Gold(I)-catalyzed macrocyclization of 1, n-enynes

Article abstract of DOI:10.1021/ol400358f

The gold(I)-catalyzed [2 + 2] cycloaddition of large 1,n-enynes (n = 10-16) provides access to 9- to 15-membered ring macrocycles incorporating a cyclobutene moiety. The reaction requires the use of a gold(I) catalyst bearing a sterically hindered biphenylphosphine ligand.

Full text of DOI:10.1021/ol400358f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Gold(I)-Catalyzed Macrocyclization
of 1,n‑Enynes
Carla Obradors, David Leboeuf, Juhanes Aydin, and Antonio M. Echavarren*
Institute of Chemical Research of Catalonia (ICIQ), Av. Paısos Catalans 16,
¨
43007 Tarragona, Spain
aechavarren@iciq.es
Received February 6, 2013
ABSTRACT
The gold(I)-catalyzed [2 þ 2] cycloaddition of large 1,n-enynes (n = 10ꢀ16) provides access to 9- to 15-membered ring macrocycles incorporating
a cyclobutene moiety. The reaction requires the use of a gold(I) catalyst bearing a sterically hindered biphenylphosphine ligand.
Macrocycles are present in a multitude of important
natural products that display a wide variety of biological
activities.1 Macrocycles are also commonly exploited in
the fields of material science2 and in supramolecular
chemistry.3 The most common methods for gaining access
to macrocycles involve macrolactonizations,4 ring-closing
metathesis,5 or cross-couplings.6,7 Gold-catalyzed cyclo-
isomerization has emerged as a powerful tool for the crea-
tion of new carbonꢀcarbon bonds due to the remarkable
carbophilic properties of gold.8 Among the possible cycli-
zations of 1,n-enynes, the formation of cyclobutenes has
been only reported in a few intramolecular processes.9
We recently reported the first example of an intermole-
cular gold(I)-catalyzed [2 þ 2] cycloaddition of terminal
alkynes with alkenes that occurred under mild condi-
tions (Scheme 1).10,11 The reaction proceeds regioselec-
tively to afford cyclobutenes using gold(I) complex A
bearing a sterically hindered biphenylphosphine ligand,
presumably through a distorted cyclopropyl gold(I)
carbene intermediate I.
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Eur. J. Org. Chem. 2005, 1949–1964. (b) Wessjohann, L. A.; Rivera,
D. G.; Vercillo, O. E. Chem. Rev. 2009, 109, 796–814. (c) Crane, E. A.;
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r
10.1021/ol400358f
XXXX American Chemical Society

Scheme 1. Intermolecular Gold(I)-Catalyzed [2 þ 2]
Scheme 3. Attempted Gold(I)-Catalyzed Cyclization of
1,10-Enyne 6
Cycloaddition of Terminal Alkynes with Alkenes
Table 1. Gold(I)-Catalyzed Macrocyclization of 1,14-Enyne 6
To Form 13-Membered Ring Macrocycle 7
Whereas the reactivity of 1,n-enynes (n = 5ꢀ8) in the
presence of gold complexes has been documented,12 ex-
amples involving larger 1,n-enynes (n > 8) are scarcer. The
largest 1,n-enyne involved in a gold-catalyzed cycloisome-
rization is a 1,9-enyne, which leads to a 10-membered ring
(Scheme 2).13 However, this cyclization required a large
amount of gold(I) catalyst (50 mol %) and leads to the
cyclic product in moderate yield.
molarity
(M)
temp
time
(h)
yielda
(%)
entry
catalyst
(°C)
1
2
3
4
A
0.25
0.07
0.07
0.007
23
23
45
23
3
23
53
A
A
A
6
3
24
12
71
(57)
56
Scheme 2. Gold(I)-Catalyzed Cyclization of 1,9-Enyne 4 To
Form 10-Membered Ring 5
5
6
7
8
A
B
C
D
0.007
0.007
0.007
0.007
45
23
23
23
3
1
26
12
12
47
73
(58)
55
9
E
0.007
0.007
23
23
12
2
10
AuClPPh3/
AgSbF6
PtCl2
PtCl4
F
10
11
12
13
14
0.007
0.007
0.007
0.007
45
45
45
45
14
14
14
14
ꢀ
ꢀ
ꢀ
ꢀ
Here we report the first examples of macrocyclization
oflarge 1,n-enynes(n = 10ꢀ16) using gold(I) catalysts bya
click-type alkyne/alkene cycloaddition.
AgSbF6
a Yields determined by 1H NMR using 1,4-diacetylbenzene as an
internal standard. Isolated yields in parentheses.
In contrast to the transformations involving small
1,n-enynes (n = 5ꢀ8) that are entropically favored, ob-
taining macrocycles from the largest 1,n-enynes (n > 9) is
more challenging. Preferably, the reactive partners must be
close in a stable conformation to perform the reaction
under mild conditions. For example, substrate 6 does not
lead to the formation of the corresponding macrocycle
with cationic catalyst A, and only the starting material is
recovered (Scheme 3).
To circumvent this problem, we decided to add a phenyl
ring in the spacer to favor the reactivity, focusing
our attention first on 1,14-enyne 8 (Table 1). We observed
that the reaction outcome was highly dependent on the
substrate concentration. Thus, when the reaction was per-
formed under concentrated conditions in the presence
of catalyst A (3 mol %) at 23 °C, the NMR yield of 13-
membered ring macrocycle 9 was not higher than 23%
(Table 1, entry 1). Gratifyingly, decreasing the concentra-
tion to 0.007 M led to the formation of the cyclobutene in a
good yield with a 2.3:1 dr (Table 1, entry 4). Heating the
(12) (a) Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002, 102,
813–834. (b) Bruneau, C. Angew. Chem., Int. Ed. 2005, 44, 2328–2334. (c)
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2296. (d) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108,
^
3326–3350. (e) Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem.,
Int. Ed. 2008, 47, 4268–4315.
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2123–2126.
ꢀ
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Gold(I)-Catalyzed Macrocyclization of Various
1,10- to 1,15-Enynesa
Figure 1. ORTEP drawing of macrocycle 11.
even more selective for the cycloaddition reaction. How-
ever, the new catalysts did not afford the corresponding
macrocyclobutene 9 in better yields (Table 1, entries 8
and 9). A direct relationship between the bulkiness around
the metal center and the reactivity can be observed. For
example, in the presence of catalyst B, a complete conver-
sion occurred within 1 h, but the cyclobutene was only
obtained in 26% yield (Table 1, entry 6). We also found
that the cationic gold(I) complexes are much more efficient
than the neutral gold(I) complex combined with a silver
salt to generate the active catalyst in situ (Table 1, entry 10),
whereas no formation of 9was observed using Pt(II), Pt(IV),
and Ag(I) salts or complexes (Table 1, entries 11ꢀ14). Based
on these different experiments, complexes A and D were
found as the optimal catalysts, although the former was
preferred because of its easier preparation.
To explore the scope of the reaction, macrocyclizations
were performed with 1,10- to 1,15-enynes bearing different
spacers (Table 2).17 In general, reactions were carried out
at 23 °C in CH2Cl2 in the presenceof 3 mol % ofcomplexA
as the catalyst (Table 2, entries 2 and 4ꢀ7). In addition, the
reactions do not require highly diluted conditions (0.15 or
0.3 M instead of 0.007 M).18 Under these reaction condi-
tions, the corresponding macrocyclic compounds were
obtained in moderate to good yields (up to 70%). Some
substrates reacted more slowly and required heating to
furnish the macrocyclic products (Table 2, entries 1 and 3).
Increasing the length of the spacer leads to better yields
(Table 2, entries 4ꢀ7), probably as a consequence of the
relief in transannular strain.
a Reactions carried out with A (3 mol %) at 23 °C. b Isolated yields.
c Reaction run at 45 °C. d Reaction run at 70 °C. e Yield determined by
1H NMR using 1,4-diacetylbenzene as an internal standard.
reaction allowed increasing the rate of the reaction but at
the expense of the isolated yields (Table 1, entries 3 and 5).
Presumably, oligomerization of the enyne or decomposi-
tion of the cyclobutene can occur more easily under these
reaction conditions. Alternative gold(I) complexes were
examined in the macrocyclization of substrate 8 to explore
the impact of the ligand on the reactivity. Catalyst A was
modified by adding methoxy or methyl groups onto the
biphenyl moiety (D and E)14ꢀ16 to increase the bulkiness
around the metal center in an attempt to make the catalyst
In the case of substrate 10, the structure of 9-membered
ring 11 was confirmed by X-ray crystallography (Figure 1).19
This method also provides access to m-cyclophanes. This
class of compound exhibits interesting chemical and physical
properties that result from their unusual architecture.20,21
ꢀ
(14) Barabe, F.; Levesque, P.; Korobkov, I.; Barriault, L. Org. Lett.
2011, 13, 5580–5583.
(15) X-ray crystallographic data: CCDC 912987 (D), CCDC
912986 (E).
(16) Related BrettPhosAuNTf and Me4tBuXPhosAuNTf2 had been
reported by the group of Zhang: (a) Ye, L.; He, W.; Zhang, L. Angew.
Chem., Int. Ed. 2011, 50, 3236–3239. (b) Wang, Y.; Ji, K.; Lan, S.; Zhang,
L. Angew. Chem., Int. Ed. 2012, 51, 1915–1918.
(17) No macrocyclization reaction occurred when the dimethyl group
was removed or replaced by styrene-type alkenes.
(18) See Supporting Information for details.
(19) X-ray crystallographic data: CCDC 912988.
(20) Gleiter, R.; Hopf, H. Modern Cyclophane Chemistry; Wiley
VCH: Weinheim, 2004.
Org. Lett., Vol. XX, No. XX, XXXX
C

(Scheme 4).22 The reaction with the largest enyne 26 required
a higher catalyst loading (5 mol %) and proceeded at 45 °C
in 2 days.
Scheme 4. Synthesis of m-Cyclophanes 25 and 27
The cyclobutene can be hydrogenated in the presence
of Pd/C in methanol at 23 °C. However, a debenzylation
of 9 was also observed (Scheme 5). This problem can be
circumvented by the addition of pyridine to furnish 29 in
82% yield.23,24
In summary, a variety of macrocycles can be assembled
in moderate to good yields from large 1,n-enynes (n > 9)
via a [2 þ 2]-cycloaddition catalyzed by gold(I) under mild
conditions. Whereas the intermolecular gold(I)-catalyzed
[2 þ 2] cycloaddition was essentially limited to aryl
alkynes,10 macrocyclization takes place satisfactorily with
alkyl-substituted alkynes. This study demonstrates that
gold catalysis is not limited to cycloisomerizations of small
1,n-enynes (n = 5ꢀ8) but can also be a valuable tool for
reactions involving larger ones.
Scheme 5. Hydrogenation of Macrocycle 9
Acknowledgment. We thank MICINN (project CTQ2010-
16088/BQU), the MEC (FPU fellowship to C. O.), the
ꢀ
AGAUR (project 2009 SGR 47 and Beatriu de Pinos
postdoctoral fellowship to D.L.), the Wenner-Gren Foun-
dation (postdoctoral fellowship to J.A.), and the ICIQ
Foundation for financial support. We are grateful to the
ICIQ X-ray Diffraction unit for the X-ray crystal struc-
tures. We thank Dr. P. McGonigal (present address:
Department of Chemistry, Northwestern University) for
helpful discussions.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In the case of substrates 24 and 26, the corresponding
macrocycles 25 and 27 were obtained in 70ꢀ71% yields
(23) Sajiki, H. Tetrahedron Lett. 1995, 36, 3465–3468.
(24) Compounds 28 and 29 were obtained as a mixture of diastereo-
isomers. See the Supporting Information for details.
(21) Gulder, T.; Baran, P. Nat. Prod. Rep. 2012, 29, 899–934 and
references cited therein.
(22) Macrocycles 25 and 27 were obtained as 4ꢀ5:1 mixtures of two
atropoisomers.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX