Construction of quaternary centres for natural polycycles: The Pauson-Khand approach

Article abstract of DOI:10.1016/j.jorganchem.2008.04.023

Construction of quaternary carbons is a challenge in PK chemistry, with few precedents in the literature. Starting from suitable functionalized enynes including an aromatic ring that templates the reaction, polycyclic ketones are obtained with a quaternar

Full text of DOI:10.1016/j.jorganchem.2008.04.023

Journal of Organometallic Chemistry 693 (2008) 2431–2437
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Construction of quaternary centres for natural polycycles:
The Pauson–Khand approach
*
Eduardo Arnáiz, Jaime Blanco-Urgoiti, Delbrin Abdi, Gema Domínguez, Javier Pérez Castells
Departamento de Química, Facultad de Farmacia, Universidad San Pablo-CEU, Boadilla del Monte 28668-Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Construction of quaternary carbons is a challenge in PK chemistry, with few precedents in the literature.
Starting from suitable functionalized enynes including an aromatic ring that templates the reaction, poly-
cyclic ketones are obtained with a quaternary carbon. Special reaction conditions are necessary including
the use of molecular sieves and co-catalysis with rhodium complexes jointly with cobalt carbonyl. The
products obtained are intermediates in the synthesis of various natural products like the Hamigeran
family and the steroidic alkaloid Conessine.
Received 25 March 2008
Received in revised form 16 April 2008
Accepted 16 April 2008
Available online 22 April 2008
Keywords:
Ó 2008 Elsevier B.V. All rights reserved.
Pauson–Khand
Natural products
Cyclizations
Cobalt
Rhodium
1. Introduction
related to Hamigerans-A and B via a PKR/elimination reaction and
precursors of the steroidic alkaloid Connessine, both from aromatic
The intramolecular Pauson–Khand reaction (PKR) is a powerful
transformation of enynes into polycyclic cyclopentenones [1]. One
of its main limitations is that, in general, substituted double bonds
at the internal position react poorly. Among the exceptions we can
find exocyclic double bonds, and conformationally constrained
enynes in which a reactive conformation is forced by any means.
Thus, Ishizaki described the use of exocyclic cyclohexenes in the
PKR and used this methodology for the synthesis of several natural
products [2]. Cyclopropyl tethered methylenecyclopropanes can
give the expected PK products or rearranged hydroindenones in
which neither of the two carbon atoms of the alkyne form part of
the cyclopentenone ring in the final product [3]. Kerr used methy-
lene cyclohexanes for the synthesis of Cedrene [4], and methylene-
pyranes also gave successfully the PK cyclization [5]. Other
substituted alkenes, included in a cyclohexane were used by Zard
in the synthesis of Dendrobine [6]. We have shown a positive effect
of molecular sieves in PKRs that allow the reaction of some substi-
tuted alkenes [7]. Our conditions were used by Winkler for the syn-
thesis of Ingenol from an exocyclic cycloheptene [8]. On the other
hand, enynes connected through an aromatic ring are interesting
substrates that have been used by us [9] and other groups [10] in
Pauson–Khand chemistry. We have used homoaromatic and in-
dole-based enynes to construct complex polycycles. As an exten-
sion of our work we present herein the synthesis structures
enynes bearing substituted alkenes.
Hamigerans are a family of metabolites isolated from the poe-
cilosclerid sponge Hamigera tarangaensis. Among them, Hamiger-
an-B has interesting biological activity as it exhibits 100% virus
inhibition against both herpes and polio viruses with little cytotox-
icity [11]. The tricyclic structural framework comprising an aro-
matic ring, has received synthetic attention from several groups.
Thus, after the first asymmetric synthesis by Nicolaou based on
an asymmetric Diels–Alder reaction [12], Clive used radical cycli-
zation to build the five membered ring performing both a racemic
and asymmetric synthesis [13]. More recently Trost used an asym-
metric allylic alkylation as the origin of asymmetry in a new syn-
thesis of Hamigeran-B [14], and Wright reported the synthesis of
Hamigeran skeleton using an efficient electro-oxidative coupling
reaction [15]. The tricyclic structure of Hamigeran has been con-
structed recently via PKR by Lovely [16]. In this case the cycliza-
tion, only took place when the olefin-containing moiety was
tethered to the aromatic framework to reduce its conformational
mobility; using a silylene protecting group. Our approach uses an
intramolecular Pauson–Khand reaction strategy that would short-
en the synthesis of an elaborated framework that could serve for
the preparation of derivatives, an important aim in view of the bio-
logical activity of this compound.
Conessine is a steroidic alkaloid that belongs to Holarrhena class
of Kurchi alkaloids. It was isolated from the bark of Holarrhena
antidysenterica, and possesses significant biological activity
against dysentery [17]. Several total syntheses can be found in
* Corresponding author. Tel.: +34 91 3724700; fax: +34 91 3510496.
E-mail address: jpercas@ceu.es (J.P. Castells).
0022-328X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2008.04.023

2432
E. Arnáiz et al. / Journal of Organometallic Chemistry 693 (2008) 2431–2437
the literature. Thus, Stork [18], Nagata [19], and Johnson [20],
disclosed racemic approaches to Conessine in early times. Stork
used intermediate C, that can be obtained from precursor D. We
envisioned the possibility of synthesizing D using a PKR from eny-
ne E. More recently, Meyers described a non-racemic synthesis of
Conessine in which polycyclic enone G was used to reach interme-
diate F [21]. Ketone C could be obtained by transformation of D. A
highly diastereoselective method for the construction of the com-
pact tetracycle of Conessine was accomplished recently from an
elaborated enyne. The chiral tetracyclic framework was created
by a Pauson–Khand reaction [22].
OH
OMe
OMe
1. Br2/Al
2. HI 55%
1. NBS/CCl4
hν
CHO
Br
3. Me2SO4,
2. NaHCO3
Br
(Bu)4N+I-
NaOH
DMSO, 115 ºC
55%
1
2
3
(ref 23)
Scheme 3. Synthesis of aldehyde 3.
OMe OH
TMS
1.
In this paper we describe the use of functionalized aromatic
enynes to perform a Pauson–Khand reaction giving intermediates
for the synthesis of Hamigerans-A and B and Conessine (Schemes
1,2).
1. TBAF, 0 ºC
Pd(PPh3)Cl2
3
2. TBSCl,
Imidazole
2.
MgCl
TMS
4
71%
48%
2. Results and discussion
OMe OTBS
OMe OTBS
2.1. Synthesis of the Hamigeran’s skeleton
Acetone
nBuLi
Starting with the synthesis of the Hamigeran’s skeleton, the
synthesis of enyne starting material was accomplished from inex-
pensive commercial 2,5-dimethylphenol 1. This product was trans-
THF, -60 ºC
86%
OH
H
5
6
formed into 2-bromo-6-methoxy-4-methylbenzaldehyde by
a
procedure described in the literature [23]. After formation of inter-
mediate 2 we modified the method towards 3, and we performed a
bromination followed by an oxidation step which gave 3 in 55%
yield (Scheme 3).
Scheme 4. Synthesis of precursors for the PKR.
From compound 3, the desired enyne was readily prepared
using Sonogashira coupling and nucleophilic attack with a Grig-
nard reagent. In addition, from enyne 4, several derivatives were
obtained to test them in the PKR. In particular, compound 6 bears
the three carbon moiety present in the Hamigerans. This com-
pound was obtained from protected derivative 5 by nucleophilic
attack of the corresponding anion to acetone (Scheme 4).
The enynes were submitted to a set of conditions for the PKR
(Scheme 5). Starting with enyne 4, we observed partial or total
decomposition of starting material in the whole set of conditions
tested. These included the use of Co2(CO)8 with promotion of
amine N-oxides (Cond. A) or molecular sieves (Cond B.) [9b], and
catalysis with Co2(CO)8/mol. sieves (Cond. C) [24], [Rh(CO)2Cl]2
(Cond. D) [25], or [Ir(cod)Cl]2 (Cond. E) [26]. Substrate 6 was com-
plexed to cobalt and under conditions A–B, the resulting complex
7, did not evolve to the desired PK product. Catalytic conditions
produced no reaction products with this compound. Finally, sub-
strate 5 gave much more interesting results. In the reaction with
cobalt this compound gave the PK cyclization with elimination of
the OTBS group, forming an additional double bond. The best result
was achieved under stoichiometric conditions B (55% yield of com-
R4
R3
OH
O
R3 OR´´
R2
R1
R4
O
Br
O
R2
R1
Me
H
R5
R5
A
B
Hamigeran B
Scheme 1. Retrosynthetic approach to Hamigeran-B.
Me
N
Me
N
H
H
Me
Conessine
O
Me
H
Me
H
N
H
Me
H
H
MeO
F
OMe OR1
OMe OTBS
TsO
4
6
dec./n.r.
Co2(CO)6
OH
O
cond A,B
cond A-E
R2
7
4: R1 = H, R2 = TMS
5: R1 = TBS, R2 = H
5
5
54%
N
MeO
MeO
cond D
cond B,C
MeO
1
R
= TBS, R2 = CMe2OH
R
C
6:
OMe
OMe
G
O
8
9
MeO
OR
O
OR
62%
cond B: 55%
cond C: 35%
E
D
Scheme 2. Retrosynthetic outline towards Conessine.
Scheme 5. PKR of enynes 4–6.

E. Arnáiz et al. / Journal of Organometallic Chemistry 693 (2008) 2431–2437
2433
pound 8), although under catalytic conditions we obtained a 35%
yield of 8. This result is remarkable as very few PKR give quater-
nary carbons.
On the other hand, compound 5 gave, under rhodium catalysis
(conditions D), a product which was identified as 9. This product
is probably the result of an enyne reorganization process, similar
to enyne metathesis, and aromatization of the resulting dihydro-
naphthalene via elimination of the OTBS group. The product was
obtained in good yield (62%). Compound 5 did not react under con-
ditions E.
2.2. Intermediates for the synthesis of conessine
TMS
Br
O
1.
Pd(PPh3)Cl2
TMS
The synthesis started from aldehyde 10, easily obtained in four
steps from commercial 4-bromo-3-methylanisol [27]. Aldehyde 10
was submitted to Sonogashira conditions, with ethynyltrimethylsi-
lane and subsequent reaction with allylmagnesium bromide giving
11, with 97% yield (Scheme 6). Then, hydroxyl group in 11 was re-
duced with superhydride giving 12. This compound was osmylated
into 13, which was obtained in 54% yield. The primary hydroxyl
was then acetylated using a bulky base (72%), and the resulting
product was oxidized, obtaining 14. The oxidation only proceeded
in good yield (75%) with Jones’ reagent. The other conditions tested
(PCC, PDC and Swern) gave poor conversions into ketone 14. The
next step was the synthesis of enyne 15, which was accomplished
with a Wittig reaction and deprotection of the alkyne. Global yield
of this enyne from starting commercial material was 14% after 12
steps. In addition, the acetyl group was changed to a chiral auxil-
iary, via alcohol 16. The menthyl group was selected and thus, 17
was obtained by reaction of 16 with (+)-menthylchloroformate in
pyridine (Scheme 6).
Enynes 15–17 were submitted to several PK reaction conditions
(Table 1). Compound 15 under stoichiometric reaction at À10 °C
did not react and at 70 °C, using as promoters trimethylamine
N-oxide (TMANO) and molecular sieves, gave 45% of the desired
compound 22 (entries 1 and 2). When applying catalytic conditions
with 0.1 equiv. of Co2(CO)8, molecular sieves and CO atm., we only
detected traces of the final product in the reaction crude residue.
Enyne 16, with less steric demand was also reacted under the latter
conditions but did not gave any cyclization product (entry 4). Thus,
we prepared the cobalt hexacarbonyl complex 18, and purified it in
an attempt to improve the yields. When this complex was reacted
at 70 °C in the presence of molecular sieves it gave a 30% of the
1. MsCl, Et3N
H
2. LiEt3BH, 70ºC
3. H2O
MeO
2.
MeO
BrMg
97%
OH
63%
10
11
TMS
OsO4,NMO
TMS
1. AcCl, EtiPr2N
2. Jones
tBuOH, 76ºC
MeO
MeO
OH
55%
54%
OH
13
12
TMS
O
1. CH3P+Ph,Br-, KHMDS
THF, 25ºC
2. TBAF/THF,0ºC
MeO
MeO
OAc
82%
OAc
15
14
(+)-Menthyl
Δ
NaOH 3N,
90%
chloroformate
MeO
OH
Py.
93%
16
O
O
MeO
O
17
Scheme 6. Synthesis of enynes 15–17.
Table 1
PKR conditions for the synthesis of 21 and 23
O
conditions
OR
Co2(CO)8
15-17
MeO
OR
MeO
21
22
23
18
19
20
15
16
R = Ac,
R = H,
17
R = MenOCO
No.
Subs.
R
Promoters
CO
T (°C)
(Co)
Other catalystsa
Rh(PPh3)2ClCO
Yield (%)
1
2
3
4
5
6
7
8
9
15
15
15
15
16
18
18
18
19
20
Ac
Ac
Ac
Ac
H
TMANO/MS 4 Å
TMANO/MS 4 Å
MS 4 Å
MS 4 Å
MS 4 Å
MS 4 Å
MS 4 Å
MS 4 Å
MS 4 Å
À10
70
70
110
70
70
70
70
70
70
1.1
1.1
0.1
3
45
>5
20
1 atm
1 atm
1 atm
0.1
Ac
Ac
Ac
H
30
60
40
Rh(PPh3)2ClCO
[RhClCO(dppp)]2
Rh(PPh3)2ClCO
Rh(PPh3)2ClCO
<5
10
R*
MS 4 Å
45b
a
When used, a 5 mol% of rhodium co-catalyst was added.
Obtained as a 1:1 mixture of diastereomers.
b

2434
E. Arnáiz et al. / Journal of Organometallic Chemistry 693 (2008) 2431–2437
final product (entry 6). We decided to use a rhodium co-catalyst in
the reaction of complex 18. With these novel conditions, we
reached the best yields, in particular with Rh(PPh3)2ClCO (entry
7), which gave better results than [RhClCO(dppp)]2 (entry 8). These
conditions were used with cobalt complexes 19–20. Complex 19
decomposed to a myriad of unidentified products (entry 9),
whereas 20 gave a 1:1 mixture of the diastereomeric final products
23 in 45% yield (entry 10).
2.63 (dd, 1H, J1 = 13.7 Hz, J2 = 9.4 Hz), 3.57 (d, 1H, J = 11.5 Hz), 3.84
(s, 3H), 4.71 (s, 1H), 4.79 (s, 1H), 5.32–5.40 (m, 1H), 6.67 (s, 1H),
6.89 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3): d = À0.2, 21.1, 22.3,
46.6, 55.4, 70.2, 98.6, 103.0, 112.7, 112.7, 121.7, 125.9, 130.9,
137.7, 142.9, 156.9 ppm. IR (film): m = 3550, 2140, 1650,
1610 cmÀ1. Calc. for C18H26O2Si (302.48): C, 71.47; H, 8.66. Found:
C, 71.30; H, 8.81%.
3.3. Synthesis of tert-butyl(1-(2-ethynyl-6-methoxy-4-methylphenyl)-
2.3. Conclusions
3-methylbut-3-enyloxy)dimethylsilane, 5
In conclusion we show here a new approach to Hamigerans-A
and B skeletons using an intramolecular PK reaction. A metathe-
sis/elimination reaction with rhodium catalysis has been observed.
The synthesis of tricyclic cyclopentenones related to intermediates
in the synthesis of Conessine is achieved using a PKR. For the con-
struction of the quaternary carbon the participation of a rhodium
co-catalyst reacting with a preformed cobalt hexacarbonyl com-
plex is necessary to reach good yields. Syntheses of natural prod-
ucts using this methodology are currently underway.
To a solution of 4 (0.13 g, 0.43 mmol) in THF (2.0 mL) at 0 °C,
0.65 mL of TBAF (1 M) were added. The mixture was stirred at
0 °C for 1 h and 1 mL of water, 1 mL of hexane and 1 mL of ether
were added. The organic layer was separated, washed with brine
(1.0 mL), dried over MgSO4, filtered and concentrated. The crude
residue was purified by column chromatography using hexane/
EtOAc (4:1) as eluent. Sixty-four milligrams (65%) of 1-(2-ethy-
nyl-6-methoxy-4-methylphenyl)-3-methylbut-3-en-1-ol as a yel-
low oil. A solution of this compound (0.18 g, 0.78 mmol) in DMF
(4 mL), 0.14 g (2.05 mmol) of imidazole, and 0.25 g (1.64 mmol)
of tert-butylchlorodimethylsilane stirred at rt for 15 h. Then, an
ice-water mixture (5 mL) was added. The reaction mixture was ex-
tracted with Et2O (3 Â 2 mL), dried over MgSO4 and concentrated.
Upon chromatography (hexane/EtOAc 49:1) 0.20 g (74%) of 5 were
obtained as a yellow oil. 1H NMR (300 MHz, CDCl3): d = À0.23 (s,
3H), 0.00 (s, 3H), 0.83 (s, 9H), 1.76 (s, 3H), 2.29 (s, 3H), 2.54 (dd,
1H, J1 = 13.2 Hz, J2 = 6.1 Hz), 2.75–2.82 (m, 1H), 3.23 (s, 1H), 3.80
(s, 3H), 4.67 (s, 1H), 4.70 (s, 1H), 5.47 (dd, 1H, J1 = 7.7 Hz,
J2 = 6.1 Hz), 6.67 (s, 1H), 6.91 (s, 1H) ppm. 13C NMR (75 MHz,
CDCl3): d = À4.9, 18.2, 21.2, 22.8, 25.8, 44.8, 55.5, 71.5, 81.0, 82.8,
112.3, 113.9, 121.5, 125.3, 127.9, 137.7, 143.3, 157.0 ppm. IR (film):
m = 3300, 3060, 2940, 2920, 2840, 2100, 1650, 1600 cmÀ1. Calc. for
3. Experimental
3.1. Synthesis of 2-bromo-6-methoxy-4-methylbenzaldehyde, 3 [23]
To a solution of 2 (9.79 g, 45.54 mmol) in 334 mL of degassed
CCl4 8.11 g (45.54 mmol) of N-bromosuccinimide were added.
The mixture was irradiated with a 150 W lamp for 16 h at 0 °C
and filtered. The filtrate was washed with water (200 mL), dried
over MgSO4, and concentrated, obtaining 1-bromo-2-(bromo-
methyl)-3-methoxy-5-methylbenzene which was used without
purification. This product was solved in DMSO (212 mL) and
66.22 g (728.70 mmol) of NaHCO3 were added to the mixture
which was heated to 115 °C and stirred for 16 h. Then, the reaction
mixture was poured into an ice-water mixture (200 mL) and ex-
tracted with Et2O (3 Â 100 mL). The organic layers were washed
with water (200 mL), dried over MgSO4, and concentrated. The
crude residue was purified by column chromatography using hex-
ane/EtOAc (9:1) as eluent. 5.74 g (55% from 2), of 3 are obtained as
an oil that solidifies in the fridge. 1H NMR (300 MHz, CDCl3):
d = 2.38 (s, 3H), 3.91 (s, 3H), 6.75 (s, 1H), 7.09 (s, 1H), 10.38 (s,
1H) ppm.
C21H32O2Si (344.56): C, 73.20; H, 9.36. Found: C, 73.30; H, 9.44%.
3.4. Synthesis of 4-(2-(1-(tert-butyldimethylsilyloxy)-3-methylbut-3-
enyl)-3-methoxy-5-methylphenyl)-2-methylbut-3-yn-2-ol, 6
To a solution of 5 (0.15 g, 0.44 mmol) in 3 mL of anhydrous THF,
0.14 mL (0.92 mmol) of TMEDA were added. The mixture was
cooled at À60 °C and 0.5 mL (0.92 mmol) of nBuLi (1.6 M) were
added, stirring the mixture for 1 h. Then, 0.32 mL (4.4 mmol) of
dry acetone were added and the resulting mixture was stirred for
3 h, when 2 mL of saturated solution of NH4Cl, were added. The
reaction mixture was extracted with EtOAc (3 Â 1 mL), dried over
MgSO4 and concentrated. Upon column chromatography (hex-
ane/EtOAc, 49:1 to 20:1) 0.15 g (86%) of 6 were obtained as a yel-
low oil. 1H NMR (300 MHz, CDCl3): d = À0.21 (br s, 3H), À0.02 (br s,
3H), 0.83 (s, 9H), 1.62 (s, 6H), 1.77 (s, 3H), 2.28 (s, 3H), 2.42–2.59
(m, 1H), 2.70–2.95 (m, 1H), 3.80 (s, 3H), 4.69 (s, 1H), 4.71 (s, 1H),
5.54 (br s, 1H), 6.62 (br s, 1H), 6.86 (br s, 1H) ppm. IR (film):
m = 3380, 3060, 2940, 2840, 1650, 1600 cmÀ1. Calc. for C24H38O3Si
(402.64): C, 71.59; H, 9.51. Found: C, 71.66; H, 9.62%.
3.2. Synthesis of 1-(2-methoxy-4-methyl-6-
((trimethylsilyl)ethynyl)phenyl)-3-methylbut-3-en-1-ol, 4
To a solution of 3 (1.45 g, 6.3. mmol) in distilled triethylamine
(30.0 mL), were added 1.8 mL (12.7 mmol) of ethynyltrimethylsi-
lane, 0.09 g (0.13 mmol) of Pd(PPh3)2Cl2 and 0.006 g (0.03 mmol)
of CuI. The mixture was stirred at 80 °C for 4 h, concentrated, redis-
solved in toluene and filtered through Celite. The crude residue
was concentrated and purified by column chromatography using
hexane/EtOAc (9:1) as eluent. 1.25 g (81%) of 2-methoxy-4-
methyl-6-((trimethylsilyl)ethynyl) benzaldehyde were obtained
as a yellow solid (m.p. 75–78 °C). To a solution of this aldehyde
(0.66 g, 2.7 mmol) in anhydrous THF (20 mL) at À78 °C, 3.0 mmol
of 2-methylallylmagnesium chloride were added dropwise. The
mixture was stirred for 2 h and then, 20 mL of saturated NH4Cl
were added. The crude residue was extracted with EtOAc
(2 Â 15 mL), washed with water (20 mL) and with brine (20 mL).
The organic layer was dried over MgSO4 filtered and concentrated.
Purification was carried out by column chromatography using hex-
ane/EtOAc (9:1) as eluent. Compound 4 was obtained (0.71 g, 88%;
71% from 3) as a yellow oil. 1H NMR (300 MHz, CDCl3): d = 0.21 (s,
9H), 1.82 (s, 3H), 2.27 (s, 3H), 2.41 (dd, 1H, J1 = 13.2 Hz, J2 = 5.0 Hz),
3.5. Synthesis of 4-(2-(1-(tert-butyldimethylsilyloxy)-3-methylbut-3-
enyl)-3-methoxy-5-methylphenyl)-2-methylbut-3-yn-2-ol-dicobalt
hexacarbonyl, 7
To a solution of 6 (0.11 g, 0.28 mmol) in 5 mL of anhydrous
Et2O, 0.13 g (0.37 mmol) of dicobalt octacarbonyl were added.
The mixture was stirred at rt for 3 h and filtered through Celite.
Upon column chromatography (hexane/EtOAc 49:1) 0.10 g (54%)
of 7 were obtained as a brown oil. 1H NMR (300 MHz, CDCl3):
d = 0.02 (s, 3H), 0.20 (s, 3H), 0.88 (s, 9H), 1.37(s, 3H), 1.57 (s, 3H),
1.68 (s, 3H), 2.35 (s, 3H), 2.76–2.84 (m, 1H), 3.08–3.15 (m, 1H),
3.85 (s, 3H), 4.32 (s, 1H), 4.71 (s, 1H), 4.76 (s, 1H), 5.45 (br s, 1H),

E. Arnáiz et al. / Journal of Organometallic Chemistry 693 (2008) 2431–2437
2435
6.68 (s, 1H), 7.02 (s, 1H) ppm. IR (film): m = 3400, 3060, 2960, 2840,
2080, 2040, 2020, 1640, 1600 cmÀ1
1610 cmÀ1. Calc. for C16H22O2Si (274.43): C, 70.03; H, 8.08. Found:
C, 69.91; H, 8.23%.
.
3.6. Synthesis of 6-methoxy-3a,8-dimethyl-3,3a-dihydro-2H-
3.9. Synthesis of ((2-(but-3-enyl)-4-
cyclopenta[a] naphthalen-2-one, 8
methoxyphenyl)ethynyl)trimethylsilane, 12
To a solution of enyne 5 (0.20 g, 0.58 mmol) in anhydrous tolu-
ene (12 mL), 1.6 g of molecular sieves, and 0.24 g (0.70 mmol) of
Co2(CO)8 were added. The resulting mixture was stirred under Ar
at rt until total complexation of the enyne (t.l.c.). Then, the reaction
mixture was refluxed for 2 days. After filtration through Celite and
solvent elimination, the residue was purified by column chromatog-
raphy (hexane/EtOAc 49:1), giving 8 (76 mg, 55%) as a yellow oil. 1H
NMR (300 MHz, CDCl3): d = 1.32 (s, 3H), 2.40 (s, 3H), 2.48 (d, 1H,
J = 17.1 Hz), 2.70 (d, 1H, J = 17.1 Hz), 3.86 (s, 3H), 6.15 (s, 1H), 6.16
(d, 1H, J = 9,9 Hz), 6.77 (s, 1H), 6.79 (d, 1H, J = 9,9 Hz), 7.01 (s, 1H)
ppm. 13C NMR (75 MHz, CDCl3): d = 21.7, 29.8, 44.9, 49.2, 55.6,
114.2, 118.8, 119.0, 119.4, 124.2, 128.8, 135.5, 138.9, 155.1, 181.2,
199.8 ppm. IR (film): m = 2890, 1680, 1580, 1540 cmÀ1. Calc. for
To a solution of 11 (2.05 g, 7.5 mmol) in anhydrous THF (60 mL)
triethylamine (4.3 mL, 30.2 mmol) was added. After cooling to 0 °C
mesyl chloride was added dropwise (1.17 mL, 15.1 mmol). The reac-
tion mixture was stirred at rt for 2 h, filtered and concentrated. Then,
EtOAc (20 mL) and water (20 mL) were added to the residue and the
organic layer was washed with saturated NaHCO3 (20 mL), dried
over MgSO4 and concentrated. Then, 37.2 mL (37.2 mmol) of lithium
triethylborohydride 1 M was added over a solution of the crude res-
idue mesyl derivative in anhydrous THF (110 mL). The reaction mix-
ture was stirred at 60 °C for 18 h and cooled to 0 °C. In this point, H2O
(30 mL), 3 N NaOH (2.2 mL) and 35% H2O2 (0.6 mL, 6.5 mmol) were
successively added, and the resulting mixture was refluxed during
1 h. After cooling, the reaction mixture was extracted with hexane,
dried over MgSO4 and concentrated. Purification was carried out
by column chromatography using hexane/EtOAc (9:1) as eluent.
12 was obtained (1.22 g, 63%) as a colorless oil. 1H NMR (300 MHz,
CDCl3): d = 2.41 (q, 2H, J = 7.7 Hz), 2.87 (t, 2H, J = 7.7 Hz), 3.19 (s,
1H), 3.82 (s, 3H), 5.00 (d, 1H, J = 9.9 Hz), 5.07 (dd, 1H, J1 = 17.3 Hz,
J2 = 1.9 Hz), 5.83–5.96 (m, 1H), 6.71 (dd, 1H, J1 = 8.8 Hz,
C16H16O2 (240.30): C, 79.97; H, 6.71. Found: C, 80.14; H, 6.82%.
3.7. Synthesis of 5-methoxy-2,7-dimethyl-1-vinylnaphthalene, 9
Seven milligrams (0.01 mmol) of [Rh(CO)2Cl]2 were solved in
anhydrous toluene (4 mL) under Ar, and the mixture was cannulat-
ed to a flask containing 120 mg (0.35 mmol) of 5. Then the mixture
was put under CO atmosphere and refluxed for 24 h. After cooling,
the reaction mixture was filtered through Celite and concentrated.
Forty-six milligrams (62%) of 9 were obtained as a yellow oil after
column chromatography (hexane/EtOAc 20:1). 1H NMR (300 MHz,
CDCl3): d = 2.48 (s, 3H), 2.50 (s, 3H), 4.00 (s, 3H), 5.41 (dd, 1H,
J1 = 17.6 Hz, J2 = 2.2 Hz), 5.75 (dd, 1H, J1 = 11.0 Hz, J2 = 2.2 Hz),
6.63 (s, 1H), 7.02 (dd, 1H, J1 = 18.1 Hz, J2 = 11.5 Hz), 7.27 (d, 1H,
J = 8.8 Hz), 7.46 (s, 1H), 8.06 (d, 1H, J = 8.2 Hz) ppm. 13C NMR
(75 MHz, CDCl3): d = 20.9, 22.6, 55.4, 105.1, 116.6, 120.6, 120.6,
122.4, 127.2, 132.9, 133.3, 133.5, 134.7, 135.5, 155.4 ppm. IR (film):
m = 2920, 1660, 1590, 1520 cmÀ1. Calc. for C15H16O (212.29): C,
84.87; H, 7.60. Found: C, 84.94; H, 7.72%.
J2 = 2.7 Hz), 6.75 (d, 1H, J = 2.2 Hz), 7.42 (d, 1H, J = 8.8 Hz) ppm. 13
C
NMR (75 MHz, CDCl3): d = 34.1, 34.4, 55.2, 79.3, 82.3, 111.3, 113.7,
114.5, 114.9, 134.2, 138.0, 146.3, 159.8 ppm. IR (film): m = 3300,
3080, 2150, 2100, 1640, 1600 cmÀ1. Calc. for C16H22OSi (258.43):
C, 74.36; H, 8.58. Found: C, 74.29; H, 8.82%.
3.10. Synthesis of 4-(5-methoxy-2-
((trimethylsilyl)ethynyl)phenyl)butane-1,2-diol, 13
To a solution of 12 (3.70 g, 14.4 mmol) in tert-butanol (130 mL),
11.80 g (100.0 mmol) of NMO and 0.36 mL (0.03 mmol) of OsO4
(2.5% in tert-butanol) were added. The mixture was stirred at
76 °C for 5 h, NaHSO3 was added and solvent was eliminated under
vacuo. The crude residue was suspended in brine (50 mL), ex-
tracted with EtOAc (3 Â 25 mL), washed with water (2 Â 50 mL)
and brine (2 Â 50 mL), dried over MgSO4, filtered and concen-
trated. Purification was carried out by column chromatography
using hexane/EtOAc (1:1) as eluent. Compound 13 was obtained
3.8. Synthesis of 1-(5-methoxy-2-((trimethylsilyl)ethynyl)phenyl)but-
3-en-1-ol, 11
To a suspension of 10 (1.07 g, 5.0 mmol) in dry triethylamine
(15 mL), ethynyltrimethylsilane (0.85 mL, 6.0 mmol), Pd(PPh3)2Cl2
(0.07 g, 0.1 mmol) and CuI (0.004 g, 0.02 mmol) were successively
added. The mixture was stirred at 60 °C for 5 h, concentrated,
redissolved in toluene and filtered through Celite. The crude resi-
due was concentrated and purified by column chromatography
using hexane/EtOAc (20:1) as eluent. 1.16 g (100%) of 5-meth-
oxy-2-((trimethylsilyl)ethynyl) benzaldehyde were obtained as a
yellow oil. To a solution of this aldehyde (2.44 g, 10.5 mmol) in
anhydrous THF (100 mL) at À78 °C, 12.6 mL (12.6 mmol) of allyl-
magnesium bromide (1.0 M) were added dropwise. The mixture
was stirred for 1.5 h and then, 100 mL of saturated NH4Cl were
added. The crude residue was extracted with EtOAc (2 Â 40 mL),
washed with water (100 mL) and with brine (100 mL). The organic
layer was dried over MgSO4 filtered and concentrated. Purification
was carried out by column chromatography using hexane/EtOAc
(9:1) as eluent. Compound 11 was obtained (2.80 g, 97% from 10)
as a yellow oil. 1H NMR (300 MHz, CDCl3): d = 0.25 (s, 9H), 2.27
(d, 1H, J = 3.8 Hz), 2.36–2.46 (m, 1H), 2.65–2.73 (m, 1H), 3.84 (s,
3H), 5.12–5.23 (m, 3H), 5.82–5.95 (m, 1H), 6.74 (dd, 1H,
J1 = 8.2 Hz, J2 = 2.2 Hz), 7.06 (d, 1H, J = 2.2 Hz), 7.38 (d, 1H,
J = 8.2 Hz) ppm. 13C NMR (75 MHz, CDCl3): d = À0.1, 42.5, 55.2,
71.2, 97.9, 102.9, 110.4, 112.2, 160.0, 148.4, 134.7, 133.7, 118.0,
112.7, IR (film): m = 3460, 3080, 2260, 2160, 1730, 1640,
(2.28 g, 54%) as
a
colorless oil. 1H NMR (300 MHz, CDCl3):
d = 0.21 (s, 9H), 1.69–1.71 (m, 2H), 2.84 (t, 2H, J = 7.7 Hz), 3.43
(dd, 1H, J1 = 11.5 Hz, J2 = 7.7 Hz), 3.59 (dd, 1H, J1 = 11.5 Hz,
J2 = 2.2 Hz), 3.65 (m, 1H), 3.73 (s, 3H), 6.63 (dd, 1H, J1 = 8.8 Hz,
J2 = 2.2 Hz), 6.70 (d, 1H, J = 2.2 Hz), 7.33 (d, 1H, J = 8.8 Hz) ppm.
13C NMR (75 MHz, CDCl3): d = 0.0, 30.5, 33.6, 55.1, 66.6, 71.3,
96.1, 104.1, 111.4, 114.5, 114.6, 133.9, 145.9, 159.8 ppm. IR (film):
m = 3350, 2950, 2140, 1610 cmÀ1. Calc. for C16H24O3Si (292.45): C,
65.71; H, 8.27. Found: C, 65.59; H, 8.16%.
3.11. Synthesis of 4-(5-methoxy-2-((trimethylsilyl)ethynyl)phenyl)-2-
oxobutyl acetate, 14
Compound 13 (0.29 g, 1.0 mmol) was solved in anhydrous DCM
(6 mL), EtiPr2N (0.52 mL, 3.0 mmol) and acetyl chloride (0.1 mL,
1.4 mmol) were added. The mixture was stirred at rt for 3 h, then,
water (10 mL) was added at 0 °C and the reaction mixture was ex-
tracted with EtOAc (3 Â 15 mL). The organic layer was washed
with water (2 Â 10 mL) and brine (2 Â 10 mL), dried over MgSO4,
filtered and concentrated. 0.24 g (71%) of the acetate was obtained
upon purification by column chromatography (hexane/EtOAc 2:1)
as a white solid (m.p. 62–65 °C). To a solution of this compound
(0.57 g, 1.7 mmol) in acetone (25 mL) at 0 °C, 1.3 mL of Jones

2436
E. Arnáiz et al. / Journal of Organometallic Chemistry 693 (2008) 2431–2437
reactive cooled to 0 °C were added. The resulting mixture was stir-
red during 2 h, isopropanol (3 mL) was added and the reaction
mixture was extracted with EtOAc (2 Â 25 mL). The organic layer
was washed with water until loss of its color, and it was dried over
MgSO4, filtered and concentrated. Purification by column chroma-
tography (hexane/EtOAc 4:1) gives 0.42 g (75%) of 14 as a yellow
oil. 1H NMR (300 MHz, CDCl3): d = 0.18 (s, 9H), 2.09 (s, 3H), 2.73
(t, 2H, J = 7.7 Hz), 2.97 (t, 2H, J = 7.7 Hz), 3.72 (s, 3H), 4.56 (s, 2H),
6.62 (dd, 1H, J1 = 8.8 Hz, J2 = 2.2 Hz), 6.67 (d, 1H, J = 2.2 Hz), 7.31
(d, 1H, J = 8.8 Hz) ppm. 13C NMR (75 MHz, CDCl3): d = À0.1, 20.3,
28.4, 38.9, 55.0, 67.7, 96.7, 103.3, 111.7, 114.4, 114.5, 133.8,
144.6, 159.7, 169.9, 202.8 ppm. IR (film): m = 2960, 2150, 1760,
1740 cmÀ1. Calc. for C18H24O4Si (332.47): C, 65.03; H, 7.28. Found:
C, 64.97; H, 7.19%.
ylcyclohexyl chlorocarbonate (0.1 g, 0.45 mmol) were added.
The mixture was stirred at room temperature for 2 h. Then, water
(10 mL) was added at 0 °C and the reaction mixture was ex-
tracted with DCM (3 Â 10 mL). The organic layer was washed
with water (10 mL) and brine (10 mL), dried over MgSO4, filtered
and concentrated. Purification was carried out by column chro-
matography using hexane/EtOAc (20:1) as eluent. Compound 17
was obtained (0.15 g, 93%) as a whitish oil. 1H NMR (300 MHz,
CDCl3): d = 0.79 (d, 3H, J = 6.6 Hz), 0.89–0.93 (m, 6H), 1.00–1.12
(m, 2H), 1.26–1.46 (m, 3H), 1.63–1.72 (m, 2H), 1.93–2.01 (m,
1H), 2.03–2.13 (m, 1H), 2.41 (t, 2H, J = 8,2 Hz), 2.93 (t, 2H,
J = 8,2 Hz), 3.18 (s, 1H), 3.79 (s, 3H), 4.22 (td, 1H, J1 = 10.9 Hz,
J2 = 4.4 Hz), 4.63 (s, 2H), 5.01 (s, 1H), 5.11 (s, 1H), 6.68–6.74
(m, 2H), 7.40 (d, 1H, J = 8.8 Hz) ppm. 13C NMR (75 MHz, CDCl3):
d = 16.2, 20.6, 21.9, 23.2, 26.0, 31.3, 33.0, 33.6, 34.0, 40.7, 46.9,
55.1, 69.7, 78.3, 79.5, 82.1, 111.5, 113.0, 113.6, 114.3, 134.2,
142.9, 145.9, 154.8, 159.8 ppm. IR (film): m = 2930, 2100, 1740,
1610 cmÀ1. Calc. for C25H34O4 (398.54): C, 75.34; H, 8.60. Found:
C, 75.08; H, 8.41%.
3.12. Synthesis of 4-(2-ethynyl-5-methoxyphenyl)-2-methylenebutyl
acetate, 15
Methyl triphenylphosphonium chloride (0.54 g, 1.5 mmol) was
suspended in anhydrous THF (8 mL) and KHMDS 0.5 M (2.6 mL,
1.3 mmol) was added dropwise. After stirring at rt for 30 min this
mixture was cannulated to a flask containing a solution of 14
(0.33 g, 1.0 mmol) in anhydrous THF (4 mL). The resulting mixture
was stirred for 30 min, poured onto a 1:1 mixture of water and
Et2O (20 mL), and extracted. The organic layer was washed with
water (2 Â 10 mL) and brine (2 Â 10 mL), dried over MgSO4 and
concentrated. After purification by column chromatography (hex-
ane/EtOAc 4:1), the resulting intermediate was solved in 6 mL of
anhydrous THF at 0 °C, and TBAF 1.0 M (2 mL, 2.0 mmol) was
added. The resulting mixture was stirred during 2 h and Et2O
(6 mL), hexane (6 mL) and water (6 mL) were added. The organic
layer was washed with water (12 mL), dried over MgSO4 and con-
centrated. Purification by column chromatography (hexane/EtOAc
4:1) gives 0.21 g (82%) of 15 as a colorless oil. 1H NMR (300 MHz,
CDCl3): d = 2.10 (s, 3H), 2.39 (t, 2H, J = 8.8 Hz), 2.92 (t, 2H,
J = 8.8 Hz), 3.19 (s, 1H), 3.79 (s, 3H), 4.58 (s, 2H), 5.00 (s, 1H),
5.08 (s, 1H), 6.70 (dd, 1H, J1 = 8.3 Hz, J2 = 2.2 Hz), 6.74 (d, 1H,
J = 2.2 Hz), 7.40 (d, 1H, J = 8.3 Hz) ppm. 13C NMR (75 MHz, CDCl3):
d = 20.9, 33.1, 33.8, 55.2, 66.8, 79.4, 82.1, 111.4, 112.9, 113.6, 114.4,
134.3, 143.2, 145.9, 159.9, 170.7 ppm. IR (film): m = 3280, 2940,
2100, 1740, 1610 cmÀ1. Calc. for C16H18O3 (258.31): C, 74.39; H,
7.02. Found: C, 74.44; H, 7.10%.
3.15. Synthesis of (7-methoxy-2-oxo-3,3a,4,5-tetrahydro-2H-
cyclopenta[a]naphthalen-3a-yl)methyl acetate, 21
To a solution of 15 (0.28 g, 1.1 mmol) in 5 mL of anhydrous
Et2O, 0.13 g (0.37 mmol) of dicobalt octacarbonyl were added.
The mixture was stirred at rt for 3 h and filtered through Celite.
Upon column chromatography (hexane/EtOAc 49:1) 0.55 g (90%)
of 18 were obtained as a brown oil. To a solution of 18 (0.55 g
1.0 mmol) in 15.0 mL of anhydrous toluene, powdered 4 Å molec-
ular sieves (two times the mass of the enyne) and Rh(PPh3)2ClCO
(0.05 mmol) were added. The mixture was stirred at 70 °C under
argon for 18 h. The crude residue was filtered through Celite, con-
centrated and purified by column chromatography (hexane/EtOAc
10:1), giving 0.17 g (60%) of 21 as a colorless oil. 1H NMR
(300 MHz, CDCl3): d = 1.88 (td, 1H, J1 = 13.2 Hz, J2 = 6.0 Hz), 2.01
(s, 3H), 2.23 (d, 1H, J = 18.1 Hz), 2.25–2.30 (m, 1H), 2.67 (d, 1H,
J = 18.1 Hz), 2.87 (dd, 1H, J1 = 17.6 Hz, J2 = 6.0 Hz), 2.96–3.08 (m,
1H), 3.82 (s, 3H), 3.87 (d, 1H, J = 11.0 Hz), 4.22 (d, 1H,
J = 11.0 Hz), 6.27 (s, 1H), 6.69 (br s, 1H), 6.81 (dd, 1H, J1 = 8.8 Hz,
J2 = 2.7 Hz), 7.54 (d, 1H, J = 8.8 Hz) ppm. 13C NMR (75 MHz, CDCl3):
d = 20.8, 26.3, 30.3, 44.8, 47.6, 55.4, 66.8, 113.6, 113.8, 121.9, 123.3,
129.3, 139.6, 161.9, 170.8, 173.3, 206.1 ppm. IR (film): m = 1750,
1690 cmÀ1. Calc. for C17H18O4 (286.32): C, 71.31; H, 6.34. Found:
C, 71.58; H, 6.17%.
3.13. Synthesis of 4-(2-ethynyl-5-methoxyphenyl)-2-methylenebutan-
1-ol, 16
3.16. (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl (7-methoxy-2-oxo-
3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-3a-yl)methyl
carbonate, 23
To a solution of 15 (0.23 g, 0.9 mmol) in THF (5.3 mL), 12.6 mL
(37.9 mmol) of 3 N NaOH were added and the resulting mixture
was refluxed for 2 h. The reaction mixture was extracted with
EtOAc (2 Â 6 mL), washed with 0.1 N HCl (20 mL), water (20 mL)
and brine (20 mL), dried over MgSO4 and concentrated. Upon puri-
fication by column chromatography using hexane/EtOAc as eluent,
0.18 g (90%) of 16 were obtained as a yellow oil. 1H NMR (300 MHz,
CDCl3): d = 2.36 (t, 2H, J = 8.2 Hz), 2.90 (t, 2H, J = 8.2 Hz), 3.17 (s,
1H), 3.77 (s, 3H), 4.10 (s, 2H), 4.90 (s, 1H), 5.05 (s, 1H), 6.67 (dd,
1H, J1 = 8.2 Hz, J2 = 2.2 Hz), 6.72 (d, 1H, J = 2.2 Hz), 7.38 (d, 1H,
J = 8.2 Hz) ppm. 13C NMR (75 MHz, CDCl3): d = 33.3, 33.7, 55.2,
65.7, 79.3, 82.3, 109.8, 111.4, 113.6, 114.3, 134.3, 146.2, 148.3,
159.9 ppm. IR (film): m = 3400, 3290, 2930, 2100, 1610 cmÀ1. Calc.
for C14H16O2 (216.28): C, 77.75; H, 7.46. Found: C, 77.80; H, 7.51%.
Following the same procedure than for the synthesis of 21, from
0.10 g of 20, which was obtained from 0.06 g (0.15 mmol) of 17,
0.03 g (45%) of a (1:1) mixture of diastereomers was obtained as
a yellow oil. Data for the mixture: 1H NMR (300 MHz, CDCl3):
d = 0.74 (d, 3H, J = 7.2 Hz), 0.86–0.90 (m, 6H), 0.96–1.08 (m, 1H),
1.23 (s, 2H), 1.39–1.42 (m, 1H), 1.57–1.67 (m, 4H), 1.82–1.91 (m,
1H), 1.98 (d, 1H, J = 12.1 Hz), 2.24 (d, 1H, J = 18.2 Hz), 2.34 (dd,
1H, J1 = 13.2 Hz, J2 = 5.5 Hz), 2.74 (d, 1H, J = 18.2 Hz), 2.88 (dd,
1H, J1 = 17.6 Hz, J2 = 6.0 Hz), 3.02 (dd, 1H, J1 = 12.6 Hz, J2 = 5.5 Hz),
3.86–3.93 (m, 1H), 4.22–4.29 (m, 1H), 4.41–4.50 (m, 1H), 6.26 (s,
1H), 6.71 (br s, 1H), 6.81 (dd, 1H, J1 = 8.8 Hz, J2 = 2.2 Hz), 7.53 (d,
1H, J = 8.3 Hz) ppm. 13C NMR (75 MHz, CDCl3): d = 14.1, 16.3,
20.7, 21.8, 22.7, 23.3, 26.0, 26.3, 29.4, 29.5, 29.6, 29.7, 29.9, 30.9,
31.4, 32.0, 34.0, 40.6, 45.2, 46.9, 47.5, 55.4, 69.8, 78.8, 113.6,
113.8, 121.9, 123.5, 129.2, 139.7, 154.8, 161.9, 173.2, 190.0,
3.14. Synthesis of 4-(2-ethynyl-5-methoxyphenyl)-2-methylenebutyl
(1S,2R,5S)-2-isopropyl-5-methylcyclohexyl carbonate, 17
To a solution of 16 (0.86 g, 0.4 mmol) in anhydrous DCM
(5.5 mL) at 0 °C, pyridine (0.1 mL) and (+)-2-isopropyl-5-meth-
196.1 ppm. IR (film): m = 1740, 1600 cmÀ1
.

E. Arnáiz et al. / Journal of Organometallic Chemistry 693 (2008) 2431–2437
2437
(b) L. Perez-Serrano, J. Blanco-Urgoiti, L. Casarrubios, G. Dominguez, J. Perez-
Castells, J. Org. Chem. 65 (2000) 3513.
Acknowledgement
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This work was supported by the spanish Ministerio de Educa-
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