Na2SO3, aqueous 6% NaHCO3 and water and dried over
Na2SO4. The solvent was evaporated to give the mixture of epox-
ides derivatives (0.22 g, 98%). This mixture of epoxides (0.22 g,
0.78 mmol) in THF/H2O (3/1, 11.0 mL) was treated with H5IO6
(0.53 g, 2.34 mmol). The reaction mixture was stirred for 2 h at
room temperature. Then it was diluted with water and extracted
with Et2O. The organic layer was washed with aqueous 10%,
Na2SO3, water and dried over Na2SO4. The solvent was removed to
afford 12 (0.17 g, 94%).
4.2.1. 15-Nor-ent-halima-1(10),12-dien-18-ol, 9. Rf (Hex/EtOAc
22
9/1)¼0.29; [
a
]
þ42.3 (c 0.6, CHCl3); IR (film): 3346, 2921, 1453,
D
1378, 1044, 666; 1H NMR (200 MHz)
d: 5.30 (1H, m, H-1), 4.93 (1H,
m, H-12), 3.43 (1H, d, J¼12.0 Hz, H-18A), 3.24 (1H, d, J¼12.0 Hz, H-
18B), 2.50 (1H, m, H-5), 2.10e1.81 (4H, m), 1.67 (3H, s, Me-14), 1.59
(3H, s, Me-16), 1.39e1.20 (7H, m), 0.87 (3H, s, Me-19), 0.84 (3H, s,
Me-20), 0.79 (3H, d, J¼6.8 Hz, Me-17); 13C NMR (50 MHz)
d: 142.0
(C-10), 132.9 (C-13), 121.8 (C-12), 119.8 (C-1), 69.5 (C-18), 43.9 (C-9),
38.9 (C-5), 38.1 (C-8), 37.6 (C-11), 36.6 (C-4), 29.5 (C-3), 28.5 (C-7),
26.3 (C-14), 23.6 (C-2), 23.2 (C-20), 22.8 (C-6), 21.1 (C-19), 18.3 (C-
16), 15.8 (C-17); EIHRMS: calcd for C19H32ONa: 299.2351; found:
299.2345.
4.5.1. 13,14,15,16-Tetranor-ent-halim-1(10)-en-12-al, 12. Rf (Hex/
EtOAc 6/4)¼0.58; IR (film): 2925, 2705, 1719,1464, 1381, 1265, 1243,
1046, 740; 1H NMR (200 MHz)
d: 9.57 (1H, m, H-12), 5.47 (1H, m,
4.3. Oxidation of 9 with TPAP to yield 10
H-1), 2.95 (1H, d, J¼14.0 Hz, H-11A), 2.12e1.77 (6H, m), 1.65e1.10
(5H, m), 1.09 (3H, s, Me-20), 0.89 (3H, s, Me-19), 0.83 (3H, s, Me-18),
To a mixture of 9 (0.80 g, 2.88 mmol), N-methylmorpholine
N-oxide (NMO) (1.18 g, 8.73 mmol) and molecular sieves (700 mg) in
anhydrous CH2Cl2 (40 ml) under Ar atmosphere, at room tempera-
ture was added TPAP (44 mg, 0.13 mmol). The reaction mixture was
stirred for 15 min and then filtered on silica gel and CeliteÒ
(EtOAc/DCM). Evaporation of the solvent followed by chromatog-
raphy on silica gel (Hex/EtOAc 9/1) yielded aldehyde 10 (0.77 g, 97%).
0.80 (3H, d, J¼6.6 Hz, Me-17); 13C NMR (50 MHz)
d: 204.5 (C-12),
140.2 (C-10), 121.4 (C-1), 51.8 (C-11), 43.8 (C-5), 42.3 (C-9), 39.3
(C-8), 33.7 (C-3), 31.7 (C-4), 28.3 (C-7), 28.3 (C-19), 25.7 (C-18), 24.1
(C-20), 23.4 (C-6), 23.1 (C-2), 14.9 (C-17).
4.6. Reduction of 12 with LAH to yield 13
A solution of compound 12 (68 mg, 0.29 mmol) in Et2O (120 ml)
was reduced with LAH (13 mg, 0.32 mmol) at 0 ꢁC for 50 min. Then,
aqueous Et2O was added and after filtration, the solvent was
evaporated to yield 13 (68 mg, 99%).
4.3.1. 15-Nor-ent-halima-1(10),12-dien-18-al, 10. Rf (Hex/EtOAc
9/1)¼0.61; IR (film): 2925, 2697, 1726, 1458, 1378, 666; 1H NMR
(200 MHz)
d: 9.37 (1H, s, H-18), 5.32 (1H, m, H-1), 4.98
(1H, t, J¼6.2 Hz, H-12), 2.42 (1H, m, H-5), 2.11e1.96 (4H, m), 1.65
(3H, s, Me-14), 1.57 (3H, s, Me-16), 1.39e1.18 (7H, m), 0.93 (3H, s,
Me-19), 0.85 (3H, s, Me-20), 0.77 (3H, d, J¼7.0 Hz, Me-17); 13C NMR
4.6.1. 13,14,15,16-Tetranor-ent-halim-1(10)-en-12-ol, 13. Rf (Hex/
EtOAc 9/1)¼0.36; [
a]
22 þ47.8 (c 0.8, CHCl3); IR (film): 3334 (broad),
D
(50 MHz)
d
: 207.1 (C-18), 141.4 (C-10), 132.4 (C-13), 121.5 (C-12),
2925, 1464, 1380, 1364, 1050, 1021; 1H NMR (200 MHz)
d
: 5.36
120.2 (C-1), 48.0 (C-4), 43.9 (C-9), 38.4 (C-8), 37.7 (C-11), 36.5 (C-5),
28.9 (C-7), 27.9 (C-3), 26.3 (C-14), 23.2 (C-2), 23.0 (C-20), 22.4
(C-6), 18.3 (C-16), 17.4 (C-19), 15.8 (C-17); EIHRMS: calcd for
C19H32ONa: 297.2189; found: 297.2171.
(1H, m, H-1), 3.54 (2H,m, H-12), 2.30 (1H, m, H-5), 2.09e1.78 (4H,
m), 1.60e1.05 (7H, m), 0.96 (3H, s, Me-20), 0.88 (3H, s, Me-19), 0.82
(3H, s, Me-18), 0.78 (3H, d, J¼6.8 Hz, Me-17); 13C NMR (50 MHz)
d:
142.1 (C-10), 120.0 (C-1), 60.2 (C-12), 43.5 (C-5), 42.1 (C-9), 41.8
(C-11), 39.6 (C-8), 33.8 (C-3), 31.7 (C-4), 29.2 (C-7), 28.3 (C-19), 25.7
(C-18), 23.6 (C-6), 23.2 (C-2), 23.0 (C-20),15.4 (C-17); EIHRMS: calcd
for C16H28O (MþNaþ): 259.2032; found: 259.2043.
4.4. Reduction of 10 to yield 11
To a solution of 10 (0.70 g, 2.57 mmol) in diethylene glycol
(23 mL), Hydrazine monohydrate 85% (3.6 mL, 16.7 mmol) and KOH
(0.89 g, 15.9 mmol) was added and the mixture was heated at
175 ꢁC for 17 h, then the condenser was removed. After 15 min, the
mixture was warmed to 230 ꢁC for 4 h 30 min. Finally, the reaction
mixture was allowed to cool to room temperature, quenched with
H2O, 6 M aqueous HCl solution, and extracted with Et2O. The or-
ganic layer washed with water and dried over NaSO4.The solvent
was evaporated and the residue, was purified by column chroma-
tography (Hex/EtOAc 95/5) to afford 11 (576 mg, 90%).
4.7. Acetylation of 13 to yield 14
To a solution of 13 (68 mg, 0.29 mmol) in dry pyridine (1.0 mL),
Ac2O (0.5 mL) was added and the mixture was stirred at room
temperature overnight. The reaction mixture was then poured into
ice water and extracted with EtOAc. The organic layer was washed
successively with 2 M aqueous HCl, 6% aqueous NaHCO3 and brine,
then dried over Na2SO4 and the solvent was evaporated to afford 14
(79 mg, 99%).
4.4.1. 15-Nor-ent-halima-1(10),12-diene, 11. Rf (Hex/EtOAc 98/2)¼
4.7.1. 13,14,15,16-Tetranor-ent-halim-1(10)-en-12-ol acetate, 14. Rf
22
22
0.91; [
a
]
þ15.0 (c 2.4, CHCl3); IR (film): 2924, 1457, 1378, 1327,
(Hex/EtOAc 9/1)¼0.63; [
a
]
þ38.1 (c 0.9, CHCl3); IR (film): 2926,
D
D

8286
I.S. Marcos et al. / Tetrahedron 66 (2010) 8280e8290
1743, 1457, 1364, 1240, 1031; 1H NMR (200 MHz)
d
: 5.34 (1H,
4.10.1. 13,14,15,16-Tetranor-ent-halim-5(10)-en-12-al, 17. Rf (Hex/
22
t, J¼3.2 Hz, H-1), 4.01 (1H, dt, J¼10.4, 6.0 Hz, H-12A), 3.86
(1H, dt, J¼10.4, 6.0 Hz, H-12B), 2.25 (1H, m, H-5), 2.02 (3H, s,
MeCOOe), 2.01e1.71 (4H, m), 1.58e1.08 (7H, m), 0.95 (3H, s, Me-
20), 0.88 (3H, s, Me-19), 0.82 (3H, s, Me-18), 0.79 (3H, d, J¼7.4 Hz,
EtOAc 9/1)¼0.73; [
a
]
þ51.7 (c 0.9, CHCl3); 1H NMR (200 MHz)
d:
D
9.57 (1H, dd, J¼4.0, 1.4 Hz, H-12) 2.48 (1H, dd, J¼16.0,1.4 Hz, H-11A),
2.32 (1H, dd, J¼16.0, 1.4 Hz, H-11B), 2.01e1.83 (4H, m), 1.62e1.05
(7H, m), 1.05 (3H, s, Me-20), 0.99 (3H, s, Me-19), 0.91 (3H, s, Me-18),
0.89 (3H, d, J¼7.0 Hz, Me-17).
Me-17); 13C NMR (50 MHz)
d: 171.4 (MeCOOe), 141.0 (C-10), 120.5
(C-1), 62.4 (C-12), 43.5 (C-5), 42.1 (C-9), 39.3 (C-8), 37.2 (C-11), 33.7
(C-3), 31.6 (C-4), 29.2 (C-7), 28.4 (C-19), 25.9 (C-18), 23.6 (C-6), 23.3
(C-2), 23.0 (C-20), 21.4 (MeCOOe), 15.4 (C-17); EIHRMS: calcd for
C18H30O2 (MþNaþ): 301.2138; found: 301.2143.
4.10.2. 13,14,15,16-Tetranor-ent-halim-5(10)-en-12-oic acid, 6. Rf
22
(Hex/EtOAc 9/1)¼0.40; [
a]
þ42.5 (c 1.0, CHCl3); IR (film): 3100
D
(broad), 2927, 1705, 1459, 1407, 1381, 1311, 1231, 944; 1H NMR
(200 MHz)
d
: 2.53 (1H, d, J¼14.2 Hz, H-11A), 2.39 (1H, d, J¼14.2 Hz,
4.8. Isomerization of 14 to yield 15
H-11B), 2.01e1.82 (4H, m), 1.62e1.09 (9H, m), 0.97 (3H, s, Me-20),
0.94 (3H, s, Me-19), 0.93 (3H, s, Me-18), 0.84 (3H, d, J¼7.0 Hz, Me-
To a solution of 14 (70 mg, 0.25 mmol) in dry benzene (3.1 mL),
17); 13C NMR (50 MHz)
d: 178.1 (C-12), 137.0 (C-5), 131.5 (C-10), 42.2
was added a solution of 57% HI (20
m
L). The reaction mixture was
(C-3), 41.1 (C-9), 39.9 (C-11), 35.0 (C-8), 34.6 (C-4), 28.9 (C-18), 28.2
(C-19), 27.1 (C-7), 26.4 (C-1), 24.1 (C-6), 21.3 (C-20), 20.2 (C-2), 16.4
(C-17); EIHRMS: calcd for C16H26O2 (MþNaþ): 273.1825; found:
273.1833.
stirred at 85 ꢁC for 35 min. Then, it was allowed to cool to room
temperature and was diluted with Et2O and H2O. The mixture was
extracted with Et2O and the organic layer was successively washed
with 10% NaHSO3, 6% NaHCO3, water and dried over Na2SO4. The
solvent was removed under vacuum to afford 15 (68 mg, 97%).
4.11. Reaction of 17 with PDC to yield 6
4.8.1. 13,14,15,16-Tetranor-ent-halim-5(10)-en-12-ol acetate, 15. Rf
To a solution of 17 (0.21 g, 0.76 mmol), in DMF (4.7 mL), PDC
(1.89 g, 5.03 mmol) was added. The reaction mixture was stirred at
room temperature for 15 h. Then it was cooled at e 0 ꢁC and diluted
with water. The resulting mixture was extracted with EtOAc and
the organic layer was washed with H2O and with 10% aq NaOH. The
organic layer was washed with H2O, dried over Na2SO4 and the
solvent was removed under vacuum to yield 17 (103 mg, 58%)
Aqueous layer was treated with aq HCl until pH¼1 and then
extracted with EtOAc, washed with H2O and dried over Na2SO4. The
solvent was evaporated to yield 6 (79 mg, 38%).
22
(Hex/EtOAc 9/1)¼0.63; [
a
]
D
þ69.2 (c 0.8, CHCl3); IR (film): 2926,
1743, 1458, 1364, 1234, 1032; 1H NMR (200 MHz)
d: 4.03 (1H, dt,
J¼11.0, 7.6 Hz, H-12A), 3.83 (1H, dt, J¼10.4, 7.6 Hz, H-12B), 2.02 (3H,
s, MeCOOe), 2.01e1.63 (6H, m), 1.60e1.09 (7H, m), 0.96 (3H, s, Me-
20), 0.94 (3H, s, Me-19), 0.86 (3H, d, J¼6.6 Hz, Me-17). 0.83 (3H, s,
Me-18); 13C NMR (50 MHz)
d: 171.5 (MeCOOe), 137.6 (C-5), 131.9 (C-
10), 62.3 (C-12), 40.1 (C-9), 40.0 (C-3), 34.6 (C-4), 35.5 (C-11), 34.6
(C-8), 29.2 (C-18), 27.9 (C-19), 27.3 (C-7), 26.1 (C-1), 25.3 (C-6), 21.3
(C-20), 21.3 (MeCOOe), 20.1 (C-2), 16.4 (C-17); EIHRMS: calcd for
C18H30O2 (MþNaþ): 301.2138; found: 301.2136.
4.12. Reaction of 6 with 2-mercaptopyridine N-oxide
4.9. Hydrolysis of 15 to yield 16
to yield 18
To a solution of 15 (66 mg, 0.24 mmol) in MeOH (1.9 mL), was
added K2CO3 (30 mg, 0.28 mmol). The reaction mixture was stirred at
room temperature for 2 h. Then, it was diluted with H2O and Et2O.
After 15 min stirring the mixture was extracted with Et2O, and the
organic layer was washed with HCl and H2O and dried over Na2SO4.
The solventwasevaporatedtoafford a residue, whichwaspurifiedby
silica gel chromatography (Hex/EtOAc 9/1) to yield 16 (56 mg, 98%).
To a solution of acid 6 (115 mg, 0.46 mmol) and 2-mercapto-
pyridine N-oxide (60 mg, 0.46 mmol) in DCM (2.7 mL), was added
DCC 1 M in DCM (0.46 mL, 0.46 mmol) under Ar atmosphere. The
reaction mixture was stirred at room temperature in the dark for
17 h. Then, the mixture was diluted with DCM, subjected to filtra-
tion over cotton to remove the DCU and the filtrate was partitioned
with aq satd NaHCO3, and extracted with DCM. The organic layer
was collected, dried over Na2SO4 and concentrated under vacuum
to afford ester 18 (86 mg, 61%).
4.9.1. 13,14,15,16-Tetranor-ent-halim-5(10)-en-12-ol, 16. Rf (Hex/
EtOAc 9/1)¼0.37; [
a
]
D
22 þ96.0 (c 1.1, CHCl3); IR (film): 3323 (broad),
2926, 1460, 1380, 1359, 1057, 1026; 1H NMR (200 MHz)
d
: 3.53 (2H,
4.12.1. Compound 18. Rf (Hex/EtOAc 8/2)¼0.28; IR (film): 2928,
m H-12), 1.99e1.80 (4H, m), 1.71e1.12 (9H, m), 0.96 (3H, s, Me-20),
0.93 (3H, s, Me-19), 0.86 (3H, d, J¼7.0 Hz, Me-17). 0.82 (3H, s, Me-
1810, 1725, 1609, 1527, 1448, 1134, 1042; 1H NMR (200 MHz)
d: 7.69
(1H, dd, J¼8.0, 1.8 Hz, H-30), 7.47 (1H, dd, J¼8.0, 1.8 Hz, H-60), 7.19
(1H, dt, J¼8.0,1.8 Hz, H-40), 6.61 (1H, dt, J¼8.0,1.8, H-50), 2.94 (1H, d,
J¼16.2 Hz, H-11A), 2.80 (1H, d, J¼16.2 Hz, H-11B), 2.05e1.90 (4H, m),
1.88e1.51 (2H, m), 1.40e1.05 (5H, m), 1.01 (3H, s, Me-20), 0.98
(3H, s, Me-18), 0.96 (3H, d, J¼6.6 Hz, Me-17), 0.94 (3H, s, Me-19).
18); 13C NMR (50 MHz)
d: 137.3 (C-5), 132.7 (C-10), 60.3 (C-12), 40.1
(C-9), 40.1 (C-3), 39.0 (C-11), 34.8 (C-8), 34.7 (C-4), 29.3 (C-18), 27.9
(C-19), 27.4 (C-7), 26.3 (C-1), 25.4 (C-6), 21.4 (C-20), 20.2 (C-2), 16.5
(C-17); EIHRMS: calcd for C16H28O (MþNaþ): 259.2069; found:
259.2065.
4.13. Reaction of 18 with p-benzoquinona to yield 19
4.10. Reaction of 16 with PDC to yield 17 and 6
A solution of ester 18 (86 mg, 0.29 mmol) and p-benzoquinone
(109 mg, 0.87 mmol) in DCM (3.5 mL), was cooled at 0 ꢁC and ir-
radiated with an halogen lamp (500 W) for 2 h. Then, the reaction
mixture was concentrated and subjected to silica gel chromatog-
raphy to afford quinone 19 (85 mg, 70%).
To a solution of 16 (98 mg, 0.42 mmol), in DMF (2.6 mL), PDC
(1.04 g, 2.77 mmol) was added. The reaction mixture was stirred at
room temperature for 7 h. Then it was cooled at e 0 ꢁC and diluted
with water. The resulting mixture was extracted with EtOAc and
the organic layer was washed with H2O and with 10% aq NaOH. The
organic layer was washed with H2O, dried over Na2SO4 and the
solvent was removed under vacuum to yield 17 (51 mg, 52%).
Aqueous layer was treated with aq HCl until pH¼1 and then
extracted with EtOAc, washed with H2O and dried over Na2SO4. The
solvent was evaporated to yield 6 (40 mg, 35%).
4.13.1. Compound 19. Rf (Hex/EtOAc 8/2)¼0.38; [
a
]
22 ꢀ115.7 (c 0.6,
D
CHCl3); IR (film): 3300 (broad), 2929, 2117, 1655, 1577, 1560,
1452, 1418, 1274, 1121; 1H NMR (400 MHz)
d: 8.28 (1H, ddd,
J6,5¼4.8, J6,4¼2.0, J6,3¼1.0 Hz, H-60), 7.54 (1H, dt, J4,5 and
J4,3¼8.0, J4,6¼2.0 Hz, H-40), 7.31 (1H, dt, J3,4¼8.0, J3,5 and J3,6¼1.0 Hz,

I.S. Marcos et al. / Tetrahedron 66 (2010) 8280e8290
8287
H-30), 7.02 (1H, ddd, J5,4¼8.0, J5,6¼4.8, J5,3¼1.0 Hz, H-50), 6.82 (2H,
4.17. Reaction of 7 with BF3$Et2O to yield 1
s, H-19, H-20), 3.15 (1H, d, J¼12.1 Hz, H-15A), 2.85 (1H, d, J¼12.1 Hz,
H-15B), 2.20e1.85 (4H, m), 1.71e1.32 (7H, m), 1.04 (3H, s, Me-
14), 0.95 (3H, s, Me-13), 0.87 (3H, s, Me-11), 0.79 (3H, d, J¼6.9 Hz,
To a stirred solution of 7 (11 mg, 0.03 mmol) in DCM (3.0 mL)
at ꢀ50 ꢁC was added BF3$Et2O (0.015 mL, 0.13 mmol). The
resulting mixture was gradually warmed to ꢀ5 ꢁC over 2 h
30 min the reaction was quenched with saturated aqueous NH4Cl
at ꢀ5 ꢁC and the mixture was extracted with DCM. The combined
extracts were washed with saturated NaCl then dried over
Na2SO4. The solvent was removed under vacuum and the residue
was purified by column chromatography (Hex/EtOAc 95/5) to
yield 1 (6 mg, 60%).
Me-12); 13C NMR (100 MHz)
d: 185.3 (C-17), 182.0 (C-20), 157.5
(C-20), 152.3 (C-21), 149.7 (C-60), 142.9 (C-16), 137.3 (C-19), 136.8 (C-
40), 136.6 (C-18), 136.1 (C-5), 130.3 (C-10), 122.9 (C-30), 120.6
(C-50), 44.3 (C-9), 39.8 (C-15), 39.7 (C-3), 35.9 (C-8), 33.9 (C-4), 29.0
(C-14), 27.8 (C-13), 27.4 (C-1), 25.9 (C-7), 22.8 (C-11), 20.7 (C-6),
19.7 (C-2), 15.6 (C-12); EIHRMS: calcd for C26H31O2NS(MþNaþ):
444.1979; found: 444.1968.
22
4.17.1. Compound 1. Rf (Hex/EtOAc 8/2)¼0.38; [
a]
ꢀ24.3 (c 0.4,
D
4.14. Reaction of 19 with Ni-Raney to yield 20
CHCl3); IR (film): 3389, 2932,1495,1456,1384,1263,1232,1186, 981,
954, 808; 1H NMR (400 MHz)
d
: 6.60 (1H, d, J¼8.6 Hz, H-18), 6.56 (1H,
A solution of 19 (17 mg, 0.04 mmol) in EtOH/H2O (1 mL), was
treated with Ni-Raney (1.2 g, excess). The reaction mixture was
stirred for 5 min and then filtered. The solvent was removed under
vacuum to afford 20 (17 mg, 99%).
dd, J¼8.6, 2.8 Hz, H-19), 6.49 (1H, d, J¼2.8 Hz, H-21), 3.37 (1H, d,
J¼17.1 Hz, H-15A), 1.96 (1H, d, J¼17.1 Hz, H-15B), 1.82e1.64 (5H, m),
1.50e1.28 (7H, m), 1.10 (3H, d, J¼7.5 Hz, Me-12), 1.06 (3H, s, Me-13),
0.92 (3H, s, Me-11), 0.78 (3H, s, Me-14); 13C NMR (100 MHz)
d: 148.3
(C-20), 145.7 (C-17), 122.2 (C-16), 117.2 (C-18), 115.0 (C-21), 113.9 (C-
19), 82.3 (C-10), 44.1 (C-5), 39.3 (C-8), 38.0 (C-9), 37.3 (C-15), 33.9 (C-
3), 33.8 (C-4), 31.9 (C-14), 29.8 (C-13), 29.2 (C-1), 27.8 (C-7), 22.2 (C-
6), 20.2 (C-11), 18.3 (C-2), 17.3 (C-12); EIHRMS: calcd for C21H30O2
(MþNaþ): 337.2143 found: 337.2138.
4.14.1. Compound 20. IR (film): 3424 (broad), 2929, 1658, 1579,
1561, 1453, 1420, 1379, 1264,1185,759, 738; 1H NMR (200 MHz)
d
: 8.43 (1H, ddd, J¼4.8, 2.0, 1.0 Hz, H-60), 7.48 (1H, dt, J¼8.0, 2.0 Hz,
H-40), 7.05 (1H, ddd, J¼8.0, 4.8, 1.0 Hz, H-50), 6.96 (1H, d,
J¼8.8 Hz, H-19), 6.91 (1H, d, J¼8.8 Hz, H-18), 6.71 (1H, dt, J¼8.0,
1.0 Hz, H-30), 5.67 (1H, s, eOH), 3.26 (1H, d, J¼14.0 Hz, H-15A), 3.00
(1H, d, J¼14.0 Hz, H-15B), 2.19e1.98 (4H, m), 1.78e1.23 (7H, m), 1.09
(3H, s, Me-14), 0.99 (6H, s, Me-13 and Me-11), 0.82 (3H, d, J¼6.8 Hz,
Me-12); EIHRMS: calcd for C26H31O2NS(MþNaþ): 446.2124 found:
446.2133.
4.18. Reaction of 7 with p-TsOH: 1 and 22
To a solution of 7 (12 mg, 0.04 mmol) in C6H6 (30 mL), was
added p-TsOH (100 mg, 0.51 mmol). After being stirred at room
temperature overnight, the reaction mixture was refluxed for 2 h.
Then aq 6% NaHCO3 was added. The resulting mixture was
extracted with EtOAc. The organic layer was washed with water
and dried over Na2SO4. The solvent was removed under vacuum to
afford a residue, which was chromatographed over silica gel (Hex/
EtOAc 8/2) to yield 1 (8 mg, 67%) and 22 (3 mg, 25%).
4.15. Reaction of 19 with Ni-Raney to yield 7
A solution of 19 (17 mg, 0.04 mmol) in EtOH (1 mL), was treated
with Ni-Raney (1.4 g, excess). The reaction mixture was stirred for
5 min and then filtered. The solvent was removed under vacuum to
yield 7 (12 mg, 99%).
22
4.18.1. Compound 22. Rf (Hex/EtOAc 7/3)¼0.75; [
a]
ꢀ42.0 (c 0.1,
D
CHCl3); IR (film): 3389, 2924, 2852, 1494, 1461, 1261, 1222, 1093; 1H
NMR (200 MHz)
22
d
: 6.69 (1H, d, J¼9.0 Hz, H-18), 6.60 (1H, dd,
4.15.1. Compound 7. Rf (Hex/EtOAc 7/3)¼0.41; [
a
]
ꢀ13.3 (c 0.5,
D
CHCl3); 1H NMR (200 MHz)
d
: 6.68 (1H, d, J¼8.0 Hz, H-18), 6.64 (1H,
J¼9.0, 3.1 Hz, H-19), 6.49 (1H, d, J¼3.1 Hz, H- 21), 4.26 (1H, s ancho,
eOH), 2.52 (2H, s, H-15), 2.10e1.95 (3H, m), 1.80e1.36 (9H, m), 1.10
(3H, s, Me-13), 0.96 (6H, s, Me-11 and Me-14), 0.75 (3H, d, J¼6.8 Hz,
Me-12); EIHRMS: calcd for C22H30O3 (MþNaþ): 337.2246; found:
337.2291.
d, J¼1.2 Hz, H-21), 6.55 (1H, dd, J¼8.0, 1.2 Hz, H-19), 4.84 (1H, s
ancho, eOH), 4.38 (1H, s ancho, eOH), 2.93 (1H, d, J¼12.6 Hz, H-
15A) 2.51 (1H, d, J¼12.6 Hz, H-15B), 2.06e1.95 (4H, m), 1.90e1.27
(7H, m), 1.05 (3H, s, Me-14), 0.99 (3H, s, Me-13), 0.98 (3H, s, Me-11),
0.83 (3H, d, J¼6.6 Hz, Me-12); EIHRMS: calcd for C21H30O2
(MþNaþ): 337.2143 found: 337.2150.
4.19. Reaction of 1/22 with Ac2O/Py: 23 and 24
To a solution of 1/22 (3:1) (11 mg, 0.035 mmol), in dry pyridine
(0.5 mL), was added Ac2O (0.5 mL). The mixture was stirred at room
temperature overnight. The reaction mixture was then poured into
ice water and extracted with EtOAc. The organic layer was washed
successively with 2 M aqueous HCl, 6% aqueous NaHCO3 and brine,
then dried over Na2SO4 and the solvent was evaporated to afford 23
(9.0 mg, 50%) and 24 (3.3 mg, 49%).
4.16. Reaction of 7 with MnO2 to yield 21
A solution of 7 (5 mg, 0.02 mmol) in Et2O (0.5 mL), was treated
with MnO2 (7 mg, 0.08 mmol) for 30 min at rt. The reaction mixture
was filtered trough CeliteÒ. The filtrate was concentrated to afford
21 (4.5 mg, 90%).
22
4.16.1. Compound 21. Rf (Hex/EtOAc 7/3)¼0.51; [
a]
þ8.2 (c 0.2,
4.19.1. Compound 23. Rf (Hex/EtOAc 95/5)¼0.50; [
a
]
22 ꢀ27.6 (c 0.3,
D
D
CHCl3); IR (film): 2929, 2119, 1656, 1598, 1522, 1457, 1289, 1068;
CHCl3); IR (film): 2934, 2872, 1763, 1494, 1466, 1385, 1206, 1140,
1H NMR (200 MHz)
d
: 6.70 (3H, m, H-18, H-19, H-21), 2.78 (1H, d,
1014, 954; 1H NMR (200 MHz)
d: 6.73 (2H, m, H-18, H-19), 6.61
J¼16.0 Hz, H-15A), 2.38 (1H, d, J¼16.0 Hz, H-15B), 2.05e1.60 (5H, m),
1.43e1.05 (6H, m), 1.00 (3H, s, Me-11), 0.93 (3H, s, Me-14), 0.88
(3H, s, Me-13), 0.81 (3H, d, J¼6.6 Hz, Me-12); 13C NMR (50 MHz)
(1H, d, J¼1.2 Hz, H-21), 3.45 (1H, d, J¼17.4 Hz, H-15A), 2.29 (3H, s,
MeCOOe), 2.25e2.12 (5H, m), 2.00 (1H, d, J¼17.4 Hz, H-15B),
1.97e1.65 (7H, m), 1.10 (3H, d, J¼7.4 Hz, Me-12), 1.06 (3H, s, Me-
13), 0.91 (3H, s, Me-11), 0.79 (3H, s, Me-14); EIHRMS: calcd for
C23H32O3(MþNaþ): 379.2244; found: 379.2260.
d
: 188.1 (C-17), 187.5 (C-20), 147.4 (C-16), 138. 3 (C-5), 137.1 (C-18),
136.2 (C-19), 134.1 (C-21), 131.4 (C-10), 42.0 (C-9), 39.9 (C-3), 34.8
(C-4), 34.3 (C-8), 34.3 (C-15), 28.8 (C-14), 28.1 (C-13), 27.1 (C-1),
26.6 (C-7), 24.4 (C-6), 22.4 (C-11), 20.0 (C-2), 16.6 (C-12); EIHRMS:
calcd for C21H28O2 (MþNaþ): 335.1987 found: 335.1995.
22
4.19.2. Compound 24. Rf (Hex/EtOAc 95/5)¼0.47; [
a
]
ꢀ6.6 (c 0.1,
D
CHCl3); IR (film): 3389, 2933, 1763, 1494, 1459, 1430, 1204, 1171,

8288
I.S. Marcos et al. / Tetrahedron 66 (2010) 8280e8290
1017, 813; 1H NMR (400 MHz),
d
: 6.78 (1H, d, J¼8.0 Hz, H-18), 6.77
EIHRMS: calcd for C27H33NO3S(MþNaþ): 474.2073; found: 474.
(1H, dd, J¼8.0, 1.2 Hz, H-19), 6.69 (1H, d, J¼1.2 Hz, H-21), 2.55 (2H,
s, H-15), 2.25 (3H, s, MeCOOe), 1.82e1.64 (5H, m), 1.50e1.28 (7H,
m), 1.11 (3H, s, Me-13), 0.91 (6H, s, Me-11 and Me-14), 0.74 (3H,
2090.
4.22. Reaction of 25/26 with NaOMe to yield 25 and 27
d, J¼6.8 Hz, Me-12); 13C NMR (100 MHz),
d: 170.0 (MeCOOe),
150.3 (C-17), 143.3 (C-20), 126.1 (C-16), 121.6 (C-21), 120.0 (C-19),
117.3 (C-18), 81.6 (C-10), 45.6 (C-5), 41.9 (C-3), 37.1 (C-9), 33.4 (C-
4), 33.4 (C-15), 32.5 (C-14), 31.7 (C-8), 28.3 (C-7), 22.3 (C-13), 21.8
(C-6), 21.0 (MeCOOe), 21.0 (C-1), 17.8 (C-2), 16.8 (C-11), 16.1 (C-
12); EIHRMS: calcd for C23H32O3(MþNaþ): 379.2244; found:
379.2229.
To a solution of 25/26 (9 mg, 0.02 mmol), in THF (0.8 mL), was
added drop wise NaOMe/MeOH (3.8 M, 0.02 mL, 0.06 mmol) at
ꢀ20 ꢁC. The reaction mixture was stirred and slowly warmed up to
2 ꢁC over 3 h. The reaction mixture was quenched with aq sat NH4Cl
and extracted with EtOAc. The organic layer was washed with
water and dried over Na2SO4. The solvent was evaporated and the
residue was chromatographed over silica gel (Hex/EtOAc 98/2) to
afford 27 (2 mg, 27%) and 25 (4 mg, 46%).
4.20. Reduction of 23 with LAH to yield 1
4.22.1. Neomamanuthaquinone methyl ether, 27. Rf (Hex/EtOAc
A solution of compound 23 (2 mg, 0.006 mmol) in Et2O (0.3 mL)
was reduced with LAH (2 mg, 0.05 mmol) at 0 ꢁC for 35 min. Then,
aqueous Et2O was added and after filtration, the solvent was
evaporated to yield 1 (1.8 mg, 100%).
7/3)¼0.51; 1H NMR (200 MHz)
d: 5.72 (1H, s, H-19), 4.03 (3H, s,
eOMe), 3.81 (3H, s, eOMe), 2.72 (1H, d, J¼10.1 Hz, H-15A), 2.55 (1H,
d, J¼10.1 Hz, H-15B), 2.16e1.82 (5H, m), 1.80e1.22 (6H, m), 1.01
(3H, s, Me-11), 0.96 (3H, s, Me-14), 0.79 (3H, s, Me-13), 0.77 (3H,
d, J¼6.6 Hz, Me-12); 13C NMR (50 MHz)
d: 183.6 (C-20),183.0 (C-17),
4.21. Reaction of 19 with NaOMe to yield 25 and 26
159.0 (C-18), 157.0 (C-21), 135.0 (C-5), 131.3 (C-10), 129.1
(C-16), 105.2 (C-19), 61.0 (eOMe), 56.4 (eOMe), 42.6 (C-9), 40.0
(C-3), 34.5 (C-4), 34.5 (C-8), 32.2 (C-15), 29.0 (C-14), 28.0 (C-13),
26.5 (C-7), 25.7 (C-1), 22.0 (C-11), 20.6 (C-6), 20.0 (C-2), 15.4
(C-12); EIHRMS: calcd for C27H33NO3S (MþNaþ): 395.2343; found:
395.2349.
To a solution of quinone 19 (24 mg, 0.06 mmol) inTHF (1.4 mL) was
added drop wise NaOMe/MeOH (2.5 M, 0.12 mL, 0.29 mmol) at ꢀ20 ꢁC.
The mixture was stirred for 10 min. The reaction mixture was treated
with aq satd NH4Cl at ꢀ20 ꢁC and extracted with EtOAc. The organic
layer was washed with water and dried over Na2SO4. The solvent was
removed under vacuum to afford a residue, which contains 25/26
(21 mg, 80%). The residue was chromatographed over silica gel (Hex/
EtOAc 95/5) to yield 25 (13 mg, 45%), and 26 (5 mg, 21%).
4.23. Reaction of 25 with Ni-Raney to yield 29
A solution of 25 (5 mg, 0.11 mmol) in EtOH (1.3 mL), was treated
with Ni-Raney (1 g, excess) for 5 min. The reaction mixture was
then filtered, the filtrate was concentrated to afford 29 (3.6 mg,
95%).
22
4.21.1. Compound 25. Rf (Hex/EtOAc 7/3)¼0.39; [
a
]
D
ꢀ70.4 (c 0.3,
CHCl3); IR (film): 3391, 2927, 2852, 1630, 1560, 1511, 1457, 1220,
1121, 1090; 1H NMR (400 MHz, C6H6)
d
: 8.09 (1H, ddd, J¼4.8, 2.0,
22
1.0 Hz, H-60), 6.99 (1H, dt, J¼8.0, 1.0 Hz, H-30), 6.77 (1H, dt,
J¼8.0, 2.0 Hz, H-40), 6.32 (1H, ddd, J¼8.0 4.8, 1.0 Hz, H-50), 5.64
(1H, s, H-18), 3.45 (1H, d, J¼12.0 Hz, H-15A), 3.13 (1H, d, J¼12.0 Hz,
H-15B), 2.79 (3H, s, eOMe), 2.01e1.60 (4H, m), 1.55e1.28 (7H, m),
1.24 (3H, s, Me-14), 1.14 (3H, s, Me-11), 1.05 (3H, s, Me-13), 0.93
4.23.1. Compound 29. Rf (Hex/EtOAc 6/4)¼0.68; [
a
]
D
þ11.5 (c 0.2,
CHCl3); IR (film): 2925, 2853, 1726, 1673, 1648, 1603, 1460, 1216; 1H
NMR (200 MHz) : 6.61 (1H, s, H-21), 5.91 (1H, s, H-18), 3.80 (3H, s,
d
eOMe), 2.80 (1H, d, J¼16.2 Hz, H-15A), 2.39 (1H, d, J¼16.2 Hz,
H-15B), 2.09e1.97 (5H, m), 1.82e1.43 (6H, m), 1.00 (3H, s, Me-11),
0.99 (3H, s, Me-14), 0.88 (3H, s, Me-13), 0.81 (3H, d, J¼6.6 Hz, Me-
(3H, d, J¼7.7 Hz, Me-12); 1H NMR (200 MHz, CDCl3)
d: 8.28 (1H, d,
J¼4.8 Hz, H-60), 7.52 (1H, t, J¼8.0 Hz, H-40), 7.30 (1H, d, J¼8.0 Hz,
H-30), 7.02 (1H, dd, J¼8.0, 4.8 Hz, H-50), 5.98 (1H, s, H-18), 3.82
(3H, s, eOMe), 3.15 (1H, d, J¼12.0 Hz, H-15A), 2.88 (1H, d, J¼12.0 Hz,
H-15B), 2.20e1.80 (4H, m), 1.75e1.10 (7H, m), 1.05 (3H, s, Me-14),
0.96 (3H, s, Me-11), 0.88 (3H, s, Me-13), 0.79 (3H, d, J¼7.7 Hz, Me-
12); 13C NMR (50 MHz)
d: 187.9 (C-17), 182.4 (C-20), 158.4 (C-19),
148.3 (C-16), 138.3 (C-5), 132.7 (C-21), 131.1 (C-10), 107.9 (C-18),
56.3 (eOMe), 41.9 (C-9), 39.9 (C-3), 34.4 (C-8), 33.7 (C-15), 33.7
(C-4), 28.7 (C-14), 28.2 (C-13), 27.1 (C-1), 26.6 (C-7), 24.3 (C-6),
22.4 (C-11), 20.0 (C-2), 16.6 (C-12); EIHRMS: calcd for
C22H30O3(MþNaþ): 365.2087; found: 365.2091.
12); 13C NMR (100 MHz, C6H6)
d: 185.1 (C-17), 176.5 (C-20), 159.5
(C-19), 158.0 (C-20), 152.7 (C-21), 149.5 (C-60), 140.6 (C-16), 136.0
(C-40), 135.9 (C-5), 131.0 (C-10), 122.5 (C-30), 119.9 (C-50), 107.5
(C-18), 54.8 (eOMe), 44.4 (C-9), 39.9 (C-3), 39.7 (C-15), 35.9 (C-8),
34.3 (C-4), 28.9 (C-14), 27.8 (C-13), 27.6 (C-1), 26.1 (C-7), 22.7 (C-11),
20.9 (C-6), 19.9 (C-2), 15.6 (C-12); EIHRMS: calcd for C27H33NO3S
(MþNaþ): 474.2073; found: 474. 2077.
4.24. Reaction of 29 with NaBH4 to yield 28
To an ice-cooled solution of 29 (35 mg, 0.10 mmol) in THF/H2O
(2.8/0.3 mL), NaBH4 (8 mg, 0.20 mmol) was added. After being
stirred at room temperature for 3 h, the reaction mixture was
recooled to 0 ꢁC and quenched with a few drops of 2 M aqueous HCl
solution, diluted with EtOAc and water and extracted with EtOAc.
The organic layer was washed with water. Evaporation of the dried
extract gave 28 (34 mg, 97%).
4.21.2. Compound 26. Rf (Hex/EtOAc 7/3)¼0.34; IR (film): 3390,
2927, 2852, 1630, 1563, 1458, 1220, 1090; 1H NMR (400 MHz, C6H6)
d
: 8.22 (1H, ddd, J¼4.8, 2.0, 1.0 Hz, H-60), 7.06 (1H, dt, J¼8.0, 1.0 Hz,
H-30), 6.83 (1H, dt, J¼8.0, 2.0 Hz, H-40), 6.39 (1H, ddd, J¼8.0, 4.8,
1.0 Hz, H-50), 5.67 (1H, s, H-19), 3.42 (1H, d, J¼12.0 Hz, H-15A), 3.09
(1H, d, J¼12.0 Hz, H-15B), 2.80 (3H, s, eOMe), 2.01e1.60 (4H, m),
1.55e1.28 (7H, m), 1.21 (3H, s, Me-14), 1.09 (3H, s, Me-11), 1.03 (3H,
s, Me-13), 0.83 (3H, d, J¼7.6 Hz, Me-12); 13C NMR (100 MHz, C6H6)
4.25. Reaction of 28 with BF3$Et2O to yield 30
To a stirred solution of 28 (34 mg, 0.10 mmol) in DCM (9.0 mL)
at ꢀ50 ꢁC was added BF3$Et2O (0.07 mL, 0.51 mmol). The resulting
mixture was gradually warmed to ꢀ5 ꢁC over 5 h 30 min the re-
action was quenched with saturated aqueous NH4Cl at ꢀ5 ꢁC and
the mixture was extracted with DCM. The combined extracts were
washed with saturated NaCl then dried over Na2SO4. The solvent
was removed under vacuum and the residue was purified by
d
ppm: 181.1 (C-17),180.9 (C-20),158.8 (C-18),158.7 (C-20), 150.9 (C-
21), 149.9 (C-60), 144.9 (C-16), 136.0 (C-40), 135.8 (C-5), 130.7 (C-10),
122.5 (C-30), 119.9 (C-50), 108.3 (C-19), 54.8 (eOMe), 44.0 (C-9), 39.9
(C-3), 39.6 (C-15), 36.0 (C-8), 34.3 (C-4), 28.9 (C-14), 27.8 (C-13),
27.6 (C-1), 26.0 (C-7), 22.7 (C-11), 20.9 (C-6), 19.8 (C-2), 15.5 (C-12);

I.S. Marcos et al. / Tetrahedron 66 (2010) 8280e8290
8289
column chromatography (Hex/EtOAc 95/5) to yield 30 (30 mg,
50%).
(C-1), 27.7 (C-7), 22.5 (C-6), 20.0 (C-11), 18.3 (C-2), 17.0 (C-12);
EIHRMS: calcd for C22H30O4 (MþNaþ): 381.2042; found: 381.2049.
22
4.25.1. 19-Methoxyaureol, 30. Rf (Hex/EtOAc 7/3)¼0.70; [
a
]
22 ꢀ32.1
4.28.2. (þ)-5-epi-Smenoqualone, 31. [
a
]
D
þ69.3 (c 0.1, CHCl3); IR
D
(c 0.4, CHCl3); IR (film): 3424, 2958, 2872, 1630, 1510, 1447, 1261,
(film): 2932, 1664, 1648, 1600, 1495, 1384, 1219, 981; 1H NMR
(200 MHz) : 5.74 (1H, s, H-19), 3.80 (3H, s, eOMe), 2.57 (1H, d,
1234,1117, 956; 1H NMR (400 MHz)
d: 6.54 (1H, s, H-21), 6.29 (1H, s,
d
H-18), 3.82 (3H, s, eOMe), 3.31 (1H, d, J¼17.0 Hz, H-15A), 1.90
(1H, d, J¼17.0 Hz, H-15B), 1.82e1.64 (5H, m), 1.50e1.28 (7H, m), 1.10
(3H, d, J¼7.5 Hz, Me-12) 1.08 (3H, s, Me-14), 0.92 (3H, s, Me-11),
J¼20.0 Hz, H-15A), 2.00 (1H, d, J¼20.0 Hz, H-15B), 1.98e1.36 (12H,
m), 1.17 (3H, s, Me-13), 0.96 (3H, s, Me-14), 0.94 (3H, s, Me-11), 0.77
(3H, d, J¼6.0 Hz, Me-12); 13C NMR (50 MHz)
d: 181.5 (C-17), 181.5
0.79 (3H, s, Me-13); 13C NMR (100 MHz)
d: 145.3 (C-19), 144.8
(C-20), 159.5 (C-18), 152.5 (C-21), 115.1 (C-16), 105.0 (C-19), 86.5
(C-10), 56.4 (eOMe), 45.5 (C-5), 41.7 (C-3), 37.0 (C-9), 33.5 (C-4),
32.5 (C-14), 32.4 (C-8), 30.3 (C-15), 29.5 (C-7), 26.7 (C-1), 22.3
(C-13), 22.0 (C-6), 17.8 (C-2), 17.0 (C-11), 16.4 (C-12); EIHRMS: calcd
for C22H30O4 (MþNaþ): 381.2042; found: 381.2051.
(C-17), 138.8 (C-20), 113.7 (C-21), 112.9 (C-16), 100.0 (C-18), 82.4
(C-10), 56.0 (eOMe), 43.9 (C-5), 39.3 (C-8), 38.1 (C-9), 36.7 (C-15),
33.8 (C-3), 33.8 (C-4), 31.9 (C-14), 29.9 (C-13), 29.2 (C-1), 27.9 (C-7),
22.2 (C-6), 20.1 (C-11), 18.3 (C-2), 17.3 (C-12); EIHRMS: calcd for
C22H32O3(MþNaþ): 367.2244; found: 367.2263.
Acknowledgements
4.26. Reaction of 18 with methoxy-p-benzoquinona: 25 and 26
The authors gratefully acknowledge the help of A. Lithgow
(NMR) and C. Raposo (MS) of Universidad de Salamanca and
MICINN CTQ2009-11557BQU, Junta de Castilla and León(GR-178,
SA063A07) for financial support. A.C.A. is grateful to the Junta de
Castilla and León for a fellowship.
A solution of ester 18 (37 mg, 0.1 mmol) and methoxy-p-ben-
zoquinone (41.4 mg, 0.3 mmol) in DCM (2.3 mL) was cooled at 0 ꢁC
and irradiated with a lamp (500 W) for 2 h. The reaction mixture
was concentrated and chromatographed over 5 g of silica gel (Hex/
EtOAc 95/5) to yield 25 (26 mg, 49%) and 26 (9 mg, 17%).
Supplementary data
4.27. Reaction of 27 with HClO4 to yield 2
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.08.038.
To a solution of 27 (10 mg, 0.03 mmol) in THF (1 mL), 0.5 mL of
60% HClO4 were added. The reaction mixture was stirred at room
temperature for 4 h. Then the reaction mixture was diluted with
water and EtOAc. The resulting mixture was extracted with EtOAc.
The organic layer was washed with aq 6% NaHCO3 and dried over
Na2SO4. The solvent was evaporated to yield 2 (6 mg, 70%).
References and notes
1. (a) Marcos, I. S.; Conde, A.; Moro, R. F.; Basabe, P.; Díez, D.; Urones, J. G. Mini-Rev.
Org. Chem. 2010, 7, 230; (b) Capon, R. J. In Studies in Natural Products Chemistry,
Structure and Chemistry (Part C); Atta-Ur Rahman, Ed.; Elsevier: Amsterdam,
1995; Vol. 15, pp 289e326.
2. Fraga, B. M. Nat. Prod. Rep. 2008, 25, 1180.
3. Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M. H.; Northcote, P. T.; Prinsep, M. R.
Nat. Prod. Rep. 2009, 26, 174.
4. Fujimoto, H.; Nakamura, E.; Kim, Y. P.; Okuyama, E.; Ishibashi, M.; Sassa, T.
J. Nat. Prod. 2001, 64, 123.
5. Zhi-Hui, D.; Ze-Jun, D.; Ji-Kai, L. Helv. Chim. Acta 2001, 84, 259.
6. Kono, K.; Tanaka, T.; Ogita, T.; Hosoya, T.; Kohama, T. J. Antibiot. 2000, 53, 459.
7. Longley, R. E.; McConell, O. J.; Essich, E.; Harmody, D. J. Nat. Prod. 1993, 56, 915.
8. Wright, A.E.; Cross, S.S.; Burres, N.S.; Koehn, F. Harbor Branch Oceanographics
Institution, USA, PCT WO 9112250 A1 August 22, 1991.
9. Utkina, N. K.; Denisenko, V. A.; Scholokova, O. V.; Virovaya, M.; Prokof’eva, N. G.
Tetrahedron Lett. 2003, 44, 101.
4.27.1. (ꢀ)-Neomamanuthaquinone, 2. Rf (Hex/EtOAc 7/3)¼0.30;
22
[
a]
ꢀ9.1 (c 0.1, CHCl3); 1H NMR (200 MHz)
d: 5.85 (1H, s, H-19),
D
3.86 (3H, s, eOMe), 2.70 (1H, d, J¼13.1 Hz, H-15A), 2.54 (1H, d,
J¼13.1 Hz, H-15B), 2.10e1.80 (5H, m), 1.55e1.32 (6H, m), 0.97
(3H, s, Me-11), 0.93 (3H, s, Me-14), 0.81 (3H, s, Me-13), 0.76 (3H, d,
J¼6.7 Hz, Me-12); 13C NMR (50 MHz)
d: 183.0 (C-20), 182.5 (C-
17), 161.5 (C-18), 153.5 (C-21), 135.0 (C-5), 131.5 (C-10), 118.0 (C-16),
105.0 (C-19), 56.4 (eOMe), 43.0 (C-9), 40.0 (C-3), 34.9 (C-8), 34.5
(C-4), 32.4 (C-15), 29.7 (C-14), 28.0 (C-13), 25.6 (C-1), 25.5 (C-7),
22.0 (C-11), 21.5 (C-6), 20.0 (C-2), 15.3 (C-12); EIHRMS: calcd for
C22H30O4(MþNaþ): 381.2034; found: 581.2022.
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4.28. Reaction of 2 with p-TsOH to yield 3 and 31
€
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F.; Urones, J. G. Synthesis 2005, 3301.
A mixture of 2 (5 mg, 0.014 mmol) and p-TsOH (12 mg,
0.07 mmol) in dry benzene (1.6 mL) was refluxed for 30 min. Then it
was quenched with aq 6% NaHCO3 and extracted with EtOAc. The
organic layer was washed with water and dried over Na2SO4. The
solvent was removed under vacuum to afford a residue, which was
purified by column chromatography over silica gel (Hex/EtOAc
98/2) to yield 3 (1.2 mg, 24%) and 31 (1 mg, 20%).
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22
4.28.1. (ꢀ)-Smenoqualone, 3. [
a
]
ꢀ63.5 (c 0.1, CHCl3); IR (film):
D
2932, 1663, 1648, 1605, 1495, 1384, 1221, 1186; 1H NMR (200 MHz)
d
: 5.70 (1H, s, H-19), 3.78 (3H, s, eOMe), 2.80 (1H, d, J¼18.6 Hz,
H-15A), 1.94 (1H, d, J¼18.6 Hz, H-15B), 1.82e1.64 (5H, m), 1.50e1.28
(7H, m), 1.07 (3H, d, J¼7.6 Hz, Me-12), 0.99 (3H, s, Me-13),
0.84 (3H, s, Me-11), 0.80 (3H, s, Me-14); 13C NMR (50 MHz)
d: 181.4
(C-17), 181.4 (C-20), 159.5 (C-18), 151.0 (C-21), 115.2 (C-16), 104.7
(C-19), 87.8 (C-10), 56.1 (-OMe), 45.0 (C-5), 39.0 (C-8), 38.0 (C-9),
33.6 (C-4), 33.4 (C-3), 32.0 (C-14), 30.6 (C-15), 29.6 (C-13), 29.0
20. Marcos, I. S.; García, N.; Sexmero, M. J.; Basabe, P.; Díez, D.; Urones, J. G.
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J. G. Synlett 2007, 2017.
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