Gold-catalyzed cyclization of oxo-1,5-enynes

Article abstract of DOI:10.1055/s-0031-1289532

Cationic gold(I) complexes catalyze the cycloisomerization of oxo-1,5-enynes to form oxatricyclic derivatives through an intramolecular Prins reaction. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289532

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49
Gold-Catalyzed Cyclization of Oxo-1,5-enynes
Cyclization of
O
xo
ú
-1,5-enynesria Huguet, Antonio M. Echavarren*
Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
Fax +34(977)920225; E-mail: aechavarren@iciq.es
Received 4 August 2011
bonyl group to form oxonium cation 5, which undergoes
an intramolecular Prins reaction to form a tricyclic inter-
mediate 6, which leads to oxatricyclic derivatives 2 or
fragmentation derivatives 3 (Scheme 1). The fragmenta-
tion process can be the predominant pathway in the anal-
ogous gold(I)-catalyzed intermolecular reaction of 1,6-
enynes with aldehydes.3 Other 1,6-enynes with a termi-
nally unsubstituted alkene react differently in intermolec-
ular processes with carbonyl compounds to give other
types of tricyclic derivatives.4
Abstract: Cationic gold(I) complexes catalyze the cycloisomeriza-
tion of oxo-1,5-enynes to form oxatricyclic derivatives through an
intramolecular Prins reaction.
Key words: gold, enynes, alkynes, cycloisomerization
Functionalized 1,n-enynes undergo cycloisomerization
reactions with gold(I) catalysts to form a wide variety of
complex carbon architectures.1 1,6-Enynes 1 bearing a
carbonyl group at the alkenyl side chain react with gold(I)
catalysts to form oxatricyclic derivatives 2 (Scheme 1).2
In this tandem [2+2+2] alkyne/alkene/carbonyl cycload-
dition process, two C–C and one C–O bonds are assem-
bled stereospecifically. In addition, monocyclic
derivatives 3 are also formed as minor products by a com-
petitive fragmentation.2
We have used the gold(I)-catalyzed [2+2+2] alkyne/
alkene/carbonyl cycloaddition for the total synthesis of
orientalol F (7), pubinernoid B (8),5 and englerin A (9)6
(Figure 1). A very similar approach was developed inde-
pendently for the synthesis of 9 using gold catalysis.7
Ph
The gold(I)-catalyzed [2+2+2] alkyne/alkene/carbonyl
cycloaddition reaction was proposed to take place by
opening of the cyclopropyl gold(I) carbenes 4 by the car-
O
HO
O
HO
H
R
O
O
O
O
AuL+
CH2Cl2, r.t.
O
O
H
H
Z
Z
H
O
9
R
7
8
H
OH
2
+
1
Figure 1
R
O
R
Z
We decided to examine the gold(I)-catalyzed cyclization
of oxo-1,5-enynes 10 for the synthesis of oxatricyclic de-
rivatives 11, via intermediates 12,8,9 to form 13 by a simi-
lar intramolecular ring-opening by the carbonyl group
(Scheme 2). Intermediate 13 could form a second C–C
bond by a Prins reaction that, in this case, would give rise
to a carbene-like intermediate 14. We expected that 14
would evolve by 1,2-H migration followed by demetala-
tion to form 11.
3
+
AuL
LAu
R
AuL+
+
O
Z
1
Z
O
H
H
4
5
The required substrates 10a–e (Z = CHSO2Ph) for the cy-
clization were readily prepared in four to six steps from
geranyl bromide via dienylenyne 17 as shown in
Scheme 3.10
AuL
O
2
3
R
+
Z
We first examined the cyclization of (E)-enynal 10a with
cationic gold(I) catalysts A–G (Figure 2), which allow the
cycloisomerization reactions to be performed under sil-
ver(I)-free conditions (Table 1).11 The cyclization pro-
ceeded satisfactorily using gold complexes A–C, bearing
bulky dialkylbiphenylphosphine ligands12 (Table 1, en-
tries 1–9) or NHC-Au(I) complex E13,14 (Table 1, entries
11 and 12), whereas poorer yields were obtained with cat-
H
6
Scheme 1
SYNLETT 2012, 23, 49–53
x
x
.x
x
.2
0
1
1
Advanced online publication: 19.11.2011
DOI: 10.1055/s-0031-1289532; Art ID: Y04211ST
© Georg Thieme Verlag Stuttgart · New York

50
N. Huguet, A. M. Echavarren
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+
R
+
t-Bu
Au
t-Bu
Au
H
H
–
–
t-Bu
t-Bu
SbF6
SbF6
Z
AuL+
P
NCMe
P
NCMe
O
i-Pr
Z
i-Pr
O
11
10
R
i-Pr
A
B
AuL+
H
– AuL+
+
LA+u
R
H
+
–
+
SbF6
Cy
Au
LAu
–
Cy
SbF6
N
N
Mes
Mes
P
NCMe
O
LAu
Z
R
i-Pr
Au
Z
Z
H
i-Pr
H
O
L
12
14
i-Pr
C
D: L = 2,4,6-(MeO)3C6H2CN
O+
H
+
–
SbF6
+
13
R
N
N
–
R
R
SbF6
N
N
Scheme 2
Et
Me
Au
L
Au
L
NaO2SPh
PhO2S
Br
DMF, r.t.
97%
F: L = 2,4,6-(MeO)3C6H2CN
E: L = PhCN
R = 2,6-i-Pr2C6H3
15
i. BuLi, THF
ii.
16
+
t-Bu
–
SbF6
AD-mix-α
PhO2S
t-Bu
O
P
Au NCPh
quantitative
3
Br
85%
17
G
Figure 2
PhO2S
PhO2S
NaIO4-SiO2
90%
O
18
10a
OH
HO
10b: R = Me (74%)
10c: R = i-Pr (50%)
10d: R = CH2CH2CH=CH2 (33%)
10e: R = Ph (80%)
PhO2S
1. RMgBr, THF
2. DMP, NaHCO3
O
R
Scheme 3
alysts D, F, G, AuCl, or AuCl3 (Table 1, entries 10 and
13–16). No cycloisomerization was observed with
NaAuCl4, PtCl2, PtCl4, AgSbF6, GaCl3, or PdCl2 (Table 1,
entries 18–22).
Figure 3 X-ray crystal structure of 11a¢
1,5-enynes 10b–e to form 11b–e and 11b–e¢ with moder-
ate stereoselectivities (Table 2).
In all cases, besides the expected cyclized derivative 11a,
its stereoisomer 11a¢ was also obtained as a minor prod-
uct, with the exception of the reaction using catalyst G,
which led to the formation of 11a and 11a¢ in a 1:1.5 ratio
(Table 1, entry 14). Their configuration was determined
by NOESY experiments and further confirmed by the de-
termination of the X-ray structure of 11a¢ (Figure 3),
which was obtained as a major product in the cyclo-
isomerization of 19 (see below).
Interestingly, the cyclization of 19 (the Z isomer of 10a),
proceeded with excellent stereoselectivity to give 11a¢
(Table 3). Although the best result was obtained using 2
mol% catalysts A (Table 3, entry 2) good results were also
obtained with catalysts B, E, and G (Table 3, entries 3–5).
When gold(I) complexes bearing donating ligands are
used as catalysts, the major cycloisomerization pathway is
stereospecific leading to 13a and 13a’ from trans- and cis-
substrates, respectively (Scheme 4). However, the overall
stereoselectivity is not complete, which is consistent with
the existence of two competitive processes. In analogy
with the Stork–Eschenmoser model,15,16 some gold(I)-cat-
alyzed cascade reactions have been proposed to be con-
The best results in the cyclization of 10a were obtained
using catalyst A, which is commercially available, in
CH2Cl2 at room temperature. This cationic gold(I) com-
plex was also the best catalyst for the cyclization of oxo-
Synlett 2012, 23, 49–53
© Thieme Stuttgart · New York

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Cyclization of Oxo-1,5-enynes
51
Table 1 Gold-Catalyzed Cyclization of (E)-Enynal 10aa
Table 2 Gold-Catalyzed Cyclization of Oxo-1,5-enynes 10b–ea
H
H
H
R
R
H
H
AuL+
PhO2S
PhO2S
+
AuL+
O
O
+
O
O
H
PhO2S
PhO2S
H
H
O
O
PhO2S
11a
11a'
PhO2S
10a
H
10b–e
R
11b–e
11b–e'
Entry Catalyst
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
toluene
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Time (h) Yield (%)Ratio 11a/11a¢
Entry 10b–e
Catalyst
Time (h) Yield (%) Ratio 11a/11a¢
1
A
13
2
54
74
65
4.2:1
4.5:1
5.6:1
4.6:1
1:1.4
3.6:1
3.3:1
3.6:1
3.1:1
2:1
1
10b
10b
10b
10b
10b
10c
10c
10d
10d
10e
A
A
E
E
G
A
E
A
A
A
14
4
98
93
97
91
12
51
32
64
89
62
3.7:1
3.1:1
3.2:1
3.2:1
1:2.5
4:1
2b
3c
4
A
2b
3
A
0.2
14
4
57d
4b
5
A
15
15
14
2
e
5
A
7
6
B
75
78
72
71
6
6
4
b
7
B
7
7
1.7:1
4:1
8
C
2
8
2
9b
C
2
9b
2
4:1
10
11
12b
13
14
15
16
17
18
19
20
21
22
D
72
13
10
14
4:1
a 5 mol% catalyst, 23 °C. Conversion ≥ 99%.
E
64
60
16
47
5
4:1
b 2 mol% catalyst.
E
2.5
4:1
Table 3 Gold-Catalyzed Cyclization of Z-Enynal 19a
F
72
7
2:1
H
H
H
G
1:1.5
4:1f
AuL+
PhO2S
O
O
+
O
AuCl
AuCl3
14
14
24
14
14
14
14
24
H
H
3.5:1f
PhO2S
11a'
PhO2S
9
19
11a
g
NaAuCl4 CH2Cl2
–
–
Entry
Catalyst
Time (h) Yield (%)
Ratio 11a¢/11a
20:1
g
PtCl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–
–
1
A
A
B
E
G
2
2
77
97
88
85
65
g
PtCl4
–
–
2b
3
30:1
g
AgSbF6
GaCl3
PdCl2
–
–
4
20:1
g
–
–
4
15
12
20:1
g
–
–
5
25:1
a 5 mol% catalyst, 23 °C. Conversion ≥ 93%.
b 2 mol% catalyst.
a 5 mol% catalyst, 23 °C. Conversion ≥ 99%.
c Reaction at 80 °C (microwave irradiation).
b 2 mol% catalyst.
d Determined by 1H NMR (1,4-diacetylbenzene as internal standard).
e Yield not determined (quantitative conversion).
f Conversion: 57–61%
the 1,5-enyne series by a tandem process that involves a
Prins reaction. Extension of these results for the synthesis
of other ring systems is under way.
g 11a/11a¢ were not detected. The starting material was partially re-
covered.
certed.17 However, the formation of minor stereoisomers
11a¢ and 11a in the cyclization reactions of 10a and 19, re-
spectively, is more consistent with a stepwise process oc-
curring through discrete intermediates such as 12a and
12a¢, which is in line with other theoretical and experi-
mental results.18
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the MICINN (CTQ2010-16088/BQU, Consolider
Ingenio 2010 Grant CSD2006-0003), the MEC (FPU predoctoral
fellowship to N.H.), the AGAUR (2009 SGR 47), Dr. E. Escudero-
In summary, these results show that the gold(I)-catalyzed
cyclization of oxo-1,5-enynes also occurs efficiently in
© Thieme Stuttgart · New York
Synlett 2012, 23, 49–53

52
N. Huguet, A. M. Echavarren
CLUSTER
100 MHz): d = 207.58 (C), 145.43 (C), 137.36 (C), 133.93
(CH), 129.25 (CH), 129.05 (CH), 116.17 (CH), 79.00 (C),
71.02 (CH), 62.99 (CH), 41.52 (CH2), 33.25 (CH2), 30.05
(CH3), 18.82 (CH2), 16.86 (CH3). IR (thin film): 3295 (CH
terminal alkyne), 1704 (C=O) cm–1. HRMS (ESI): m/z [M +
Na]+ calcd for C17H20O3SNa: 327.1031; found: 327.1030
(11) General procedure for the cyclization of oxo-1,5-enynes:
1,5-Oxoenyne and the gold(I) complex A–G (2–5 mol%)
were dissolved in CH2Cl2 (0.5–1.2 mL) and stirred at room
temperature until full conversion was observed (reaction
monitored by TLC). One drop of Et3N was added and the
crude reaction was filtered through Celite and the solvent
was evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel to provide
the cyclized product. (1S,3aS,4S,7R,7aR)-7-Methyl-1-
[(phenylperoxy)thio]-3a,4,5,6,7,7a-hexahydro-1H-4,7-
epoxyindene (11a): 1H NMR (500 MHz, CDCl3): d = 7.89–
7.85 (m, 2 H), 7.75–7.62 (m, 1 H), 7.61–7.51 (m, 2 H), 5.99
(dt, J = 5.7, 2.0 Hz, 1 H), 5.77 (dt, J = 4.3, 1.9 Hz, 1 H), 4.48
(t, J = 5.6 Hz, 1 H), 4.00–3.98 (m, 1 H), 3.34–3.01 (m, 1 H),
2.74 (dt, J = 9.5, 2.0 Hz, 1 H), 1.73–1.51 (m, 1 H), 1.51–1.33
(m, 2 H), 1.27–1.25 (m, 1 H), 1.21 (s, 3 H). 13C NMR
(CDCl3, 125 MHz): d = 141.36 (CH), 136.91 (C), 133.97
(CH), 129.49 (CH), 129.12 (CH), 125.04 (CH), 86.01 (C),
79.03 (CH), 72.35 (CH), 56.03 (CH), 52.88 (CH), 30.32
(CH2), 28.58 (CH2), 20.18 (CH3). HRMS (ESI): m/z [M +
Na]+ calcd for C16H18O3SNa: 313.0874; found: 313.0869.
(1S,3aS,4R,7S,7aR)-7-Methyl-1-[(phenylperoxy)thio]-
3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyindene (11a¢):
1H NMR (500 MHz, CDCl3): d = 7.88–7.85 (m, 2 H), 7.73–
7.60 (m, 1 H), 7.63–7.49 (m, 2 H), 5.92 (dt, J = 5.7, 2.2 Hz,
1 H), 5.62 (dt, J = 5.7, 2.1 Hz, 1 H), 4.26–4.18 (m, 1 H), 4.14
(d, J = 5.1 Hz, 1 H), 2.96 (ddd, J = 7.0, 4.6, 2.3 Hz, 1 H),
2.72 (dd, J = 7.2, 3.1 Hz, 1 H), 1.82–1.74 (m, 1 H), 1.62–
1.58 (m, 1 H), 1.56–1.48 (m, 2 H), 1.32 (s, 3 H). 13C NMR
(CDCl3, 125 MHz): d = 139.30 (CH), 137.71 (C), 133.90
(CH), 129.23 (CH), 129.17 (CH), 126.02 (CH), 84.58 (C),
78.97 (CH), 74.25 (CH), 58.21 (CH), 50.34 (CH), 36.31
(CH2), 30.75 (CH2), 17.99 (CH3). HRMS (ESI): m/z [M +
Na]+ calcd for C16H18O3SNa: 313.0874; found: 313.0882
(12) (a) Nieto-Oberhuber, C.; López, S.; Echavarren, A. M.
J. Am. Chem. Soc. 2005, 127, 6178. (b) Herrero-Gómez, E.;
Nieto-Oberhuber, C.; López, S.; Benet-Buchholz, J.;
Echavarren, A. M. Angew. Chem. Int. Ed. 2006, 45, 5455.
(c) Pérez-Galán, P.; Delpont, N.; Herrero-Gómez, E.;
Maseras, F.; Echavarren, A. M. Chem. Eur. J. 2010, 16,
5324.
LAu
LAu+
PhO2S
H
H
H
10a
11a
O+
H
O
O
PhO2S
H
12a
13a
H
H
LAu
LAu+
H
H
PhO2S
19
H
11a'
H
O+
PhO2S
H
12a'
13a'
Scheme 4
Adán (ICIQ X-ray Diffraction unit), and the ICIQ Foundation for
financial support
References and Notes
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(10) (E)-4-Methyl-6-(phenylsulfonyl)non-4-en-8-ynal (10a):
Yellow solid; mp 52–54 °C. 1H NMR (400 MHz, CDCl3):
d = 9.73 (t, J = 1.5 Hz, 1 H), 7.97–7.73 (m, 2 H), 7.69–7.60
(m, 1 H), 7.56–7.52 (m, 3 H), 5.08 (ddd, J = 10.3, 2.6,
1.3 Hz, 1 H), 3.95 (td, J = 10.2, 3.8 Hz, 1 H), 2.98 (ddd, J =
16.7, 3.8, 2.8 Hz, 1 H), 2.60 (ddd, J = 16.7, 10.2, 2.7 Hz,
2 H), 2.47 (tm, J = 7.5 Hz, 2 H), 2.32 (t, J = 7.4 Hz, 2 H),
1.94 (t, J = 2.7 Hz, 1 H), 1.32 (d, J = 1.3 Hz, 3 H). 13C NMR
(CDCl3, 100 MHz): d = 201.27 (CHO), 144.80 (C), 137.37
(C), 134.02 (C), 129.33 (CH), 129.28 (CH), 129.13 (CH),
116.85 (CH), 71.11 (CH), 63.03 (CH), 41.66 (CH2), 31.8
(CH2), 18.86 (CH2), 16.83 (CH3). IR (thin film): 3244 (CH
terminal alkyne), 1712 (C=O) cm–1. HRMS (ESI): m/z [M +
Na]+ calcd for C16H18O3SNa: 313.0874; found: 313.0867.
(E)-5-Methyl-7-(phenylsulfonyl)dec-5-en-9-yn-2-one
(10b): Yellow solid; mp 53–55 °C. 1H NMR (400 MHz,
CDCl3): d = 7.84–7.82 (m, 2 H), 7.65 (t, J = 7.4 Hz, 1 H),
7.56–7.52 (m, 2 H), 5.06 (dd, J = 10.3, 1.2 Hz, 1 H), 3.95 (td,
J = 10.2, 3.8 Hz, 1 H), 2.99 (ddd, J = 16.7, 3.5, 2.9 Hz, 1 H),
2.61 (ddd, J = 16.7, 10.1, 2.6 Hz, 1 H), 2.48 (dd, J = 8.6,
6.6 Hz, 2 H), 2.27 (t, J = 7.8 Hz, 2 H), 2.15 (s, 3 H), 1.94 (t,
J = 2.6 Hz, 1 H), 1.31 (d, J = 1.2 Hz, 3 H). 13C NMR (CDCl3,
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Synlett 2012, 23, 49–53
© Thieme Stuttgart · New York

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2008, 350, 2617. (c) Sethofer, S. G.; Mayer, T.; Toste, F. D.
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Cyclization of Oxo-1,5-enynes
53
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