Efficient generation of an oxidopyrylium ylide using a Pd catalyst and its [5+2] cycloadditions with several dipolarophiles

Article abstract of DOI:10.1039/c7cc09552j

An efficient method for the generation of an oxidopyrylium ylide from 6-acetoxy-6-acetoxymethyl-2H-pyran-3(6H)-one using a Pd catalyst and [5+2] cycloadditions of the resulting ylide are described. Among substituted styrene derivatives as dipolarophiles, electron-rich styrenes showed higher yield (up to 80%). The [5+2] cycloaddition reactions can also be applied to exo-methylene cyclic compounds, and an improved method for the synthesis of polygalolide intermediate has been demonstrated.

Full text of DOI:10.1039/c7cc09552j

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Efficient generation of an oxidopyrylium ylide
using a Pd catalyst and its [5+2] cycloadditions
with several dipolarophiles†
Cite this:DOI: 10.1039/c7cc09552j
Received 13th December 2017,
Accepted 5th January 2018
Hiroyuki Suga, * Taichi Iwai, Masahiro Shimizu, Kie Takahashi and
Yasunori Toda
DOI: 10.1039/c7cc09552j
rsc.li/chemcomm
An efficient method for the generation of an oxidopyrylium ylide
from 6-acetoxy-6-acetoxymethyl-2H-pyran-3(6H)-one using a Pd
catalyst and [5+2] cycloadditions of the resulting ylide are
described. Among substituted styrene derivatives as dipolarophiles,
electron-rich styrenes showed higher yield (up to 80%). The [5+2]
cycloaddition reactions can also be applied to exo-methylene
cyclic compounds, and an improved method for the synthesis of
polygalolide intermediate has been demonstrated.
A number of natural products containing an 8-oxabicyclo[3.2.1]-
octane skeleton, such as englerins,1 intricarene,2 anthecularin,3
polygalolides,4 descurainin,5 and cartorimine,6 are biologically
and medicinally important compounds (Fig. 1). In addition to
being a common structural motif in numerous natural products,
the [3.2.1]oxabicyclic ring system has also been shown to be a
versatile intermediate for transformation to functionalized seven-
membered carbon skeletons.7 The [5+2] cycloaddition between
oxidopyrylium ylides and alkenes is one of the best synthetic
approaches to the 8-oxabicyclo[3.2.1]octane scaffold.8 In fact,
these [5+2] cycloadditions were used for the construction of
[3.2.1]oxabicyclic rings as the key step in the syntheses of
englerins A and B,9 polygalolides A and B,10 descurainin,11 and
cartorimine11 (Fig. 1).12 Typically, oxidopyrylium ylides are
generated from 2H-pyran-3(6H)-one derivatives by thermal,
base-promoted, or acid-mediated elimination (Fig. 2, classical
method).8,13,14 However, depending on the substitution pattern
of the precursors such as 6-acetoxy-6-acetoxymethyl-2H-pyran-
Fig. 1 The oxidopyrylium ylide [5+2] cycloadditions for syntheses of
selected natural products containing an 8-oxabicyclo[3.2.1]octane skeleton.
3(6H)-one (1), low yields of the cycloadducts can be problematic Indeed, it has been known that [3+2] trimethylenemethane
for the practical synthesis of the [3.2.1]oxabicyclic core. To cycloaddition reactions are catalyzed by Pd(0) species effectively,
overcome this issue, we hypothesized that Pd catalysis would in which 3-acetoxy-2-trimethylsilylmethyl-1-propene undergoes
enable efficient generation of the oxidopyrylium ylides through oxidative addition to form the p-allyl intermediate.16,17 Thus, we
the formation of a p-allyl palladium species15 followed by expected that p-allyl formation by a Pd catalyst may facilitate
deprotonation with a base (Fig. 2, a novel Pd-catalyzed method). deprotonation by enhancing the acidity of the carbonyl a-proton.
Furthermore, the catalytic generation under mild conditions
would enable evaluation of the reactivity of dipolarophiles toward
Department of Materials Chemistry, Faculty of Engineering, Shinshu University,
oxidopyrylium ylides based on their electronic properties. Herein,
Wakasato, Nagano 380-8553, Japan. E-mail: sugahio@shinshu-u.ac.jp
we report that the addition of a catalytic amount of [Pd(Z3-
† Electronic supplementary information (ESI) available: Experimental details,
spectral data, and copies of NMR charts. See DOI: 10.1039/c7cc09552j
C3H5)Cl]2 in the presence of i-Pr2NEt was found to be effective
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products (entries 5 and 6). The use of Pd2(dba)3 (5 mol%)
shortened the reaction time to 5 h for 100% conversion,
affording 16% (NMR yield) of cycloadducts 3a, albeit with
33% (NMR yield) of dimer 4 (entry 7). The Pd2(dba)3-catalyzed
reaction in the presence of 5.0 equiv. of 2a resulted in 26% yield
of 3a and 29% yield of 4 (entry 8). Finally, [Pd(Z3-C3H5)Cl]2 was
found to be the most suitable catalyst to obtain the highest
yield of 3a among the Pd catalysts tested (entries 9–12). After
investigation of catalyst loading and reaction temperature, the
conditions shown in entry 12 (10 mol% [Pd(Z3-C3H5)Cl]2 at
35 1C) led to the best result [3a: 71% (isolated); 4: 13% yield],
which indicates that at least 84% of the corresponding oxido-
pyrylium ylide was generated.19
Fig. 2 Our novel Pd-catalyzed method vs. classical method.
With the optimized conditions in hand, the substrate scope
of several electron-deficient and electron-rich styrene derivatives
was investigated (Scheme 1a). The reactions with styrenes 2b–2d
possessing electron-withdrawing substituents at the para-
position resulted in lower yields (3b–3d: 53–69%) compared
with that of styrene (71%), with the formation of dimer 4 in
12–16% yields. In contrast, electron-rich styrenes 2e–2i afforded
higher yields (3e–3i: 75–80%), especially in the case of o- or
p-methoxy substituted styrenes, where the dimer formation was
for the efficient generation of an oxidopyrylium ylide from
2H-pyran-3(6H)-one 1.
Initially, the reaction of 2H-pyran-3(6H)-one 1 with styrene
(2a: 2.0 or 5.0 equiv.) as a model reaction was carried out in the
presence of i-Pr2NEt (1.0 equiv.) in CH2Cl2 (Table 1).18 In the
absence of a Pd catalyst, low conversion (10–41%) of starting
material 1 was observed even at 100 1C in toluene (entries 1–3).
The addition of PdCl2 (10 mol%) in CH2Cl2 (0.063 M) at 25 1C
using 2.0 equiv. of 2a resulted in 100% conversion of 1 in 16 h,
and [5+2] cycloadducts 3a were obtained in 24% NMR yield
(endo/exo = 80 : 20) along with 15% NMR yield of by-product 4,
which corresponds to the dimer of the oxidopyrylium ylide
(entry 4). PdCl2/PPh3 or Pd(PPh3)4 did not show satisfactory
results in terms of the yield of the desired cycloaddition
Table 1 Optimization of reactions of 2H-pyran-3(6H)-one 1 with styrene
(2a)a
Pd-Catalyst
(mol%)
Temp
(1C)
Time
(h)
Conv.
(%)
Yield (%) of 3a
(endo/exo)b,f
Entry
1
2
3
None
None
None
PdCl2 (10)
PdCl2/PPh3 (10)
Pd(PPh3)4 (10)
Pd2(dba)3 (5)
Pd2(dba)3 (5)
25
35
100
25
25
25
25
25
25
25
35
35
16
16
16
16
16
16
5
10
25
41
8 (81 : 19)
16c (82 : 18)
36c (78 : 22)
24c (80 : 20)
27c (79 : 21)
0c
4d
5d
6d
7d
8
100
100
100
100
100
100
100
100
100
16c (84 : 16)
26 (81 : 19)
68 (79 : 21)
65 (80 : 20)
60 (82 : 18)
71 (81 : 19)
3
e
9
[Pd(al)Cl]2e (5)
72
42
24
20
10
11
12
[Pd(al)Cl]2e (10)
[Pd(al)Cl]2e (5)
[Pd(al)Cl]2 (10)
a
The reaction of 2H-pyran-3(6H)-one 1 (0.063 M) with styrene (5.0 equiv.) was
carried out in the presence of i-Pr2NEt (1.0 equiv.) in CH2Cl2. b Combined
yield (isolated). The selectivity (endo/exo) was determined by 1H NMR analysis.
c Determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal
standard. d 2.0 equiv. of 2a. e [Pd(Z3-C3H5)Cl]2. f Yield of 4 (%); entry 2: trace,
entry 4: 15%, entry 5: 25%, entry 7: 33%, entry 8: 29%, entry 9: trace, entry 10:
10%, entry 11: 8%, entry 12: 13%.
Scheme 1 Pd-Catalyzed [5+2] cycloadditions of styrenes, vinyl ethers,
and electron-deficient alkenes with the oxidopyrylium ylide generated
from 2H-pyran-3(6H)-one 1.
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minimized as expected (see the ESI†). To investigate the scope of
electron-rich alkenes further, we selected n-propyl vinyl ether
(5a) as a candidate for the dipolarophile. Although additional
optimization of reaction conditions was required to suppress
the production of dimer 4 (see the ESI† for details), the optimal
yield (6a: 71%, endo only) was obtained using 0.2 equiv. of
i-Pr2NEt at a concentration of 0.13 M at 35 1C (Scheme 1b).
Ethyl, cyclohexyl, and t-butyl vinyl ethers 5b–5d also provided
only endo-cycloadducts 6b–6d in good yields (60–76%, Scheme 1b)
under the same conditions. On the other hand, the Pd-catalyzed
reactions with electron-deficient alkenes such as acrylic acid
derivatives 7a and 7b and N-phenylmaleimide (7c) proceeded
smoothly to give cycloadducts 8a–8c in moderate yields
(62–65%, Scheme 1c). It is noteworthy that the employment of
exo-methylene cyclic compounds 9a–9e as dipolarophiles in the
cycloaddition reactions resulted in mostly good to high yields of
cycloadducts (10a–10e: 61–88%), probably due to their relatively
high reactivity as dipolarophiles on the basis of the exo-methylene
structure (Scheme 2).
Conversion of cycloadduct 10c to polygalolide intermediate
11 was accomplished according to the modified Snider’s
method (Scheme 3).10 Treatment of 10c with Cs2CO3 in a 1 : 1
mixture of THF/H2O solvents at 35 1C for 14 h, followed by
acidification with 10% hydrochloric acid to pH 1 furnished 11
in 76% yield over the two steps. The synthetic method of
polygalolides A and B from 11 has already been reported by
Nakamura and Hashimoto.20 The overall yield from 1 to 11
(54%) was improved by the sequence of Pd-catalyzed [5+2]
cycloaddition, hydrolysis, and intramolecular cyclization.
Finally, to gain insight into the mechanism of Pd catalysis
for the generation of the oxidopyrylium ylide, control experiments
using Pd2(dba)3 (10 mol%) in the absence and presence of i-Pr2NEt
(1.0 equiv.) were conducted and compared with the conditions of
the non-catalytic reaction shown in entry 2 of Table 1 (Scheme 4).21
Scheme 4 Mechanistic studies: control experiments using Pd2(dba)3 in
the absence and presence of i-Pr2NEt.
In the presence of Pd2(dba)3 and i-Pr2NEt, cycloadducts 3a (24%)
and dimer 4 (29%) were obtained along with 2-pyranone 12 (6%),
whereas only 2-pyranone 12 (72%) was afforded with the use of
Pd2(dba)3 in the absence of i-Pr2NEt, albeit with 100% conversion
of 1a in both cases. Based on these results, we propose a plausible
mechanism for this [5+2] cycloaddition as follows. (a) The initial
reaction of 2H-pyran-3(6H)-one 1 with the Pd(0) species, which
could also be generated from [Pd(Z3-C3H5)Cl]2 and i-Pr2NEt,
produces the p-allyl palladium intermediate.15,22 (b) In the presence
of i-Pr2NEt, the oxidopyrylium ylide is generated by deprotonation of
the carbonyl a-proton of the p-allyl intermediate, wherein the Pd(0)
species is regenerated along with formation of i-Pr2NEtÁHOAc.
(c) The oxidopyrylium ylide reacts not only with dipolarophiles
to afford cycloadducts but also with itself to afford a certain
amount of dimer 4 depending on the reaction conditions. Since
only b-elimination proceeds in the absence of i-Pr2NEt and the
combined use of a Pd catalyst and base obviously accelerates the
cycloaddition, the transient p-allyl species seems to undergo
deprotonation by i-Pr2NEt more effectively than starting material 1.
In conclusion, we have demonstrated the productive generation
of an oxidopyrylium ylide from 6-acetoxy-6-acetoxymethyl-2H-pyran-
3(6H)-one (1) through Pd catalysis. A variety of dipolarophiles,
including styrenes, vinyl ethers, and exo-methylene cyclic com-
pounds, were tolerated to afford the cycloadducts in good to high
yields. Conversion of the a-methylene-g-butyrolactone cycloadduct
to the polygalolide intermediate was also accomplished in an
acceptable total yield (54%). Further studies for efficient generation
methods and synthetic applications of oxidopyrylium ylide cyclo-
additions are currently underway in our laboratory.
This work was supported in part by the Japan Society for the
Promotion of Science (JSPS) through a Grant-in-Aid for Scientific
Research (C) (No. JP15K05497).
Conflicts of interest
Scheme 2 Pd-Catalyzed [5+2] cycloadditions of exo-methylene cyclic
There are no conflicts to declare.
compounds.
Notes and references
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Scheme 3 Conversion of cycloadduct 10c to polygalolide intermediate 11.
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