Regiodivergent Hydration-Cyclization of Diynones under Gold Catalysis

Article abstract of DOI:10.1021/acs.orglett.0c02892

Skipped diynones, efficiently prepared from biomass-derived ethyl lactate, undergo a tandem hydration-oxacyclization reaction under gold(I) catalysis. Reaction conditions have been developed for a switchable process that allows selective access to 4-pyrones or 3(2H)-furanones from the same starting diynones. Further application of this methodology in the total synthesis of polyporapyranone B was demonstrated.

Full text of DOI:10.1021/acs.orglett.0c02892

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Letter
Regiodivergent Hydration−Cyclization of Diynones under Gold
Catalysis
́
̃
Marta Solas, Miguel A. Munoz, Samuel Suarez-Pantiga, and Roberto Sanz*
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ABSTRACT: Skipped diynones, efficiently prepared from biomass-derived ethyl lactate, undergo a tandem hydration−
oxacyclization reaction under gold(I) catalysis. Reaction conditions have been developed for a switchable process that allows
selective access to 4-pyrones or 3(2H)-furanones from the same starting diynones. Further application of this methodology in the
total synthesis of polyporapyranone B was demonstrated.
ecause of the availability and renewability of biomass-
Bderived chemicals, the development of useful synthetic
organic procedures that employ eco-friendly and sustainable
feedstocks represents a major challenge in current chemistry.1
For example, ethyl lactate (EL) has demonstrated great
potential as a green solvent and building block for the
preparation of value-added products.2 In this field, we have
recently reported the synthesis of symmetric 1,4-diyn-3-ones 2
by the oxidative cleavage of the corresponding 1,2-diols 1 using
EL as a carbonyl source (Scheme 1, eq 1).3 These skipped
diynones 2 are interesting functionalized molecules that
possess a wide variety of synthetic applications.4
On the other hand, oxygenated heterocycles, such as γ-
pyrones and 3(2H)-furanones, are interesting compounds as
well as intermediates for the preparation of other products with
relevant biological activities. The 4-pyrone ring occurs in many
therapeutic agents and bioactive molecules.5 In the same way,
several natural products that possess antibiotic and antitumoral
properties present the 3(2H)-furanone core as a key structure.6
Thus, the synthesis of these heterocyclic frameworks has
attracted considerable attention in recent years, and so many γ-
pyrone and 3(2H)-furanone derivatives and their synthetic
methods have been disclosed in the literature, traditionally
related with condensation cyclization reactions of carbonyl
compounds typically involving multistep sequences or limited
scope.7 More recently, different strategies based on transition-
metal-catalyzed cyclizations have been reported.8 However,
one of the simplest and most atom-economical approaches
involves the hydration/cyclization of diynones or the
cyclization of acetylenic β-diketones. The first one has been
developed by different authors toward the synthesis of 4-
pyrones using Brønsted acids, such as triflic9 acid or p-
toluenesulfonic acid,10 as catalysts (Scheme 1, eq 2).
Nevertheless, this useful reaction suffers from moderate yields
when the substituent of the alkyne is an alkyl group or a
hydrogen atom, and no examples have been reported with
alkenyl groups as substituents. Using 4-pentyn-1,3-diones as
starting materials, which are synthesized from ynals and silyl
enol ethers in two steps, their cyclization provides mixtures of
3(2H)-furanones, via 5-exo, and γ-pyrones, via 6-endo. The
latter alternative is the most favorable pathway with an
additional influence of the alkyne substituent (Scheme 1, eq
3).11 Both approaches face a critical challenge: the regiocontrol
of the cyclization: 5-exo vs 6-endo. This regiochemistry affair in
cyclization reactions is relatively general allowing, in an ideal
situation, the access of two different scaffolds from the same
starting material.12
Taking advantage of our efficient procedure for accessing
diynones 2,3 as well as from our experience in gold
chemistry,13 we planned to tackle their selective transformation
in the corresponding 4-pyrones 3 and 3(2H)-furanones 4 by
an hydration−cyclization sequence catalyzed by gold com-
plexes (Scheme 1, eq 5). However, a 1,3-transposition of
skipped diynones 2 to the corresponding conjugated isomers 5
has been reported by Gevorgyan et al., thus adding an
additional competitive pathway to our initial proposal (Scheme
1, eq 4).14 Also in this field, the hydration of ynones to 1,3-
diketones has been reported.15 Herein, we report the gold(I)-
Received: August 28, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02892
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Scheme 1. Previous Work and Proposed Hydration−
Cyclization of Skipped Diynones
Table 1. Optimization of the Reaction Conditions for the
Hydration−Cyclization of 2a
a
time
b
ent.
catalyst
Ph3PAuNTf2
(h)
products (yield, %)
3a/4a
c
1
3
3a (11) + 4a (64) +
5a (7)
1/5.8
2
3
4
Ph3PAuCl/AgOTf
Ph3PAuCl/AgNTf2
5
5
3a (7) + 4a (71) +
5a (5)
3a (8) + 4a (65) +
5a (7)
3a (4) + 4a (78)
3a (8) + 4a (53) +
5a (10)
1/9.6
1/8.4
Ph3PAuCl/AgSbF6
Ph3PAuCl/AgSbF6
5
6
1/19
1/6.6
d
5
6
7
8
9
10
(t-Bu)3PAuCl/AgSbF6
(C6F5)3PAuCl/AgSbF6
AgSbF6
SPhosAuNTf2
JohnPhosAu(MeCN)
SbF6
XPhosAuNTf2
IPrAuNTf2
IPrAuCl/AgNTf2
5
5
8
3
5
3a (11) + 4a (69)
3a (30) + 4a (52)
3a (12) + 4a (18)
3a (56) + 4a (29)
3a (60) + 4a (25)
1/6.3
1/1.7
1/1.5
1.9/1
2.4/1
e
f
11
12
13
3
1
5
3a (67) + 4a (11)
3a (73) + 4a (8)
3a (58) + 4a (26)
6/1
9/1
2.2/1
f
a
Reaction conditions: H2O (1 mL) was added to the catalyst (5 mol
%) in dioxane (1 mL) and submerged into an oil bath at 100 °C, then
2a (0.2 mmol) in dioxane (1 mL) was added and the mixture stirred
b
1
catalyzed pathway-switchable tandem hydration-oxacyclization
to 4-pyranones and 3(2H)-furanones from skipped diynones.16
We selected symmetric diynone 2a as a model substrate for
attempting the proposed hydration−cyclization reaction. After
having assayed a variety of Lewis acids, we found that only
gold(I) complexes17 possess significant activity for the planned
sequence using dioxane as solvent.18 Gagosz’s catalyst,19
Ph3PAuNTf2, led to a ca. 1/6 mixture of the oxacyclic
products 3a and 4a, along with the rearranged conjugated
diynone 5a, which was the only compound at rt (Table 1, entry
1). The effect of the presence of silver was then tested (entries
2−4),20 observing a positive effect on the regioselectivity of the
process in favor of 4a. Moreover, the counterion of the gold
complex also had a significant effect on the 3a/4a ratio,
at 100 °C for the specified time. Determined by H NMR analysis
c
using 1,3,5-trimethoxybenzene as internal standard. At rt for 24 h,
d
only 5a was obtained with 50% conversion. H2O (0.1 mL instead 1
e
f
mL). 31% conversion. At rt for 16 h the major compound was 5a
(∼50%).
diynones 2, which provides a variety of 4-pyrones 3 in high
yields. Diynones bearing aryl substituents with either electron-
donating groups or electron-withdrawing groups (entries 2−5)
led to the corresponding 4-pyrones 3b−e with even higher
regioselectivity compared with model 2a (entry 1). A
heteroaromatic group is also suitable, although a slightly
lower regioselectivity was observed (entry 6). Changing to
(cyclo)alkyl-substituted diynones 2h−j, the corresponding
pyrones 3h−j were also efficiently obtained with an almost
complete selectivity (entries 7−9). Interestingly, alkenyl
substituents were also well-tolerated, allowing access to 4-
pyrones 3k,l with excellent regioselectivity (entries 10 and 11).
It is worthy to note that 3k could not be prepared by any of the
reported Brønsted acid catalyzed methods.21 Finally, we also
expand successfully the scope of this reaction to diynones 2m,n
bearing additional functional groups on the alkyne substituent
(entries 12 and 13).
Having evaluated the synthesis of 4-pyrones 3 from diynones
2, we decided to explore the scope of the process to gain access
to the isomeric 3(2H)-furanones 4 (Table 3). By using the
catalytic conditions established in the optimization study
(Table 1, entry 4), a variety of furanones 4a−g possessing
(hetero)aromatic groups were synthesized in high yields
(entries 1−7). In contrast to (hetero)aryl-substituted diynones
2a−g, the presence of linear aliphatic or cyclopropyl-
substituted alkynes greatly influences the regioselectivity of
−
resulting that SbF6 provided an almost complete selectivity
toward 4a (entry 4). Not unexpectedly, decreasing the amount
of water led to the competitive formation of conjugated
diynone 5a (entry 5). Other phosphines were tested, although
lower regioselectivities were observed (entries 6 and 7). Silver
salts, on their own, did not provide satisfactory results (entry
8). Interestingly, a switch to bulkier phosphine ligands caused a
change in the regioselectivity of the cyclization leading to the
major formation of 3a (entries 9−11). Looking for an even
more successful switch of the regioselectivity, we gratifyingly
found that the use of IPrAuNTf2, bearing a bulky NHC ligand,
gave rise to 3a with a higher regioselectivity in a shorter
reaction time (entry 12). In this case, the presence of silver led
to a significant decrease in the regioselectivity (entry 13).
With the optimal reaction conditions in hand for both
regiodivergent cyclizations, we investigated the scope of the
gold-catalyzed formation of 4-pyrones 3. Table 2 shows the
results obtained in the hydration−cyclization of a selection of
B
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Letter
a
Table 2. Synthesis of 4-Pyrones 3
b
c
entry
diynone
R
3/4
product
yield (%)
d
1
2
3
4
5
6
7
8
9
10
11
12
13
2a
2b
2c
2d
2e
2f
2h
2i
2j
2k
2l
2m
2n
Ph
p-Tol
4-MeOC6H4
3-MeOC6H4
4-FC6H4
3-Th
n-Bu
c-C3H5
(CH2)2Ph
c-C6H9
9/1
10/1
12/1
>20/1
10/1
3a
3b
3c
3d
3e
3f
3h
3i
3j
73 (78)
81
83
78
79
70
81
80
86
67
74
65
70
e
f
5/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
g
3k
3l
3m
C(CH3)=CH2
CH2O(4-MeOC6H4)
CH2O[3,5-(MeO)2C6H3]
3n
a
b
Reaction conditions: 2 (0.5 mmol), IPrAuNTf2 (5 mol %), H2O (1 mL) in dioxane (2 mL) at 100 °C for 1 h. Determined by 1H NMR analysis
c
d
e
f
of the crude mixture. Isolated yield after column chromatography. Reaction carried out at 4 mmol scale. 10 mol % of catalyst was used. 3-
Thienyl. Cyclohexen-1-yl.
g
a
Table 3. Synthesis of 3(2H)-Furanones 4
Scheme 2. Mechanistic Investigation and Proposal
b
c
entry
diynone
R
4/3
product
yield (%)
d
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
p-Tol
4-MeOC6H4
3-MeOC6H4
4-FC6H4
3-Th
2-Th
n-Bu
c-C3H5
18/1
11/1
>20/1
>20/1
10/1
18/1
18/1
1/1.5
1/2.5
4a
4b
4c
4d
4e
4f
4g
4h
4i
80 (79)
77
81
79
70
79
74
35
26
e
f
g
h
8
9
h
a
Reaction conditions: 2 (0.5 mmol), Ph3PAuCl/AgSbF6 (5 mol %),
b
H2O (1 mL) in dioxane (2 mL) at 100 °C for 5 h. Determined by
c
1H NMR analysis of the crude mixture. Isolated yield after column
d
e
chromatography. Reaction carried out at 4 mmol scale. 10 mol % of
catalyst was used. 3-Thienyl. 2-Thienyl. Reaction time: 8 h.
f
g
h
the process.22 Diynones 2h,i gave rise to mixtures of 3 and 4,
with ratios in favor of the products 3, though the furanones
4h,i could even be isolated in low to moderate yields (entries 8
and 9).
To gain some insight into the plausible mechanism, some
control experiments were carried out. Using D2O instead of
H2O, dideuterated 3a-D2 and 4a-D2 were obtained under the
respective standard conditions with almost complete deute-
rium incorporation (Scheme 2, eq 1). We prepared known
alkynyl-1,3-diketone 6a23 and submitted it to both of the gold-
catalyzed oxacyclization conditions in the presence and in the
absence of water. Surprisingly, 3a was selectively generated
with the two gold catalytic systems, with a slight influence of
the presence of water on the regioselectivity (Scheme 2, eq
2).24 Next, alkynyl-1,2-diketone 7a25 was treated under two
different gold-catalyzed conditions leading exclusively to
furanone 4a (Scheme 2, eq 3). So, both diketones 6 and 7,
or their tautomers 6′ and 7′, seem to be plausible
intermediates. Next, the role of the catalyst was evaluated.
Xu, Hammond, and co-workers26 have pointed that
Ph3PAuOTf complex is unstable, causing disproportionation
into Au(0), Au(III), and OPPh3, being accelerated at higher
temperatures. Based on these findings, it is conceivable that
under the described reaction conditions, this process could
take place, affording Au(0) clusters or nanoparticles that may
be responsible for the differential reactivity leading to the
formation of furanones 4, whereas more stable catalysts27 such
C
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Table 4. Oxacyclization of Unsymmetrical Diynones 8
a
b
b
entry
1
2
8
R1
R2
products
9/10 + 10′
10/10′
1/0
8a
8a
8b
8c
8d
8e
8e
Ph
Ph
Ph
Ph
n-Bu
n-Bu
9a (35) + 10a (42)
9a (82)
9b (37) + 10b (35)
10c (71)
9d (8) + 10d (72)
9e (74)
1/1.25
>20/1
1/1.1
1/20
1/10
c
3
4
5
6
c-C3H5
4-MeOC6H4
4-MeOC6H4
14/1
3/1
4/1
4-FC6H4
Ph
H
H
>20/1
>20/1
c
7
Ph
9e (76)
a
b
1
The isolated yield for each compound after column chromatography is shown in parentheses. Determined by H NMR analysis of the crude
c
mixture. Carried out with IPrAuNTf2 for 1 h (8a) and 5 h (8e).
as IPrAu+ favor the formation of pyrones 3. When Ph3PAuCl/
AgSbF6 was heated at 100 °C in dioxane/water mixtures,
considerable amounts of OPPh3 were observed from the crude
by 31P NMR analysis, which could suggest the formation of
Au(0) species.18 Additionally, the higher stabilization of the
was undertaken (Scheme 3). Rukachaisirikul and co-workers
isolated this pyrone derivative from two seagrass-derived fungi
Scheme 3. Synthesis of Polyporapyranone B
gold complex provided by the NTf2 counteranion26 over
−
−
SbF6 also explains the lower ratio 3/4 observed (Table 1,
entries 3 vs 4).
Thus, our mechanistic proposal involves a key initial
gold(I)-catalyzed hydration of ynone moiety that would lead
to 6′ or 7′ depending on the Michael or anti-Michael addition
pathway (Scheme 2, eq 4). Then an intramolecular
oxacylization would take place, giving rise to six- or five-
membered O-heterocycles A and B, depending on the diketone
intermediate. Lastly, protodeauration affords the final com-
pounds 3 and 4 recovering the catalytic species. Thus, our
results indicate that the regiocontrol of the process is
determined by the initial hydration reaction instead of by a
more intuitive 6-endo vs 5-exo oxacyclization from a common
intermediate 6′.
Polyporales, and it is a rare example of naturally occurring 2-
substituted γ-pyrones.29 Our synthetic route involves the
preparation of asymmetric diynone 8f, which was accessed
from commercially available 2,4-dimethoxyiodobenzene in an
overall, though nonoptimized, 40% yield, through standard
reactions: (a) Sonogashira coupling with propargylic alcohol;
(b) oxidation; (c) addition of ethynylmagnesium bromide, and
(d) oxidation.18 The key gold-catalyzed oxacyclization of 8f
proceeds efficiently under our established conditions leading to
γ-pyrone 11 in high yield (Scheme 3).
Finally, products 3 or 4 can be readily prepared on gram
scale,18 enabling further transformations as shown in Scheme
4. First, treatment of pyrone 3b with a Grignard reagent and
subsequent addition of HBF4 led to the pyrylium salt 12. This
type of compound has been demonstrated as a useful organic
At this point, starting skipped diynones 8 bearing two
different alkyne units were also evaluated under the conditions
favoring the furanone formation (Table 4).28 Initially, diynones
8a,b possessing an aryl- and a (cyclo)alkyl-substituted alkyne
were used, giving rise to ∼1/1 mixtures of the corresponding
pyrones 9 and furanones 10 (entries 1 and 3). In both cases,
the furanone derivative obtained possesses a benzylidene
moiety. These results seem to indicate that the initial hydration
takes place over the two alkynes in a similar extension, but in a
Michael mode on the alkyl-substituted alkyne and in an anti-
Michael way onto the aryl-substituted one. Upon employing
unsymmetrical diynones 8c,d, bearing two different aryl-
substituted alkyne moieties, the furanone formation was, not
unexpectedly, favored (entries 4 and 5). In these cases,
although two regioisomeric furanones (10 and 10′) can be
formed, the one derived from an initial anti-Michael hydration
of the more electron-poor alkyne moiety is favored. Finally, an
unsymmetrical diynone 8e bearing a terminal alkyne was
studied. With this substrate both catalytic conditions led to the
same result, the selective formation of 4-pyrone 9e (entries 6
and 7), thus suggesting a favored initial Michael addition of
water onto the terminal alkyne.
Scheme 4. Synthetic Applications of Selected 4-Pyranone 3b
and Furanones 4a,b
Additionally, the first total synthesis of polyporapyranone B
(11) employing the reaction reported herein as the key step
D
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photoredox catalyst.30 Meanwhile, furanones such as 4a,b react
with N-nucleophilic reagents leading to functionalized N-
heterocycles such as 5-hydroxy-2-pyrrolin-4-one 1331 and 4,5-
dihydroisoxazoles 1432 (Scheme 4).
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02892.
Full experimental procedures, characterization data, and
copies of NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1b, 1d, 1e, 2b, 2d, 2e, 3a, 3a-d2, 3b−f, 3h−
n, 4a, 4a-d2, 4b−i, 6a, 7a, 8a−f, 9a, 9b, 9e, 10a−d, 11−
13, 14a, 14b, IIf, IIIf, IVa−f (ZIP)
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AUTHOR INFORMATION
■
Corresponding Author
́
́
́
Roberto Sanz − Area de Quımica Organica, Departamento de
́
Quımica, Facultad de Ciencias, Universidad de Burgos, 09001
Burgos, Spain; orcid.org/0000-0003-2830-0892;
Email: rsd@ubu.es
Authors
́
́
́
Marta Solas − Area de Quımica Organica, Departamento de
́
Quımica, Facultad de Ciencias, Universidad de Burgos, 09001
Burgos, Spain
́
́
́
Miguel A. Mun
̃
oz − Area de Quımica Organica, Departamento
́
de Quımica, Facultad de Ciencias, Universidad de Burgos,
09001 Burgos, Spain
́
́
́
́
Samuel Suarez-Pantiga − Area de Quımica Organica,
́
Departamento de Quımica, Facultad de Ciencias, Universidad
de Burgos, 09001 Burgos, Spain; orcid.org/0000-0002-
4249-7807
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02892
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
We gratefully acknowledge Ministerio de Ciencia e Innovacion
and FEDER (CTQ2016-75023-C2-1-P) and Junta de Castilla
́
y Leon and FEDER (BU291P18) for financial support. M.S.
́
́
and S.-S.-P. thank Junta de Castilla y Leon (Consejerıa de
́
Educacion) and Fondo Social Europeo for predoctoral and
postdoctoral contracts, respectively.
E
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