Synthesis of bicyclic ethers by a gold/palladium/gold-catalyzed cyclization/cross coupling sequence

Article abstract of DOI:10.1002/ejoc.200901010

The stereoselective gold-catalyzed 6-endo cyclization of various β-hydroxyallenes in the presence of N-iodosuccinimide affords iodinated dihydropyrans in good yield, Subsequent functionalization by palladium-catalyzed cross cou-pling opens an access to α-hydroxyallenes that are converted in a second gold-catalyzed cyclization into furopyrans which occur in various natural products.

Full text of DOI:10.1002/ejoc.200901010

FULL PAPER
DOI: 10.1002/ejoc.200901010
Synthesis of Bicyclic Ethers by a Gold/Palladium/Gold-Catalyzed
Cyclization/Cross Coupling Sequence
Birgit Gockel[a] and Norbert Krause*[a]
Keywords: Allenes / Cycloisomerization / Gold / Homogeneous catalysis / Oxygen heterocycles
The stereoselective gold-catalyzed 6-endo cyclization of
various β-hydroxyallenes in the presence of N-iodosuccin-
imide affords iodinated dihydropyrans in good yield. Subse-
quent functionalization by palladium-catalyzed cross cou-
pling opens an access to α-hydroxyallenes that are converted
in a second gold-catalyzed cyclization into furopyrans which
occur in various natural products.
A common structural feature of these target molecules is
the furopyran core. Previously, these bicyclic ethers have
been prepared by radical cyclization or alkyne trimeri-
zation.[6] Based on our experience in the stereoselective syn-
thesis of chiral five- and six-membered heterocycles by
gold-catalyzed[7] cycloisomerization of functionalized all-
enes,[8,9] we envisaged an alternative route to these heterocy-
cles (Scheme 1). Thus, gold-catalyzed cyclization of β-hy-
droxyallenes 1[8c] in the presence of N-iodosuccinimide
(NIS) should afford iodinated dihydropyrans 2 which are
converted into exocyclic α-hydroxyallenes 3 by Sonogashira
coupling, epoxidation, and copper-mediated SN2Ј-substitu-
tion. Finally, a second gold-catalyzed cyclization of 3[8]
should give the desired furopyrans 4.
Introduction
The synthesis of annulated cyclic ethers is of high interest
in organic chemistry due to the occurrence of this heterocy-
clic structure unit in a variety of natural products and bio-
logically active compounds (Figure 1).
Figure 1. Natural products containing annulated cyclic ethers.
The phytoalexins (+)-Maackiain and (+)-Pisatin are pro-
duced by garden pea and chickpea and have antifungal ac-
tivity.[1] Furthermore, (+)-Maackiain shows antimalarial
activity against P. falciparum[2] and antitumor activity in
mice.[3] Trifolirhizin also exhibits antitumor activity, has ty-
rosinase inhibitory effects and suppresses the melanin syn-
thesis in B16 melanoma cells,[3,4] whereas Citridone D dis-
plays miconazole activity against Candida albicans.[5]
Scheme 1. Proposed route to furopyrans 4.
Herein we report the synthesis of bicyclic ethers 4 by the
gold/palladium/gold-catalyzed cyclization/cross coupling
sequence shown in Scheme 1. Besides affording an efficient
and stereoselective access to furopyrans, the use of NIS in-
duces a tremendous acceleration of the gold-catalyzed cycli-
zation of functionalized allenes, a behavior that is both very
useful in synthesis and highly interesting from the mechan-
istic point of view.
[a] Dortmund University of Technology, Organic Chemistry,
44227 Dortmund, Germany
Fax: +49-2317553884
E-mail: norbert.krause@tu-dortmund.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901010.
Eur. J. Org. Chem. 2010, 311–316
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
311

B. Gockel, N. Krause
FULL PAPER
Table 1. Gold-catalyzed cyclization of β-hydroxyallene 1a to di-
hydropyran 2a in the presence of NIS.
Results and Discussion
The starting materials of our study, the β-hydroxyallenes
1a–j, were prepared in two different ways (Scheme 2). The
terminally disubstituted allenes 1a–c were obtained by re-
duction of the corresponding β-allenic esters[10] which were
synthesized by either 1,6-cuprate addition to 2-en-4-
ynoates[11] or by orthoester Claisen rearrangement of pro-
pargylic alcohols.[12] In contrast, the β-hydroxyallenes 1d–j
were formed by copper-mediated SN2Ј-substitution of pro-
pargylic oxiranes,[8] followed by a protection-deprotection
sequence.[13,14] The allenes 1e–i were obtained in dia-
stereomerically pure form, whereas compound 1j had a dia-
stereomeric ratio of 92:8.
Entry [Au]
mol-%
Solvent
Time
Yield [%]
1
2
3
AuCl3[a]
5
CH2Cl2 1 min
CH2Cl2 1 min
CH2Cl2 15 min
toluene
toluene
CH2Cl2 1 min
CH2Cl2 20 min
CH2Cl2 1 h
67
50
42
52
42
56
49
47
50
45
AuCl3[a]
0.5
0.05
5
AuCl3[a]
4
5
Ph3PAuCl/AgBF4
Ph3PAuCl/AgBF4 0.5
1 min
15 min
6
AuCl
AuCl
AuCl
AuCl/Pyridine
5
0.5
5
5
–
7
8[b]
9
CH2Cl2 1 min
toluene
10
–
2 d
[a] 0.166  solution in MeCN. [b] At –20 °C.
(Table 2, entry 2) whereas slower cyclizations and decreased
chemical yields were observed for the substrates 1b and 1d
bearing more bulky groups at the allene moiety (Table 2,
entries 1 and 3). The presence of an acetate group in the
substrate is tolerated (Table 2, entry 3).
Gold-catalyzed cycloisomerizations of α- or β-function-
alized allenes to five- or six-membered heterocycles usually
take place with axis-to-center chirality transfer.[8,9] In the
case of the gold-catalyzed/NIS-mediated cyclization of
β-hydroxyallenes 1e–j to the corresponding iodinated di-
Scheme 2. Synthesis of β-hydroxyallenes 1.
Previously, it has been shown that N-iodosuccinimide hydropyrans 2, the chirality transfer was found to depend
(NIS) can be used successfully as electrophile in gold-cata- on the reaction conditions, in particular the gold precatalyst
lyzed transformations of acetylenic substrates.[15] Moreover, (Table 2). Whereas dihydropyrans 2e and 2i were obtained
a tremendous accelerating effect of NIS in the gold-cata- with good yield (69:68%) and diastereoselectivity (dr =
lyzed cyclization of bis(α-hydroxyallenes) was discovered re- 88:12:93:7) with 5 mol-% of AuCl in CH2Cl2 (Table 2, en-
cently.[8j] β-Hydroxyallenes (e.g., 1a) are also quite unreac- tries 4 and 11), diminished yield and selectivity was ob-
tive substrates and require several days at room temperature served with allene 1f under identical conditions (Table 2,
for a complete cyclization with gold(I) or gold(III) chloride entry 5). Thus, extensive epimerization of the allenic chiral-
alone.[8c] In contrast, it takes just one minute for the full ity axis is taking place.[8d,9a] The stereoselectivity was im-
conversion of 1a to iodinated dihydropyran 2a[16] in the proved slightly by performing the reaction at –20 °C
presence of 5 mol-% of AuCl3, AuCl, or Ph3PAuCl/ (Table 2, entry 6) or without the gold catalyst (Table 2, en-
[17]
AgBF4
and 1.1–1.5 equiv. of NIS[18] (Table 1, entries 1, try 7). In contrast to this, use of the cationic gold catalyst
4, 6)! Very fast reactions were also observed with decreased Ph3PAuBF4 instead of AuCl afforded dihydropyran 2f with
catalysts loadings of 0.5 mol-% (Table 1, entries 2, 5, 7) and an improved yield of 73% and a high level of chirality
even 0.05 mol-% (Table 1, entry 3). The cyclization product transfer (dr = 89:11; Table 2, entry 8). These conditions
2a was obtained with 42–67% yield under these conditions. proved to be efficient for allenes 1g and 1h as well which
Attempts to improve the yield by decreasing the reaction gave the diastereomerically pure cyclization products
temperature to –20 °C (Table 1, entry 8) or by using pyr- 2g/h[21] with good yield (Table 2, entries 9 and 10). Dihydro-
idine as additive[8c,8d] (Table 1, entry 9) were not successful. pyran 2j was also obtained with good yield of 69%, but an
N-bromo- and N-iodosuccinimide (as well as iodine) are acceptable diastereoselectivity could only be achieved in the
known to induce cyclization reactions of functionalized all- absence of a gold catalyst (Table 2, entry 12 vs. 13).
enes in the absence of a transition metal.[19,20] In the case
Another interesting observation is the formation of the
of β-hydroxyallene 1a, it takes two days at room tempera- iodinated 2,5-dihydrofurans 5 as side product (up to 14%
ture to complete the conversion to dihydropyran 2a with yield; Table 2, entries 4–10, 12, 13). These may be formed
NIS alone (Table 1, entry 10), proving a cooperative effect by (gold-catalyzed?) acetate migration from the secondary
of the gold catalyst and NIS.
We next extended the scope of the reaction to the β-allen- lyzed cyclization of the α-hydroxyallene formed.
ols 1b–d (Table 2). Expectedly, the sterically less hindered At this point, there appear to be two possible explana-
substrate 1c gave a good yield of 61% in a very fast reaction tions for the strong acceleration of the gold-catalyzed cycli-
to the primary hydroxy group,[8c] followed by gold-cata-
312
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 311–316

Au-Catalyzed Cyclization of β-Hydroxyallenes
Table 2. Gold-catalyzed cyclization of β-hydroxyallenes 1b–j in the presence of NIS.
Entry
1
R1
R2
R3
R4
Conditions[a] Time
2
Yield [%]
dr
5
Yield [%]
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
nBu
Me
nBu
iPr
H
H
H
H
H
H
H
tBu
Me
nBu
nBu
nBu
nBu
nBu
nBu
iPr
Bn
Ph
Ph
Ph
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
A
B
B
C
C
D
E
A
A
A
C
C
E
1 h
2b
2c
2d
2e
2f
2f
2f
2f
2g
2h
2i
24
61
52
69
52
52
22
73
73
71
68
69
69
–
–
–
–
–
–
–
–
–
1 min
10 min
50 min
1 min
10 h
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OMe
OAc
OAc
88:12
61:39
82:18
71:29
89:11
Ͼ95:5
Ͼ95:5
93:7
5e
5f
5f
5f
5f
5g
5h
–
traces
12
8
11
10
traces
14
–
1f
1f
1f
2 h
1 min
1 min
1 min
1 h
30 min
1 d
9
1g
1h
1i
10
11
12
13
1j[b]
1j[b]
H
H
2j
60:40
89:11
5j
5j
4
11
2j
[a] Conditions: A: 5 mol-% Ph3PAuCl/AgBF4, toluene; B: 1 mol-% AuCl, CH2Cl2; C: 5 mol-% AuCl, CH2Cl2; D: 5 mol-% AuCl, CH2Cl2,
–20 °C; E: without gold salt in CH2Cl2. [b] dr (1j) = 92:8.
zation of β-hydroxyallenes 1 in the presence of N-iodosuccin- (Ph3P)2PdCl2/CuI, NEt3] in THF as solvent,[24] or a palla-
imide. Thus, the nature of the gold catalyst might be dium/copper catalyst in the presence of an N-heterocyclic
changed in the presence of electrophilic iodine, e.g., by for- carbene as ligand.[25] The former conditions gave acceptable
mation of gold iodide species and/or oxidation of gold(I) to good yields (49–81%) only for substrate 2a (Table 3, en-
to gold(III). Alternatively, the accepted mechanistic model tries 1–3) whereas very slow conversion (Table 3, entries
(consisting of activation of the allene by the carbophilic 4 and 5) or no reaction at all (Table 3, entries 10 and 12)
gold catalyst, intramolecular attack, and electrophilic cap- was observed with other dihydropyrans. This issue was
ture of the σ-gold species formed)[8c,9a] might not be opera- solved by using the more reactive combination of (Ph3P)2-
tive in the presence of NIS. Investigations dedicated to clar- PdCl2/CuI and SIMes·HCl which gave the desired coupling
ify this point will be subject of subsequent publications.
products 7 with excellent yield (80–95%; Table 3, entries 6–
With the iodinated dihydropyrans in hand, we examined 9, 11, 13), except for enyne 7gd which was obtained with
their utility in palladium-catalyzed cross coupling reac- 54% yield (Table 3, entry 14). The reaction tolerates acetate
tions.[22] Thus, the Suzuki coupling of heterocycles 2a and groups at the dihydropyran, and alkyl, phenyl and silyl
2f under standard conditions proceeded smoothly to afford groups, as well esters and benzyl ethers at the alkyne. The
the expected products 6a and 6f with 85% and 51% yield, diastereomeric ratio of the coupling products obtained from
respectively (Scheme 3). In the case of dihydropyran 2f, the dihydropyrans 2f and 2g was identical to that of the precur-
ratio of diastereomers remained unchanged.
sor.
Epoxidation of the enynes 7cc/cd with mCPBA and subse-
quent copper-mediated SN2Ј-substitution[8,26] afforded the
diastereomerically pure α-hydroxyallenes 3a–c with good
yield (52–60% over 2 steps; Scheme 4). The low yield of 17%
for allene 3d, however, is due to a very sluggish SN2Ј-substi-
tution reaction of the corresponding propargyl oxirane with
n-butylmagnesium cuprate. In all cases, the allene formation
took place with complete anti-stereoselectivity.[8,26]
The same reaction sequence was used for the synthesis
of the α-hydroxyallenes 3e–g (Scheme 5). In the case of en-
ynes 7aa and 7fa, the trimethylsilyl group was removed with
nBu4NF prior to the copper-mediated SN2Ј-substitution.
The chemical yields of the α-hydroxyallenes 3e–g were com-
Scheme 3. Suzuki coupling of dihydropyrans 2a and 2f.
For the conversion into furopyrans 4, the iododihydro- parable to those of their counterparts 3a–c. Since the epox-
pyrans 2 have to undergo a Sonogashira coupling.[22,23] The idation of the chiral enynes took place with modest dia-
reaction of heterocycles 2a, 2c, 2d, 2f, and 2g with a variety stereoselectivity only, the allenes 3e–g were obtained as mix-
of terminal alkynes was examined under two reaction con- tures of diastereomers (the diastereomeric ratio could not
ditions, either using the “classical” catalyst system [cat. be determined for 3g).
Eur. J. Org. Chem. 2010, 311–316
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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313

B. Gockel, N. Krause
FULL PAPER
Table 3. Sonogashira coupling of iodinated dihydropyrans 2.
Entry
2
R1
R2
R3
R4
R5
Conditions[a] Time
7
Yield [%]
Yield [%]
of recovered 2
1
2a
2a
2a
2c
2c
2c
2c
2c
2d
2f
Me
Me
Me
Me
Me
Me
Me
Me
nBu
H
H
H
H
H
nBu
nBu
nBu
Me
Me
Me
Me
Me
nBu
nBu
nBu
nBu
iPr
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OAc
OAc
OAc
OAc
OAc
OAc
SiMe3
nBu
Ph
SiMe3
nBu
Ph
(CH2)2OBn
(CH2)8CO2Et
(CH2)2OBn
SiMe3
SiMe3
Ph
A
A
A
A
A
B
B
B
B
A
B
A
B
B
20 h
6 d
2 d
3 d
2 d
14 h
14 h
14 h
17 h
3 d
18 h
7 d
7aa
7ab
7ac
7ca
7cb
7cc
7cd
7ce
7dd
7fa
7fa
7fc
81
49[c]
64[c]
26[c]
24[c]
95
85
85
80
–
93
–
86
54
–
43[c]
12[c]
32[c]
35[c]
–
–
–
–
87
–
2
3[b]
4
5
6
7
8
9
H
10
11
12
13
14
Me
Me
Me
Me
Me
2f
2f
2g
2g
96
–
–
Ph
18 h
18 h
7gc
7gd
iPr
(CH2)2OBn
[a] Conditions: A: 1.05 equiv. alkyne, 2 mol-% (PhP3)2PdCl2, 4 mol-% CuI, 1.5 equiv. NEt3, THF, room temp.; B: 1.3 equiv. alkyne,
2 mol-% (Ph3P)2PdCl2, 5 mol-% SIMes·HCl, 5 mol-% CuI, iPr2NH, 80 °C. [b] 2.1 equiv. of alkyne was used. [c] Separation of the starting
material from the product by column chromatography was not possible.
Scheme 4. Synthesis of α-hydroxyallenes 3a–d.
Scheme 5. Synthesis of α-hydroxyallenes 3e–g.
The final gold-catalyzed cycloisomerization of the α-hy-
droxyallenes 3a–d to the corresponding furopyrans 4 was
carried out with Ph3PAuCl/AgBF4 as precatalyst in toluene the phenyl-substituted allenes reacted rather slowly with
(Table 4, entries 1–4). The desired bicyclic products were slight epimerization of the allenic chirality axis (Table 4, en-
obtained with good to excellent yield (76–96%). Whereas tries 1 and 2),[8d] the corresponding benzyloxyethyl-substi-
Table 4. Gold-catalyzed cyclization of α-hydroxyallenes 3a–d to furopyrans 4.
Entry
3
R1
R2
X
Cond.[a]
4
Yield [%]
dr
1
2
3
4
5
6
3a
3b
3c
3d
3a
3a
Ph
Ph
iPr
nBu
iPr
nBu
iPr
iPr
H
H
H
H
I
A, 2 h
4a
76
96
84
77
84
79
89:11
96:4
Ͼ 95:5
Ͼ 95:5
Ͼ 95:5
Ͼ 95:5
A, 1.5 h
A, 1 min
A, 1 min
B, 25 min
C, 1 min
4b
(CH2)2OBn
(CH2)2OBn
Ph
4c
4d
4aЈ
4aЈ
Ph
I
[a] Conditions: A: Ph3PAuCl/AgBF4, toluene; B: 1.5 equiv. NIS, Ph3PAuCl/AgBF4, toluene; C: 1.5 equiv. NIS, AuCl, CH2Cl2.
314 Eur. J. Org. Chem. 2010, 311–316
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Au-Catalyzed Cyclization of β-Hydroxyallenes
tuted allenes cyclized very quickly and with complete axis-
to-center chirality transfer (Table 4, entries 3 and 4). The
accelerating effect of N-iodosuccinimide was again ob-
served in the cyclization of α-hydroxyallene 3a which af-
forded the iodinated furopyran 4aЈ[27] with Ph3PAuCl/
AgBF4 or AuCl as precatalyst (Table 4, entries 5 and 6 vs.
1). This opens the possibility for attaching another dihy-
drofuran ring to the furopyran 4aЈ which, however, was not
examined further.
The α-hydroxyallenes 3e–g also underwent cycloisomeri-
zation to afford the corresponding furopyrans 4 with mod-
erate to good yield (46–70%) in the presence of 5 mol-%
of Ph3PAuCl/AgBF4 (Scheme 6). The bicyclic ethers were
formed as complex mixtures of diastereomers, indicating
that the gold catalyst induces epimerization of the allene
and/or the heterocyclic rings (possibly by ring-opening/ring-
closing).[8d,9a]
Experimental Section
General Procedure for the Gold-Catalyzed Cyclization of β-Hy-
droxyallenes 1 in the Presence of NIS: To a solution of 1 equiv. of
the allene in dry toluene (60 µL/mg 1) was added under argon 1.1–
1.5 equiv. of NIS, 5 mol-% of Ph3PAuCl and 5 mol-% of AgBF4.
The reaction mixture was stirred until full conversion of the start-
ing material was observed by TLC. The solvent was evaporated and
the crude product was adsorbed on silica gel, followed by flash
column chromatography on silica gel with cyclohexane/ethyl ace-
tate (30:1 to 10:1). The product, still dissolved in the column eluent,
was washed with an aqueous 0.5  Na2S2O3 solution to remove
traces of iodine, dried with Na2SO4, and the solvent was evaporated
to afford analytically pure dihydropyran 2.
General Procedure for the Sonogashira Coupling of Dihydropyrans
2 in the Presence of SIMes: In a Schlenk tube, 2 mol-% of (Ph3P)2-
PdCl2 and 5 mol-% of SIMes·HCl were dissolved under argon in
dry iPr2NH (0.4 mL/mmol 2). The mixture was heated in the sealed
tube at 80 °C for 1.5 h. After cooling down to room temp.,
5 mol-% of CuI, 1 equiv. of 2, and dry iPr2NH (0.9 mL/mmol 2)
were added, followed by dropwise addition of 1.3 equiv. of the ter-
minal alkyne. The reaction mixture was heated to 80 °C for 14–
18 h. After cooling to room temp., the crude product was filtered
through a pad of silica gel and celite (elution with Et2O). The sol-
vent was evaporated, followed by flash column chromatography of
the residue on silica gel with cyclohexane/ethyl acetate (10:1) to
afford analytically pure enyne 3.
General Procedure for the Gold-Catalyzed Cycloisomerization of
α-Hydroxyallenes 3: To a solution of 1 equiv. of the allene in dry
toluene (60 µL/mg 3) was added under argon 5 mol-% of Ph3PAuCl
and 5 mol-% of AgBF4. The reaction mixture was stirred until full
conversion of the starting material was observed by TLC. The sol-
vent was evaporated and the crude product was purified by flash
column chromatography on silica gel with cyclohexane/ethyl ace-
tate (30:1 to 10:1) to afford analytically pure furopyran 4.
Scheme 6. Gold-catalyzed cycloisomerization of α-hydroxyallenes
3e–g to furopyrans 4.
Supporting Information (see also the footnote on the first page of
this article): Procedures, spectroscopic data, and copies of NMR
spectra of reported compounds.
Conclusions
We have developed an efficient and stereoselective access
to furopyrans 4 from β-hydroxyallenes 1 by a gold/palla-
dium/gold-catalyzed cyclization/cross coupling sequence. In
Acknowledgments
Financial support by the Deutsche Forschungsgemeinschaft
the first of three transition metal-catalyzed steps, a tremen- (DFG) and the European Community is gratefully acknowledged.
dous accelerating effect of N-iodosuccinimide (NIS) on the
gold-catalyzed cyclization of β-hydroxyallenes 1 was uti-
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in good yield. Reactivity problems in the subsequent Sono-
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N-heterocyclic carbene. After allene formation by epoxida-
tion and copper-mediated SN2Ј-substitution, a second gold-
catalyzed cyclization afforded the desired furopyrans 4 with
good to excellent yield. Whereas the bicyclic ethers 4a–4d
were obtained in diastereomerically enriched or pure form,
epimerization was observed during the formation of prod-
ucts 4e–g. Further investigations are devoted to elucidate a
mechanistic rationale for the strong accelerating effect of
NIS on gold-catalyzed transformations, as well as to the
application of the Au/Pd/Au-catalyzed cyclization/cross
coupling sequence in target-oriented synthesis.
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B. Gockel, N. Krause
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Received: September 4, 2009
Published Online: November 30, 2009
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