Mild and rapid method for the generation of o-quinone methide intermediates. Synthesis of puupehedione analogues

Article abstract of DOI:10.1016/j.tet.2006.04.004

A route to simpler analogues to bioactive puupehedione derivatives involving a hetero Diels-Alder cycloaddition of a o-quinone methide is described. These intermediate species are generated via fluoride-induced desilylation of silyl derivatives of o-hydro

Full text of DOI:10.1016/j.tet.2006.04.004

Tetrahedron 62 (2006) 6012–6017
Mild and rapid method for the generation of o-quinone methide
intermediates. Synthesis of puupehedione analogues
a
a
a
Alejandro F. Barrero,a, Jose F. Quılez del Moral, M. Mar Herrador, Pilar Arteaga,
*
´
Manuel Cortes, Julio Benites and Antonio Rosellon
´
b
a
a
´
ꢀ
aDepartment of Organic Chemistry, Institute of Biotechnology, University of Granada, Avda. Fuentenueva, 18071 Granada, Spain
b
´
Facultad de Quımica, Pontificia Universidad Catolica de Chile, Casilla 306, Correo 22, Santiago, Chile
ꢀ
Received 23 February 2006; revised 31 March 2006; accepted 3 April 2006
Available online 4 May 2006
Abstract—A route to simpler analogues to bioactive puupehedione derivatives involving a hetero Diels–Alder cycloaddition of a o-quinone
methide is described. These intermediate species are generated via fluoride-induced desilylation of silyl derivatives of o-hydroxybenzyl
iodides. Remarkable short reaction times and very mild experimental conditions are the main features of this method.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
of materials appropriate for clinical follow-up has led
to much research to develop simpler and more accessible
analogues for broad biological evaluation.4 In this context,
we devised that the benzopyran nucleus of these compounds
could be generated by reaction of o-quinone methides inter-
mediates, obtained via fluoride-induced desilylation o-silyl-
oxybenzyl derivatives, with appropriate dienophiles (Scheme
1). Although different reports on this subject were described
by Rokita et al.,5 this group used the o-quinone methide in
DNA alkylating studies. Thus, to our knowledge, the only
use of this reaction in organic synthesis was described by
Young et al., in their synthesis of (ꢀ)-thielocin Alb.6
The benzopyran moiety is contained in a variety of natural
products, many of which present interesting biological
properties.1 Among them, puupehedione (1) and other
related marine derivatives, as puupehenone (2) and 15-oxo-
puupehenol (3), have been attracting our attention during
the last years due to the wide range of biological properties
they present, including antitumor, antiviral antimalarial,
antibiotic antituberculosis, antioxidant, insecticidal and
antifungal activities.2
OH
O
OH
OH
O
O
R
R
O
F
X
O
O
O
O
OTBS
O
Y
Y
X: leaving group
1
2
3
Scheme 1.
Thus, as a part of a programme to identify useful anti-
angiogenic agents, some of us proved that some puupehe-
dione-related derivatives completely inhibited the in vivo
angiogenesis in the CAM assay at doses equal or lower
than 30 nmol/egg, which makes them attractive drugs for
further evaluation.3 The scarce availability of many bio-
active compounds from their natural sources together with
the impracticality of many syntheses for producing amounts
o-Quinone methides are extremely reactive transient spe-
cies, which undergo dimerisation processes in the absence
of nucleophiles or electron-rich alkenes.7 Although different
strategies have been reported for their generation, most of
them rely on the use of catalysts, acidic or basic conditions,
high temperatures or long reaction times.8 Among the recent
advances in this subject,9 special relevance should be given
to the works of Pettus et al., which include a low-temperature
anionic method for generating o-quinone methides and their
enantioselective cycloaddition with a chiral enol ether.10
Keywords: Cyclisation; Epoxides; Titanium; Radical reaction; Terpenoids.
* Corresponding author. Tel./fax: +34 958 243318; e-mail: afbarre@ugr.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.004

A. F. Barrero et al. / Tetrahedron 62 (2006) 6012–6017
6013
To start the development of this synthetic method, we ad-
dressed the search of the corresponding oxa-dienic precursor
starting from commercial 2,5-dihydroxybenzaldehyde, 4,
following the straightforward transformations shown in
Scheme 2.
of the potential nucleophilic salt TBAI, by-product of the
reaction). It is worth noting that this yield was obtained in
a very short reaction time, 2 min, and at room temperature,
which are unprecedently mild experimental conditions for
this kind of reaction. Although the use of the corresponding
enol ether as the solvent for the reaction has been reported to
increase the yield in many of these hetero Diels–Alder pro-
cesses,12 different assays were performed in order to check
to what extent the quantity of ethyl vinyl ether could be
lowered (entries 6–9, Table 1). Thus, an acceptable yield
was still obtained using 35 equiv of ethyl vinyl ether, only
a moderate result was found when the quantity of this
reagent was reduced to 20 equiv, while the use of 10 equiv
led to minor quantities of the desired adduct.
OH
OBn
OBn
(c)
(b)
(a)
H
OHC
OHC
OH
OH
O
OTBS
4
5
6
OBn
OBn
(d)
8a
8b
8c
8a R = OAc
8b R = OTs
8c R = I
(e)
(f)
Having found the conditions to efficiently achieve the gener-
ation and ensuing cycloaddition of the o-quinone methide
derived from 8c, we then turned our efforts to study the ver-
satility of this process. Thus, two variations of this protocol
were studied. On one hand, 8c was caused to react with other
dienophiles as 10 and 12 (Scheme 3).
OH OTBS
7
R
OTBS
8
Scheme 2. Reagents and conditions: (a) NaHCO3, KI, BnBr, CH3CN,
reflux, 24 h, 51%; (b) TBSCl, imidazole, DMF, rt, 4 h, 82%; (c) NaBH4,
MeOH, rt, 2 h, 98%; (d) Ac2O, Py, rt, 42 h, 94%; (e) TsCl, Py, DMAP, reflux,
7 h, 68%; (f) Ph3P, imidazole, I2, CH3CN/toluene, 60 ꢁC, 10 min, 83%.
OBn
OBn
Thus, 4 was monobenzylated using the mixture BnBr, KI
and NaHCO3 to afford 5 in a 51% yield. An additional
11
(a)
SEt
10
+
+
36% of the corresponding dibenzylated derivative was also
obtained. Protection of the hydroxyl group of 5 as silyl ether
and subsequent treatment with NaBH4 furnished primary
alcohol 7. Different leaving groups were then installed on
this primary position (8a–8c) in order to test our hypothesis.
The results obtained in the reaction of these derivatives with
ethyl vinyl ether in the presence of TBAF are shown in
Table 1.
O
I
OTBS
8c
SEt
11 (83%)
OBn
OBn
OH
OBn
OEt
OEt
12
(a)
+
O
EtO2C
I
OTBS
8c
14 (18%)
EtO OEt
13 (56%)
When the corresponding acetate or tosylate benzyl deriva-
tives were treated for 10 min with TBAF (1.5 equiv) in the
presence of 100 equiv of ethyl vinyl ether in DCM at 0 ꢁC,
only decomposition of starting material was observed. The
hoped-for conversion took place when iodide was used as
leaving group (entry 3, Table 1). More efficient conversion
(up to 88%) occurred when benzene was used as solvent
(entry 5, Table 1) (surely due to the less solubility in benzene
Scheme 3. Reagents and conditions: (a) TBAF, benzene, rt, 2 min.
The results found with 10 and 12 showed that the reaction
proceeded as satisfactorily as it did when ethyl vinyl ether
was employed. With respect to the formation of the alkyl-
thiochroman derivative 11, it should be remarked that
although o-quinone methides have been reported to undergo
[4+2] cycloadditions with vinyl ethers, furans, enamines and
imines, to the best of our knowledge, this is the first report of
a sulfide ether acting as a dienophile in a cycloaddition reac-
tion with an in situ generated o-quinone methide. Further-
more, the synthesis of 11 is of additional interest since
different thiochromone derivatives related to it are contained
in a patent useful for the treatment of Alzheimer disease,
Down syndrome, vascular dementia and parkinsonism.13
Other noteworthy adduct include the direct formation of
the o-alkyl phenol derivative 14, since o-functionalized phe-
nols are ubiquitous among natural products.14,12
Table 1. Reaction of 8a–c with ethyl vinyl ether
OBn
OBn
OEt
+
O
R
OTBS
8
OEt
9
Entry
R
Temperature Time Solvent Equiv of
(ꢁC)
Yield (%)
dienophile
1
2
3
4
5
6
7
8
9
OAc
OTs
0
0
0
10
10
10
2
2
2
2
2
2
DCM
DCM
DCM
DCM
100
100
100
100
0
0
The second variation introduced with the aim of widening
the scope of this procedure was the use of a different oxa-
dienic moiety. Thus, starting from commercial 2-hydroxy-
benzaldehyde (15), the corresponding o-silyloxybenzyl
iodide, 17, was obtained after straightforward transforma-
tions (Scheme 4). When this compound was caused to react
with ethyl vinyl ether, the reaction was found to proceed
similarly. TLC monitoring and NMR control of the reaction
I
I
I
I
I
I
I
40
41
88
87
70
45
5–10
0
25
25
25
25
25
Benzene 100
Benzene
Benzene
Benzene
Benzene
50
35
20
10

6014
A. F. Barrero et al. / Tetrahedron 62 (2006) 6012–6017
crude showed that chroman 18 was the only compound gen-
erated. The noticed volatility of 18 is postulated to account
for the moderate yields obtained.
terms of reaction times, reaction temperatures and the ease
of generation of the methide precursor. This reaction was
applied to the synthesis of a simpler analogue of biologically
active puupehedione-related compounds, a part of a pro-
gramme to identify useful anti-angiogenic agents. In the
hope of widening the possibilities offered by this method,
further studies with the aim of obtaining more analogues
of puupehedione and other interesting chroman derivatives
are being carried out.
(c)
(b)
(a)
OHC
O
OH
15
OH OTBS
16
I
OTBS
17
OEt
18
Scheme 4. Reagents and conditions: (a) (i) TBSCl, imidazole, DMF, rt, 4 h;
(ii) NaBH4, MeOH, rt, 2 h, 81% in two steps; (b) Ph3P, imidazole, I2,
CH3CN/toluene, 60 ꢁC, 10 min, 73%; (c) TBAF, ethyl vinyl ether, benzene,
rt, 2 min 51%.
2. Experimental
2.1. General
With the above results in mind, we felt that puupehedione
analogue 24 could be expeditiously synthesized using this
procedure from commercially available 3,4-dimethoxybenz-
aldehyde (19) and 1-cyclohexene-1-carboxaldehyde (20)
(Scheme 5).
All air- and water-sensitive reactions were performed in
flasks flame-dried under a positive flow of argon and con-
ducted under an atmosphere of argon. Reagents were pur-
chased at the higher commercial quality and used without
further purification, unless otherwise stated. Silica gel SDS
60 (35–70 mm) was used for flash column chromatography.
Reactions were monitored by thin layer chromatography
(TLC) carried out on 0.25 mm E. Merck silica gel plates
(60F-254) using UV light as the visualising agent and a solu-
tion of phosphomolybdic acid in ethanol and heat as devel-
oping agent. IR spectra were recorded with a Matson
model Satellite FTIR instrument as NaCl plates (films).
NMR studies were performed with a Bruker ARX 400 (1H
400 MHz/13C 100 MHz) spectrometer. The accurate mass
determination was carried out with a AutoSpec-Q mass
spectrometer arranged in a EBE geometry (Micromass
Instrument, Manchester, UK) and equipped with a FAB
(LSIMS) source.
OMe
O
OMe
OMe
OMe
(a)
ref 2b
+
Br
CHO
19
OTBS
21
20
OMe
OMe
OMe
O
OMe
c)
OMe
OMe
RO
OTBS
O
(b)
22 R = OH
23 R = OAc
24
2.1.1. General procedure for the generation of benzo-
pyranes via o-methide quinone intermediates. To a solu-
tion of iodo derivative (0.22 mmol) in dry benzene (4 mL)
was added 1.08 mL of ethyl vinyl ether and the resulting
solution is stirred for 5 min. Then, it was added 0.32 mL
of a 1 M solution of TBAF. The mixture was further stirred
for 2 min and then diluted with EtOAc and washed with
brine. The organic layer was dried over Na2SO4 and concen-
trated under reduced pressure. The resulting crude product
was purified by column chromatography.
Scheme 5. Reagents and conditions: (a) 21, THF, ꢂ78 ꢁC, tBuLi, 15 min,
then 20, 15 min, 81%; (b) Ac2O, Py, 0 ꢁC, 1 h; (c) benzene, TBAF, 2 min,
rt, 62% two steps.
It should be noted that the synthetic proposal for 24 involves
an intramolecular hetero Diels–Alder cycloaddition. Thus,
the success of this approach would suppose a significant
widening of the possibilities of this protocol, although the
ultimate aim of this synthesis is to test whether compound
24 or related derivatives would retain the activity of
metabolites such as puupehedione (1), puupehenone (2)
and 15-oxopuupehenol (3).
2.2. Synthesis of oxa-dienic precursors
2.2.1. Synthesis of 8c.
The synthesis of 24 began with the addition of the organo-
lithium derived from commercial 19 to aldehyde 20 to
give alcohol 22 in 81% yield (Scheme 2). Compound 22
was acetylated and treated without further purification
with TBAF. The hoped-for conversion took place efficiently,
a 62% of 24 being obtained as a result of an electrocyclic
process.15 Contrary to what were observed in the intermolec-
ular version of the process, an acetate group was now found
to be an efficient leaving group.
2.2.1.1. 5-(Benzyloxy)-2-(t-butyldimethylsilyloxy) benz-
aldehyde (6). To a solution of 2 g (14.5 mmol) of commer-
cial 2,5-dihidroxybenzaldehide (4), 1.388 g (16.53 mmol) of
NaHCO3 and 0.241 g (1.45 mmol) of KI in 30 mL of dry
acetonitrile heated to 60 ꢁC, 2.23 mL of BnBr (3.22 g,
18.85 mmol) were added. The reaction mixture was then
stirred under argon at reflux for 24 h. The solvent was
removed to afford a crude product, which was re-dissolved
in EtOAc (50 mL) and washed with 1 N HCl and brine.
The residue was purified by column chromatography.
Eluting with hexane/EtOAc, 3:1, afforded 1692 mg of the
corresponding monobenzylated derivative 5 (51%).16 To a
solution of 1090 mg of 5 in 30 mL of DCM under argon
was added imidazole (810 mg, 12.05 mmol) and TBSCl
(1090 mg, 7.23 mmol). The reaction was stirred at room
In conclusion, we have proved that o-quinone methides can
be generated from o-silyloxybenzyl derivatives via fluoride-
induced desilylation. These methides reacted with electron-
rich alkene to afford different chroman nuclei. This new
method compares favourably with existing alternatives in

A. F. Barrero et al. / Tetrahedron 62 (2006) 6012–6017
6015
temperature for 4 h and then diluted with EtOAc and washed
with H2O, 1 N HCl, saturated NaHCO3 and brine and
worked up as usual. The product obtained was purified by
chromatography on silica gel (hexane/EtOAc, 4:1) to give
960 mg (82% yield) of 6 as yellow oil. IR (film) n: 3065,
3034, 2955, 2930, 2858, 1681, 1611, 1489, 1426, 1388,
oil. IR (film) n: 3069, 3036, 2955, 2929, 2885, 2858, 1599,
1581, 1491, 1454, 1361, 1266, 1202, 1155, 1040, 924,
832, 781, 753, 704, 662 cmꢂ1 1H NMR (400 MHz,
.
CDCl3) d 0.36 (s, 6H), 1.13 (s, 9H), 4.52 (s, 2H), 6.82 (dd,
J¼8.1, 1.0 Hz, 1H), 6.92 (dt, J¼7.6, 1.0 Hz, 1H), 7.19
(ddd, J¼1.6, 8.0, 7.6 Hz, 1H), 7.35 (dd, J¼1.6, 7.6 Hz,
1H). 13C NMR (100 MHz, CDCl3) d ꢂ3.9, 1.8, 18.4, 25.8,
118.6, 121.4, 129.4, 129.7, 130.7, 153.5 ppm. HRFABMS
calcd for C13H21ONaSiI [M+Na]+ 371.0304, found
371.0300.
1
1273, 1211, 1155, 1026, 908, 841, 782 cmꢂ1. H NMR
(400 MHz, CDCl3) d 0.18 (s, 6H), 1.00 (s, 9H), 5.02 (s,
2H), 6.81 (d, J¼9.0 Hz, 1H), 7.12 (dd, J¼9.0, 3.4 Hz, 1H),
7.36 (d, J¼3.4 Hz, 1H), 7.45–7.30 (m, 5H), 10.39
(1H, s) ppm. 13C NMR (100 MHz, CDCl3) d ꢂ4.4, 18.1,
25.6, 70.2, 110.8, 121.4, 124.1, 127.0, 127.3, 127.8, 128.3,
136.5, 153.0, 153.1, 189.2 ppm. HRFABMS calcd for
C20H26O3NaSi [M+Na]+ 365.1549, found 365.1551.
2.3. Reactions of heterocyclisation. Synthesis of
chromanes
2.3.1. 6-(Benzyloxy)-2-ethoxychroman (9). After subject-
ing 8c (133 mg, 0.3 mmol) to the heterocyclisation con-
ditions, the resulting crude was purified by column
chromatography on silica gel. Eluting with hexane/t-BuOMe
(6:1) furnished 74 mg of 9 (88%) as a colourless oil. IR
(film) n: 3032, 2926, 2856, 1754, 1612, 1465, 1454, 1377,
2.2.1.2.
[5-Benzyloxy-2-(t-butyldimethylsilyloxy)-
phenyl] methanol (7). To a solution of 265 mg of NaBH4
(7 mmol) in MeOH (11 mL) was added 6 (400 mg,
1.02 mmol) in 6 mL of MeOH. The mixture was stirred at
room temperature and refluxed for 2 h. MeOH was then
removed and the resulting crude re-dissolved in EtOAc
and washed with 2 N HCl and brine. Removal of the solvent
afforded a crude residue, which was purified by flash chro-
matography (hexane/t-BuOMe 6:1) to give 398 mg (98%)
of 7. IR (film) n: 3402, 3064, 3035, 2955, 2929, 2885,
2858, 1606, 1585, 1494, 1463, 1381, 1268, 1222, 1155,
1192, 1058, 877 cmꢂ1 1H NMR (400 MHz, CDCl3),
.
d 1.19 (t, J¼7.1 Hz, 3H), 1.93 (m, 1H), 2.03 (m, 1H), 2.60
(ddd, J¼3.6, 5.9, 16.3 Hz, 1H), 2.97 (ddd, J¼6.1, 11.7,
17.2 Hz, 1H), 3.63 (dq, J¼7.0, 9.8 Hz, 1H), 3.88 (dq,
J¼7.0, 9.8 Hz, 1H), 4.99 (s, 2H), 5.22 (t, J¼2.8 Hz, 1H),
6.70 (s, 1H), 6.76 (s, 2H), 7.30–7.45 (m, 5H). 13C NMR
(100 MHz, CDCl3) d 15.2, 20.9, 26.6, 63.6, 70.6, 96.8,
114.2, 115.1, 117.5, 123.3, 127.5, 127.9, 128.6, 137.5,
146.3, 152.8 ppm. HRFABMS calcd for C18H20O3Na
[M+Na]+ 307.1310, found 307.310.
1027, 902, 839, 780, 736, 696 cmꢂ1. H NMR (400 MHz,
1
CDCl3) d 0.16 (s, 6H), 0.95 (s, 9H), 4.58 (s, 2H), 4.95 (s,
2H), 6.66 (d, J¼8.8 Hz, 1H), 6.71 (dd, J¼8.8, 3.0 Hz, 1H),
6.92 (d, J¼3.0 Hz, 1H), 7.20–7.40 (m, 5H). 13C NMR
(100 MHz, CDCl3) d ꢂ4.4, 18.0, 25.7, 61.1, 70.3, 114.2,
114.6, 118.9, 127.4, 127.7, 128.4, 132.4, 137.2, 146.8,
153.2 ppm. HRFABMS calcd for C20H28O3NaSi [M+Na]+
367.1705, found 367.1698.
2.3.2. 6-(Benzyloxy)-2-(ethylthio)chroman (11). After
subjecting 8c (100 mg, 0.22 mmol) to the heterocyclisation
conditions but using ethyl vinyl sulfide as dienophile, the
resulting crude was purified by column chromatography on
silica gel. Eluting with hexane/t-BuOMe (4:1) furnished
55 mg of 11 (83%) as a colourless oil. IR (film) n: 2964,
2927, 2869, 1732, 1608, 1494, 1453, 1376, 1265, 1193,
2.2.1.3. 4-Benzyloxy-1-(t-butyldimethylsilyloxy)-2-
iodomethylbenzene (8c). A solution of 114 mg of 7
(0.33 mmol), 130 mg of PPh3 (0.5 mmol), 34 mg of imi-
dazole (0.5 mmol) and 127 mg of I2 (0.5 mmol) in 2 mL of
acetonitrile and 8 mL of toluene was heated at 60 ꢁC for
10 min. The reaction mixture was then diluted with EtOAc
and subsequently washed with saturated Na2S2O3, brine,
dried and evaporated. The resulting crude was purified by
column chromatography (hexane/t-BuOMe, 4:1) on silica
gel to afford 125 mg (83%) of 8c as yellowish oil. IR
(film) n: 3068, 3036, 2955, 2930, 2884, 2857, 1599, 1581,
1
1076, 987, 734 cmꢂ1. H NMR (400 MHz, CDCl3), d 1.24
(t, J¼7.4 Hz, 3H), 2.02 (m, 1H), 2.21 (m, 1H), 2.37–2.78
(m, 3H), 2.88 (ddd, J¼6.4, 10.2, 16.6 Hz, 1H), 4.93 (s, 2H),
5.46 (t, J¼4.0 Hz, 1H), 6.62 (s, 1H), 6.68 (s, 2H), 7.20–
7.40 (m, 5H). 13C NMR (100 MHz, CDCl3) d 15.2, 22.9,
24.7, 27.4, 70.6, 80.2, 114.5, 115.3, 118.1, 122.6, 127.5,
127.9, 128.6, 137.5, 146.6, 153.2 ppm. HRFABMS calcd
for C18H20O2SNa [M+Na]+ 307.1310, found 307.1310.
1492, 1454, 1267, 1154, 906, 838, 781, 735 cmꢂ1 1H
.
NMR (400 MHz, CDCl3) d 0.27 (s, 6H), 1.05 (s, 9H), 4.42
(s, 2H), 4.97 (s, 2H), 6.68 (d, J¼8.8 Hz, 1H), 6.78
(dd, J¼8.8, 3.0 Hz, 1H), 6.94 (d, J¼3.0 Hz, 1H), 7.30–
7.45 (m, 5H). 13C NMR (100 MHz, CDCl3) d ꢂ3.9, 1.8,
18.4, 26.0, 61.1, 70.6, 115.9, 116.5, 119.4, 127.6, 128.0,
128.6, 130.3, 137.1, 147.5, 152.9 ppm. HRFABMS calcd
for C20H27O2NaSiI [M+Na]+ 477.0718, found 477.0723.
2.3.3. 6-(Benzyloxy)-2,2-diethoxychroman (13). After
subjecting 8c (131 mg, 0.28 mmol) to the heterocyclisation
conditions but using 1,1-diethoxyethene as dienophile, the
resulting crude was purified by column chromatography on
silica gel. Eluting with hexane/t-BuOMe (20:1) furnished
53 mg of 13 (56%) and 16 mg of 14 (18%). Compound 13,
colourless oil. IR (film) n: 2976, 2928, 1729, 1613, 1496,
1
1442, 1380, 1205, 1091, 1047, 969, 879, 734 cmꢂ1. H
2.2.2. Synthesis of 17.
NMR (400 MHz, CDCl3) d 1.12 (t, J¼7.1 Hz, 6H), 2.00 (t,
J¼6.8 Hz, 2H), 2.77 (t, J¼6.8 Hz, 2H), 3.62 (m, 4H), 4.92
(s, 2H), 6.60–6.85 (m, 3H), 7.20–7.40 (m, 5H). 13C NMR
(100 MHz, CDCl3) d 15.3, 23.9, 27.8, 57.4, 70.6, 112.4,
114.1, 114.7, 117.4, 122.8, 127.6, 127.9, 128.6, 137.4,
148.5, 153.0 ppm. Compound 14, colourless oil. IR (film)
n: 3417, 2979, 2931, 2869, 1730, 1709, 1505, 1196, 1027,
737 cmꢂ1. 1H NMR (400 MHz, CDCl3) d 1.21 (t, J¼7.2 Hz,
2.2.2.1. 1-(t-Butyldimethylsilyloxy)-2-iodomethyl benz-
ene (17). This compound was prepared starting from com-
mercial 2-hydroxybenzaldehyde, 15. Following the same
procedures used for 8c, this compound was subsequently
protected as silyl ether, reduced to give phenol 16,17 and
treated with I2 in the presence of PPh3 to give the iodo deriv-
ative 17 in an 60% overall yield. Compound 17, colourless

6016
A. F. Barrero et al. / Tetrahedron 62 (2006) 6012–6017
3H), 2.68 (t, J¼6.4 Hz, 2H), 2.84 (t, J¼6.4 Hz, 2H), 4.12 (q,
J¼7.2 Hz, 2H), 4.96 (s, 2H), 6.70–6.81 (m, 3H), 7.20–7.40
(m, 5H). 13C NMR (100 MHz, CDCl3) d 14.2, 24.9, 35.3,
61.4, 70.7, 114.1, 117.0, 118.0, 122.8, 127.6, 127.8, 127.9,
128.6, 128.7, 137.4, 148.5, 153.0, 177.0 ppm. HRFABMS
calcd for C18H20O4Na [M+Na]+ 323.1260, found 323.1261.
The organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The resulting crude product was
purified by column chromatography to afford 60 mg of 24
(62% for two steps). Colourless oil. IR (film) n: 3032,
2926, 2856, 1754, 1612, 1465, 1454, 1377, 1192, 1058,
877 cmꢂ1 1H NMR (400 MHz, CD3)2CO) d 1.23 (qt,
.
J¼3.6, 12.9 Hz, 1H), 1.42 (qt, J¼3.6, 12.9 Hz, 1H), 1.61
(m, 1H), 1.70 (m, 1H), 1.78 (m, 1H), 1.97 (m, 1H), 2.06
(m, 1H), 2.97 (br d, J¼14.3 Hz, 1H), 3.64 (s, 3H), 3.68 (s,
3H), 4.79 (br dd, J¼5.5, 10.9 Hz, 1H), 5.91 (t, J¼1.9 Hz,
1H), 6.25 (s, 1H), 6.46 (s, 1H) ppm. 13C NMR (100 MHz,
CD3)2CO) d 24.9, 27.4, 33.3, 35.8, 56.2, 57.1, 77.6, 101.3,
111.8, 114.4, 116.9, 136.1, 144.4, 148.4, 150.5 ppm.
HRFABMS calcd for C15H18O3 [M]+ 246.1256, found
246.1255.
2.3.4. 2-Ethoxychroman (18). After subjecting 17 (125 mg,
0.4 mmol) to the heterocyclisation conditions, the resulting
crude was purified by column chromatography on silica
gel. Eluting with hexane/t-BuOMe (6:1) furnished 33 mg
of 1818 (51%). Compound 18, colourless oil. IR (film) n:
2955, 2923, 2853, 1732, 1605, 1456, 1376, 1262, 1097,
1
1015, 802, 743 cmꢂ1. H NMR (400 MHz, CDCl3) d 1.12
(t, J¼7.1 Hz, 6H), 1.87 (m, 1H), 1.98 (m, 1H), 2.57 (ddd,
J¼3.9, 5.7, 16.8 Hz, 1H), 2.91 (ddd, J¼5.7, 11.2, 16.8 Hz,
1H), 3.58 (dq, J¼7.0, 9.7 Hz, 1H), 3.82 (dq, J¼7.1,
9.7 Hz, 1H), 5.18 (t, J¼3.0 Hz, 1H), 6.75–6.85 (m, 2H),
6.95–7.10 (m, 2H). HRFABMS calcd for C11H14O2Na
[M+Na]+ 201.0892, found 323. 201.0884.
Acknowledgements
This research was supported by the Spanish Ministry of
Science and Technology. Project BQU 2002-03211. The
authors thank the Spanish Ministry of Education, Culture
and Sport and the Regional Andalucian Government for
2.4. Synthesis of the puupehedione analogue 24
ꢀ
grant to Antonio Rosellon.
2.4.1. Synthesis of alcohol 22. A 1.7 M solution of tert-
butyllithium in pentane (3.4 mL) was added at ꢂ78 ꢁC to
a solution of 21 (1800, 5.17 mmol) in diethyl ether
(75 mL), under argon atmosphere. After stirring for 30 min
at this temperature, 20 (625 mg, 5.69 mmol) was added
and the mixture was further stirred for 15 min at ꢂ78 ꢁC.
The reaction crude was diluted with ether and then water
was added. The organic layer was then washed with brine,
dried and concentrated to give a crude, which was chromato-
graphed on silica gel column (H/E, 2:1) to give 1582 mg of
22 (81%) as a colourless oil. IR (film) n: 3507, 2966, 2950,
2929, 2856, 1609, 1510, 1463, 1446, 1400, 1255, 1202,
References and notes
1. (a) Nicolau, K. C.; Pfefferkorn, J. A.; Barluenga, S.; Mitchell,
H. J.; Roecker, A. J.; Cao, G.-Q. J. Am. Chem. Soc. 2000, 122,
9968–9976; (b) Nicolau, K. C.; Pfefferkorn, J. A.; Roecker,
A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem.
Soc. 2000, 122, 9939–9953; (c) Nicolau, K. C.; Pfefferkorn,
J. A.; Mitchell, H. J.; Roecker, A. J.; Barluenga, S.; Cao,
G.-Q. J. Am. Chem. Soc. 2000, 122, 9954–9967; (d) Jones,
R. M.; Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2002, 67,
6911–6915.
1114, 1008, 909, 837, 780 cmꢂ1 1H NMR (400 MHz,
.
CDCl3) d 0.20 (s, 3H), 0.22 (s, 3H), 0.99 (s, 9H), 1.50–
1.65 (m, 4H), 1.79–2.00 (m, 2H), 2.03 (m, 2H), 3.80 (s,
6H), 5.28 (br s, 1H), 5.70 (br s, 1H), 6.37 (s, 1H), 6.81 (s,
1H). 13C NMR (100 MHz, CDCl3) d ꢂ3.9, 22.6, 22.7,
25.0, 25.6, 25.9, 55.9, 56.3, 72.2, 103.6, 111.0, 122.6,
123.9, 138.9, 143.4, 146.9, 148.4 ppm. HRFABMS calcd
for C21H34O4SiNa [M+Na]+ 378.2226, found 378.2217.
2. For previous work of our group in this subject, see: (a) Barrero,
´
A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.; Cortes, M.;
Armstrong, V. Tetrahedron 1999, 55, 15181; (b) Armstrong,
´
V.; Barrero, A. F.; Alvarez-Manzaneda, E. J.; Cortes, M.;
Sepulveda, B. J. Nat. Prod. 2003, 66, 1382–1383; For biologi-
´
cal properties displayed by puupehedione and analogues, see:
´
Alvarez-Manzaneda, E. J.; Chahboun, R.; Barranco Perez, I.;
Cabrera, E.; Alvarez, E.; Alvarez-Manzaneda, R. Org. Lett.
2005, 7, 1477–1480 and references cited therein.
2.4.2. Acetate 23. To a solution of 150 mg (0.40 mmol) of 22
in 2 mL of pyridine was added 1 mL of Ac2O at 0 ꢁC. After
stirring for 15 min at this temperature, the reaction mixture
was worked up as usual to give 160 mg of 23, which was
used without further purification. Colourless oil. IR (film)
n: 3507, 2950, 2931, 2857, 1739, 1612, 1510, 1447, 1400,
3. Castro, M. E.; Gonzalez-Iriarte, M.; Barrero, A. F.; Salvador-
Tormo, N.; Munoz-Chapuli, R.; Medina, M. A.; Quesada,
A. R. Int. J. Cancer 2004, 110, 31–38.
4. Yang, Z.-Q.; Kwok, B. H. B.; Lin, S.; Koldobsliy, M. A.; Crews,
C. M.; Danishefski, S. M. Chembiochem 2003, 4, 508–513.
5. (a) Zeng, Q.; Rokita, S. E. J. Org. Chem. 1996, 61, 9080–9081;
(b) Rokita, S. E.; Yang, J.; Pande, P.; Greenberg, W. A. J. Org.
Chem. 1997, 62, 3010–3012; (c) Veldhuyzen, W. F.; Pande, P.;
Rokita, S. E. J. Am. Chem. Soc. 2003, 125, 14005–14013.
1
1232, 1204, 1115, 1015, 902, 839, 780 cmꢂ1. H NMR
(400 MHz, CDCl3) d 0.21 (s, 3H), 0.23 (s, 3H), 1.99 (s,
9H), 1.52–1.70 (m, 4H), 1.82 (m, 1H), 1.93–2.06 (m, 3H),
2.08 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H), 5.55 (br s, 1H),
6.38 (s, 1H), 6.42 (br s, 1H), 6.79 (s, 1H). 13C NMR
(100 MHz, CDCl3) d ꢂ4.9, ꢂ3.9, 21.3, 22.3, 22.5, 25.0,
25.7, 25.9, 55.9, 56.5, 72.9, 103.4, 111.2, 120.4, 123.6,
135.9, 143.4, 147.2, 148.9, 169.9 ppm.
´
6. Genisson, Y.; Tyler, P. C.; Ball, R. G.; Young, R. N. J. Am.
Chem. Soc. 2001, 123, 11381–11387.
7. Turner, A. B. Quart. Rev. 1964, 18, 347–360.
8. Van der Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58,
5367–5405.
2.4.3. Synthesis of 24. To a solution in benzene (5 mL) of
the above crude containing 23 was added 0.5 mL of a 1 M
solution of TBAF. The mixture was further stirred for
2 min and then diluted with EtOAc and washed with brine.
9. (a) Chiang, A.; Kresge, J. A.; Zhu, Y. J. Am. Chem. Soc. 2002,
124, 6349–6356; (b) Nakamura, S.; Uchiyama, M.; Ohwada, T.
J. Am. Chem. Soc. 2003, 125, 5282–5283; (c) Leo, E. A.;
ꢀ
Delgado, J.; Domingo, L. R.; Espinos, A.; Miranda, M. A.;

A. F. Barrero et al. / Tetrahedron 62 (2006) 6012–6017
6017
´
Tormos, R. J. Org. Chem. 2003, 68, 9643–9647; (d) Rodrıguez,
R.; Adlington, R. M.; Moses, J. E.; Cowley, A.; Baldwin, J. E.
14. Jones, R. M.; Van der Water; Lindsey, C. C.; Hoarau, C.; Ung,
T.; Pettus, T. R. R. J. Org. Chem. 2001, 66, 3435–3441.
15. Recently, a tricyclic compound related to 24 has been synthe-
sized via a route different to that described herein, as a part
of programme to identify antitubercular agents for animal
and human use: Kraus, G. A.; Nguyen, T.; Bae, J.; Hostetter,
J.; Steadham, E. Tetrahedron 2004, 60, 4223–4225.
16. Haraldsson, G. G.; Baldwin, J. E. Tetrahedron 1997, 53,
215–224.
17. Khan, A. T.; Ghosh, S.; Choudhury, L. H. Eur. J. Org. Chem.
2004, 10, 2198–2204.
18. Chambers, J. D.; Crawford, J.; Williams, H. W. R.; Dufresne,
C.; Scheigetz, J.; Bernstein, M. A.; Lau, C. K. Can. J. Chem.
1992, 70, 1717–1732.
´
Org. Lett. 2004, 6, 3617–3619; (e) Rodrıguez, R.; Moses, J. E.;
Adlington, R. M.; Baldwin, J. E. Org. Biomol. Chem. 2005, 3,
3488–3495.
10. (a) Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2004, 69, 9196–
9203; (b) Selenski, C.; Mejorado, L. H.; Pettus, T. R. R. Synlett
2004, 1101–1103.
11. Mendelson, W.; Holmes, M.; Dougherty, J. Synth. Commun.
1996, 26, 593–601.
12. Van der Water, R. W.; Magdziak, D. J.; Chau, J. N.; Pettus,
T. R. R. J. Am. Chem. Soc. 2000, 122, 6502–6503.
13. Kawakami, Z.; Tamaguchi, T.; Tabuchi, M.; Sata, S. JP
10087485 A2 19980407, 1998.