Synthesis of hexahydrocarbazoles by cyclisation of 3-(but-3-enyl) indole derivatives

Article abstract of DOI:10.1016/j.tet.2009.09.090

A new cyclisation of 3-(but-3-enyl) indole derivatives that produces policyclic compounds with a hexahydrocarbazole structure is described. In this reaction three stereogenic centres are generated in one step, and this process can be considered as evidenc

Full text of DOI:10.1016/j.tet.2009.09.090

Tetrahedron 65 (2009) 10235–10242
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of hexahydrocarbazoles by cyclisation of 3-(but-3-enyl)
indole derivatives
*
Isidro S. Marcos , Rosalina F. Moro, Isabel Costales, Miguel A. Escola, Pilar Basabe,
´
David Dıez, Julio G. Urones
´
´
´
Departamento de Quımica Organica, Facultad de Ciencias Quımicas, 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 2 July 2009
Received in revised form
21 September 2009
Accepted 23 September 2009
Available online 25 September 2009
A new cyclisation of 3-(but-3-enyl) indole derivatives that produces policyclic compounds with a hexa-
hydrocarbazole structure is described. In this reaction three stereogenic centres are generated in one
step, and this process can be considered as evidence of the biogenetic relationship between anominine
and tubingensin A.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
ent-Halimic acid
Indol diterpenes
Thiersindole
Anominine
Tubingensin A
1. Introduction
interesting goal; this reaction could be the keystone of just such as
approach to the synthesis of analogues of tubingensin A.
Indole diterpene alkaloids isolated from fungi are very in-
teresting natural compounds as a result of structural diversity and
the bioactivity, which is often observed.1 Tremorgenic,2 antiinsect,3
pollen growth inhibition,4 antitumour5 and antiviral activities6 are
the most frequently found.
Until now, more than one hundred indole diterpenes are known
whose structure and biosynthesis have been fully established,
although not many display the carbazole system present in tubin-
gensins A and B.6 The latter are diterpenes that show antiviral and
antitumoural activity and have in their structure a 9H-octahy-
dronaphto[2,1-b]carbazole ring system.
Furthermore, our observation of this cyclisation strongly sup-
ports the hypothesis that anominine9 is the biogenetic precursor of
tubingensin A.
H
N
H
N
H
N
1
9
2
3
10
20
4
27
12
H
H
28
11
16
15
21
HO
HO
HO
29
23
Recently our group has published the synthesis of (þ)-thier-
sindole C7 and preliminary studies towards the synthesis of thier-
sindoles A and B8 are in progress. In this paper we will describe the
discovery of a cyclisation reaction that, in one step, generates
three new stereogenic centres with total stereoselection, to give
a compound identified as a hexahydrocarbazole derivative. The
development of methodologies for the synthesis of complex poly-
cyclic systems present in natural products and analogues is an
Thiersindole A
Thiersindole B
(-)-Thiersindole C
26
24
25
H
N
NH
NH
OH
HO
HO
Tubingensin A
Tubingensin B
Anominine
* Corresponding author. Tel.: þ34 923 294474; fax: þ34 923294574.
E-mail address: ismarcos@usal.es (I.S. Marcos).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.090

10236
I.S. Marcos et al. / Tetrahedron 65 (2009) 10235–10242
In this paper we describe this new cyclisation of 3(but-3-enyl)
indole derivatives that leads to polycyclic hexahydrocarbazoles.
indole derivative 3 was obtained in an excellent yield. Reduction of
3 followed by acetylation gave compound 5.
The starting material for the next cyclisation reaction, com-
pound 12, was obtained as shown in Scheme 3.
2. Results and discussion
H
N
H
N
H
N
The aim of this work is to study the cyclisation of indole de-
rivatives giving rise to hexahydrocarbazoles that could be consid-
ered analogues of tubingensins. The indole derivatives 5, 12, 16 and
20, all of which were obtained from compound 2, Scheme 1, were
selected as the starting materials for this study. Compound 2 was
synthesised in six steps in 75% yield, from ent-halimic acid 1,7 and
was an intermediate in the synthesis of thiersindole C.
b
a
H
H
H
CHO
CH2OH
7
MeO
8/9
4
15 CH2OH
H
c
1 N
9
16
11
2
3
CHO
H
13
20
H
N
H
N
N
4
10
20
22
19
1
23
17
a
11
15
10
19
17
8
e
4
3
d
16
H
H
H
24
19
H
H
H
21CH2OAc
18COOMe
COOMe
TsOH2C
HOH2C
5
1
2
11
10
12
H
N
H
Scheme 3. Reagents and conditions: (a) TPAP, NMO, molecular sieves, CH2Cl2, rt,
30 min, 95%; (b) MeOCH2PPh3Cl, NaHMDS, THF, ꢁ78 ꢀC, 30 min, (8: 33%, 9: 57%); (c) (i)
p-TsOH, Me2CO–H2O, rt, 3 h; ii) NaBH4, EtOH, 30 min, 36%; (d) TsCl, Py, rt, 90 min, 80%;
(e) 2-methylallylmagnesium chloride, THF, 0 ꢀC-rt, overnight, 58%.
H
N
N
Compound 12 is an analogue of (þ)-thiersindole C, of which it is
the 17-desoxy derivative with and olefin introduced at C-19. The
synthesis was achieved following a similar scheme to that used for
(þ)-thiersindole C, that is, elongation of the side chain by one
carbon atom via a Wittig and then introduction of the remaining
four carbon atoms by substitution of an appropriate electrophile
derived from this intermediate.
H
H
H
20
12
16
OAc
CH2OAc
Scheme 1. Aldehyde2forthesynthesisofthestartingmaterialforthecyclisation.(a)Ref. 7.
TPAP oxidation11 of 4 gave aldehyde 7, which upon reaction
with MeOCH2PPh3Cl12 gave the enol ether mixture 8/9. The next
sequence is the introduction of the four carbon atoms. Hydrolysis of
8/9 with p-toluensulfonic acid gives an unstable aldehyde, that was
submitted to reduction with NaBH4 to give the hydroxy derivative
10.13 Tosylation of 10 and substitution of the tosyl derivative 11
with 2-methylallylmagnesium chloride14 gave, in good yield, the
indole diterpene 12, the analogue of thiersindole C.
For the synthesis of the next starting material, 16, the route
shown in Scheme 4 was followed. Horner–Wadsworth–Emmons
reaction of aldehyde 7 with (EtO)2P(O)CH2COOEt in the presence of
sodium hydride15 gave 13, which was chemoselectively hydroge-
nated with Wilkinson’s catalyst (Ph3P)3RhCl in the presence of
Et3SiH and HCl,16 giving 14. Reduction of the latter compound with
LAH followed by acetylation of the hydroxyl derivative 15 pro-
duced 16.
Next, the transformation of trinorderivative 2 into the various
indole diterpenes will be described, starting in Scheme 2 with the
synthesis of compound 5.
15
CH2OH
H
N
16
CHO
13
11
20
1
17
a
10
b
8
4
3
H
H
H
19
COOMe
18COOMe
COOMe
2
3
1
c
H
N
H
N
The final starting material for the cyclisation, the indole diter-
pene 20, was synthesised starting from 15 (Scheme 5).
TPAP oxidation of 15 followed by addition of isopropyl-
magnesium chloride to the aldehyde 18 gave the hydroxy derivative
19, which, on acetylation under the usual conditions led to the re-
quired compound 20.
Once the starting materials, 5, 12, 16 and 20, had been obtained
the cyclisation reactions were tried on them in the presence of
hydroiodic acid (Scheme 6).
Treatment of 5 with HI at reflux in benzene gave a pentacyclic
compound 6 (Scheme 6). The hexahydrocabazole structure for this
compound was deduced from bidimensional NMR experiments,
1H/13C NMR (HMQC and HMBC). The upfield shifts of signals for
H-2 and H-10 in 1H NMR show that the indole group has been
d
H
H
CH2OAc
CH2OH
5
4
Scheme 2. Reagents and conditions: (a) Ref. 7; (b) PhNHNH2, HOAc, rt, 2 h, then
120 ꢀC, 2 h, 95%; (c) LAH, Et2O, 97%; (d) Ac2O, Py, 95%.
For the introduction of the indole group Fischer methodology10
was used. Thus, by reaction of 2 with phenylhydrazine in acetic acid
for two hours at room temperature and then heating to 120 ꢀC, the

I.S. Marcos et al. / Tetrahedron 65 (2009) 10235–10242
10237
H
N
H
N
H
N
b
a
c
7
H
H
H
R
13
14
15 H
d
COOEt
CH2OR
COOEt
16 Ac
Scheme 4. Reagents and conditions: (a) (EtO)2P(O)CH2COOEt, NaH, C6H6, 0 ꢀC, 15 min, then, rt, 30 min, 73%; (b) (Ph3P)3RhCl, Et3SiH, HCl, C6H6, 70 ꢀC, 14 h, 99%; (c) LAH, Et2O,
45 min, 93%; (d) Ac2O, Py, rt, overnight, 94%.
H
N
H
N
H
N
a
b
H
H
H
R
19
20
OH
OAc
15
18
c
CH2OH
CHO
R
Scheme 5. Reagents and conditions: (a) TPAP, NMO, molecular sieves, CH2Cl2, rt, 20 min, 90%; (b) i-PrMgCl, THF, rt, overnight, 44%; (c) Ac2O, Py, rt, overnight, 98%.
H
N
H
N
H
N
H
N
H
H
H
H
CH2OAc
5
12
16
20
CH2OAc
OAc
HI
HI
59%
H
HI
HI 98%
H
H
HN
H
HN
H
HN
H
3
HN
10
22
H
2
H
18
19
H
H
20
15
H
H
17
CH2OAc
24
CH2OAc
OAc
6
Scheme 6. Cyclisation reactions with HI.
involved in the reaction. The shift of H-19 and the correlation of C-
2 with H-18, indicate that a reaction of the ring double bond and
the indole group has taken place, forming a new carbocyclic sys-
tem between C-2 and C-19. Besides, in the 13C NMR spectrum two
quaternary carbons at 133.3 and 135.3 ppm, that showed a 1,3
relationship with H-24 and H-22, respectively, were observed,
confirming the cyclisation at C-19 and the presence of a tetrasub-
Reaction of 16 with HI gave the hexahydrocarbazole 17, as
determined by spectroscopic analysis, that shows similar NOEs and
correlations as for 6.
Preliminary trials for the cyclisation of 12 and 20, in acidic
media, only gave complex mixtures, from which no could be iso-
lated cyclisation product. It appears that for the cyclisation to
hexahydrocarbazoles only substrates without any additional func-
tionality that can be involved in the acidic media reaction can be
used.
stituted olefin D15(20)
.
The cyclisation reaction is stereoselective and generates three
new stereocentres in one step. NOEs from H-2 with H-3 and H-19,
and from Me-22 with H-3 and H-19 permit the stereochemistry to
be determined as 2R, 3R, 19R for the new stereocentres. So, hy-
This result can be explained by a protonation of the indole group
at C-3, that generates two stereoisomers, 3R and 3S, by protonation
on the
a side or b side of the molecule, respectively. Both in-
drogens H-2, H-3 and H-19 are on the
molecule.
a
side of the pentacyclic
termediates I and II generated in the reaction are in equilibrium
with the starting material. It seems that intermediate I can more

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I.S. Marcos et al. / Tetrahedron 65 (2009) 10235–10242
H
H
H
3(R)
HN
H
HN
HN
H
H
H
-H+
Quick
α-Prot..
H
H
H
N
α
OAc
OAc
OAc
H
6
III
I
β
H
OAc
3(S)
H
5
HN
β-Prot..
Slow
or
No reaction
AcO
H
OAc
II
Scheme 7. Mechanism proposal for the cyclisation step.
easily adopt the conformation for the double bond attack than
intermediate II. Once that the cyclisation has taken place a penta-
cyclic intermediate with a trisubstituted carbocation III is obtained,
which loses a proton to give 6 (Scheme 7).
4. Experimental
4.1. General
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available and were used without further
purification. IR spectra were recorded on an AVATAR 370 FTIR
Thermo Nicolet spectrophotometers. 1H and 13C NMR spectra were
performed in CDCl3 and referenced to the residual peak of CHCl3 at
3. Conclusions
In conclusion, two compounds with a hexahydrocarbazole
structure have been obtained (analogous to that of tubingensin
A) by cyclisation of unsaturated 3-alkylindoles. This reaction would
suggest anominine as a possible biogenetic precursor of tubin-
gensin A and B (Scheme 8). This reaction can open a new route to
the synthesis of anominine and tubingensin derivatives.
d
7.26 ppm and
200 VX and Bruker DRX 400 instruments. Chemical shifts are
reported in parts per million and coupling constants (J) are given in
d
77.0 ppm, for 1H and 13C, respectively, using Varian
d
hertz. MS were performed using a VG-TS 250 spectrometer at 70 eV
HO
NH
Tubingensin A
[Ox]
H
HO
HO
HO
NH
NH
NH
+
H
+
Anominine
HO
HO
[
]
Ox
HO
NH
NH
NH
+
+
Tubingensin B
Scheme 8. Anominine as biogenetic precursor of tubingensin A and B.

I.S. Marcos et al. / Tetrahedron 65 (2009) 10235–10242
10239
ionising voltage. Mass spectra are presented as m/z (% rel int.). HRMS
were recorded on a VG Platform (Fisons) spectrometer using chem-
ical ionisation (ammonia as gas) or Fast Atom Bombardment (FAB)
technique. For some of the samples, QSTAR XL spectrometer was
employed for electrospray ionisation (ESI). Optical rotations were
determined on a Perkin–Elmer 241 polarimeter in 1 dm cells. Diethyl
ether and THF were distilled from sodium, and dichloromethane was
distilled from calcium hydride under argon atmosphere.
dd, J¼3.8 and 2.6 Hz, H-19), 3.93 (1H, d, J¼10.6 Hz, HA-21), 3.78 (1H,
d, J¼10.6 Hz, HB-21), 3.12 (1H, d, J¼14.8 Hz, HA-10), 2.89 (1H, d,
J¼14.8 Hz, HB-10),1.97 (3H, s, -OOCMe), 2.33–1.01 (10H, m), 0.92 (3H,
s, Me-22), 0.89 (3H, s, Me-24), 0.82 (3H, d, J¼7.0 Hz, Me-23); 13C NMR
d: 171.8 (–OOCMe), 141.8 (C-20), 135.9 (C-9), 129.4 (C-4), 122.9 (C-2),
121.6 (C-7), 120.4 (C-6), 119.5 (C-5), 119.2 (C-19), 113.4 (C-3), 111.1
(C-8), 71.3 (C-21), 44.8 (C-11), 38.4 (C-15), 38.1 (C-12), 35.4 (C-16),
34.9 (C-10), 29.6 (C-17), 29.2 (C-13), 23.7 (C-22), 23.2 (C-18), 22.6
(C-14), 21.1 (–OOCMe), 20.7 (C-24), 16.1 (C-23); EIHRMS: calcd for
C25H33NO2Na (MþþNa): 402.2404, found: 402.2403.
4.1.1. Compound 3. To a solution of 2 (1.54 g, 5.27 mmol) in acetic
acid (20 mL) was added phenylhydrazine (0.6 mL, 6.10 mmol) and
the mixture was stirred at room temperature for 2 h, and at 130 ꢀC
for 2 h more. Then, the reaction mixture was diluted with EtOAc
and washed with 6% aqueous NaHCO3 and brine. Evaporation of the
solvent after drying over Na2SO4 gave a residue, which was chro-
matographed on silica gel (Hex/EtOAc 95/5) to afford 3 (1.83 g,
4.1.4. Compound 7. To
a mixture of 4 (167 mg, 0.49 mmol),
N-methylmorpholine-N-oxide (NMO) (232 mg, 1.72 mmol) and
molecular sieves (248 mg, 500 mg/mmol) in anhydrous CH2Cl2
(1.1 mL) under Ar at room temperature, TPAP (9 mg, 0.025 mmol)
was added and the mixture was stirred for 30 min. The reaction
mixture was filtered through a pad of Celite and silica gel (CH2Cl2
and EtOAc). Evaporation of the solvent yielded the aldehyde 7
95%).
22
Rf¼0.58 (hexane/EtOAc 8:2); [
a
]
ꢁ45.7 (c 0.81, CHCl3); mp
D
129–132 ꢀC; IR (film, cmꢁ1): 3399, 3052, 2949, 1727, 1457, 1434,
(157 mg, 95%).
1379, 1255, 1232, 1198, 1112, 739; 1H NMR
d: 8.01 (1H, br s, H-1),
Rf¼0.39 (hexane/EtOAc 8:2); [
a]
ꢁ23.5 (c 0.026, CHCl3); IR
22
D
7.63 (1H, d, J¼7.6 Hz, H-5), 7.34 (1H, d, J¼7.6 Hz, H-8), 7.16 (1H, t,
J¼7.6 Hz, H-7), 7.10 (1H, t, J¼7.6 Hz, H-6), 6.94 (1H, s, H-2), 5.25 (1H,
s, H-19), 3.72 (3H, s, –COOMe), 3.09 (1H, d, J¼14.2 Hz, HA-10), 2.98
(1H, d, J¼14.2 Hz, HB-10), 1.18 (3H, s, Me-24), 2.39–1.04 (10H, m),
(film, cmꢁ1): 3415, 2922, 1718, 1457, 1093, 739; 1H NMR
d: 9.46 (1H,
s, H-21), 8.01 (1H, br s, H-1), 7.63 (1H, d, J¼7.0 Hz, H-5), 7.33 (1H, d,
J¼7.0 Hz, H-8), 7.17 (1H, t, J¼7.0 Hz, H-7), 7.11 (1H, t, J¼7.0 Hz, H-6),
6.94 (1H, s, H-2), 5.32 (1H, t, J¼1.5 Hz, H-19), 3.13 (1H, d, J¼17.6 Hz,
H-10A), 3.00 (1H, d, J¼17.6 Hz, H-10B), 2.80 (1H, t, J¼8.4 Hz, H-15),
2.20–1.18 (9H, m), 1.04 (3H, s, Me-24), 0.92 (3H, s, Me-22), 0.85 (3H,
0.88 (3H, s, Me-22), 0.83 (3H, d, J¼6.8 Hz, Me-23); 13C NMR
d: 179.2
(C-21), 141.4 (C-20), 135.6 (C-9), 129.5 (C-4), 123.3 (C-2), 121.5 (C-7),
120.2 (C-6), 119.7 (C-5), 119.2 (C-19), 113.6 (C-3), 111.0 (C-8), 52.1
(–COOMe), 45.4 (C-16), 44.7 (C-11), 38.9 (C-15), 37.9 (C-12), 35.2
(C-10), 31.9 (C-17), 28.7 (C-13), 23.6 (C-22), 22.9 (C-14), 23.0 (C-18),
16.3 (C-23), 18.8 (C-24); EIHRMS: calcd for C24H31NO2 (Mþ):
365.2353, found: 365.2355.
d, J¼7.0 Hz, Me-23); 13C NMR
d: 207.2 (C-21), 123.3 (C-2), 141.5
(C-20), 135.8 (C-9), 129.4 (C-4), 121.7 (C-7), 120.7 (C-6), 119.6 (C-5),
119.3 (C-19), 113.9 (C-3), 111.2 (C-8), 48.5 (C-16), 44.8 (C-11), 38.0
(C-15), 36.2 (C-12), 35.1 (C-10), 28.8 (C-17), 28.2 (C-13), 23.6 (C-22),
23.3 (C-18), 22.4 (C-14), 16.9 (C-24), 16.2 (C-23); EIHRMS: calcd for
C23H29NONa (MþNa): 358.2141, found: 358.2143.
4.1.2. Compound 4. An ice cooled solution of 3 (316 mg, 0.87 mmol)
in Et2O (9 mL), was treated with LAH (33 mg, 0.87 mmol) and the
mixture was stirred at room temperature for 1 h. Then, the reaction
mixture was cooled back to 0 ꢀC, wet Et2O was added and the
mixture was filtered. The resulting organic phase was dried over
4.1.5. Compounds 8/9. To
a
suspension of methoxymethyl-
triphenylphosphonium chloride (812 mg, 2.36 mmol) in THF
(4.7 mL) at ꢁ78 ꢀC under Ar atmosphere, 0.6 M NaHMDS in toluene
(4.0 mL, 2.4 mmol) was added dropwise and the mixture was stir-
red for 30 min. Then a solution of 7 (263 mg, 0.78 mmol) in THF
(4.0 mL) was added dropwise and the resulting mixture was stirred
for 30 min. After that it was allowed to warm up to room temper-
ature, quenched with aqueous saturated NH4Cl and extracted with
Et2O. The organic layer was washed with brine and dried over
Na2SO4. The residue obtained after removing the solvent was
purified by column chromatography (Hex/EtOAc 95/5) to afford the
mixture 8 (99 mg, 33%) and 9 (171 mg, 57%).
Na2SO4, filtered and evaporated to get 4 (283 mg, 97%).
22
Rf (hexane/EtOAc 7:3)¼0.39; [
a
]
ꢁ4.7 (c 0.94, CHCl3); IR (film,
D
cmꢁ1): 3415, 3052, 2925, 1457, 1378, 1040, 908, 737, 665; 1H NMR
d:
7.99 (1H, br s, H-1), 7.61 (1H, dd, J¼6.8 and 1.6 Hz, H-5), 7.33 (1H, dd,
J¼6.8 and 1.6 Hz, H-8), 7.15 (1H, td, J¼6.8 and 1.6 Hz, H-7), 7.06 (1H,
td, J¼6.8 and 1.6 Hz, H-6), 6.95 (1H, d, J¼2.2, H-2), 5.27 (1H, dd, J¼4.0
and 3.0 Hz, H-19), 3.47 (1H, d, J¼10.8 Hz, HA-21), 3.31 (1H, d,
J¼10.8 Hz, HB-21), 3.17 (1H, d, J¼14.6 Hz, HA-10), 2.86 (1H, d,
J¼14.6 Hz, HB-10), 2.36–1.02 (10H, m), 0.93 (3H, s, Me-22), 0.86 (3H, s,
Me-24), 0.84 (3H, d, J¼7.0 Hz, Me-23); 13C NMR
d
: 142.0 (C-20), 135.8
4.1.5.1. Compound 8. Rf¼0.34 (hexane/EtOAc 9:1); [
a
]
ꢁ282.5
22
D
(C-9), 129.4 (C-4), 123.1 (C-2), 121.5 (C-7), 120.5 (C-6), 113.5 (C-3),
119.6 (C-5), 119.2 (C-19), 111.1 (C-8), 70.1 (C-21), 44.9 (C-11), 38.4
(C-15), 37.5 (C-12), 36.9 (C-16), 34.9 (C-10), 29.6 (C-17), 29.5 (C-13),
23.9 (C-22), 23.2 (C-18), 22.7 (C-14), 20.3 (C-24),16.2 (C-23); EIHRMS:
calcd for C23H31NONa (MþþNa): 360.2298, found: 360.2296.
(c 0.02, CHCl3); IR (film, cmꢁ1): 3415, 2929, 1649, 1455, 1379, 1210,
1097, 740; 1H NMR
d
: 7.95 (1H, br s, H-1), 7.63 (1H, d, J¼7.0 Hz, H-5),
7.33 (1H, d, J¼7.0 Hz, H-8), 7.16 (1H, t, J¼7.0 Hz, H-7), 7.10 (1H, t,
J¼7.0 Hz, H-6), 6.98 (1H,br s, H-2), 5.74 (1H, d, J¼7.4 Hz, H-22), 5.25
(1H, t, J¼1.8 Hz, H-19), 4.22 (1H, d, J¼7.4 Hz, H-21), 3.53 (3H, s,
–OMe), 3.06 (1H, d, J¼14.6 Hz, H-10A), 2.96 (1H, d, J¼14.6 Hz,
H-10B), 2.57 (1H, m, H-15), 2.15–1.10 (9H, m), 1.10 (3H, s, Me-24),
4.1.3. Compound 5. To a solution of 4 (890 mg, 2.64 mmol) in dry
pyridine (3.3 mL), Ac2O (3.3 mL) was added and the mixture was
stirred at room temperature overnight. The reaction mixture was
poured into ice-water and extracted with EtOAc. The organic layer
was washed successively with 2 M aqueous HCl, 6% aqueous
NaHCO3 and brine, dried over Na2SO4 and concentrated to afford
a residue, which was purified by column chromatography (Hex/
0.89 (3H, s, Me-22), 0.83 (3H, d, J¼7.0 Hz, Me-23); 13C NMR
d: 145.6
(C-22), 142.2 (C-20), 135.8 (C-9), 123.2 (C-2), 129.6 (C-4), 121.5 (C-7),
120.7 (C-5), 119.7 (C-6), 119.2 (C-19), 117.1 (C-21), 113.9 (C-3), 111.0
(C-8), 59.8 (–OMe), 44.7 (C-11), 42.8 (C-15), 38.4 (C-12), 36.8 (C-16),
34.9 (C-10), 32.6 (C-17), 29.3 (C-13), 23.5 (C-18), 23.4 (C-14), 23.1
(C-27), 22.4 (C-29)16.3 (C-28); EIHRMS: calcd for C25H33NONa
(MþNa): 386.2454, found: 386.2456.
EtOAc 9/1) to afford 5 (293 mg, 95%).
22
Rf¼0.49 (hexane/EtOAc 8:2); [
a
]
ꢁ15.2 (c 0.97, CHCl3); IR (film,
D
cmꢁ1): 3409, 3052, 2926, 1740, 1458, 1376, 1242, 1035, 739, 666; 1H
NMR
4.1.5.2. Compound 9. Rf¼0.30 (hexane/EtOAc 9:1); [
a
]
ꢁ47.4 (c
22
D
d
: 8.10 (1H, br s, H-1), 7.59 (1H, dd, J¼7.0 and 1.6 Hz, H-5), 7.30
0.03, CHCl3); IR (film, cmꢁ1): 3415, 2929,1649,1455,1379,1210,1097,
740; 1H NMR
: 8.01 (1H, br s, H-1), 7.62 (1H, d, J¼7.2 Hz), 7.34 (1H, d,
J¼7.2 Hz, H-8), 7.17 (1H, t, J¼7.2 Hz, H-7), 7.10 (1H, t, J¼7.2 Hz, H-6),
(1H, dd, J¼7.0 and 1.6 Hz, H-8), 7.14 (1H, td, J¼7.0 and 1.6 Hz, H-7),
7.08 (1H, td, J¼7.0 and 1.6 Hz, H-6), 6.89 (1H, d, J¼2.2, H-2), 5.29 (1H,
d

10240
I.S. Marcos et al. / Tetrahedron 65 (2009) 10235–10242
6.93 (1H, br s, H-2), 6.30 (1H, d, J¼12.8 Hz, H-22), 5.30 (1H, br s,
H-19), 4.91 (1H, d, J¼12.8 Hz, H-21), 3.54 (3H, s, –OMe), 3.02 (1H, d,
J¼14.0 Hz, H-10A), 2.96 (1H, d, J¼14.0 Hz, H-10B), 2.57 (1H, m, H-15),
2.15–1.12 (9H, m), 0.98 (3H, s, Me-24), 0.91 (3H, s Me-22), 0.83 (3H, d,
H-10B), 2.18–1.10 (14H, m), 1.98 (2H, t, J¼6.6 Hz, H-23), 1.71 (3H, s,
Me-26), 0.88 (3H, s, Me-27), 0.83 (3H, s, Me-29), 0.81 (3H, d,
J¼7.0 Hz, Me-28); 13C NMR (100 MHz, CDCl3)
d: 146.3 (C-24), 143.2
(C-20), 135.5 (C-9), 129.3 (C-4), 122.7 (C-2), 121.3 (C-7), 120.2 (C-6),
119.4 (C-5), 118.9 (C-19), 113.6 (C-3), 110.9 (C-8), 109.6 (C-25), 44.4
(C-11), 41.7 (C-15), 40.0 (C-21), 38.7 (C-23), 38.0 (C-12), 34.2 (C-16),
34.1 (C-10), 31.5 (C-17), 29.0 (C-13), 23.4 (C-27), 22.8 (C-14), 22.6
(C-18), 22.4 (C-26), 22.2 (C-29), 21.5 (C-22), 15.9 (C-28).
J¼7.0 Hz, Me-23); 13C NMR
d: 145.9 (C-22), 141.8 (C-20), 135.8 (C-9),
129.5 (C-4), 123.2 (C-2), 121.6 (C-7), 120.6 (C-5), 119.7 (C-6), 119.2
(C-19), 115.1 (C-21), 113.7 (C-3), 111.1 (C-8), 56.4 (–OMe), 44.6 (C-11),
43.4 (C-15), 37.8 (C-12), 36.9 (C-16), 35.5 (C-10), 29.0 (C-17), 28.7 (C-
13), 23.9 (C-27), 23.2 (C-18), 20.7 (C-29), 22.2 (C-14), 16.3 (C-28);
EIHRMS: calcd for C25H33NONa (MþNa): 386.2454, found: 386.2456.
4.1.9. Compound 13. To a mixture of NaH (365 mg 60% in mineral
oil, 15.22 mmol) and benzene (6.0 mL) cooled at 0 ꢀC, methyl
diethylphosphonoacetate (1.8 mL) was added under argon atmo-
sphere and the resulting solution was stirred at room temperature
15 min. Then a solution of 7 (298 mg, 0.89 mmol) in benzene
(3.0 mL) was added via canula and the mixture was stirred 30 min
at room temperature. Then it was quenched with saturated NH4Cl
aqueous solution and extracted with EtOAc. The organic layer was
washed with brine and dried over Na2SO4. The solvent was evap-
orated to give a crude oil, which was chromatographed on silica gel
4.1.6. Compound 10. To a solution of the mixture 8/9 (39 mg,
0.11 mmol) in acetone/H2O 98:2 (3.6 mL), p-toluenesulfonic acid
(7 mg, 0.035 mmol) was added at room temperature and the mix-
ture was stirred for 3 h. It was quenched by adding water and
extracted with Et2O. The organic layer was washed with a 6%
aqueous NaHCO3 and brine and dried over Na2SO4. The residue
obtained after removing the solvent was purified by column
chromatography (Hex/EtOAc 8/2) to afford 10 (14 mg, 36%).
22
Rf¼0.21 (hexane/EtOAc 7:3); [
a
]
ꢁ8.21 (c 0.03, CHCl3); IR (film,
(Hex/EtOAc 9/1) to afford 13 (265 mg, 73%).
D
cmꢁ1): 3583, 3414, 2925, 1456, 1380, 1092; 1H NMR
d
: 7.98 (1H, br s,
Rf¼0.47 (hexane/EtOAc 8:2); [
a
]
D
ꢁ66.2 (c 0.06, CHCl3); IR (film,
22
H-1), 7.61 (1H, dd, J¼7.0 and 1.8 Hz, H-5), 7.34 (1H, dd, J¼7.0 and
1.8 Hz, H-8), 7.17 (1H, dt, J¼7.0 and 1.8 Hz, H-7), 7.10 (1H, dt, J¼7.0
and 1.8 Hz, H-6), 6.96 (1H, d, J¼2.6 Hz, H-2), 5.32 (1H, br s, H-19),
3.68 (1H, ddd, J¼11.0, 7.0 and 7.0 Hz, H-22A), 3.64 (1H, ddd, J¼11.0,
7.0 and 7.0 Hz, H-22B), 3.08 (1H, d, J¼14.6 Hz, H-10A), 2.92 (1H, d,
J¼14.6 Hz, H-10B), 2.15–1.05 (12H, m), 0.93 (3H, s, Me-27), 0.87 (3H,s,
cmꢁ1): 3413, 3054, 2925, 1702, 1644, 1456, 1379, 1307, 1184, 1095,
1036, 739; 1H NMR
d
: 8.19 (1H, br s, H-1), 7.63 (1H, d, J¼7.0 Hz, H-5),
7.32 (1H, d, J¼7.0 Hz, H-8), 7.12 (1H, d, J¼14.0 Hz, H-21), 7.12 (1H, t,
J¼7.0 Hz, H-7), 7.08 (1H, t, J¼7.0 Hz, H-7), 6.91 (1H, d, J¼2.2 Hz, H-
2), 5.87 (1H, d, J¼14.0 Hz, H-22), 5.32 (1H,br s, H-19), 4.28 (2H, c,
J¼7.0 Hz, –OCH2CH3), 3.06 (1H, d, J¼14.2 Hz, H-10A), 2.93 (1H, d,
J¼14.2 Hz, H-10B), 2.40–1.08 (10H, m), 1.34 (3H, t, J¼7.0 Hz,
–OCH2CH3), 1.06 (3H, s, Me-29), 0.91 (3H, s, Me-27), 0.85 (3H, d,
Me-29), 0.82 (3H, d, J¼7.0 Hz, Me-28); 13C NMR
d: 142.2 (C-20),135.8
(C-9), 129.5 (C-4), 123.0 (C-2), 121.7 (C-7), 120.3 (C-6), 119.7 (C-5),
119.3 (C-19), 113.7 (C-3), 111.1 (C-8), 59.9 (C-22), 44.7 (C-11), 42.9 (C-
21), 41.9 (C-15), 38.1 (C-12), 35.0 (C-10), 33.9 (C-16), 32.3 (C-17), 29.3
(C-13), 23.8 (C-27), 23.1 (C-18), 23.0 (C-29), 22.8 (C-14), 16.2 (C-28);
EIHRMS: calcd for C24H33NONa (MþNa): 374.2454, found: 374.2467.
J¼7.0 Hz, Me-28); 13C NMR
d: 167.8 (C-23), 159.5 (C-21), 141.2
(C-20), 135.9 (C-9), 129.5 (C-4), 123.5 (C-2), 121.5 (C-7), 120.7 (C-6),
119.6 (C-5), 119.2 (C-19), 118.2 (C-22), 113.3 (C-3), 111.2 (C-8), 60.6
(-OCH2CH3), 44.9 (C-11), 41.6 (C-15), 38.9 (C-16), 37.9 (C-12), 35.3
(C-10), 33.4 (C-17), 28.9 (C-13), 22.9 (C-14), 22.9 (C-18), 23.9 (C-27),
20.0 (C-29), 16.3 (C-28), 14.6 (–OCH2CH3); EIHRMS: calcd for
C27H35NO2Na (MþNa): 428.5600, found (MþNa) 428.2568.
4.1.7. Compound 11. To a solution of 10 (16 mg, 0.045 mmol) in
pyridine (0.22 mL) was added TsCl (29 mg, 0.152 mmol) and the
mixture was stirred at room temperature for 1 h and 30 min. The
reaction mixture was poured into ice-water and extracted with
Et2O. The extracts were washed successively with 2 M aqueous HCl,
6% aqueous NaHCO3 and brine and dried over Na2SO4. Filtration,
4.1.10. Compound 14. To a solution of 13 (147 mg, 0.36 mmol) and
Wilkinson’s catalyst (Ph3P)3RhCl (53 mg, 0.057 mmol) in benzene
(3.6 mL) under Ar atmosphere was added Et3SiH (0.6 mL, 3.6 mmol)
and the mixture was stirred at 70 ꢀC for 14 h. Then it was allowed to
cool to room temperature and it was quenched with 2 M aqueous
HCl. Water was added and the solution was extracted with EtOAc.
The organic layer was washed with 6% aqueous NaHCO3 and brine,
dried over Na2SO4, filtered and concentrated to give a residue that
was chromatographed on silica gel (Hex/EtOAc 95/5) to yield 14
and evaporation of the solvent gave 11 (19 mg, 80%).
22
Rf¼0.41 (hexane/EtOAc 9:1); [
a
]
ꢁ21.1 (c 0.01, CHCl3); IR (film,
D
cmꢁ1): 3422, 1655; 1H NMR
d
: 8.00 (1H, s, H-1), 7.75 (2H, d,
J¼8.4 Hz, H-20 and H-60), 7.57 (1H, d, J¼7.0 Hz, H-5), 7.34 (1H, d,
J¼7.0 Hz, H-8), 7.28 (2H, d, J¼8.4 Hz, H-30 and H-40), 7.16 (1H, t,
J¼7.0 Hz, H-7), 7.09 (1H, t, J¼7.0 Hz, H-6), 6.91 (1H, d, J¼2.0 Hz,
H-2), 5.29 (1H, t, J¼2.8 Hz, H-19), 4.08 (2H, m, H-22), 2.97 (1H, d,
J¼14.4 Hz, H-10A), 2.88 (1H, d, J¼14.4 Hz, H-10B), 2.38 (3H, s,
MeC6H4SO3ꢁ), 2.18–1.03 (12H, m), 0.90 (3H, s, Me-27), 0.81 (3H, s,
Me-29), 0.79 (3H, d, J¼7.0 Hz, Me-28).
145 mg (99%).
22
Rf¼0.51 (hexane/EtOAc 8:2); [
a
]
ꢁ22.9 (c 0.08, CHCl3); IR (film,
D
cmꢁ1): 3412, 2922, 1718, 1457, 1096; 1H NMR
d: 8.07 (1H, br s, H-1),
7.60 (1H, d, J¼7.6 Hz, H-5), 7.31 (1H, d, J¼7.6 Hz, H-8), 7.16 (1H, t,
J¼7.6 Hz, H-7), 7.10 (1H, t, J¼7.6 Hz, H-6), 6.93 (1H, d, J¼2.0 Hz, H-2),
5.31 (1H, br s, H-19), 4.17 (2H, c, J¼7.0 Hz, –OCH2CH3), 3.07 (1H, d,
J¼14.4 Hz, H-10A), 2.93 (1H, d, J¼14.4 Hz, H-10B), 2.38–1.08 (14H,
m),1.26 (3H, t, J¼7.0 Hz, –OCH2CH3), 0.94 (3H, s, Me-29), 0.85 (3H, s,
4.1.8. Compound 12. To a solution of 11 (23 mg, 0.045 mmol) in
tetrahydrofuran (0.22 mL) cooled at 0 ꢀC under Ar atmosphere
0.5 M in THF 2-methylpropenylmagnesium chloride (3.15 mL,
1.55 mmol) was added and the mixture stirred at room tempera-
ture overnight. Then, the solution was cooled back to 0 ꢀC,
quenched with saturated NH4Cl aqueous solution and extracted
with Et2O. The organic layer was washed with brine and dried over
Na2SO4. The residue was chromatographed on silica gel (Hex/EtOAc
Me-27), 0.83 (3H, d, J¼7.0 Hz, Me-28); 13C NMR
d: 175.0 (C-23),
142.1 (C-20), 135.9 (C-9), 129.5 (C-4), 123.2 (C-2), 121.6 (C-7), 120.4
(C-6), 119.6 (C-5), 119.2 (C-19), 113.6 (C-3), 111.1 (C-8), 60.6
(–OCH2CH3), 44.8 (C-11), 41.6 (C-15), 38.2 (C-12), 35.0 (C-10), 35.0
(C-21), 34.2 (C-16), 31.5 (C-17), 29.4 (C-22), 29.2 (C-13), 22.9 (C-14),
23.7 (C-27), 23.1 (C-18), 22.2 (C-29), 16.2 (C-28), 14.5 (–OCH2CH3);
EIHRMS: calcd for C27H37NO2Na (MþNa): 430.2717, found:
430.2700.
98/2) to yield 12 (10 mg, 58%).
22
Rf¼0.74 (hexane/EtOAc 95:5); [
a
]
ꢁ22.6 (c 0.01, CHCl3); IR
D
(film, cmꢁ1): 3412, 2958,1458, 1383, 1261,1094; 1H NMR (400 MHz,
CDCl3)
d
: 7.95 (1H, br s, H-1), 7.61 (1H, d, J¼7.6 Hz, H-5), 7.33 (1H, d,
J¼7.6 Hz, H-8), 7.15 (1H, t, J¼7.6 Hz, H-7), 7.11 (1H, t, J¼7.6 Hz, H-6),
6.93 (1H, s, H-2), 5.27 (1H, s, H-19), 4.71 (1H, s, H-25A), 4.68 (1H, s,
H-25B), 3.05 (1H, d, J¼14.5 Hz, H-10A), 2.93 (1H, d, J¼14.5 Hz,
4.1.11. Compound 15. An ice cooled solution of 14 (116 mg,
0.285 mmol) in dry Et2O (2.9 mL) was treated with LiAlH4 (50 mg,
1.31 mmol) and the mixture was stirred at room temperature for

I.S. Marcos et al. / Tetrahedron 65 (2009) 10235–10242
10241
45 min. Then, the solution was cooled back to 0 ꢀC, wet Et2O was
added and the mixture was filtered. The resulting organic phase was
2.92 (1H, d, J¼14.2 Hz, H-10B), 2.15–1.10 (14H, m), 0.93 (3H, s, Me-
29), 0.89 (6H, d, J¼6.6 Hz, Me-25 and Me-26), 0.83 (3H, s, Me-29),
dried over Na2SO4, filtered and evaporated affording 15 (97 mg, 93%).
0.83 (3H, d, J¼7.0 Hz, Me-28); 13C NMR
d: 142.3 (C-20), 135.8 (C-9),
22
Rf¼0.36 (hexane/EtOAc 7:3); [
a
]
ꢁ3.3 (c 0.08, CHCl3); IR (film,
129.5 (C-4), 123.1 (C-2), 121.6 (C-7), 120.4 (C-6), 119.6 (C-5), 119.2
(C-19), 113.8 (C-3), 111.0 (C-8), 77.9 (C-23), 44.7 (C-11), 42.1 (C-15),
38.3 (C-12), 36.3 (C-21), 34.9 (C-10), 34.2 (C-16), 33.3 (C-24), 31.5
(C-17), 29.4 (C-22), 28.3 (C-13), 23.8 (C-27), 23.3 (C-18), 23.0 (C-14),
22.7 (C-29), 19.3 (C-25), 17.2 (C-26), 16.2 (C-28); EIHRMS: calcd for
C28H41NONa (MþNa): 430.3080, found: 430.3083.
D
cmꢁ1): 3416, 2954, 1456, 1060, 739; 1H NMR
d
: 8.18 (1H, br s, H-1),
7.63 (1H, d, J¼7.0 Hz, H-5), 7.32 (1H, d, J¼7.0 Hz, H-8), 7.17 (1H, t,
J¼7.0 Hz, H-7), 7.10 (1H, t, J¼7.0 Hz, H-6), 6.94 (1H, br s, H-2), 5.32
(1H, br s, H-19), 3.55 (2H, t, J¼7.0 Hz, H-23), 3.10 (1H, d, J¼14.6 Hz,
H-10A), 2.91 (1H, d, J¼14.6 Hz, H-10B), 2.28–1.10 (15H, m), 0.93 (3H,
s, Me-29), 0.84 (3H, d, J¼7.0 Hz, Me-28), 0.83 (3H, s, Me-27); 13C
NMR
d: 142.3 (C-20), 135.8 (C-9), 129.5 (C-4), 123.1 (C-2), 121.6 (C-
4.1.15. Compound 20. To a solution of 19 (19 mg, 0.05 mmol) in dry
pyridine (1.0 mL), acetic anhydride (1.0 mL) was added and the
mixture was stirred for 13 h at room temperature. The reaction
mixture was poured then into ice-water and extracted with EtOAc.
The organic layer was washed successively with aqueous 2 M HCl,
aqueous 6% NaHCO3 and brine. It was then dried over Na2SO4
filtered and evaporated to yield 20 (22 mg, 98%).
7), 120.3 (C-6), 119.6 (C-5), 119.2 (C-19), 113.6 (C-3), 111.1 (C-8), 64.2
(C-23), 44.7 (C-11), 41.9 (C-15), 38.4 (C-12), 36.1 (C-21), 34.5 (C-10),
34.1 (C-16), 31.5 (C-17), 29.5 (C-13), 27.2 (C-22), 23.8 (C-18), 23.3
(C-27), 23.0 (C-29), 22.8 (C-14), 16.2 (C-28); EIHRMS: calcd for
C25H35NONa (MþNa): 388.2611, found: 388.2595.
4.1.12. Compound 16. To a solution of 15 (41 mg, 0.113 mmol) in dry
pyridine (0.3 mL), acetic anhydride (0.3 mL) was added and the
mixture was stirred overnight at room temperature. The reaction
mixture was poured into ice-water and extracted with EtOAc. The
organic layer was washed successively with aqueous 2 M HCl,
aqueous 6% NaHCO3 and brine and the resulting solution was then
Rf¼0.47 (hexane/EtOAc 9:1); IR (film, cmꢁ1): 3399, 2923, 1720,
1459, 1384, 1246, 1093; 1H NMR
d: 8.37 (1H, br s, H-1), 7.59 (1H, d,
J¼7.0 Hz, H-5), 7.33 (1H, d, J¼7.0 Hz, H-8), 7.14 (1H, t, J¼7.0 Hz, H-6),
7.08 (1H, t, J¼7.0 Hz, H-7), 6.90 (1H, br s, H-2), 5.21 (1H, br s, H-19),
4.81 (1H, m, H-23), 4.65 (1H, m, H-230), 3.30 (1H, d, J¼14.4 Hz,
H-10A), 2.74 (1H, d, J¼14.4 Hz, H-10B), 2.15–1.10 (14H, m), 2.09 (3H,
s, –OOCMe), 2.00 (3H, s, –OOCMe0), 0.92 (3H, d, J¼6.6 Hz, Me-25),
0.90 (3H, s, Me-29), 0.89 (3H, d, J¼6.6 Hz, Me-26), 0.84 (3H, s, Me-
27), 0.83 (3H, d, J¼6.8 Hz, Me-28); EIHRMS: calcd for C30H43NO2Na
(MþNa): 472.3186 found: 472.3171.
dried over Na2SO4 and evaporated to yield 16 (43 mg, 94%).
22
Rf¼0.36 (hexane/EtOAc 7:3); [
a
]
ꢁ3.3 (c 0.08, CHCl3); IR (film,
D
cmꢁ1): 3413, 2927, 1735, 1457, 1383, 1244, 1052, 739; 1H NMR
d:
8.06 (1H, br s, H-1), 7.61 (1H, d, J¼7.0 Hz, H-5), 7.34 (1H, d, J¼7.0 Hz,
H-8), 7.17 (1H, t, J¼7.0 Hz, H-7), 7.12 (1H, t, J¼7.0 Hz, H-6), 7.05 (1H,
s, H-2), 5.29 (1H, br s, H-19), 4.03 (2H, t, J¼6.6 Hz, H-23), 3.11 (1H, d,
J¼14.4 Hz, H-10A), 2.90 (1H, d, J¼14.4 Hz, H-10B), 2.15–1.20 (14H,
m), 2.05 (3H, s, CH3COO–), 0.94 (3H, s, Me-29), 0.84 (3H, s, Me-27),
4.1.16. Compound 6. To a solution of 5 (920 mg, 2.43 mmol) in
benzene (140 mL) was added 57% aqueous HI (0.5 mL) and the
mixture was stirred at 85 ꢀC for 45 min. The reaction mixture was
diluted with Et2O and washed with 10% aqueous NaHSO3, 6%
aqueous NaHCO3 and brine. Evaporation of the solvent after drying
0.82 (3H, d, J¼6.8 Hz, Me-28); 13C NMR
d: 171.6 (MeCOO–), 142.2
(C-20), 135.8 (C-9), 129.5 (C-4), 123.0 (C-2), 121.6 (C-7), 120.4 (C-6),
119.6 (C-5), 119.2 (C-19), 113.6 (C-3), 111.1 (C-8), 65.6 (C-23), 44.8
(C-11), 42.0 (C-15), 38.5 (C-12), 36.1 (C-21), 34.9 (C-10), 34.2 (C-16),
31.2 (C-22), 29.9 (C-17), 29.4 (C-13), 23.7 (C-27), 23.3 (C-18), 23.0
(C-14), 22.6 (MeCOO–), 21.3 (C-29), 16.2 (C-28).
over Na2SO4 gave 6 (910 mg, 98%).
22
[a
]
þ51.3 (c 0.52, CHCl3); IR (film, cmꢁ1): 3368, 2929, 1739,
D
1610, 1464, 1371, 1242, 1036, 738, 667; 1H NMR (400 MHz)
d: 7.07
(1H, d, J¼7.4 Hz, H-5), 7.01 (1H, t, J¼7.4 Hz, H-7), 6.70 (1H, t,
J¼7.4 Hz, H-6), 6.64 (1H, d, J¼7.4 Hz, H-8), 4.08 (1H, d, J¼10.8 Hz,
HA-21), 3.99 (1H, d, J¼10.8 Hz, HB-21), 3.77 (1H, dd, J¼6.0 and
4.6 Hz, H-2), 3.11 (1H, dt, J¼12.2 and 6.0 Hz, H-3), 2.71–2.64 (1H, m,
H-19), 2.03 (3H, s, –OOCMe), 2.15–1.18 (11H, m), 1.03 (3H, s, Me-22),
4.1.13. Compound 18. To a mixture of 15 (63 mg, 0.173 mmol), N-
methylmorpholine-N-oxide (NMO) (69 mg, 0.51 mmol) and mo-
lecular sieves (110 mg, 500 mg/mmol) in anhydrous CH2Cl2 (1.1 mL)
under Ar at room temperature, TPAP (3 mg, 0.01 mmol) was added
and the mixture was stirred for 20 min. The reaction mixture was
filtered through a pad of Celite and silica gel and washed with
CH2Cl2 and EtOAc. Evaporation of the solvent yielded the aldehyde
18 (56 mg, 90%).
1.02 (3H, s, Me-24), 0.84 (3H, d, J¼6.4 Hz, Me-23); 13C NMR
d: 171.4
(–OOCMe), 149.9 (C-9), 135.7 (C-4), 135.3 (C-20), 133.3 (C-15), 127.1
(C-7), 123.1 (C-5), 118.7 (C-6), 110.0 (C-8), 70.0 (C-21), 66.6 (C-2),
41.8 (C-10), 40.2 (C-12), 38.5 (C-3), 38.5 (C-16), 38.0 (C-11), 33.6
(C-19), 31.7 (C-17), 27.0 (C-13), 25.7 (C-14), 23.5 (C-18), 23.0 (C-24),
21.0 (–OOCMe), 18.1 (C-22), 16.2 (C-23); EIHRMS: calcd for
C25H34NO2 (MþþH) 380.2584, found: 380.2574.
1H NMR
d: 9.67 (1H, br s, H-23), 8.07 (1H, br s, H-1), 7.60 (1H, d,
J¼7.0 Hz, H-5), 7.32 (1H, d, J¼7.0 Hz, H-8), 7.15 (1H, t, J¼7.0 Hz, H-7),
7.09 (1H, t, J¼7.0 Hz, H-6), 6.94 (1H, br s, H-2), 5.33 (1H, br s, H-19),
3.12 (1H, d, J¼14.0 Hz, H-10A), 2.90 (1H, d, J¼14.0 Hz, H-10B), 2.40–
1.10 (14H, m), 0.95 (3H, s, Me-29), 0.82 (3H, d, J¼6.8 Hz, Me-28),
0.81 (3H, s, Me-27).
4.1.17. Compound 17. To a solution of 16 (43 mg, 0.106 mmol) in
benzene (7.0 mL) was added 57% aqueous HI (0.02 mL) and the
mixture was stirred at 85 ꢀC for 2 h. The reaction mixture was di-
luted with Et2O and washed with 10% aqueous NaHSO3, 6% aqueous
NaHCO3 and brine. Evaporation of the solvent after drying over
Na2SO4 gave a residue, which was chromatographed on silica gel
4.1.14. Compound 19. To a solution of 18 (25 mg, 0.07 mmol) in tet-
rahydrofuran (0.4 mL) cooled at 0 ꢀCunderAratmosphere2.0 MinTHF,
isopropenylmagnesium chloride (1.8 mL, 3.6 mmol) was added and the
mixture stirred at room temperature overnight. It was cooled back to
0 ꢀC, quenched with saturated NH4Cl aqueous solution and extracted
with EtOAc. The organic layer was washed with brine, dried over
Na2SO4, filtered and concentrated to give a residue that was chroma-
(Hex/EtOAc 95/5) to afford 17 (25 mg, 59%).
22
Rf¼0.61 (hexane/Et OAc8:2); [
a
]
D
þ80.3 (c 0.02, CHCl3); IR (film,
cmꢁ1): 3368, 2924, 1736, 1482, 1383, 1244, 1040; 1H NMR
(400 MHz, C6D6)
d
: 7.21 (1H, br s, H-1), 7.13 (1H, d, J¼7.2 Hz, H-5),
7.12 (1H, t, J¼7.2 Hz, H-7), 6.87 (1H, t, J¼7.2 Hz, H-6), 6.60 (1H, d,
J¼7.2 Hz, H-8), 4.05 (2H, m, H-23), 3.47 (1H, dd, J¼6.0 and 4.0 Hz, H-
2), 3.00 (1H, dt, J¼12.0 and 6.0 Hz, H-3), 2.46 (1H, br s, H-19), 2.10–
1.10 (15H, m), 1.73 (3H, s, MeCOO–), 1.00 (3H, s, Me-29), 0.96 (3H, s,
tographed on silica gel (Hex/EtOAc 98/2) to yield 19 (13 mg, 44%).
22
Rf¼0.29 (hexane/EtOAc 75:25); [
a
]
D
ꢁ10.9 (c 0.04, CHCl3); IR
(film, cmꢁ1): 3411, 2927, 1458, 1384, 1092; 1H NMR
d
: 8.03 (1H,br s,
H-1), 7.61 (1H, d, J¼7.0 Hz, H-5), 7.32 (1H, d, J¼7.0 Hz, H-8), 7.19 (1H,
t, J¼7.0 Hz, H-6), 7.13 (1H, t, J¼7.0 Hz, H-7), 6.97 (1H, s, H-2), 5.31
(1H, br s, H-19), 3.25 (1H, m, H-23), 3.10 (1H, d, J¼14.2 Hz, H-10A),
Me-27), 0.82 (3H, d, J¼6.8 Hz, Me-28); 13C NMR (100 MHz, C6D6)
d:
169.9 (MeCOO–), 150.5 (C-9), 135.9 (C-4), 135.3 (C-20), 134.0 (C-15),
127.1 (C-7), 123.3 (C-5), 118.2 (C-6), 110.2 (C-8), 67.2 (C-2), 65.0

10242
I.S. Marcos et al. / Tetrahedron 65 (2009) 10235–10242
3. (a) Gloer, J. B.; Rinderkmecht, B. L. J. Org. Chem. 1989, 54, 2530; (b) Belofsky, G.
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6987.
(C-23), 42.5 (C-10), 40.6 (C-12), 39.0 (C-3), 38.1 (C-16), 37.0 (C-11),
36.1 (C-21), 33.1 (C-19), 32.3 (C-17), 27.2 (C-13), 25.8 (C-14), 25.8 (C-
27), 23.7 (C-22), 23.5 (C-18), 20.3 (MeCOO–),17.6 (C-29),16.2 (C-28).
5. Gatenby, W. A.; Munday-Finch, S. C.; Wilkins, A. L.; Miles, C. O. J. Agric. Food
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Acknowledgements
´
D.; Mollinedo, F.; Urones, J. G.
7. Marcos, I. S.; Escola, M. A.; Moro, R. F.; Dıez,
Synlett 2007, 2017.
The authors gratefully acknowledge the help of A. Lithgow (NMR)
and C. Raposo (MS) of Universidad de Salamanca and MICINN
8. Li, C.; Gloer, J. B.; Wicklow, D. T. J. Nat. Prod. 2003, 66, 1232.
9. Bradshaw, B.; Etxebarria-Jardı´, G.; Bonjoch, J. Org. Biomol. Chem. 2008, 6,
7772.
´
(CTQ2009-11557BQU), JuntadeCastilllayLeonGR-178andSA063A07
´
for financial support. I.C. is grateful to the Junta de Castilla y Leon for
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The Fischer Indole Synthesis; Wiley-Interscience: New York, NY, 1982;
(c) Trudell, M. L.; Fukada, N.; Cook, J. M. J. Org. Chem. 1987, 52, 4293.
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a fellowship. Dr. Howard B. Broughton helped with proof-reading.
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