Acid-catalyzed intramolecular [2+2] Cycloaddition of ene-allenones: Facile access to bicyclo[n.2.0] frameworks

Full text of DOI:10.1002/anie.200902471

Communications
DOI: 10.1002/anie.200902471
Fused-Ring Systems
Acid-Catalyzed Intramolecular [2+2] Cycloaddition of Ene-allenones:
Facile Access to Bicyclo[n.2.0] Frameworks**
Jun-Feng Zhao and Teck-Peng Loh*
The fused cyclobutane fragment is a key motif found in many
biologically important natural products, such as sterpurene
and illudene derivatives.[1] Among the strategies, the [2+2]-
cycloaddition reaction stands out as one of the most versatile
highly efficient acid-catalyzed intramolecular [2+2] cyclo-
addition between the distal allenic double bond and unac-
tivated alkene moieties, with excellent chemo-, regio-, and
diastereoselectivities under very mild reaction conditions.
In the course of our efforts toward the development of
cationic polyene cyclization,[13] we became interested in an
methods for the construction of such fused systems.[2]
A
noteworthy class of this reaction is the intramolecular version,
involving an allene and an alkene in a single molecule, which
enables the stereocontrolled construction of complex poly-
cyclic compounds containing methylenecyclobutane frame-
works.[3] Photochemical and thermal [2+2] cycloadditions
between allenes and alkenes have been extensively inves-
tigated.[4] However, most of the reported procedures involve
the use of activated alkenes and suffer from many limitations
including harsh reaction conditions and narrow substrate
scope.
Furthermore, selective [2+2]-cycloaddition reactions
involving the distal allenic double bond remain a contempo-
rary challenge to synthetic chemists. Snider and co-workers[5]
and Hoffmann et al.[6] independently reported Lewis acid
catalyzed [2+2] cycloadditions of allenic esters under mild
conditions. However, the efficiencies and substrate scopes
were limited in both cases. Although the [2+2] cycloadditions
of allenyl sulfones by Padwa et al. demonstrated that the
regioselectivity could be controlled by using different sub-
strates,[7] the sulfonyl group must be removed for further
elaboration and the regioselectivity may be inconsistent in
complex molecules.[4d] Recently, difluoroallenes,[8] b-lactam-
tethered allenes,[9] diyne-diallenes,[10] and allenynes[11] have
also been employed as substrates to overcome such draw-
backs. Unfortunately, many of these reactions involved high-
temperature conditions that would limit their use in the
synthesis of complex molecules. Intramolecular [2+2] cyclo-
additions of ene-allenones, such as 1a, which would offer a
convenient access to the carbon bicyclo[n.2.0] framework
with an a,b-unsaturated ketone fragment, have remained
unexplored, possibly due to the facile cycloisomerization and
dimerization of allenones that take place in the presence of
Lewis acids or transition metals.[12] Herein, we describe a
À
alternative initiating model by activation of C C double
bonds with carbophilic transition metals.[14] Very recently,
Gagnꢀ and co-workers[15] and Fꢁrstner and Morency[16]
reported gold(I)-complex-catalyzed ene-allene and enyne
cycloisomerizations, respectively. Both transformations were
presumed to involve a carbocationic mechanism. Inspired by
their work and considering the parallels in the reactivity of
allenes and alkynes toward metal-mediated nucleophilic
additions,[17] we hypothesized that allenes could also be used
as the “head” to initiate cationic polyene cyclization by using
a gold(I) complex as the carbophilic p-acid catalyst. Surpris-
ingly, when 1a was treated with 5 mol% of Ph3PAuCl and
silver trifluoromethanesulfonate (AgOTf) in 0.1m MeNO2,
only the [2+2]-cycloaddition product 3a was obtained, as a
single diastereomer, accompanied by a small amount of dimer
4a (Scheme 1). No trace of the cationic polyene cyclization
product 2 was observed. The structure of 3a was confirmed by
an X-ray diffraction study of the ester derivative (see the
Supporting Information).[18]
Scheme 1. Preliminary study of the [2+2]-cycloaddition reaction.
[*] J. F. Zhao, Prof. Dr. T. P. Loh
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637616 (Singapore)
Fax: (+65)6791-1961
Further optimization of the conditions demonstrated that
this reaction is sensitive to solvent, as well as to the catalyst
used (Table 1). Generally, polar solvents gave 3a as the major
product, whereas nonpolar solvents provided mainly cyclo-
isomerization product 5a (Table 1, entries 1–7). Interestingly,
we did not observe the coexistence of 3a and 5a in any of
these cases, but rather a single diastereomer of dimer 4a
accompanied by 3a or 5a. To our delight, the formation of
cycloisomerization product 5a and dimer 4a could be sup-
E-mail: teckpeng@ntu.edu.sg
[**] We gratefully acknowledge Nanyang Technological University and
the Ministry of Education Academic Research Fund Tier 2 (grant
nos. T206B1221 and T207B1220RS) for funding of this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902471.
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Chemie
Table 1: Optimization studies.[a]
Table 2: In(OTf)3-catalyzed [2+2] cycloadditions.[a]
Entry
1
Substrate
Product[b]
Yield [%][c]
94
1a
7
3a
20
21
Entry Solvent
Catalyst
Yield [%][b] Ratio (3a/4a/5a)[c]
1
THF
AuClPPh3/AgOTf
AuClPPh3/AgOTf
AuClPPh3/AgOTf
AuClPPh3/AgOTf
84
65/32
44/45
45/44
70
0:5:95
0:50:50
0:33:67
67:33:0
86:14:0
68:32:0
94:6:0
2
3
83
81
2
3
4
CHCl3
toluene
CH2Cl2
8
5
(CH2Cl)2 AuClPPh3/AgOTf
6
MeCN
AuClPPh3/AgOTf
AuClPPh3/AgOTf
AgOTf
In(OTf)3
InBr3
40/40
85
7
8
9
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
88
94
84
90
81
79
92
88
82
71
79
80
>99:1:0
>99:1:0
>99:1:0
>99:1:0
>99:1:0
>99:1:0
>99:1:0
>99:1:0
>99:1:0
>99:1:0
>99:1:0
>99:1:0
4
5
9
22
23
76
80
10
11
12
13
14
15
16
17
18
19
InCl3
Cu(OTf)2
BF3·Et2O
TiCl4
SnCl4
TfOH
HCl (4n)
CF3CO2H
p-TSA·H2O
10
6
7
11
12
24
25
85
89
[a] Reactions were carried out on a 0.2 mmol scale with 0.1m substrate.
THF: tetrahydrofuran; p-TSA: toluene-4-sulfonic acid. [b] Yield of major
product after isolation. [c] The ratio was determined by 1H NMR analysis
of the crude product mixture.
8
13
14
15
26
27
28
95
70
85
9
pressed by using common Lewis acids as the catalyst (Table 1,
entries 8–15). For example, 5 mol% of AgOTf alone is
efficient enough to offer 3a in 88% yield by suppressing the
cycloisomerization (Table 1, entry 8). A series of Lewis and
Brønsted acids were examined and all of them catalyzed the
reaction smoothly to give the [2+2]-cycloaddition product
exclusively in good to excellent yields (Table 1, entries 8–19).
Finally, the use of 5 mol% of In(OTf)3 in MeNO2 was
identified as the best conditions in terms of economy,
practicality, selectivity, and yield of 3a (Table 1, entry 9).
Various substrates were prepared to test the generality of
the acid-catalyzed intramolecular [2+2] cycloaddition of ene-
allenones under the optimal conditions, and the results are
summarized in Table 2. The intramolecular [2+2]-cycloaddi-
tion reactions proceeded readily for all of the tested ene-
allenones to give the strained bicyclo[n.2.0] frameworks in
good to excellent yields and with excellent diastereoselectiv-
ities. Variation in the tail length had little effect on the
reaction efficiency (Table 2, entries 3, 4, and 12). Interest-
ingly, ene-allenones possessing an a substituent at the
allenone motif gave the [2+2]-cycloaddition products in
good yields (Table 2, entries 5 and 6). With both a,b-
unsaturated ketone and vinylsilane fragments concurrently,
adduct 24 is rendered more versatile for further modification
(Table 2, entry 6).[19] The most promising case is the intra-
molecular [2+2] cycloaddition of ene-allenone 17, which
10
11
16
29
91
12
17
18
30
31
70
76
13[d]
19
(n=2)
14
32
82
[a] Reactions were carried out on a 0.2 mmol scale with 0.1m substrate.
[b] Single diastereomer (as determined by 1H and 13C NMR analysis).
[c] Yield of isolated product. [d] The reaction time was 16 h.
constructed the core structure of sterpurene and illudene
derivatives[1] in one operation. Notably, the [2+2] cyclo-
addition went smoothly to furnish the bicyclo[4.2.0] frame-
work in good yield, albeit with a longer reaction time
required, when an electron-withdrawing group was intro-
duced to the alkene motif (Table 2, entry 13). In addition, the
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Communications
bicyclo[5.2.0] framework 32 could also be obtained with good
ties demonstrate that it is feasible to perform reactions
selectively at the distal allenic double bond of the ene-
allenones. The mild reaction conditions, excellent yields and
diastereoselectivities, easy functionalization of the product,
and the simplicity of the reaction procedure make this method
attractive for the synthesis of complex molecules. The
development of the asymmetric version and the application
of this methodology to the total synthesis of natural products
are ongoing in our laboratory.
yield and excellent diastereoselectivity (Table 2, entry 14).
To probe the mechanism of this [2+2]-cycloaddition
reaction, the stereospecificity and steric effects on the
alkene motif were examined. Substrates 33 and 35 were
designed and treated under the standard conditions
(Scheme 2). Both 33 and 35, in the absence of the methyl
Experimental Section
General procedure for the Lewis acid catalyzed intramolecular [2+2]
cycloaddition of ene-allenones: Ene-allenone (0.2 mmol) was added
slowly to a mixture of Lewis acid (5 mol%) and nitromethane (2 mL),
and the reaction mixture was stirred at room temperature. The
reaction was monitored by TLC analysis until the ene-allenone was
consumed completely. The reaction was quenched by adding satu-
rated NaHCO3 solution. The layers were separated, and the aqueous
layer was extracted with Et2O (3 ꢂ 5 mL). The combined organic
layers were washed with brine and dried over MgSO4. The solvent was
removed under vacuum, and the crude residue was purified by silica
gel column chromatography to give the desired products.
Scheme 2. Investigation of stereospecificity and steric effects of the
[2+2] cycloaddition.
Received: May 9, 2009
Revised: July 8, 2009
Published online: August 28, 2009
group on the alkene motif, were transformed smoothly to give
[2+2]-cycloaddition products 34 and 36 with excellent yields
and diastereoselectivities, which suggested that the methyl
group has no significant effect on the efficiency of the [2+2]
cycloadditions. Another interesting observation is that the cis
and trans products were obtained exclusively from the Z and
E alkenes, respectively, which demonstrated that this is a
stereospecific process.
Although stepwise mechanisms have been proposed in
some Lewis acid catalyzed [2+2] cycloadditions,[2i,7,8,20] the
debate between a concerted or a stepwise mechanism for
[2+2] cycloaddition is still ongoing.[7b,21] We have not detected
any cationic intermediate in this reaction.[22] Considering the
similar behaviors of allenic esters and allenones in the
presence of Lewis acids, we believe that the mechanism
proposed for the [2+2] cycloaddition of allenic esters[5,6] could
also be used to rationalize the intramolecular [2+2] cyclo-
addition of ene-allenones. So far, our experimental results[23]
support the idea that this reaction may prefer a [p2s+p2a]
concerted mechanism, which involves the vinyl-cation reso-
nance structure,[19a,24] as shown in Scheme 3. However, the
stepwise mechanism cannot be excluded at this stage.
Keywords: acid catalysis · cycloaddition · cyclobutanes ·
.
fused-ring systems · multiple bonds
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