Construction of methylenecycloheptane frameworks through 7-exo-dig cyclization of acetylenic silyl enol ethers catalyzed by triethynylphosphine- gold complex

Article abstract of DOI:10.1021/ol101860j

Figure Presented. A cationic gold(I) complex bearing a semihollow-shaped triethynylphosphine ligand efficiently catalyzed the 7-exo-dig cyclization of silyl enol ethers with an ω-alkynic substituent. The reaction gave various methylenecycloheptane derivatives with an exo- or endocyclic carbonyl group. The protocol was applicable not only to cyclic substrates that form bicyclic frameworks but also to acyclic ones with or without substituents in a carbon chain tether.

Full text of DOI:10.1021/ol101860j

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4380-4383
Construction of Methylenecycloheptane
Frameworks through 7-Exo-Dig
Cyclization of Acetylenic Silyl Enol
Ethers Catalyzed by
Triethynylphosphine-Gold Complex
Hideto Ito, Hirohisa Ohmiya, and Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido UniVersity,
Sapporo 060-0810, Japan
sawamura@sci.hokudai.ac.jp
Received August 9, 2010
ABSTRACT
A cationic gold(I) complex bearing a semihollow-shaped triethynylphosphine ligand efficiently catalyzed the 7-exo-dig cyclization of silyl enol
ethers with an ω-alkynic substituent. The reaction gave various methylenecycloheptane derivatives with an exo- or endocyclic carbonyl group.
The protocol was applicable not only to cyclic substrates that form bicyclic frameworks but also to acyclic ones with or without substituents
in a carbon chain tether.
Metal-catalyzed intramolecular reactions of silyl enol ethers
with alkynes are powerful methods for the construction of
carbocyclic compounds.1,2 To date, 5-exo-, 5-endo-, 6-exo-,
and 6-endo-dig cyclizations have been developed by using
various metal catalysts such as mercury,1a-d tungsten,1e-l
rhodium,1m rhenium,1n,o platinum,1p palladium,1q silver,1r and
gold.2 This method, however, has yet to be extended toward
a seven-membered ring formation, which seems to be
difficult because of the distal location of the nucleophilic
center and the alkyne moiety.3,4
panding the scope of the reactions to six- and seven-
membered ring formations, which had been difficult with
the conventional catalytic systems.5b,c,6 We proposed that
the cavity in the ligand forces the nucleophilic center close
to gold-bound alkyne, resulting in the entropy-based rate
enhancement.
Here, we report the efficient construction of seven-
membered rings through a 7-exo-dig cyclization of acetylenic
silyl enol ether catalyzed by the triethynylphosphine
(L1)-gold(I) complex. The cyclization reactions afforded a
variety of methylenecycloheptane derivatives that are difficult
to prepare by other methods (Figure 1).
Previously, we reported that semihollow-shaped triethyl-
nylphosphine L1 (Figure 1)5a exerted marked acceleration
effects in the gold(I)-catalyzed Conia-ene reactions of
acetylenic keto esters and enyne cycloisomerizations, ex-
First, we optimized reaction conditions for the construction
of a 2-methylene bicyclo[4.3.1]decane framework, which is
10.1021/ol101860j  2010 American Chemical Society
Published on Web 09/07/2010

Figure 1. Semihollow-shaped triethynylphosphine (L1).
Figure 2. Natural terpenoids that involve a part structure relevant
to the 7-exo-dig cyclization products of ω-acetylenic silyl enol
found in natural diterpenoid (+)-sanadaol 4 (Figure 2).7 As
a result, the reaction of a cyclic silyl enol ether 1a (0.1 mmol)
bearing an ω-alkynic substituent was efficiently cata-
lyzed by a cationic gold-triethynylphosphine complex
ethers.
of tBuOH as a proton source did not affect the result (entry
2). The reaction without an alcohol resulted in a poor yield
and afforded unidentified side products (entry 3), indicating
that a proton source is indispensable for the formation of
2a. The reaction without MS4A yielded 2a in low yield
(50%) along with direct protonation product 3a in 34% yield
(entry 4). A similar result was obtained in the absence of
t
[Au(NTf2)(L1)] (5 mol %) in the presence of BuOH (0.10
mmol) and MS4A (100 mg) in anhydrous CH2Cl2 (5.0 mL)
at rt; the reaction was complete within 5 min to afford 7-exo-
dig cyclization product 2a in 99% isolated yield (Table 1,
entry 1). Notably, the reaction was not accompanied by either
the direct protonation of the silyl enol ether (1a) or the double
bond shift of the ꢀ,γ-unsaturated ketone (2a) to a conjugated
enone, which are common side reactions of the metal-
catalyzed cyclization of acetylenic silyl enol ethers.1,2
Observations concerning the reaction conditions are sum-
marized in Table 1, entries 2-12. The use of MeOH instead
t
both BuOH and MS4A (entry 5).
Cationic Au catalysts with counteranions other than NTf2
-
such as [Au(SbF6)(L1)], [Au(OTf)(L1)], and [Au(BF4)(L1)]
were less effective (entries 6-8). The use of PPh3 as a ligand
resulted in no reaction (entry 9). A gold complex with a
phosphite ligand such as P(OPh)3, whose electron-donating
power is as low as the triethynylphosphine L1,5a was virtually
inactive, suggesting that the rate enhancement by L1 is not
due to an electronic effect (entry 10). While the ligands such
as IPr and X-Phos are commonly employed for gold(I)-
catalyzed reactions as sterically demanding and/or strongly
electron-donating ligands,6 gold complexes with these ligands
did not reach full conversions of 1a even after 3 h (entries
11 and 12). Further extension of the reaction time did not
improve the yields.
With the optimal reaction conditions in hand, we examined
various cyclic silyl enol ether substrates for the construction
of bicyclo[4.n.1]alkane or bicyclo[m.4.1]alkane frameworks
through 7-exo-dig cyclization (Table 2). Triisopropylsilyl
enol ether 1b was less reactive than the TBS ether 1a but
was rapidly (e5 min) and quantitatively converted to 2a at
80 °C (entry 1). The reaction of the substrate bearing benzoyl
group 1c required slight heating (40 °C) and resulted in a
(1) For metal-mediated cyclization of acetylenic silyl enol ether, see:
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R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991. (b) Lee, K.;
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Ed. 2010, 49, 4269.
(4) For examples of the synthesis of seven- or eight-membered rings
via gold catalysis, see: (a) Ferrer, C.; Raducan, M.; Nevado, C.; Claverie,
C. K.; Echavarren, A. M. Tetrahedron 2007, 63, 6306. (b) Bae, H. J.; Baskar,
B.; An, S. E.; Cheong, J. Y.; Thangadurai, D. T.; Hwang, I.-C.; Rhee, Y. H.
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(3) Gold-catalyzed 7-exo- or 7-endo-dig cyclization reactions have been
reported. Most studies employed the substrates biased for cyclization bearing
gem-substituents or double bonds in a linker chain. See: (a) Wilckens, K.;
Uhlemann, M.; Czekelius, C. Chem.sEur. J. 2009, 15, 13323. (b)
Odabachian, Y.; Gagosz, F. AdV. Synth. Catal. 2009, 351, 379. (c) Comer,
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Org. Lett., Vol. 12, No. 19, 2010
4381

Table 1. Optimization of Reaction Conditionsa
yield (%)
entry
Au cat.
alcohol
time (min)
convnb (%)
2ab
99e
100
20
50
53
3ac
1
2
3
[Au(NTf2)(L1)]
[Au(NTf2)(L1)]
[Au(NTf2)(L1)]
[Au(NTf2)(L1)]
[Au(NTf2)(L1)]
[Au(SbF6)(L1)]
[Au(OTf)(L1)]
tBuOH
MeOH
none
5
5
720
5
100
100
45
100
100
33
12
18
0
21
0
0
0
34
20
3
0
0
0
1
4d
5d
6
tBuOH
none
5
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
180
180
180
180
180
180
180
22
7
8
9
10
11
12
trace
trace
0
1
39
[Au(BF4)(L1)]
[Au(NTf2)(PPh3)]
[Au(NTf2){P(OPh)3}]
[Au(NTf2)(IPr)]
[Au(NTf2)(X-Phos)]
39
28
0
3
17
b
a Reaction conditions: Au cat., 1a (0.10 mmol), alcohol (1.0 equiv), and MS4A (100 mg) in CH2Cl2 (5.0 mL) at 25 °C. Determined by H NMR.
1
c Determined by GC. d Without MS4A. e Isolated yield.
Next, we applied the gold(I)-triethynylphosphine (L1)
Table 2. Cyclization of Cyclic Alkynyl Silyl Enol Ethera
complex to the synthesis of monocyclic methylenecyclohep-
tane frameworks from acyclic silyl enol ethers, which are
thought to be more challenging substrates due to their
conformational flexibilities (Table 3). The acethylenic Z-
configurated silyl enol ether (1g) without any substituent in
the linker chain cyclized rapidly at rt to give ꢀ-methylenecy-
cloheptane derivative (2g) with an exocyclic carbonyl group
in 93% yield (entry 1). Notably, no double bond isomeriza-
tion was observed even in this monocyclic case. While the
substitution at the ꢀ-position of the acyclic substrate with a
methyl group caused a slight decrease in the speed of the
reaction, a trans-isomer of vicinally disubstituted methyl-
(5) For our previous works with triethynylphosphines, see: (a) Ochida,
A.; Sawamura, M. Chem.sAsian J. 2007, 2, 609. (b) Ochida, A.; Ito, H.;
Sawamura, M. J. Am. Chem. Soc. 2006, 128, 16486. (c) Ito, H.; Makida,
Y.; Ochida, A.; Ohmiya, H.; Sawamura, M. Org. Lett. 2008, 10, 5051.
(6) For recent reviews on gold-catalyzed reactions, see: (a) Hashmi,
A. S. K. Chem. ReV. 2007, 107, 3180. (b) Li, Z.; Brouwer, C.; He, C. Chem.
ReV. 2008, 108, 3239. (c) Arcadi, A. Chem. ReV. 2008, 108, 3266. (d)
Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem. ReV. 2008, 108, 3326. (e)
Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV. 2008, 108, 3351. (f)
Patil, N. T.; Yamamoto, Y. Chem. ReV. 2008, 108, 3395. (g) Hashmi,
A. S. K.; Rudolph, M. Chem. Soc. ReV. 2008, 37, 1766. (h) Marion, N.;
Nolan, S. P. Chem. Soc. ReV. 2008, 37, 1776. (i) Shapiro, N. D.; Toste,
F. D. Synlett 2010, 675. (j) Wang, S.; Zhang, G.; Zhang, L. Synlett 2010,
692. (k) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232.
(7) (a) Ishitsuka, M.; Kusumi, T.; Kakisawa, H. Tetrahedron Lett. 1982,
23, 3179. (b) Kirkup, M. P.; Moore, R. E. Phytochemistry 1983, 22, 2527.
(c) Nagaoka, H.; Kobayashi, K.; Matsui, T.; Yamada, Y. Tetrahedron Lett.
1987, 28, 2021. (d) Nagaoka, H.; Kobayashi, K.; Yamada, Y. Tetrahedron
Lett. 1988, 29, 5945. (e) Miyaoka, H.; Yamada, Y. Bull. Chem. Soc. Jpn.
2002, 75, 203.
a
t
Conditions: Au(NTf2)(L1) (5 mol %), 1 (0.10 mmol), BuOH (0.10
mmol), MS4A (100 mg), CH2Cl2 (5.0 mL). b Isolated yield. c DCE (5 mL)
was used as solvent.
moderate yield (entry 2). Bicyclo[4.2.1]nonane (2d), bicyclo-
[4.4.1]undecane (2e), and bicyclo[5.4.1]dodecane (2f) frame-
works were obtained from the corresponding cyclic silyl enol
ethers 1d-f at rt in excellent yields (entries 3-5).
4382
Org. Lett., Vol. 12, No. 19, 2010

(Z)-1j bearing ꢀ-methyl group in addition to the malonate
insert gave trans-isomer 2j8 exclusively (entry 4). The
reaction of the phenyl-substituted substrate (Z)-1k did not
lead to completion even after 24 h at 80 °C and afforded
diastereomerically pure 2k8 in a moderate yield (51%, entry
5). The diester substitution at the bishomopropargyl position
as in 1l did not significantly affect the reactivity, affording
2l in 83% yield (entry 6). Overall, the Thorpe-Ingold effects
by the malonate inserts did not operate in the gold-catalyzed
7-exo-dig cyclization (entry 1 vs entries 3 and 6).
Table 3. Cyclization of Linear Alkynyl Silyl Enol Ethera
The cyclization of the E isomer of 1j gave the same
stereoisomer of 2j as that of (Z)-1j (entries 4 vs 7), while
the reaction time was prolonged to 2 h at 80 °C (entry 7).
The excellent anti diastereoselectivity observed in the
reactions of (Z)-1h,j,k and (E)-lj can be explained by steric
repulsions between the silyl enol ether moieties and the
methyl or phenyl groups as described in the literature.2e
Notably, the methylenecycloheptane framework with an
exocyclic carbonyl group in 2g-l thus prepared (Table 2,
entries 1-7) is reminiscent of a partial structure of diterpe-
noid salvigenolide 5 (Figure 2).9
The reaction of silyl enol ethers 1m and 1n afforded
methylenecycloheptane derivatives 2m and 2n involving an
endocyclic carbonyl group, respectively, in excellent yields
(entries 8 and 9). These compounds can be structurally
related to natural sesquiterpenoid cynaropicrin 6 and their
derivatives (Figure 2).10
In summary, the 7-exo-dig cyclization of silyl enol ethers
with an ω-alkynic substituent was efficiently catalyzed by a
cationic gold(I) complex bearing a semihollow-shaped tri-
ethynylphosphine ligand. The reaction furnished various
methylenecycloheptane derivatives with exo- or endocyclic
carbonyl groups. The protocol was applicable not only to
cyclic substrates that form bicyclic frameworks but also to
acyclic ones with or without substituents in a carbon chain
tether. Further studies to expand the applicability of the
semihollow-shaped ligand are ongoing.
a
t
Conditions: Au(NTf2)(L1) (5 mol %), 1 (0.10 mmol), BuOH (0.10
mmol), MS4A (100 mg), CH2Cl2 (5.0 mL) at 25 °C or CH2Cl2 (5.0 mL) at
40 °C or DCE (5.0 mL) at 80 °C. b Isolated yield. c An isomeric mixture
was used as a substrate [1g, E/Z 14:86; 1h, E/Z 13:87; 1i, E/Z 10:90; 1k,
E/Z 4:96; 1l, E/Z 19:81; (E)-1j, E/Z 86:14]. d 0.60 mmol scale in CH2Cl2
(30 mL).
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research on Priority Area (No. 20037003,
“Chemistry of Concerto Catalysis”) from MEXT. H.I. thanks
JSPS for a fellowship.
enecycloheptane 2h was obtained from (Z)-1h as a single
diastereomer8 in high yield at rt (entry 2).
The Z-silyl enol ether (1i) with a dimethyl malonate insert
in the linker chain was less reactive than the substrate with
a nonsubstituted linker (1g) but cyclized rapidly (e5 min)
at 80 °C, giving 2i in 93% yield (entry 3). The reaction of
Supporting Information Available: Experimental pro-
cedures and NMR spectra for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL101860J
(9) Esquivel, B.; Ca´rdenas, J.; Toscano, A.; Soriano-Garcia, M.;
Rodr´ıguez-Hahn, L. Tetrahedron 1985, 41, 3213.
(10) Pandey, M. M.; Rastogi, S.; Rawat, A. K. S. J. Ethnopharmacol.
2007, 110, 379.
(8) The relative configurations of 2h, 2j, and 2k were determined by
X-ray crystal structure analysis and 1H NMR. For details, see the Supporting
Information.
Org. Lett., Vol. 12, No. 19, 2010
4383