Diversity of products in the gold-catalyzed cyclization of 1-epoxy-1-alkynylcyclopropanes by using 1-oxyallyl cations

Article abstract of DOI:10.1002/chem.200903419

(Chemical Presented) A highly stereoselective AuCl₃-catalyzed hydrative cyclization of 1-epoxy-1-alkynylcyclopropanes was observed for cis-epoxides. Since this cyclization produced 1-oxyallyl cations efficiently, we accomplished a two-step [4+2

Full text of DOI:10.1002/chem.200903419

DOI: 10.1002/chem.200903419
Diversity of Products in the Gold-Catalyzed Cyclization of
1-Epoxy-1-alkynylcyclopropanes by Using 1-Oxyallyl Cations
Chun-Yao Yang, Min-Shiun Lin, Hsuan-Hung Liao, and Rai-Shung Liu*[a]
Metal-catalyzed cycloaddition reactions are powerful
tools in organic synthesis to access complex molecular
frameworks.[1] The gold-catalyzed activation of alkynes ena-
bles the generation of unusual intermediates to react with
dipolarophiles in a cycloaddition fashion.[2] Although 1-oxy-
allyl cations[3,4] are versatile intermediates in the [4+2] cy-
cloaddition with dienes, such metal-free cationic species
have not been elaborated in gold catalysis. As part of our
continued interest in gold-catalyzed reactions of epoxyal-
kyne substrates,[5,6] we report the diversity of complex oxa-
cyclic products derived from readily available 1-epoxy-1-al-
kynylcyclopropanes; the success of this catalysis relies on
the stereoselective generation of cyclic 1-oxyallyl cations.
Herein, we also report the unprecedented [4+2] cycloaddi-
tion of enones with such cations.
We prepared cis-epoxides 1a and 1b and their trans iso-
mers 3a and 3b to illustrate the effect of epoxy substituents
on gold-catalyzed oxacyclization, as depicted in Scheme 1.
Treatment of the cis forms 1a and 1b with a mixture of
AuCl3 (5 mol%) and water (2 equiv) in dry CH2Cl2 (258C,
40 min) delivered bicyclic oxacyclic alcohols 2a and 2b (79–
83% yield) with high diastereoselectivities (d.r.>10:1).[7]
Notably, the same catalysis on trans-epoxide 3a lacks stereo-
control in the cyclization, giving a combined 63% yield of
products 2a and 2a’ (2a’/2a=1.65:1), whereas the other spe-
cies 3b gave a complex mixture of products. The structures
Scheme 1. Gold-catalyzed oxycyclization of epoxy-substituted com-
pounds.
cies B or its resonance structure B’.[9] In structure A, the
À
epoxy C(2) O bond is expected to be aligned with the
À
C(4) C(5) bond to shorten the distance between the inter-
acting C and O atoms, facilitating a 6-endo-dig cyclization.
À
Herein, the C(2) O s* orbital overlaps efficiently with the
1
À
of products 2a and 2a’ are confirmed by their H NOE spec-
cyclopropyl C C bond near the R group, inducing an SN2
tra.[8] To rationalize the stereochemistry of alcohols 2a and
2b, we propose that the mechanism of formation of com-
pounds 2 is likely to involve a concerted electrocyclization
as shown by p-alkyne A, including an SN2-type 1,2-migration
migration. We attribute the high stereoselectivity of cis-ep-
oxides 1a and 1b to their cis R groups that force the alkynyl
group to move toward the epoxy functionality, as depicted
in Figure 1. In contrast, the alkynyl group of trans-epoxide
3a is far away from the epoxide and not favorable for the
proposed electrocyclization. Accordingly, cis-epoxide 1b
(R=n-C5H11) is superior to 1a (R=Me) in terms of stereo-
selectivity.[10]
À
of the cyclopropyl C C bond, giving key p-cycloallene spe-
[a] C.-Y. Yang, M.-S. Lin, H.-H. Liao, Prof. Dr. R.-S. Liu
Department of Chemistry, National Tsing-Hua University
Scheme 2 shows a control experiment to assess a hypo-
thetical SN2-type cyclopropyl expansion. We prepared chiral
trisubstituted (R)-epoxide 4 (65% enantiomeric excess (ee))
containing only one stereogenic carbon;[11] the same cataly-
sis gave the desired bicyclic oxacyclic alcohol 5 without com-
Hsinchu, 30043, TaiwanACTHNUTRGNE(NUG ROC)
Fax : (+886)3-5711082
E-mail: rsliu@mx.nthu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903419.
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Chem. Eur. J. 2010, 16, 2696 – 2699

COMMUNICATION
dry CH2Cl2 solution with 2,3-dimethylbutadiene (2–5 equiv)
and AuCl3 (5 mol%) at 288C (1–8 h) failed to give the de-
sired cycloadduct, which was as expected because no inter-
molecular cycloaddition has been reported for gold–p-allene
species, such as B (or B’) with a dipolarophile.[9,12] We
sought to accomplish this cycloaddition with gold-free 1-oxy-
allyl cation D, generated from the ionization of alcohol 2a.
After screening various gold complexes and a Brønsted
acid,[13] we found that PPh3AuCl/AgSbF6 efficiently cata-
lyzed the [4+2] cycloaddition of the 1-oxyallyl cation D
with 2,3-dimethylbutadienes. In a standard procedure, once
the complete conversion of epoxide 1a to bicyclic oxacyclic
alcohol 2a in the initial AuCl3 catalysis step was observed,
the resulting CH2Cl2 solution was filtered through a short
silica pad before treatment of this filtrate with 2,3-dimethyl-
butadiene (2 equiv) and PPh3AuCl/AgSbF6 (10 mol%). This
two-step procedure provided tricyclic compound 5a as a
single diastereomer, with an overall 65% yield. Pleasingly,
we found that this tandem reaction is even applicable to
substrates, such as but-3-en-2-one, giving the tricyclic oxacy-
clic compound 6a, of which the structure was carefully de-
Figure 1. Molecular models for 1a (left) and 3a (right). The phenyl group
was omitted for clarity; the epoxy oxygen and methyl carbon are marked
as red and yellow balls, respectively.
1
termined with H NOE spectra.[8] We envisage that the suc-
Scheme 2. A control experiment to assess a hypothetical cyclopropyl ex-
pansion.
cess of this novel enone cycloaddition relies on the strong s
character of the carbocation associated with the cyclobutyl
carbon of 1-oxyallyl cation D. In this mechanism, the result-
ing tricyclic oxonium species F reacts with water through a
bifunctional oxonium–enol (acid–base) pair, ultimately
giving the observed product 6a with the release of one
proton.
Table 1 shows additional examples to assess the generality
of the enone cycloaddition reaction. This reaction sequence
is extendible to the cis-epoxides 1b–1e containing an n-
pentyl group (R1) and various phenyl groups (R2 =H, Me,
OMe, and F) at their epoxy and alkynyl functionalities, re-
spectively; the resulting tricyclic oxacyclic compounds 6b–
6e were obtained with yields exceeding 71%. Entries 5–10
plete loss of chirality. The observed 23% ee supports a hy-
pothetical SN2 mechanism that is operable for a significant
proportion of (R)-epoxide 4. Loss of the chirality is proba-
bly attributable to a competitive generation of free cation C
that is stabilized by dimethyl substituents.
Scheme 3 shows our efforts to achieve a cyclization/cyclo-
addition sequence on epoxyalkyne 1a. Treatment of 1a in a
Table 1. Gold-catalyzed cyclization/cycloaddition reactions with enones.
Entry
Epoxide[a]
R2
Enone
R3
t [h]
Product
(yield [%])[b]
R1
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8
n-C5H11
n-C5H11
n-C5H11
n-C5H11
Me
n-C5H11
Me
n-C5H11
n-C5H11
n-C5H11
Ph (1b)
Me
Me
Me
Me
Et
Et
n-C5H11
n-C5H11
n-C5H11
n-C5H11
10
6
8
8
6
8
6
9
10
10
6b (85)
6c (71)
6d (81)
6e (73)
6 f (80)
6g (79)
6h (89)
6i (91)
6j (81)
6k (71)
4-MeC6H4 (1c)
4-MeOC6H4 (1d)
4-FC6H4 (1e)
Ph (1a)
Ph (1b)
Ph (1a)
Ph (1b)
4-MeOC6H4 (1d)
4-FC6H4 (1e)
9
10
Scheme 3. Gold-catalyzed cyclization/cycloaddition sequences on epoxy-
[a] [epoxide]=0.05m, enone (2 equiv), L=PPh3, X=SbF6. [b] Yields are
alkyne 1a.
reported after separation on a silica column.
Chem. Eur. J. 2010, 16, 2696 – 2699
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www.chemeurj.org
2697

R.-S. Liu et al.
(Table 1) illustrate the applicability of this gold catalysis
protocol to the cyclization reactions of cis-epoxides 1a, 1b,
1d, and 1e with pent-1-en-3-one and oct-1-en-3-one; we ob-
tained the desired products 6 f–6k efficiently and stereose-
lectively: only one diastereomeric product was formed.
1H NOE spectra were obtained for compounds 6a, 6 f, and
6h to confirm their stereochemistry.
As shown in Table 2, various butadienes were suitable for
this new [4+2] cycloaddition, including 2,3-dimethylbuta-
diene, 1-methylbutadiene, 1,3-hexadiene, and 1,2-dimethyl-
Table 2. Gold-catalyzed cyclization and cycloaddition with dienes.
Scheme 4. Availability of various oxacyclic compounds from the inter-
mediate alcohol 2b; Bn=benzyl.
oxacyclic products in this synthesis truly reflects its synthetic
value.
Entry
Epoxide[a]
R1
Diene
R3
t [h]
Product
(yield [%])[b]
In summary, we observed a high stereoselectivity for the
AuCl3-catalyzed hydrative cyclization of 1-epoxy-1-alkynyl-
cyclopropanes for the cis-epoxides rather than their trans
analogues. An electrocyclization appears to be a suitable
model, as determined with the use of chiral epoxides and
control experiments. Since this cyclization produced 1-oxy-
allyl cations efficiently, we accomplished a two-step [4+2]
annulation of epoxyalkynes 1 with dienes, and also with
enones, to provide complex oxacyclic compounds with excel-
lent diastereoselectivity. The successful 1-oxyallyl cation/
enone cycloaddition is unprecendented in literature reports.
To highlight the use of this gold-catalyzed protocol, we dem-
onstrated the diversity of oxacyclic products through the
functionalization of alcohol intermediate 2.
R2
R4
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
n-C5H11 (1b)
Me (1a)
n-C5H11 (1b)
Me (1a)
n-C5H11 (1b)
Me (1a)
n-C5H11 (1b)
Me
Me
Me
H
H
H
Me
H
H
H
H
H
H
H
Et
Et
Me
Me
7
6
7
6
8
6
8
5b (78)
5c (61)
5d (61)
5e (70)
5 f (70)
5g (46)
5h (45)
Me
Me
H
[a] [substrate]=0.05m, diene (2 equiv). [b] Yields are reported after sepa-
ration on a silica column.
butadiene. Gold-catalyzed cyclization of these dienes with
epoxides 1a and 1b gave the desired [4+2] cycloadducts
5b–5h with satisfactory yields in most cases. Such a cycliza-
tion/cycloaddition sequence proceeds with high stereo- and
regiocontrol, allowing the formation of only one diastereo-
meric product. The H NMR spectral data of these products
resemble those of compound 5a, indicative of the same ste-
reochemistry. We have obtained H NOE spectra to deter-
mine the structure of cycloadduct 5e.
Scheme 4 shows the availability of various oxacyclic com-
pounds by using alcohol 2b as the key intermediate. Addi-
tion of nucleophiles, namely, MeOH, PhOH, TsNH2 (Ts=
tosyl), and allyl silane and addition of the PPh3AuCl/
AgSbF6 catalyst (10 mol%) to a CH2Cl2 solution of alcohol
2b, generated from the AuCl3 catalysis, delivered products
7a–7d in good yields; only one isomeric product was pro-
duced here. With nitrone and PPh3AuCl/AgSbF6
(10 mol%), we obtained the [3+2] cycloadduct 8 as a 1.5:1
mixture of two diastereomers. Treatment of species 2b in
the original CH2Cl2 solution with N-chlorosuccinimide
(NCS, 2 equiv) and Ph3PO provided eight-membered oxacy-
clic compound 9 in 63% yield; in this one-pot synthesis, Cl+
approaches the cyclobutyl ring opposite the hydroxyl group
to facilitate the SN2-type ring opening. Notably, formation of
compound 9 from epoxyalkyne 1b involves two consecutive
expansions of carbocyclic rings. The availability of diverse
1
Experimental Section
Compound 1b (80 mg, 0.30 mmol) and H2O (5.4ꢁ10À3 mL, 2 equiv) were
added dropwise, at 238C, to a solution of AuCl3 (4.5 mg, 0.015 mmol,
5 mol%) in dichloromethane (3.0 mL) and the solution was stirred for
40 min. The resulting solution was filtered through a pad of Celite and
eluted through a silica-gel column (hexane/ethyl acetate=10:1) to give
compound 2b as a colorless oil (67 mg, 0.23 mmol, 79%).
1
Acknowledgements
The authors thank the National Science Council, Taiwan for supporting
this work.
Keywords: alkynes
· cycloaddition · epoxides · gold ·
oxycyclization
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Gold-Catalyzed Cyclization
COMMUNICATION
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Received: December 14, 2009
Published online: January 29, 2010
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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