Gold(I)-catalyzed endo-selective intramolecular α-alkenylation of β-yne-furans: Synthesis of seven-membered-ring-fused furans and dft calculations

Article abstract of DOI:10.1002/anie.201306965

Alkenylation of furans: An efficient gold-catalyzed endo-selective intramolecular α-alkenylation of β-alkyne-substituted furans has been developed to synthesize challenging seven-membered-ring-fused furans in good to excellent yields. Preliminary DFT calc

Full text of DOI:10.1002/anie.201306965

Angewandte
Chemie
DOI: 10.1002/anie.201306965
Gold Catalysis
Gold(I)-Catalyzed endo-Selective Intramolecular a-Alkenylation of
b-Yne-Furans: Synthesis of Seven-Membered-Ring-Fused Furans and
DFT Calculations**
Zhe Dong, Cheng-Hang Liu, Yi Wang, Mu Lin, and Zhi-Xiang Yu*
Dedicated to Professor Kendall N. Houk on the occasion of his 70th birthday
Furan derivatives are widely found in natural products with
impressive biological properties. In many of these natural
products, the furan system is fused to other rings with various
sizes. Some of the natural products that incorporate seven-
membered-ring-fused furans are shown in Figure 1.[1] Among
Figure 1. Natural products with seven-membered-ring-fused furans.
these natural products, frondosin B inhibits the binding of
interleukin-8 (IL-8) in the low micromolar range.[1a] Liphagal
is a selective inhibitor of phosphatidylinositol 3-kinase a
(PI3K a).[1b] These days, the synthesis of seven-membered
Scheme 1. a) Different reaction pathways of a-yne-furans and b-yne-
furans under gold catalysis. b) Transition-metal-catalyzed a-alkenyla-
tion of b-yne-furans and b-yne-thiophenes.
ring systems still represents a great challenge for synthetic
organic chemists.[2] Consequently, the development of reac-
tions or the design of strategies to build the fused cyclo-
heptafuran skeleton is, in many cases, a challenging part of the
synthesis of natural products with seven-membered-ring-
fused furans, such as frondosin B, and their analogues.[3]
Transition-metal-catalyzed alkenylation reactions of
arenes,[4] such as substituted benzenes,[5] indoles,[6] or pyr-
roles,[7] with alkynes have been rapidly developed over the
past decade, owing to the discovery of alkyne activation by
electrophilic transition-metal complexes.[8] However, in most
cases, transition-metal-catalyzed intramolecular reactions of
furans with alkynes give products where the furan ring has
opened rather than alkenylated furans.[9–13] The cationic spiro
intermediate A (Scheme 1a) was proposed as a common
intermediate of gold-catalyzed a-yne-furan cycloisomeriza-
tions.[14] Intermediate A may undergo 1,2-migration to form
the annulated intermediate B, which gives the b-alkenylated
furan product after proton transfer. However, in most cases,
À
Aundergoes C O bond cleavage, and further steps occur that
lead to a furan-ring-opened product.
Considering that the a position of furans is more nucle-
ophilic than the b position,[15] we wondered whether we could
develop an a-alkenylation strategy that uses furan substrates
with the alkyne chain attached at the b position of the furan
ring; then, the annulated furan intermediate C would be
formed directly (no 1,2-migration needed), and consequently,
fewer side reactions should occur (Scheme 1a). We found that
only five examples of transition-metal-catalyzed a-alkenyla-
tion reactions of b-yne-furans have been reported by the
groups of Echavarren (Pt), Sames (Pt), Yamamoto (Pd),
Nishizawa (Hg), and Banwell (Au).[16] However, only fused
cyclohexafurans were formed by an exo-selective Friedel–
Crafts type cyclization. We envisioned that there are two
possible competing a-alkenylation pathways for b-yne-furans
that would give the six- and seven-membered-ring products,
respectively. We wondered whether this regioselectivity could
be tuned by electronic effects through the introduction of
suitable substituents on the alkyne moiety or on the tether of
[*] Z. Dong,[+] C.-H. Liu,[+] Y. Wang, Dr. M. Lin, Prof. Dr. Z.-X. Yu
Beijing National Laboratory of Molecular Sciences (BNLMS)
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
College of Chemistry, Peking University
Beijing, 100871 (China)
E-mail: yuzx@pku.edu.cn
Homepage: http://www.chem.pku.edu.cn/zxyu/index.htm
[+] These authors contributed equally to this work.
[**] We thank the Natural Science Foundation of China (21232001) and
the National Basic Research Program of China-973 Program
(2010CB833203) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306965.
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Table 1: Scope of the gold-catalyzed intramolecular a-alkenylation.
the starting materials to realize the challenging synthesis of
fused cycloheptafurans by an endo-selective cyclization
(Scheme 1b).
Herein, we report the synthesis of fused cycloheptafurans
from b-yne-furans under mild conditions with an endo-
selective a-alkenylation strategy. Also, we report DFT
calculations on the experimentally observed regioselectivity.
Furthermore, mechanistic insights obtained through the DFT
calculations enabled further exploration of the a-alkenylation
strategy to synthesize other seven-membered-ring-fused
furans.
Entry Substrate
t [h]
Product, yield[a]
+
We commenced our study with b-yne-furan 1a as the
standard substrate. After extensive optimization (see the
Supporting Information for details), we found that treatment
of 1a with 4 (5 mol%; 4 = [JohnPhosAu(NCMe)]SbF6, John-
Phos = 2-(di-tert-butylphosphino)biphenyl) in DME gave the
desired fused cycloheptafuran 2a in 90% yield, along with an
unexpected alkyne-hydration by-product 3a in 1% yield
(Table 1, entry 1). The six-membered-ring product was not
observed, which suggests that the reaction has a very good
regioselectivity, with a preference for the 7-endo over the 6-
exo pathway. Our attempts to reduce the amount of by-
product 3a by adding molecular sieves (4 ꢀ) to remove water
from the solvent failed. No reaction occurred, and the starting
material remained intact (Table 1, entry 2). This result
suggests that water may act as a proton shuttle in the present
system. When one drop of water was added to the system, 3a
became the major product (Table 1, entry 3). These results
indicate that a catalytic amount of water is required for the a-
alkenylation reaction, but that too much water is detrimental.
We found that the alkyne part of the substrate can be
substituted with a bulky substituent, such as cyclopropyl
group, or by an alkenyl group, without affecting the endo
selectivity and reaction yields (Table 1, entries 4 and 5).
Substrates that bear aryl groups with different electronic
characters at the alkyne moiety can also be converted into the
corresponding products in very good yields (Table 1,
entries 6–8). We also investigated whether the furan moiety
of the b-yne-furans can be replaced by other arenes. The yne-
benzofurans 1g and 1h (Table 1, entries 9 and 10) both gave
the seven-membered-ring products in good yields. The
skeleton of product 2h, which bears a seven-membered-
ring-fused benzofuran, is similar to those of frondosin B and
liphagal (Figure 1), which indicates that the present strategy
might be suitable for the synthesis of these natural products
and/or their analogues. Under the optimized conditions, b-
yne-thiophene 1i was transformed into the target seven-
membered-ring product 2i and the hydration by-product 3i in
46% and 39% yield, respectively (Table 1, entry 11). It was
previously reported by Sames and co-workers that using
PtCl4, the O-tethered substrate 1j gave only the product of
furan ring-opening.[16b] With our system, however, 1j can give
the corresponding product 2j in toluene in a moderate yield
(Table 1, entry 12). Unfortunately, C-tethered substrates
could not be converted into the desired cyclization products.
1k slowly decomposed under gold catalysis (Table 1,
entry 13), whereas 1l gave the alkyne-hydration product 3l
in moderate yield (Table 1, entry 14).[17] Fortunately, the
alkenylation of C-tethered substrates can be realized by
1
1a
1a
1a
3
2a, 90%
3a, 1%
3a, 63%
2[b]
3[c]
24 no reaction
8
2a, 19%
4
5
6
7
8
1b, R=cyclopropyl
1c, R=2-propenyl
1d, R=Ph
1e, R=p-ClC6H4
1 f, R=p-MeOC6H4
3
3
4
3
3
2b, 91%
2c, 88%
2d, 76%
2e, 90%
2 f, 98%
9
10
1g, R1 =H
2
6
2g, 71%
2h, 74%
1h, R1 =OMe
+
11
1i
20 2i, 46%
3i, 39%
12[d] 1j, X=O
13
20 2j, 60%
48 decomposed
1k, X=CH2
14
1l
96 3l, 76%
[a] Yields of isolated products. [b] Molecular sieves (4 ꢀ) were added.
[c] One drop of water was added.[d] Reaction carried out in toluene.
DME=1,2-dimethoxyethane, Ts=p-toluenesulfonyl.
another strategy using a carbonyl linker (see below and
Scheme 3b).
Reactions of terminal-alkyne-bearing substrates pro-
ceeded with very different regioselectivity, in accordance
with previous reports on the Pt- and Hg-catalyzed var-
iants.[10,12d] Under the optimized cyclization conditions for the
gold-catalyzed variant, the terminal-alkyne-substituted sub-
strates 1m, 1n, and 1o with nitrogen, oxygen, or carbon
tethers can also undergo intramolecular a-alkenylation to
generate six-membered-ring products 2m, 2n, and 2o in
moderate yields through the 6-exo-dig pathway (Scheme 2).
To understand how the substituents at the alkyne moiety
of the substrates affect the regiochemistry and to enable
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exclusively (Figure 2). These results are in good agreement
with our previous findings (Table 1 and Scheme 2). We
reasoned that the polarization of the triple bond, which is
induced by the terminal substituent, is a crucial factor in
determining the regioselectivity.[21] Natural population anal-
ysis (NPA) was performed to obtain the charges on the C1 and
C2 atoms of the gold–alkyne complexes (COMs) with differ-
ent substituents to evaluate which carbon is more electro-
philic and therefore more reactive towards nucleophilic
attack of the furan ring (Figure 2).[22] In the parent system
(R = H), the 3-furanylmethoxymethyl tether, which can be
regarded as a stronger p-donor than a hydrogen atom, leads
to a less negative (relatively more positive) charge on the
C2 atom (À0.008 e on C2 vs. À0.264 e on C1), resulting in
a preference for exo-selective cyclization in a Markovnikov
manner. With internal alkynes, electron-donating R groups,
such as Me and Ph, show stronger electron-donating effects
than the tether, which makes the C1 atom more positively
charged than the C2 atom (Figure 2, inset), and therefore the
7-endo pathway becomes favored over the 6-exo pathway.[23]
The mechanistic insights obtained by the DFT calcula-
tions suggest that the regioselectivity of the a-alkenylation
reaction could be reversed with electron-withdrawing groups
as the terminal substituents. Electron-withdrawing groups
would induce a charge on the C2 atom that is more positive
than that of the C1 atom (0.014 e on C2 vs. À0.122 e on C1 for
R = CO2Me), so that formation of the six-membered ring is
favored. This can explain why fused cyclohexafurans were
obtained with ketone-substituted b-yne-furans under gold
catalysis in the total synthesis of crassifolone by Menon and
Banwell.[16d] However, the stereochemistry of such a cycliza-
tion reaction has not been studied in depth. We speculated
that ester-substituted b-yne-furan substrates could also give
fused cyclohexafurans under gold catalysis. Calculations
supported this hypothesis, showing that the exo pathway is
favored by 2.9 kcalmolÀ1 when R = CO2Me (Figure 2). When
we treated the ynoate ester substrates 1p and 1q with gold
catalyst 4, we were excited to isolate the computationally
predicted six-membered-ring products 2p and 2q as single
isomers with Z configuration in good yields (Scheme 3a).[24]
Scheme 2. Gold-catalyzed exo-selective intramolecular a-alkenylation
with terminal alkynes.
further exploration of the a-alkenylation strategy by mech-
anistic insights, we performed preliminary DFT calcula-
tions[18] using the B3LYP functional (for details, see the
Supporting Information). We propose that the cyclization
reaction begins with coordination of the alkyne to the cationic
AuL+ center, which generates the gold–alkyne complex
COM. Then, 7-endo-dig cyclization or nonclassical cyclo-
propanation[19] gives the homoallylic carbocation INT1,
which then undergoes water-assisted proton transfer to form
the bicyclic product P1. Alternatively, the 6-exo-dig pathway
may also occur, which would give P2. Therefore, the
formation of P1 or P2 depends on the relative energies of
the alkenylation transition states TS1 and TS2 (Figure 2).
DFT calculations suggest that the exo pathway is favored
by 2.3 kcalmolÀ1 for the parent substrate (R = H) with
Au(PMe3)+ as the catalyst, which implies that the fused
cyclohexafuran product will predominantly be generated
(Figure 2).[20] With R = Me and R = Ph, the endo pathway is
favored by 3.1 and 4.8 kcalmolÀ1, respectively, which suggests
that the fused cycloheptafuran products will be generated
Figure 2. DFT-calculated free energy surface of the two competing a-
alkenylation pathways calculated at the B3LYP/SDD-6-31G(d) level of
theory. P.T.=proton transfer.
Scheme 3. Further exploration of the substrate scope. Bn=benzyl.
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Furthermore, when electron-withdrawing groups were
introduced at the proximal end instead of at the distal end of
the triple bond, the 6-exo cyclization pathway would be
disfavored owing to the polarization induced by the carbonyl
linker. Pleasingly, the challenging seven-membered carbo-
cycles could indeed be synthesized with this method. When
the ynone substrates 1r and 1s were subjected to the standard
reaction conditions (Scheme 3b), the corresponding seven-
membered carbocycles 2r and 2s were formed in good
yields.[25]
Finally, we tested the influence of the tether length. Only
a substrate with an elongated tether that bears a terminal
alkyne (1t) gave the fused cycloheptafuran 2t through 7-exo
cyclization (Scheme 3c). Substrates with internal alkynes did
not react or gave hydration products (see the Supporting
Information for details).
In summary, a novel and efficient gold-catalyzed endo-
selective intramolecular a-alkenylation of furans has been
developed to synthesize challenging seven-membered-ring-
fused furans in good to excellent yields under very mild
conditions. Six-membered-ring-fused furans can also be
obtained through the a-alkenylation strategy through exo-
selective cyclization for substrates with terminal alkynes.
Preliminary DFT calculations have been carried out to
understand the experimentally observed regioselectivity.
Further applications of this reaction are currently developed.
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Hashmi, J. P. Weyrauch, E. Kurpejovic, T. M. Frost, B. Miehlich,
Received: August 8, 2013
Revised: September 30, 2013
Published online: November 19, 2013
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Keywords: alkenylations · density functional calculations ·
.
furans · fused-ring systems · gold catalysis
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[20] The effects of the JohnPhos ligand and the solvent were also
studied by DFT calculations, and the results obtained are very
similar to those shown in Figure 2. For details, see the Supporting
Information.
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[17] DFT calculations suggest that the CH2-tethered substrate 1k is
less reactive than the oxygen-tethered substrate 1j by about
1 kcalmolÀ1 (see the Supporting Information for details). We
speculate that some unknown side reactions may become
favored over the alkenylation reaction for the carbon-tethered
substrates. Consequently, these side reactions could lead to the
decomposition of these substrates. To increase the electro-
philicity of the gold-coordinated alkyne moiety, a carbonyl group
was introduced next to the triple bond; in this case, the
alkenylation of C-tethered substrates can be realized (Sche-
me 3b).
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[23] Analysis of charges can be easily understood by chemists;
however, it is not the only approach to explain the regioselec-
tivity of a nucleophilic addition. For in-depth analyses of the
effects of the substituents on the observed regioselectivity, see
the Supporting Information.
[24] In a similar reaction with the ynoate ester 1p that was reported
by Yamamoto et al. (Ref. [16c]), the E isomer was observed in
24% yield under Pd catalysis. Substrate 1q (Ref. [16a,b]) gave
a 1:1 mixture of the Z and E isomers using PtCl4. The Z isomer
2q can be obtained in 29% yield using PtCl2 as the catalyst.
[25] When AlCl3 was used as the catalyst, substrate 1r decomposed,
and the desired product 2r was not observed. We also found that
ynone substrates with a hydrogen atom or a trimethylsilyl group
at the terminal position decomposed quickly under the standard
reaction conditions. For details, see the Supporting Information.
[18] Gaussian09, RevisionA.02, M. J. Frisch, et al. Gaussion, Inc.,
Wallingford CT, 2009, see the Supporting Information.
Angew. Chem. Int. Ed. 2013, 52, 14157 –14161
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 14161