Construction of eight-membered carbocycles through gold catalysis with acetylene-tethered silyl enol ethers

Article abstract of DOI:10.1002/anie.201300265

Semihollow triethynylphosphanes were synthesized and employed as ligands in the gold-catalyzed 8-exo-dig cyclization of acetylene-tethered silyl enol ethers to obtain eight-membered-ring carbocycles (see scheme). The gold-phosphane catalysts promoted eith

Full text of DOI:10.1002/anie.201300265

Angewandte
Chemie
DOI: 10.1002/anie.201300265
Cyclization
Construction of Eight-Membered Carbocycles through Gold Catalysis
with Acetylene-Tethered Silyl Enol Ethers**
Tomohiro Iwai, Hiori Okochi, Hideto Ito, and Masaya Sawamura*
The development of efficient methods for the construction of
medium-sized (eight- to eleven-membered) carbocycles
remains an important challenge in organic synthesis.[1]
Despite their ubiquitous existence within various biologically
active natural products and pharmaceuticals (Figure 1),[2] the
formation of medium-sized rings is generally difficult because
of entropic effects and transannular interactions.[3]
Figure 1. Natural products that possess an eight-membered carbo-
cycle. Bz=benzoyl.
Figure 2. Semihollow triethynylphosphanes.
Although various metal-catalyzed or metal-mediated
methods have been developed, the direct formation of
medium-sized carbocycles through the cyclization of acyclic
precursors has remained relatively unexplored.[4–6] Studies
involving homogeneous gold catalysis have shown that the
silyl enol ethers toward the formation of eight-membered-
ring carbocyclic compounds. Our methodology is applicable
not only to annulations leading to bicyclic structures, but also
to the cyclization of acyclic molecules in the formation of
nonfused carbocycles.
À
ionization of nonpolar unsaturated carbon carbon bonds
We previously demonstrated the utility of a semihollow
triethynylphosphane ligand that possesses bulky triarylsilyl
groups at the alkyne termini (Si-dtbm, Figure 2) in the
formation of seven-membered carbocyclic compounds
through gold-catalyzed 7-exo-dig cyclizations of acetylene-
tethered silyl enol ethers.[10,11] For these reactions, we
proposed that the gold-bound substrates adopt a bent con-
formation to fit into the cavity of the semihollow ligand,
resulting in an entropy-based rate enhancement of the
nucleophilic attack of the silyl enol ether on the ionized
alkyne moiety as a result of the proximity between the two
reaction sites.[12,13] Specifically, the cationic gold(I)/Si-dtbm
complex catalyzed the cyclization of 1a to afford the seven-
membered-ring compound 2a quantitatively. In contrast, such
cyclizations were not observed using conventional ligands,
such as Ph3P (Scheme 1).[10,14] Unfortunately, attempts to
expand our methodology to the formation of more challeng-
ing eight-membered or larger rings have been less successful;
for instance, the reaction of 3a at 858C for one hour afforded
methylene cyclooctane derivative 4a in merely 12% yield
with 14% substrate conversion (Table 2, entry 1). The
triethynylphosphane ligand (Si-btms, Figure 2) with trime-
thylsilyl (TMS) groups on the aromatic rings did not induce
any cyclization (Table 2, entry 2).
through gold p-coordination can initiate a variety of cycliza-
tion reactions with remarkably high efficiencies, thus provid-
ing powerful strategies for the construction of cyclic struc-
tures.[7] Such strategies, however, have not yet been success-
fully employed in the direct ring closure of medium-sized
rings.[8] To date, the construction of benzannulated structures
mostly involves highly constrained aromatic molecules, with
the single exception featuring the formation of a nine- or ten-
membered ring using 1,9- or 1,10-diynes with one or more
unsaturated moieties in the linker.[8c] Herein, we report the
use of novel semihollow triethynylphosphane ligands (abbre-
viated hereafter as C-dtbm and C-btms, Figure 2)[9] in the
gold-catalyzed 8-exo-dig cyclization of acetylene-tethered
[*] Dr. T. Iwai, H. Okochi, Dr. H. Ito, Prof. Dr. M. Sawamura
Department of Chemistry, Faculty of Science, Hokkaido University
Sapporo, 060-0810 (Japan)
E-mail: sawamura@sci.hokudai.ac.jp
Homepage: http://wwwchem.sci.hokudai.ac.jp/~orgmet
[**] This work was supported by Grants-in-Aid for Scientific Research on
Challenging Exploratory Research, MEXT and ACT-C, JST to M.S.
and by Grant-in-Aid for Young Scientists (Start-up), JSPS to T.I. H.I.
thanks JSPS for support through a scholarship.
In an attempt to overcome this problem, we synthesized
various novel triethynylphosphanes (C-type triethynylphos-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300265.
Angew. Chem. Int. Ed. 2013, 52, 4239 –4242
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4239

.
Angewandte
Communications
(100 mg) in anhydrous 1,2-dichloroethane (0.01m) at 858C
for one hour; it is important to note that the concentration of
the reaction mixture is moderately low. On the other hand,
under similar reaction conditions, the gold complex involving
the other C-type ligand (C-btms) with Me3Si substituents at
the aromatic rings was also effective and afforded 4a, albeit
with a lower yield (37%; Table 2, entry 4). In contrast,
conventional monodentate ligands, such as Ph3P, (PhO)3P,
XPhos, and IPr, were not effective in promoting this cycliza-
tion reaction.[16]
Scheme 1. Gold(I)-catalyzed 7-exo-dig cyclization of acetylene-tethered
silyl enol ether 1a.
phanes C-dtbm and C-btms, Figure 2) featuring trityl-based
end caps at the acetylenyl terminus of the triethynylphos-
phane instead of the triarylsilyl end caps (as in Si-type
triethynylphosphanes Si-dtbm and Si-btms). The synthesis of
these phosphanes was straightforward and efficient
(Scheme 2). According to molecular modeling (Spartan/
Interestingly, the reaction was affected by the nature of
À
the counteranion in the complex; the use of NTf2 was
essential for the activity of the [Au(C-dtbm)]+ catalyst,
whereas anions such as SbF6À, OTfÀ, and BARFÀ decreased
the yields to 7%, 0%, and 6%, respectively (Table 2,
entries 5–7). With regard to
the proton source, switching
from tBuOH to MeOH sig-
nificantly improved the cat-
alytic activity of [Au(NTf2)-
(C-dtbm)], thus increasing
the yield of 4a to 83% with
Scheme 2. Synthesis of the C-type semihollow triethynylphosphanes (C-dtbm and C-btms).
99% conversion of 3a
(69% yield of analytically
pure product;[17] Table 2,
MMFF), the new phosphane ligands possess a deeper cavity
with a narrower opening than Si-dtbm; the estimated depths
(d) and opening diameters (l) of the cavities are listed in
Table 1. Furthermore, according to the 31P NMR spectra of
the free ligands and their [AuCl(phosphane)]-type gold(I)
complexes (Table 1), substitution of the Si with the C atom
caused only marginal differences in the electronic properties
(electron density and hybridization) of the central P atom. As
a note, the air and moisture stability behavior was similar
among the triethynylphosphane ligands.
entry 3 versus entry 8). Substitution of the tert-butyldimethyl-
silyl (TBS) group in the siloxyalkene moiety with either
triethylsily or triisopropylsilyl groups resulted in lower
yields.[16]
Gold catalysts with C-type triethynylphosphane ligands
were also effective in the 8-exo-dig annulation of monocyclic
silyl enol ethers with different ring sizes in the construction of
various bicyclo[5.n.1]alkane frameworks (Table 3). In the
case of cyclopentanone-based silyl enol ether 3b, the use of C-
btms, which possesses 3,5-bis(trimethylsilyl)phenyl substitu-
Interestingly, the cationic gold complex that was coordi-
nated with C-type triethynylphosphane C-dtbm, [Au(NTf2)-
(C-dtbm)] (5 mol%), was significantly more effective than
those with Si-type ligands, promoting the 8-exo-dig cyclization
of 3a to afford 4a in 70% yield with 91% conversion (Table 2,
entry 3). The reaction was carried out in the presence of
tBuOH (1 equiv) and activated 4ꢀ molecular sieves[15]
Table 2: Gold(I)-catalyzed 8-exo-dig annulation of 3a under various
conditions.[a]
Entry
Au cat.
ROH
Conv. of
Yield of
Table 1: Estimated structural parameters: depth (d), opening diameter
(l), and 31P NMR chemical shifts of the semihollow triethynylphosphane
ligands (L) and the gold(I) complexes (Spartan/MMFF).
3a [%][b]
4a [%][b]
1
2
3
4
5
6
7
8
[Au(NTf2)(Si-dtbm)]
[Au(NTf2)(Si-btms)]
[Au(NTf2)(C-dtbm)]
[Au(NTf2)(C-btms)]
[Au(SbF6)(C-dtbm)]
[Au(OTf)(C-dtbm)]
[Au(BARF)(C-dtbm)]
[Au(NTf2)(C-dtbm)]
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
MeOH
14
10
91
66
14
11
47
99
12
0
70
37
7
0
6
83 (69)[c]
Entry Phosphane Depth Opening diameter d [ppm] d [ppm]
(d) [ꢀ]
(l) [ꢀ]
of L
of [AuCl(L)]
[a] Reaction conditions: Au catalyst (5.0 mmol, 5.0 mol%), 3a
(0.10 mmol), alcohol (0.10 mmol), 4ꢀ molecular sieves (100 mg), 1,2-
dichloroethane (10 mL), 858C, 1 h. [b] Determined by 1H NMR spec-
troscopy. [c] Yield after purification by column chromatography on silica
gel followed by gel-permeation chromatography (GPC).
BARF=tetrakis[3,5-bis(trifluoromethyl)phenyl]borate; Tf=trifluorome-
thanesulfonyl.
1
2
3
4
Si-dtbm
Si-btms
C-dtbm
C-btms
4.1
4.1
4.3
4.5
17
18
13
14
À85.2[a] À62.5[a]
À83.0[a] À61.8[a]
À81.5
À81.8
À63.9
À60.4
[a] The 31P NMR chemical shifts (in CDCl3) were taken from Ref. [12b].
4240 www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 4239 –4242

Angewandte
Chemie
Table 3: Gold-catalyzed 8-exo-dig cyclization of monocyclic siloxyalkenes
with w-acetylenic alkyl pendants in the construction of bicyclo-
[5.n.1]alkane frameworks.[a]
Table 4: Synthesis of dibenzocyclooctane 4e.[a]
Entry
Substrate 3
Ligand
Product 4
Yield [%][b]
1
2
C-dtbm
C-btms
28
Entry
Ligand
Catalyst loading [mol%]
Yield of 4e [%][b]
52 (30)[c]
1
2
3
4
C-dtbm
C-dtbm
C-btms
PPh3
5
1
5
5
92 (85)[c]
82
80
9
3
4
C-dtbm
C-btms
73 (62)[c]
69
[a] Reaction conditions: [Au(NTf2)(ligand)] (5.0 mmol, 5.0 mol% or
1.0 mmol, 1.0 mol%), 3e (0.10 mmol), tBuOH (0.10 mmol), 4ꢀ molec-
ular sieves (100 mg), 1,2-dichloroethane (10 mL), 858C, 1 h. [b] Deter-
mined by 1H NMR spectroscopy. [c] Yield after purification by column
chromatography on silica gel followed by GPC.
5
6
C-dtbm
C-btms
60 (48)[c]
38
[a] Reaction conditions: [Au(NTf2)(ligand)] (5.0 mmol, 5.0 mol%), 3
(0.10 mmol), tBuOH (0.10 mmol), 4ꢀ molecular sieves (100 mg), 1,2-
dichloroethane (10 mL), 858C, 1 h. [b] Determined by 1H NMR spec-
troscopy. [c] Yield after purification by column chromatography on silica
gel followed by GPC.
Table 5: Construction of nonfused eight-membered carbocycles through
a gold(I)-catalyzed 8-exo-dig cyclization of acyclic acetylene-tethered
siloxyalkenes.[a]
Entry Substrate 3
Ligand Product 4
Yield [%][b]
ents, resulted in a high yield of bicyclo[5.2.1]decane derivative
4b (52%; Table 3, entry 2). The use of C-dtbm was however
not very effective, resulting in a relatively low yield (28%;
Table 3, entry 1), which may be attributable to the ring strain
of the bicyclo[5.2.1]decane framework, or to the unfavorable
directionality of the w-acetylenic alkyl pendant relative to the
p-face of the siloxyalkene. In contrast, C-dtbm was more
effective than C-btms in the formation of bicyclo-
[5.5.1]tridecane 4d from cyclic silyl enol ether 3d (Table 3,
entries 5 and 6). Both C-dtbm and C-btms were effective in
enhancing the reaction of cycloheptenone-derived siloxyal-
kene 3c to afford bicyclo[5.4.1]dodecane derivative 4c in
useful yields (Table 3, entries 3 and 4). Unfortunately, neither
C-dtbm nor C-btms were effective in the cyclization of
nonterminal acetylene-tethered silyl enol ethers or the
formation of nine-membered rings.
1
2
C-dtbm
C-btms
9
22 (23)[c]
3
4
C-dtbm
C-btms
18
69 (59)[c]
5
6
C-dtbm
C-btms
66
60 (50)[c]
7
8
C-dtbm
C-btms
51
54 (47)[c]
With both C-dtbm and C-btms as ligands, the cyclization
of acetylenic silyl enol ether 3e, which features a biphenyl-
based rigid linker, occurred more readily than that of the
aliphatic monocyclic substrates 3a–d, affording dibenzocy-
clooctane derivative 4e in 92% and 80% yield, respectively
(Table 4, entries 1 and 3). Furthermore, the catalyst loading of
[Au(NTf2)(C-dtbm)] can be reduced to 1 mol% without
significant reduction of the yield (82%; Table 4, entry 2). The
cyclization proceeded even when a PPh3-based catalyst
(5 mol%) was used, albeit with much lower efficacy (9%
yield; Table 4, entry 4).[5] It is important to note that cycliza-
tion product 4e contains the dibenzocyclooctane core struc-
ture of the lignan family of natural products, some of which
possess important biological properties;[3a,b] in particular,
gomisin G has exhibited potent anti-HIV activity (Fig-
ure 1).[2a]
9
10
C-dtbm
C-btms
42
57 (48)[c]
11
12
C-dtbm
C-btms
37
58 (42)[c]
13
14
C-dtbm
C-btms
37
54 (43)[c]
15
16
C-dtbm
C-btms
32
72 (66)[c]
Moreover, the gold catalysts were also effective in the 8-
exo-dig cyclization of acyclic substrates to afford nonfused
methylenecyclooctane derivatives (Table 5). The reaction of
substrate 3 f, which possesses an unbranched linker between
the siloxyalkene and acetylene moieties, in the presence of
[a] Reaction conditions: [Au(NTf2)(ligand)] (5.0 mmol, 5.0 mol%), 3
(0.10 mmol), tBuOH (0.10 mmol), 4ꢀ molecular sieves (100 mg), 1,2-
dichloroethane (10 mL), 858C, 1 h. [b] Determined by 1H NMR spec-
troscopy. [c] Yield after purification by column chromatography on silica
gel followed by GPC or preparative thin-layer chromatography (PTLC).
Angew. Chem. Int. Ed. 2013, 52, 4239 –4242
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4241

.
Angewandte
Communications
[3] a) J. Chang, J. Reiner, J. Xie, Chem. Rev. 2005, 105, 4581; b) G.
Bringmann, T. Gulder, T. A. M. Gulder, M. Breuning, Chem.
Rev. 2011, 111, 563; c) B. M. Fraga, Nat. Prod. Rep. 2003, 20, 392;
d) D. J. Faulkner, Nat. Prod. Rep. 1999, 16, 155; e) G. Molander,
Acc. Chem. Res. 1998, 31, 603.
gold complexes with either the C-dtbm or the C-btms ligand
(858C, 1 h) afforded 2-acylmethylenecyclooctane 4 f, albeit in
yields of merely 9% and 22%, respectively (Table 5, entries 1
and 2). In both cases, starting material 3 f was almost
completely consumed, unfortunately resulting in the forma-
tion of a ketone by-product as a result of the protonation at
the siloxyalkene moiety, along with other unidentified com-
pounds. The low cyclization efficacy can be attributed to the
flexibility of the unbranched substrate.
Although the reaction of the siloxyalkene 3g, which
features a dimethyl malonate moiety at the homoallylic
position, with C-dtbm produced 4g in an unsatisfactory yield
as low as 18%, more efficient cyclization occurred with C-
btms, improving the yield to 69% (Table 5, entries 3 and 4).
The higher cyclization efficacy of the formation of 4g
compared to that of 4 f can be attributed to the Thorpe–
Ingold effect.
In the case of benzyl-substituted terminal siloxyalkene 3h,
the reactions involving both C-dtbm and C-btms proceeded
smoothly to form methylenecyclooctane derivative 4h
(Table 5, entries 5 and 6; 66 and 60% yield, respectively),
which possesses an endocyclic carbonyl group and is structur-
ally related to spartidienedione (Figure 1).[2b] Substituents
such as methoxy (3i), bromo (3j and 3k), or iodo groups (3l)
at the ortho or para position of the aromatic ring of 3h did not
significantly affect the cyclization efficiencies, with either C-
dtbm or C-btms ligands; in all cases, the corresponding
carbocycles 4i–4l were obtained in useful yields (Table 5,
entries 7–14). Silyl enol ether 3m, which possesses two
terminal alkyne moieties, was also converted to the mono-
cyclic compound 4m (Table 5, entries 15 and 16); in the case
of C-btms, the product was obtained with a yield of 72%.
In summary, the use of two triethynylphosphane ligands
(C-dtbm and C-btms) enabled the gold(I)-catalyzed 8-exo-dig
cyclization of acetylene-tethered silyl enol ethers to eight-
membered carbocycles. These novel semihollow triethynyl-
phosphanes possess a cavity that is smaller than that of the
corresponding silicon-type ligands, and were synthesized in
a straightforward manner. Further studies to expand the
applicability of the semihollow triethynylphosphanes are
ongoing.
[4] L. Yet, Chem. Rev. 2000, 100, 2963.
[5] For the formation of medium-sized rings through the indium-
(III)-catalyzed Conia-ene cyclization of acetylene-tethered b-
keto esters, see: Y. Itoh, H. Tsuji, K.-i. Yamagata, K. Endo, I.
Tanaka, M. Nakamura, E. Nakamura, J. Am. Chem. Soc. 2008,
130, 17161.
[6] Ring-closing metathesis can also serve as a powerful strategy for
the construction of medium-sized rings. For reviews, see: a) G. C.
Vougioukalakis, R. H. Grubbs, Chem. Rev. 2010, 110, 1746;
b) R. R. Schrock, Chem. Rev. 2009, 109, 3211.
[7] For selected reviews on gold-catalyzed cyclizations, see:
a) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180; b) D. J. Gorin,
B. D. Sherry, F. D. Toste, Chem. Rev. 2008, 108, 3351; c) Z. Li, C.
Brouwer, C. He, Chem. Rev. 2008, 108, 3239; d) A. Corma, A.
Leyva-Pꢂrez, M. J. Sabater, Chem. Rev. 2011, 111, 1657; e) H.
Huang, Y. Zhou, H. Liu, Beilstein J. Org. Chem. 2011, 7, 897.
[8] For the construction of medium-sized rings by gold catalysis, see:
a) C. Ferrer, C. H. M. Amijs, A. M. Echavarren, Chem. Eur. J.
2007, 13, 1358; b) E. Comer, E. Rohan, L. Deng, J. A. Porco, Jr.,
Org. Lett. 2007, 9, 2123; c) Y. Odabachian, X. F. L. Goff, F.
Gagosz, Chem. Eur. J. 2009, 15, 8966; d) I. D. G. Watson, S.
Ritter, F. D. Toste, J. Am. Chem. Soc. 2009, 131, 2056.
[9] The terms “dtbm” and “btms” are abbreviations for 3,5-di-tert-
butyl-4-methoxyphenyl
respectively.
and
3,5-bis(tri-methylsilyl)phenyl,
[10] H. Ito, H. Ohmiya, M. Sawamura, Org. Lett. 2010, 12, 4380.
[11] For gold-catalyzed cyclization of silyl enol ethers, see: a) S. T.
Staben, J. J. Kennedy-Smith, D. Huang, B. K. Corkey, R. L.
LaLonda, F. D. Toste, Angew. Chem. 2006, 118, 6137; Angew.
Chem. Int. Ed. 2006, 45, 5991; b) K. Lee, P. H. Lee, Adv. Synth.
Catal. 2007, 349, 2092; c) E. C. Minnihan, S. L. Colletti, F. D.
Toste, H. C. Shen, J. Org. Chem. 2007, 72, 6287; d) F. Barabꢂ, G.
Bꢂtournay, G. Bellavance, L. Barriault, Org. Lett. 2009, 11, 4236;
e) H. Kusama, Y. Karibe, Y. Onizawa, N. Iwasawa, Angew.
Chem. 2010, 122, 4365; Angew. Chem. Int. Ed. 2010, 49, 4269;
f) F. Barabꢂ, P. Levesque, I. Korobkov, L. Barriault, Org. Lett.
2011, 13, 5580; g) B. Sow, G. Bellavance, F. Barabe, L. Barriault,
Beilstein J. Org. Chem. 2011, 7, 1007; h) J.-F. Brazeau, S. Zhang,
I. Colomer, B. K. Corkey, F. D. Toste, J. Am. Chem. Soc. 2012,
134, 2742.
[12] a) A. Ochida, H. Ito, M. Sawamura, J. Am. Chem. Soc. 2006, 128,
16486; b) A. Ochida, M. Sawamura, Chem. Asian J. 2007, 2, 609;
c) H. Ito, Y. Makida, A. Ochida, H. Ohmiya, M. Sawamura, Org.
Lett. 2008, 10, 5051; d) H. Ito, T. Harada, H. Ohmiya, M.
Sawamura, Beilstein J. Org. Chem. 2011, 7, 951.
Received: January 11, 2013
Published online: March 4, 2013
[13] M. Ebisawa, H. Kusama, N. Iwasawa, Chem. Lett. 2012, 41, 786.
[14] The C-dtbm ligand was also effective in the gold-catalyzed 7-
exo-dig cyclization of acetylene-tethered silyl enol ethers; 2a
was obtained in 95% yield under conditions that were otherwise
the same. C-dtbm and Si-dtbm showed comparable ligand
performances in other gold-catalyzed alkyne cyclizations
toward five- to seven-membered rings that we reported pre-
viously (Refs. [12a,c,d]).
Keywords: cyclization · gold · medium-ring compounds ·
phosphanes · siloxyalkenes
.
[1] a) M. A. Winnik, Chem. Rev. 1981, 81, 491; b) G. Mehta, V.
Singh, Chem. Rev. 1999, 99, 881.
[2] Gomisin G: a) D.-F. Chen, S.-X. Zhang, L. Xie, J.-X. Xie, K.
Chen, Y. Kashiwada, B.-N. Zhou, P. Wang, L. M. Cosentino, K.-
H. Lee, Bioorg. Med. Chem. 1997, 5, 1715; spartidienedione:
b) M. Norte, F. Cataldo, A. Sꢁnchez, A. G. Gonzꢁlez, Tetrahe-
dron Lett. 1993, 34, 5143; paclitaxel (taxol): c) M. C. Wani, H. L.
Taylor, M. E. Wall, P. Coggon, A. T. McPhail, J. Am. Chem. Soc.
1971, 93, 2325.
[15] For effects of 4ꢀ molecular sieves, see Ref. [10].
[16] See the Supporting Information for details.
[17] On a few occasions, traces of impurities derived from the
triethynylphosphanes or silyl enol ethers were detected in the
products following column chromatography on silica gel. In
these cases, the products were further purified using GPC or
PTLC to obtain analytically pure products.
4242 www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 4239 –4242