Synthesis of oxacyclic dienes via ring-closing enyne metathesis: Difference in construction of eight-membered rings

Article abstract of DOI:10.1016/j.tetlet.2012.04.107

A series of oxacyclic diene compounds, especially eight-membered products bearing a single oxygen atom which have not been reported previously, were successfully synthesized via ring-closing enyne metathesis using the second-generation Grubbs catalyst. In contrast to the construction of the five-membered rings, completely opposite substrate selectivity that methyl substituted internal alkyne showed much higher reactivity than terminal alkyne was observed in building eight-membered ring derivatives.

Full text of DOI:10.1016/j.tetlet.2012.04.107

Tetrahedron Letters 53 (2012) 3389–3392
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of oxacyclic dienes via ring-closing enyne metathesis: difference
in construction of eight-membered rings
⇑
⇑
Lin-Lin Zhang, Wen-Zhen Zhang , Xiang Ren, Xin-Yan Tan, Xiao-Bing Lu
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of oxacyclic diene compounds, especially eight-membered products bearing a single oxygen
atom which have not been reported previously, were successfully synthesized via ring-closing enyne
metathesis using the second-generation Grubbs catalyst. In contrast to the construction of the five-mem-
bered rings, completely opposite substrate selectivity that methyl substituted internal alkyne showed
much higher reactivity than terminal alkyne was observed in building eight-membered ring derivatives.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 15 January 2012
Revised 14 April 2012
Accepted 24 April 2012
Available online 28 April 2012
Keywords:
Enyne metathesis
Grubbs’ catalyst
Eight-membered ring
Oxacyclic dienes
Ruthenium-catalyzed enyne metathesis with regard to Grubbs
catalyst 1 and 2 (Scheme 1)1,2 has become a powerful strategy to
construct various 1,3-diene compounds that are not easily synthe-
sized by common methods.3 The reaction process involves in inter-
molecular cross4 or intramolecular ring-closing enyne metathesis.
The latter offers a more convenient access to various five-, six-
and seven-membered cyclic diene compounds, including carbocy-
cles, heterocycles, b-lactams, unnatural amino acids, carbohydrates
and other biologically active compounds.5,6 Importantly, ring-clos-
ing enyne metathesis has been elegantly used and become a crucial
step in the total synthesis of many natural products.7,8
However, the construction of eight-membered rings via ring-
closing enyne metathesis is thought to be relatively difficult due
to unfavorable entropy loss. As a result, rare reports concerned
the synthesis of this kind of compounds.9–11 It was reported that
bicyclic compounds containing eight-membered ring could be
built by tandem metathesis of dienynes.9 Alternatively, cyclic
structure or more than one heteroatom were inevitably involved
in the enyne substrates to restrict conformational freedom,10
thereby facilitating bidentate coordination of enyne substrates to
metal center of the catalyst.12 No product13 or only very low yield10
was observed in synthesizing monocyclic eight-membered ring
bearing a single heteroatom. Therefore, the synthesis of eight-
membered oxacyclic diene compounds, which was frequently
found in natural products, remains undeveloped. Herein, we report
the synthesis of five- to eight-membered oxacyclic diene
compounds via ring-closing enyne metathesis using Grubbs
ruthenium catalysts. In contrast to the construction of the five-
membered rings, a completely opposite substrate selectivity that
methyl substituted internal alkyne showed much higher reactivity
than terminal alkyne was observed in building eight-membered
ring derivatives.
Initially, synthesis of five-membered oxacyclic diene com-
pounds via ring-closing enyne metathesis was systemically stud-
ied. The second-generation Grubbs catalyst 2, which exhibits
higher catalytic activity and stability than the first-generation
Grubbs catalyst 1, was used as catalyst in our experimental inves-
tigations. As shown in Table 1, a variety of allyl propargyl ether
derivatives were used as substrates and their reactivities toward
ring-closing enyne metathesis were tested.
It seems that propargylic substitution has little influence on the
reactivity (Table 1, entries 2, 5, 6, 8, 10–12 and 14). Contrarily, the
ring-closing enyne metathesis turned out to be sensitive to alkyne
substitution. For the allyl ether substrates 3a–3d, compared with
terminal alkyne 3a, methyl substituted alkyne 3b gave slightly
decreased yield (Table 1, entries 1 and 2), while n-octyl (3c) and
phenyl (3d) substituted alkynes failed to yield the corresponding
⇑
Corresponding authors. Tel.: +86 411 84986257; fax: +86 411 84986256.
E-mail addresses: zhangwz@dlut.edu.cn (W.-Z. Zhang), lxb-1999@163.com
(X.-B. Lu).
Scheme 1. The first-generation (1) and second-generation (2) Grubbs catalyst.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.107

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L.-L. Zhang et al. / Tetrahedron Letters 53 (2012) 3389–3392
Table 1
Table 2
Synthesis of five-membered oxacyclic diene compoundsa
Synthesis of six-, seven-, and eight-membered oxacyclic diene compoundsa
Entry Substrates
R
Products
Yieldb (%)
6a 45
Entry Substrates
R
Products
Yieldb (%)
1c,d
2c,d
5a
H
1
2
3a
3b
3c
H
Me
C8H17
Ph
4a
4b
4c
89
84
<1
<1
5b Me
6b 42
3c
4c
3d
4d
5d
3e
4e
99
3
5c
6c 98
6
3f
3g
H
Me
4f
4g
80
21
7d
4
5
5d
5e Me
H
6d 98
6e 96
8
3h
3i
H
Me
4h
4i
81
<1
9c
6
5f
6f 95
10
11
3j
3k
Me
Ph
4j
4k
80
92
7e
7a
7a
H
H
8a <1
8a <1
8e,f
9
10
7b Me
7c Et
7d CH2OH
8b 82
8c 81
8d <1
12e
3l
H
4l
83
11e
13c,e
3m Me
4m <1
12e
13
7e
H
8e
8
7f Me
8f 93
14e
15
7g
7h Me
H
8g <1
8h 89
14e
3n
4n
96
a
16e,g
7i
7i
H
H
8i <1
8i <1
Reaction conditions: 2 (5 mol %), substrates (0.2–0.4 mmol), CH2Cl2 (0.05 M),
17d,e,g
12 h, room temperature.
b
18g
7j Me
8j 96
Isolated yields.
c
Yields were determined by 1H NMR, more than 90% substrates remained.
d
Yields were determined by 1H NMR.
e
Reaction time: 36 h.
a
Reaction conditions: 2 (5 mol %), substrates (0.2–0.4 mmol), CH2Cl2 (0.05 M),
12 h, room temperature.
b
Isolated yields.
c
Yields were determined by 1H NMR.
five-membered oxacyclic diene products at the same conditions
(Table 1, entries 3 and 4).
d
Reaction temperature: 40 °C.
e
Yields were determined by 1H NMR, more than 90% substrates remained.
When cinnamyl ethers were used as substrates, 80% yield of
6,5-spirocyclic diene product was obtained for terminal alkynes
3f, while a dramatic decrease in yield was observed for methyl
substituted alkynes 3g (Table 1, entries 6 and 7). Cinnamyl propar-
gyl ether 3h conducted ring-closing enyne metathesis reaction
smoothly, however, cinnamyl 2-butynyl ether 3i failed to undergo
this reaction (Table 1, entries 8 and 9). The ring-closing enyne
metathesis reaction of substrates 3l and 3n containing trisubsti-
tuted alkene and terminal alkyne groups could be successfully car-
ried out although the reactions were completed in a prolonged
time (Table 1, entries 12 and 14). Methyl substituted alkyne
(3m) with a prenyl group gave no ring-closing enyne metathesis
product (Table 1, entry 13).
f
The reaction was conducted in the presence of 1 atm ethylene gas.
Reaction time: 36 h.
g
Scheme 2. Synthesis of eight-membered oxacyclic diene compounds via enyne
metathesis of 3-butynyl ether.
Subsequently, synthesis of six-, seven-, and eight-membered
oxacyclic diene compounds via ring-closing enyne metathesis
was performed at the same conditions as previously (Table 2).
The substrates bearing terminal alkene group were transferred into
six- and seven-membered oxacyclic diene compounds in moderate
to excellent yield (Table 2, entries 1–6). Undheim and coworker re-
ported that 6,6-spirocycles were accessible while 6,7-spirocyclic
products were not achieved in their synthesis of unnatural amino

L.-L. Zhang et al. / Tetrahedron Letters 53 (2012) 3389–3392
3391
Scheme 3. Synthesis of eight-membered nitrogen-containing heterocyclic diene compounds via enyne metathesis.
acids via ring-closing enyne metathesis using catalyst 1.14 In our
reaction system, both 6,6- and 6,7-spirofused oxacycles were ob-
tained (Table 2, entries 3–5). Likewise, terminal alkynes 5a and
5d provided slightly higher yields than corresponding methyl
substituted alkynes 5b and 5e (Table 2, entries 1, 2, 4 and 5).
In striking contrast to the construction of the smaller sized
rings, when eight-membered oxacyclic dienes were targeted, ter-
minal alkyne substrates showed no or very low reactivity toward
ring-closing enyne metathesis (Table 2, entries 7, 12, 14 and 16),
even at enhanced temperatures (Table 2, entry 17).15 Mori et al. re-
ported that ethylene gas could accelerate the ring-closing enyne
metathesis of terminal alkyne.16 However, in the presence of ethyl-
ene gas, no observable improvement was found in the ring-closing
enyne metathesis regarding those terminal alkynes suitable sub-
strates in our system (Table 2, entry 8). Methyl substituted alkynes
7b, 7f, 7h, 7j proceeded ring-closing enyne metathesis smoothly
affording corresponding eight-membered oxacyclic diene in good
yield (Table 2, entries 9, 13, 15 and 18). It is noteworthy that
6,8-spirofused oxacycles can also be achieved (Table 2, entry 13).
Interestingly, with hydroxymethyl substituted alkynes 7d as sub-
strate, no ring-closing product was detected, probably due to the
deactivation the ruthenium catalyst (Table 2, entry 11).
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.04.107.
References and notes
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Likewise, when the heteroatom in the enyne substrate was
changed from oxygen to nitrogen, terminal alkyne 9a gave no
diene product in ring-closing enyne metathesis, while methyl
substituted alkyne 9b and 9c produced corresponding eight-mem-
bered nitrogen-containing heterocyclic diene 10b and 10c in mod-
erate yields (Scheme 3).
In conclusion, a variety of oxacyclic diene compounds, espe-
cially eight-membered products bearing a single oxygen atom,
were successfully synthesized via ring-closing enyne metathesis
using the second-generation Grubbs catalyst. In striking contrast
to the synthesis of the smaller sized rings, completely opposite
substrate selectivity that methyl substituted internal alkyne
showed much higher reactivity than terminal alkyne was observed
in the construction of eight-membered rings. Mechanistic explora-
tion and further application study are in progress in our laboratory.
Acknowledgments
This work is supported by National Natural Science Foundation
of China (Grant 20802007, 21111120073) and National Basic Re-
search Program of China (973Program: 2009CB825300).
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Supplementary data (experimental procedure, characterization
of products and copies of NMR spectra) associated with this article

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L.-L. Zhang et al. / Tetrahedron Letters 53 (2012) 3389–3392
15. Terminal alkynes were not suitable substrates also see: Ref. 6a, 13 and (a)
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