Synthesis of 2,5-disubstituted dihydrofuran-3(2 H)-ones via [2,3]-sigmatropic rearrangement of oxonium ylides generated from α-oxo gold carbenes

Article abstract of DOI:10.1055/s-0033-1339662

Novel [2,3]-sigmatropic rearrangements of oxonium ylides generated from α-oxo gold carbenes were discovered. An efficient synthetic method of 2,5-disubstituted dihydrofuran-3(2H)-ones via gold-catalyzed intermolecular oxidation of the allyl homopropargyl ethers with N-oxide was developed. And the synthetic utility of the current method has been proved by concise formal synthesis of (±)-kumausallene. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339662

LETTER
▌2077
lSetyternthesis of 2,5-Disubstituted Dihydrofuran-3(2H)-ones via [2,3]-Sigmatropic
Rearrangement of Oxonium Ylides Generated from α-Oxo Gold Carbenes
2,5-Disubstituted Dihydrofuran-3(2H)-ones
Miyeon Han, Joohee Bae, Juhee Choi, Jinsung Tae*
Department of Chemistry, Yonsei University, Seoul 120-749, Korea
Fax +82(2)3647050; E-mail: jstae@yonsei.ac.kr
Received: 01.07.2013; Accepted after revision: 25.07.2013
OR
OR
O
[Au]
R = H
Abstract: Novel [2,3]-sigmatropic rearrangements of oxonium
ylides generated from α-oxo gold carbenes were discovered. An
efficient synthetic method of 2,5-disubstituted dihydrofuran-3(2H)-
ones via gold-catalyzed intermolecular oxidation of the allyl homo-
propargyl ethers with N-oxide was developed. And the synthetic
utility of the current method has been proved by concise formal syn-
thesis of (±)-kumausallene.
[Au]
X
X
X
O–H
insertion
N-oxide
O
O
B
C
A
(Zhang et al.)
ylide formation
R = allyl
Key words: carbenes, catalysis, dihydrofuran-3(2H)-ones, α-oxo
gold carbenes, rearrangement
[2,3]
O
O
this
work
X
X
O
O
D
E
Over the past decade, numerous synthetic methods based
on homogeneous gold catalysis have been developed.1
Among them, the gold-catalyzed oxidation of alkynes into
α-oxo gold carbenes has been a key strategy in a variety of
transformations,2 such as cyclopropanation, C–H inser-
tion, O–H insertion, and dipolar cycloaddition. Especial-
ly, intermolecular oxidations of terminal alkynes offer
versatile approaches to α-oxo metal carbenes which are
typically prepared from the corresponding α-diazo car-
bonyl compounds. α-Oxo gold carbenes display reactivi-
ties analogous to that of metal carbenoids derived from
diazo carbonyl compounds.3 Although most of the known
metal carbenoid chemistries have been reproduced by
α-oxo gold carbenes, the [2,3]-sigmatropic rearrange-
ments of oxonium ylides mediated by gold catalysis have
not been well documented until now.4
Scheme 1 [2,3]-Sigmatropic rearrangements of allyl oxonium ions
generated from α-oxo gold carbenes
conditions utilizing 8 mol% of gold catalyst and 2.0
equivalents of N-oxide in dichloroethane (DCE) at 60 °C,
the reaction of 1b with strong nucleophilic oxidants such
as pyridine and quinoline N-oxides (4a and 4b)3a–g,3j,m,5 in
the presence of different gold catalysts proved to be insuf-
ficient to promote the desired rearrangement (Table 1, en-
tries 1 and 2). Fortunately, the oxidation of 1b with gold
catalyst 3a and N-oxide 4b provided the expected product
2b in 38% (Table 1, entry 3). After screening other com-
mercially available N-oxides, we found that 4-nitroquino-
line N-oxide (4c) is better suited for this transformation.
Among gold catalysts examined (Table 1, entries 4–7),
catalyst 3a proved to be most efficient when combined
with 4c (54% yield of 2b, Table 1, entry 4). To optimize
the conditions, we have tested other solvent systems, such
as dichloromethane, 1,4-dioxane, toluene, and THF (Ta-
ble 1, entries 9–13). But other solvents proved to be less
efficient than DCE. Increasing the reaction temperature
from 60 °C to 80 °C in DCE was not effective in promot-
ing the rearrangement reaction (Table 1, entry 8). Opti-
mized yield (62%) of 2b was obtained by using 3.0
equivalents of N-oxide 4c and gold catalyst 3a in DCE at
60 °C (Table 1, entry 14). Using excess of 4c (4.0 equiv)
did not further increased the yields (Table 1, entry 15).
The diastereomeric ratio determined by HPLC indicates
that the trans isomer is slightly favored over cis
(trans/cis = 61:39), which is consistent with the trend ob-
served in the related rearrangements of diazo carbonyl
compounds.6,7
Recently, the Zhang group reported the synthesis of four-
and five-membered oxacycles by intramolecular O–H in-
sertion of α-oxo gold carbenes3e,f as shown in Scheme 1.
When R = H, O–H insertion reactions of the α-oxo gold
carbenes (B) yield the substituted dihydrofuran-3(2H)-
ones (C). However, if R = allyl, intramolecular trapping
of B by the allyl ether oxygen could lead the formation of
the oxonium ylides (D). Subsequent [2,3]-sigmatropic
rearrangements are expected to give the substituted di-
hydrofuran-3(2H)-ones (E). Here, we report our prelimi-
nary results on the efficient synthesis of 2,5-disubstituted
dihydrofuran-3(2H)-ones via gold-catalyzed intermolecu-
lar oxidation of the allyl homopropargyl ethers.
The allyl homopropargyl ether 1b, which is readily avail-
able from the benzyl glycidyl ether, was chosen as the
substrate for our model studies. Under the typical reaction
Under the optimal reaction conditions, various allyl
homopropargyl ethers were tested to examine the general-
ity of this reaction. The substrates were prepared from al-
dehydes by propargylation reaction using indium (1.0
SYNLETT 2013, 24, 2077–2080
Advanced online publication: 28.08.2013
DOI: 10.1055/s-0033-1339662; Art ID: ST-2013-U0608-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2078
M. Han et al.
LETTER
Table 1 Optimization of Reaction Conditionsa
gyl ethers 1a–j as shown in Scheme 2. Substrate 1b
(R = BnOCH2) is prepared from the benzyl glycidyl ether
5 by epoxide opening with TMS acetylide.9
O
Au(I) catalyst 3 (8 mol%)
N-oxide 4 (2.0 equiv)
O
BnO
BnO
As shown in Table 2, the rearrangement reactions proceed
smoothly with various substrates to give 2,5-disubstituted
dihydrofuran-3(2H)-ones in 23–70% yields under the op-
timized conditions. A range of functional groups were tol-
erated, including aliphatic substituents (Table 2, entries 8
and 9), alkene (Table 2, entry 10), and protected hydroxy
groups (Table 2, entries 2–5). In addition, aromatic rings,
such as phenyl and furan, are also allowed (Table 2, en-
tries 6 and 7). The diastereomeric ratios of 2b–j are deter-
mined by HPLC and 1H NMR (see Supporting
Information). In general, the trans isomers are favored
over cis isomers in all cases, which could be explained by
the preferred transition state F as shown in Scheme 3.6
O
1b
2b
3a: [Au{P(t-Bu)2(o-biphenyl)}(MeCN)]+ SbF6
3b: Ph3PAuCl
–
3c: [(2-biphenyl)Cy2PAuCl]
NO2
4a:
4b:
4c:
+
N
+
N
+
N
Br
Me
O–
O–
O–
Entry Catalyst (8 N-Oxide (2 Conditions
Yield (%)b
mol%)
equiv)
(trans/cis)c
1
2
3a
4a
DCE, 60 °C
DCE, 60 °C
DCE, 60 °C
DCE, 60 °C
DCE, 60 °C
DCE, 60 °C
DCE, 60 °C
DCE, 80 °C
n.r.
O
3c/AgNTf2 4b
trace
O
R
H
+
O
H
+
O
–
H
3
3a
3a
4b
4c
38 (99:1)
54 (70:30)
dec.
–
H
R
4
F
favored
G
5
3b/AgSbF6 4c
3b/AgNTf2 4c
3c/AgNTf2 4c
6
dec.
cis
trans
7
18 (71:29)
46 (69:31)
39 (68:32)
Scheme 3 Proposed transition state for the [2,3]-sigmatropic rear-
rangements of allyl oxonium ions
8
3a
3a
3a
3a
3a
3a
3a
3a
4c
4c
4c
4c
4c
4c
9
CH2Cl2, reflux
Table 2 Synthesis of 2,5-Disubstituted Dihydrofuran-3(2H)-ones
via Gold-Catalyzed Rearrangement of Oxonium Ylides
10
11
12
13
14
15
TFA, CH2Cl2, reflux 20 (71:29)
1,4-dioxane, 60 °C 32 (70:30)
R
O
catalyst 3a (8 mol%)
O
N-oxide 4c (3 equiv)
toluene, 60 °C
THF, reflux
17 (71:29)
17 (84:16)
62 (61:39)
57 (61:39)
DCE (0.05 M), 60 °C, 15 h
R
O
2
1
4c (3 equiv) DCE, 60 °C
4c (4 equiv) DCE, 60 °C
Entry Product
Yield (%)a dr (trans/cis)b
a Reaction conditions: Au(I) catalyst (8 mol%), N-oxide (2 equiv), sol-
vent (0.05 M).
O
b Isolated yield.
1
38
62
–
c Diastereomeric ratios are determined by HPLC.
O
2a
equiv)/propargyl bromide (1.0 equiv)8 in H2O–MeOH
(2:1). The homopropargyl alcohols 7a–j are then reacted
with NaH and allyl bromide to give the allyl homopropar-
O
BnO
2
3
61:39
O
1. n-BuLi, HMPA, THF
2b
SiMe3
BnO
O
O
2. K2CO3, MeOH
BnO
5
70
52
74:26
n.d.c
OH
R
O
Br
O
R
2c
NaH, DMF
7a–j
1a–j
O
O
BnO
H2O–MeOH (2:1)
indium
R
H
4
6
Br
O
2d
Scheme 2 Synthesis of allyl homopropargyl ethers
Synlett 2013, 24, 2077–2080
© Georg Thieme Verlag Stuttgart · New York

LETTER
2,5-Disubstituted Dihydrofuran-3(2H)-ones
2079
Table 2 Synthesis of 2,5-Disubstituted Dihydrofuran-3(2H)-ones
via Gold-Catalyzed Rearrangement of Oxonium Ylides (continued)
We started from compound 2b which is properly function-
alized for the synthesis of (±)-kumausallene (12). Al-
though trans-2b and cis-2b isomers are separable, we
checked the isomerization reaction between them. Under
equilibrium conditions using 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) in MeOH, cis-2b proved to be the fa-
vored isomer. Thus, trans-2b is converted into cis-2b in a
trans/cis = 22:78 mixture as shown in Scheme 4. The
combined cis-2b was treated with NaBH4 at low tempera-
ture to provide the known alcohol 8 in 83% yield. The rel-
ative stereochemistries of 8 are confirmed by comparison
with known data.12 All the three stereochemistries of 8 are
consistent with those of kumausallene (12).
R
O
catalyst 3a (8 mol%)
O
N-oxide 4c (3 equiv)
DCE (0.05 M), 60 °C, 15 h
R
O
2
1
Entry Product
Yield (%)a dr (trans/cis)b
TBSO
O
5
6
52
43
80:20
>99:1
O
2e
H
H
H
H
O
O
DBU
MeO
BnO
BnO
MeOH
40 °C
O
O
O
cis-2b (t/c = 22:78)
trans-2b
O
1. 9 (10 mol%)
2f
H
H
O
NaBH4
(7 equiv)
CO2Me
BnO
MeOH
–78 °C
CH2Cl2, reflux
O
O
OH
2. NaOMe (20 equiv)
MeOH, 0 °C
(86% for 2 steps)
7
50
>99:1
8
(83%)
O
(ref.12)
2g
H
H
O
H
H
O
O
H2, Pd/C
HO
BnO
O
EtOAc–MeOH (1:1)
(71%)
8
9
32
23
50
74:26
71:29
76:24
H
O
CO2Me
O
H
CO2Me
2h
10
(ref.13)
11
O
(ref.13)
H
Mes
N
N
Mes
Ph
Br
O
Cl
H
O
Ru
2i
Br
Cl
PCy3
O
O
H
9
( )-kumausallene (12)
10
O
Scheme 4 Formal synthesis of (±)-kumausallene
2j
a Isolated yields.
We then attempted the cross metathesis (CM)–conjugate
addition strategy to install the second tetrahydrofuran
ring. Reaction of 8 with excess of methyl acrylate in the
presence of the second-generation Grubbs catalyst (9) un-
der refluxing dichloromethane provided the cross-meta-
thesis product mixture in 93% yield. Subsequent
treatment with NaOMe in methanol at 0 °C furnished
compound 10. The relative stereochemistries are con-
firmed after conversion into the known alcohol 1111e,13 by
deprotection of the benzyl group. The primary alcohol 11
was converted into kumausallene (12) in the Overman
synthesis,13 and this completes a formal synthesis of (±)-12.
b Diastereomeric ratios are determined by HPLC and 1H NMR.
c Isomeric peaks are not clearly separated; n.d. = not determined.
To verify the synthetic utility of the present method and to
confirm the relative stereochemistry of 2,5-disubstituted
dihydrofuran-3(2H)-ones, we examined the formal total
synthesis of related bioactive natural products. (–)-Ku-
mausallene (12),10 a natural product isolated from the alge
Laurencia nipponica yamada, has been an active synthet-
ic target for several decades.11 Stereoselective synthesis of
one of the two 2,5-disubstituted tetrahydrofuran rings in
the dioxabicyclo[3.3.0]octane core of kumausallene is
crucial for the total synthesis.
In summary, we have developed a flexible and general
solution for the synthesis of various 2,5-disubstituted
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2077–2080

2080
M. Han et al.
LETTER
(5) Tavakoli-Hoseini, N.; Bamoharram, F. F.; Heravi, M. M.
Synthesis and Reactivity in Inorganic, Metal-Organic, and
Nano-Metal Chemistry; 2010, 40, 912.
dihydrofuran-3(2H)-ones via [2,3]-sigmatropic rear-
rangements of oxonium ylides generated from α-oxo gold
carbenes which are formed by the gold-catalyzed intermo-
lecular oxidation of the allyl homopropargyl ethers with
N-oxide.14,15 The synthetic utility of the present method
has been proved by the concise formal synthesis of (±)-
kumausallene.
(6) (a) Roskamp, E. J.; Johnson, C. R. J. Am. Chem. Soc. 1986,
108, 6062. (b) Clark, J. S. Tetrahedron Lett. 1992, 33, 6193.
(c) Clark, J. S.; Fessard, T. C.; Wilson, C. Org. Lett. 2004, 6,
1773. (d) Li, Q.-R.; Gu, C.-Z.; Yin, H. Chin. J. Chem. 2006,
24, 72. (e) Nesbitt, C. L.; McErlean, C. S. P. Tetrahedron
Lett. 2009, 50, 6318. (f) Clark, J. S.; Yang, G.; Osnowski, A.
P. Org. Lett. 2013, 15, 1464. (g) Yakura, T.; Ozono, A.;
Matsui, K.; Yamashita, M.; Fujiwara, T. Synlett 2013, 24,
65.
(7) The relative stereochemistry of cis isomer was confirmed by
NOSEY experiments (see Supporting Information).
(8) (a) Lee, P.-H.; Kim, H.; Lee, K.-Y. Adv. Synth. Catal. 2005,
347, 1219. (b) Haddad, T. D.; Hirayama, L. C.; Buckley, J.
J.; Singaram, B. J. Org. Chem. 2012, 77, 889.
Acknowledgment
This work was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (No.2011-
0007015).
(9) (a) Ooi, R.; Kagoshima, N.; Ichikawa, H.; Maruoka, K. J.
Am. Chem. Soc. 1999, 121, 3328. (b) Stephen, A.; Hashmi,
K.; Choi, J. H.; Bats, J. W. J. Prakt. Chem. 1999, 341, 342.
(10) Suzuki, T.; Koizumi, K.; Suzuki, M.; Kurosawa, E. Chem.
Lett. 1983, 12, 1639.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References and Notes
(11) (a) Brown, M. J.; Harrison, T.; Overman, L. E. J. Am. Chem.
Soc. 1991, 113, 5378. (b) Evans, P. A.; Murthy, V. S.;
Roseman, J. D.; Rheingold, A. L. Angew. Chem. Int. Ed.
1999, 38, 3175. (c) Lee, E.; Yoo, S.-K.; Choo, H.-A.; Song,
H. Y. Tetrahedron Lett. 1998, 39, 317. (d) Werness, J. B.;
Tang, W. Org. Lett. 2011, 13, 3664. (e) Fernández de la
Pradilla, R.; Alhambra, C.; Castellanos, A.; Fernández, J.;
Manzano, P.; Montero, C.; Ureña, M.; Viso, A. J. Org.
Chem. 2005, 70, 10693.
(12) Nesbitt, C. L.; McErlean, C. S. P. Tetrahedron Lett. 2009,
50, 6318.
(13) Grese, T. A.; Hutchinson, K. D.; Overman, L. E. J. Org.
Chem. 1993, 58, 2468.
(14) Procedure for the Gold-Catalyzed Rearrangement
To the allyl homopropargyl ether 1b (15 mg, 0.065 mmol) in
DCE (1.3 mL) were added 4c (25 mg, 0.13 mmol) and 3a (4
mg, 8 mol%), and the reaction mixture was heated at 60 °C
for 15 h. The reaction mixture was quenched with 1 M HCl
solution (5 mL) and extracted with EtOAc (3 × 5 mL). The
combined organic layers were washed with brine (5 mL),
dried over anhydrous MgSO4, and condensed. The crude
product was purified by flash column chromatography on
silica gel (hexane–EtOAc, 20:1) to give trans-2b (6 mg) and
cis-2b (4 mg) as yellow oils in 62% (trans/cis = 61:39).
(15) Spectral Data
(1) For selected recent reviews on gold-catalyzed reactions, see:
(a) Rudolph, M.; Hashmi, A. S. K. Chem. Soc. Rev. 2012,
41, 2448. (b) Corma, A.; Leyva-Pérez, A.; Sabater, M. J.
Chem. Rev. 2011, 111, 1657. (c) Fürstner, A. Chem. Soc.
Rev. 2009, 38, 3208. (d) Sohel, S. M. A.; Liu, R.-S. Chem.
Soc. Rev. 2009, 38, 2269. (e) Patil, N. T.; Yamamoto, Y.
Chem. Rev. 2008, 108, 3395. (f) Gorin, D. J.; Sherry, B. D.;
Toste, F. D. Chem. Rev. 2008, 108, 3351. (g) Jiménez-
Núñez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326.
(h) Arcadi, A. Chem. Rev. 2008, 108, 3266. (i) Li, Z.;
Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239.
(j) Bongers, N.; Krause, N. Angew. Chem. Int. Ed. 2008, 47,
2178. (k) Fürstner, A.; Davies, P. W. Angew. Chem. Int. Ed.
2007, 46, 3410. (l) Hashmi, A. S. K. Chem. Rev. 2007, 107,
3180.
(2) For a recent review on α-oxo gold carbenes, see: Xiao, J.; Li,
X. Angew. Chem. Int. Ed. 2011, 50, 7226.
(3) (a) Wang, Y.; Ji, K.; Lan, S.; Zhang, L. Angew. Chem. Int.
Ed. 2012, 51, 1915. (b) He, W.; Li, C.; Zhang, L. J. Am.
Chem. Soc. 2011, 133, 8482. (c) Ye, L.; He, W.; Zhang, L.
Angew. Chem. Int. Ed. 2011, 50, 3236. (d) Lu, B.; Li, C.;
Zhang, L. J. Am. Chem. Soc. 2010, 132, 14070. (e) Ye, L.;
He, W.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 8550.
(f) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc.
2010, 132, 3258. (g) Dateer, R. B.; Pati, K.; Liu, R.-S. Chem.
Commun. 2012, 48, 7200. (h) Qian, D.; Zhang, J. Chem.
Commun. 2012, 48, 7082. (i) Mukherjee, A.; Dateer, R. B.;
Chaudhuri, R.; Bhunia, S.; Karad, S. N.; Liu, R.-S. J. Am.
Chem. Soc. 2011, 133, 15372. (j) Vasu, D.; Hung, H.-H.;
Bhunia, S.; Gawade, S. A.; Das, A.; Liu, R.-S. Angew.
Chem. Int. Ed. 2011, 50, 6911. (k) Qian, D.; Zhang, J. Chem.
Commun. 2011, 47, 11152. (l) Davies, P. W.; Cremonesi, A.;
Martin, N. Chem. Commun. 2011, 47, 379. (m) He, W.; Xie,
L.; Xu, Y.; Xiang, J.; Zhang, L. Org. Biomol. Chem. 2012,
10, 3168. (n) Li, G.; Zhang, L. Angew. Chem. Int. Ed. 2007,
46, 5156. (o) Luo, Y.; Ji, K.; Li, Y.; Zhang, L. J. Am. Chem.
Soc. 2012, 134, 17412.
Compound trans-2b (major): Rf = 0.48 (hexane–
EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.36–7.26 (m,
5 H), 5.82 (dddd, J = 17.1, 10.1, 7.0, 7.0 Hz, 1 H), 5.14 (m,
2 H), 4.55 (m, 3 H), 4.14 (dd, J = 7.2, 4.8 Hz, 1 H), 3.72 (dd,
J = 10.2, 3.4 Hz, 1 H), 3.54 (dd, J = 10.2, 3.8 Hz, 1 H), 2.57
(m, 3 H), 2.31 (m, 1 H). 13C NMR (100.6 MHz, CDCl3): δ =
215.4, 137.9, 133.2, 128.6, 127.9, 127.6, 118.4, 79.6, 74.6,
73.6, 72.9, 38.8, 36.1. HRMS: m/z calcd for C15H18O3Na [M
+ Na]+: 269.1148; found: 269.1147.
Compound cis-2b (minor): Rf = 0.44 (hexane–EtOAc, 3:1).
1H NMR (400 MHz, CDCl3): δ = 7.39–7.27 (m, 5 H), 5.82
(dddd, J = 17.2, 10.3, 6.9, 7.0 Hz, 1 H), 5.12 (m, 2 H), 4.62
(s, 2 H), 4.38 (m, 1 H), 3.91 (dd, J = 6.8, 4.4 Hz, 1 H), 3.67
(m, 2 H), 2.55 (m, 1 H), 2.49 (d, J = 6.0 Hz, 1 H), 2.37 (m, 2
H). 13C NMR (100.6 MHz, CDCl3): δ = 214.9, 138.0, 133.2,
128.6, 127.9, 127.8, 118.2, 81.0, 75.2, 73.7, 71.6, 39.7, 35.5.
IR (film): 3071, 3030, 2919, 2862, 1756, 1642, 1454, 1101,
920, 739, 698 cm–1. HRMS: m/z calcd for C15H18O3Na [M +
Na]+: 269.1148; found: 269.1147.
(4) Recently, the Yang and Tang group reported on the gold-
catalyzed rearrangements of allylic oxonium ylides
generated by oxidation of alkynes conjugated by an ester
group. See: Fu, J.; Shang, H.; Wang, Z.; Chang, L.; Shao,
W.; Yang, Z.; Tang, Y. Angew. Chem. Int. Ed. 2013, 52,
4198.
Synlett 2013, 24, 2077–2080
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.