Rate-accelerating effect by the neighboring-group participation of protecting groups in the dehydrative cyclization of 1,3,5-triketones

Article abstract of DOI:10.1021/ol800860p

(Chemical Equation Presented) Neighboring-group participation of an acyl protecting group efficiently promotes the Bronsted acid-catalyzed dehydrative cyclization of 1,3,5-triketones to γ-pyrones, whereas a bulky silyloxy group in the β-position retards t

Full text of DOI:10.1021/ol800860p

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2569-2572
Rate-Accelerating Effect by the
Neighboring-Group Participation of
Protecting Groups in the Dehydrative
Cyclization of 1,3,5-Triketones
Akira Sakakura,† Hitoshi Watanabe,‡ and Kazuaki Ishihara*,‡
Graduate School of Engineering, Nagoya UniVersity, Chikusa, Nagoya, 464-8603 Japan,
and EcoTopia Science Institute, Nagoya UniVersity, Chikusa, Nagoya, 464-8603 Japan
ishihara@cc.nagoya-u.ac.jp
Received April 15, 2008
ABSTRACT
Neighboring-group participation of an acyl protecting group efficiently promotes the Brønsted acid-catalyzed dehydrative cyclization of 1,3,5-
triketones to γ-pyrones, whereas a bulky silyloxy group in the ꢀ-position retards the cyclization. This reaction provides an efficient synthetic
route for a common intermediate for the synthesis of γ-pyrone-containing bioactive natural products.
Polypropionate-derived γ-pyrones are very important het-
erocycles that have attracted considerable interest from
chemists due to their unique structure and remarkable
biological activities.1 The biosynthesis of naturally occurring
γ-pyrones appears to involve the dehydrative cyclization of
1,3,5-triketones. Although several methods have been re-
ported for the cyclization of 1,3,5-triketones to γ-pyrones
using stoichiometric dehydrating reagents,2,3 few successful
catalytic methods have been reported.
(1a) and 4,6,9-trimethyldecan-3,5,7-trione was effectively
promoted by N-(2,6-diphenylphenyl)-N-mesitylammonium
pentafluorobenzenesulfonate (3) to give the corresponding
γ-pyrones in good yield.4–6 However, the reactivity of 1c
was very low, and the corresponding γ-pyrone 2c was
obtained in only 53% yield (Scheme 1). γ-Pyrone 2c is one
of the most important common intermediates for the synthesis
of many γ-pyrone-containing bioactive compounds,7 and the
development of an efficient method for the synthesis of 2c
is needed.
Recently, we reported that bulky diarylammonium pen-
tafluorobenzenesulfonates effectively promoted the dehy-
drative cyclization of 1,3,5-triketones under reaction
conditions without the removal of generated water. The
dehydrative cyclization of 4,6-dimethylnonan-3,5,7-trione
(4) Sakakura, A.; Watanabe, H.; Nakagawa, S.; Ishihara, K. Chem. Asian
J. 2007, 2, 477
.
(5) For ester condensation catalyzed by bulky diarylammonium pen-
tafluorobenzenesulfonates, see: (a) Ishihara, K.; Nakagawa, S.; Sakakura,
A. J. Am. Chem. Soc. 2005, 127, 4168. (b) Sakakura, A.; Nakagawa, S.;
Ishihara, K. Tetrahedron 2006, 62, 422. (c) Sakakura, A.; Nakagawa, S.;
† EcoTopia Science Institute, Nagoya University.
‡ Graduate School of Engineering, Nagoya University.
(1) Davies-Coleman, M. T.; Garson, M. J. Nat. Prod. Rep. 1998, 15,
477.
Ishihara, K. Nat. Protoc. 2007, 2, 1746
.
(6) For other catalytic dehydrative cyclizations of 1,3,5-triketones, see:
TsOH (ca. 60% yield): (a) Asami, T.; Yoshida, S.; Takahashi, N. Agric.
Biol. Chem. 1986, 50, 4695% methanolic H2SO4 (50% yield): (b) Harris,
T. M.; Murphy, G. P.; Poje, A. J. J. Am. Chem. Soc. 1976, 98, 77330.5 M
HCl (50% yield): (c) Dorman, L. C. J. Org. Chem. 1967, 32, 4105concd
H2SO4 (59-91% yield): (d) Light, R. J.; Hauser, C. R. J. Org. Chem. 1960,
25, 53845% HBr or polyphosphoric acid (no data on yields): (e) O’Sullivan,
(2) (a) Arimoto, H.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett.
1990, 31, 5491. (b) Arimoto, H.; Nishiyama, S.; Yamamura, S. Tetrahedron
Lett. 1990, 31, 5619
.
(3) For a review of the synthesis of γ-pyrone-containing marine natural
products, see: Yamamura, S.; Nishiyama, S. Bull. Chem. Soc. Jpn. 1997,
70, 2025
.
W. I.; Hauser, C. R. J. Org. Chem. 1960, 25, 1110.
10.1021/ol800860p CCC: $40.75
Published on Web 05/27/2008
2008 American Chemical Society

reactivity of 1c may be the steric hindrance due to a methyl
group at its 2-position. In fact, 2,4,6-trimethylnonan-3,5,6-
trione (1b) was slightly less reactive than 1a (entries 1 and
2). However, low reactivity of 1c can mainly be attributed
to the TBDPS group, since 1c was much less reactive than
1b (entry 2 vs entry 4). As in the case of 1c, 1,3,5-triketones
1g and 1j, which have a TBDPS group, were much less
reactive than 1a and 1b, despite the fact that 1g and 1j did
not have an additional methyl group at the R-position of the
carbonyl group (entries 10 and 13). The TBDPS group is
conventionally used to protect a hydroxyl group in 1,3,5-
triketones but is not suitable for the present catalytic
dehydrative cyclization.
Therefore, we examined protecting groups for the hydroxyl
group in 1,3,5-triketone to improve their reactivities. Surpris-
ingly, we found that 1,3,5-triketone 1d, the hydroxyl group
of which is protected by a pivaloyl group, showed high
reactivity (82% yield, entry 6). When the reaction was
conducted for 24 h, γ-pyrone 2d was obtained in 95% yield.
Since 1d was more reactive than 1a and 1b, the pivaloyl
group may effectively promote the acid-catalyzed dehydrative
cyclization of 1,3,5-triketones. This rate-accelerating effect
of a pivaloyl group can be attributed to intramolecular
neighboring-group participation, since the reaction of 1b in
the presence of methyl pivalate (1 equiv) gave the same result
(65% yield, entry 3) as that of 1b in the absence of the
additive (entry 2). When the reaction of 1d was conducted
in toluene, the product 2d was obtained in low yield (50%,
entry 7). This lower reactivity in toluene of 1d may be
attributed to the stronger solvatation, which resulted in
inhibition of the neighboring-group participation. 1,3,5-
Triketones 1h and 1k were also much more reactive than
1g and 1j (entries 10, 11, 13, and 14). The pivaloyl group
of 2d can be removed in 93% yield using LiAlH4 (2.0 equiv)
without a loss of optical purity.
Scheme 1. Dehydrative Cyclization of 1,3,5-Triketone 1c
Catalyzed by N-(2,6-Diphenylphenyl)-N-mesitylammonium
Pentafluorobenzenesulfonate (3)
We first examined the reactivities of various 1,3,5-
triketones 18 for dehydrative cyclization catalyzed by pen-
tafluorobenzenesulfonic acid (C6F5SO3H, 5 mol %) in
heptane under heating conditions without the removal of
water (Table 1). 1,3,5-Triketone 1c was much less reactive
Table 1. Dehydrative Cyclization of 1,3,5-Triketones 1 to
γ-Pyrones 2a
Further investigation of the protecting group for the
hydroxyl group revealed that 1,3,5-triketone 1e, which has
a p-methoxybenzoyloxy group, was more reactive than 1d
(Table 1, entry 8). This rate-accelerating effect may be
attributed to the insolubility of the corresponding γ-pyrone
2e under the reaction conditions, in addition to the neighbor-
ing-group participation of the p-methoxybenzoyloxy group.
It is conceivable that the catalyst preferentially activated 1e
and efficiently promoted the reaction because 2e was
insoluble. In fact, benzyl-protected 1,3,5-triketone 1f, which
gave insoluble γ-pyrone 2f, was slightly more reactive than
1b (entry 9), despite the fact that 1,3,5-triketone 1f did not
have an acyloxy group. 1,3,5-Triketones 1i and 1l also gave
insoluble γ-pyrones 2i and 2l, and were more reactive than
1h and 1k (entries 11, 12, 14, and 15).
We next investigated the dehydrative cyclization of
1,3,5,7-tetraketones 4 (Table 2). In principle, the reaction
of 4 would produce γ-pyrones 5 and 6. When the reaction
of 1,3,5,7-tetraketone 4a was conducted with C6F5SO3H (5
mol %) in heptane under heating conditions (80 °C) without
the removal of water, a 1:1 mixture of 5a and 6a was
obtained in 39% yield, along with some byproducts (entry
a Reactions of 1 (0.1 mmol) were carried out with C6F5SO3H (5 mol
%) in heptane (2 mL) at 80 °C for 8 h without the removal of water.
b Isolated yield. c Y, soluble in the reaction mixture; N, insoluble in the
reaction mixture. d The reaction was conducted with methyl pivalate (1
equiv). e The reaction was conducted with 3 (5 mol %) instead of C6F5SO3H.
f The reaction was conducted for 24 h. g The reaction was carried out in
toluene.
than 1a (entries 1 and 4). When the reaction was conducted
with 3 (5 mol %) instead of C6F5SO3H, the reactivity of 1c
was slightly improved, but the yield of 2c was still insuf-
ficient (53%, entry 5). One of the reasons for the low
(7) (a) Arimoto, H.; Cheng, J.-F.; Nishiyama, S.; Yamamura, S.
Tetrahedron Lett. 1993, 34, 5781. (b) Paterson, I.; Franklin, A. S.
Tetrahedron Lett. 1994, 35, 6925. (c) Arimoto, H.; Yokoyama, R.; Okumura,
Y. Tetrahedron Lett. 1996, 37, 4749. (d) Arimoto, H.; Yokoyama, R.;
Nakamura, K.; Okumura, Y.; Uemura, D. Tetrahedron 1996, 52, 13901.
(e) Paterson, I.; Chen, D. Y.-K.; Acen˜a, J. L.; Franklin, A. S. Org. Lett.
2000, 2, 1513. (f) Paterson, I.; Chen, D. Y.-K.; Franklin, A. S. Org. Lett.
2002, 4, 391.
(8) For the synthesis of 1,3,5-triketones 1, see Supporting Information.
Org. Lett., Vol. 10, No. 12, 2008
2570

Table 2. Dehydrative Cyclization of 1,3,5,7-Tetraketones 4 to
γ-Pyrones 5 and 6a
Scheme 2. Proposed Mechanism for the Dehydrative
Cyclization of 1d with the Aid of Neighboring-Group
Participation
entry tetraketone 4
catalyst
yield of 5 and 6 (%)b 5/6b
1c
2
3
4
5
4a
4a
4b
4b
4c
C6F5SO3H
C6F5SO3H
C6F5SO3H
Tf2NH
39
68
83
78
71
1:1
1:1
2:1
3:1
1:1
C6F5SO3H
a Reaction of 4 (0.1 mmol) was carried out with C6F5SO3H (5 mol %)
in cyclohexane (2 mL) under azeotropic reflux conditions for 8 h.
b Determined by 1H NMR analysis. c The reaction was conducted in heptane
(2 mL) at 80 °C without the removal of water.
The preferential formation of 5b in the dehydrative
cyclization of 1,3,5,7-tetraketone 4b could also be explained
by the neighboring-group participation of the p-methoxy-
benzoyl group (Scheme 3). The p-methoxybenzoyl group was
1). The generation of byproducts can be attributed to
decomposition by water. In fact, the reaction of 4a in
cyclohexane (bp ) 80.7 °C) under azeotropic reflux condi-
tions increased the yield of 5a and 6a (68%), while the ratio
of 5a and 6a did not change (entry 2). As in the case of
1,3,5,7-tetraketone 4b bearing a p-methoxybenzoyloxy group,
the reactivity increased and the corresponding γ-pyrones 5b
and 6b were obtained in 83% yield under azeotropic reflux
conditions (entry 3). Interestingly, the reaction of 4b gave a
2:1 mixture of 5b and 6b. This preferential production of
5b might be attributed to the intramolecular participation of
the p-methoxybenzoyl group. In contrast, 1,3,5,7-tetraketone
4c, bearing a TBDPS group, showed reactivity similar to
4a, and gave a 1:1 mixture of 5c and 6c (entry 5). To improve
the selectivity of 5b, we examined several acid catalysts.
We were pleased to find that the use of bulky Brønsted acid
catalysts such as trifluoromethanesulfonimide (Tf2NH) gave
a better result (5b/6b ) 3:1, entry 4).
On the basis of the results described above, we propose a
mechanism for rate acceleration by the intramolecular
pivaloyl group and for rate deceleration by the TBDPS group,
as shown in Scheme 2. 1,3,5-Triketone 1d is thought to be
in equilibrium with enol 7c, as well as 7a and 7b. Intramo-
lecular hydrogen bondings restrict the free rotation of the
C5-C6 bond of 7a and the C4-C5 bond of 7b. In contrast,
intramolecular participation of the pivaloyl group in 7c
resulted in free rotation of the C4-C5 bond, which helped
7c to adopt a conformation suitable for cyclization. Further-
more, this intramolecular participation increased the nucleo-
philicity of the enol oxygen. After protonation at the C-7
carbonyl oxygen of 7c, cyclization proceeded rapidly with
the assistance of intramolecular abstraction of the enol proton
by the pivaloyl group.9
Scheme 3
.
Proposed Mechanism for the Preferential Production
of 5b in the Dehydrative Cyclization of 4b
thought to form an intramolecular hydrogen bond with the
closest enol proton. The enol oxygen at the C-7 position,
which would be activated through intramolecular hydrogen
bonding, could rapidly react with the protonated C-3 carbonyl
group to give 5b preferentially. In contrast, cyclization of
the enol oxygen at the C-9 position to the C-5 carbonyl group
would proceed slowly due to steric hindrance around the C-5
carbonyl group. It is conceivable that Tf2NH, a bulky
Brønsted acid, would increase the preference for the proto-
nation at the terminal C-3 carbonyl group, which improved
the ratio of 5b and 6b.
(9) The neighboring-group participation of the acyl protecting groups
might explain the rate acceleration for the reaction of 1,3,5-triketones 1d
and 1e, as we proposed in Scheme 2. However, this neighboring-goup
participation is still controversial, especially for the reaction of 1h, 1i, 1k,
and 1l, which might proceed via a 9- or 11-membered cyclic transition
state. A detailed mechanistic study on the rate-accelerating effect by the
acyl groups is currently underway.
Org. Lett., Vol. 10, No. 12, 2008
2571

examined showed almost same chemical shifts for C-1 (29.3
ppm) and C-3 (39.9 ppm), except that the C-3 carbon of 9.
However, the chemical shifts for C-2 carbons of 8a (205.6
ppm) and 8b (204.0 ppm), which had a silyoxy group, were
slightly higher than those (203.4 ppm) of other compounds
without a siloxy group. These results imply the existence of
intramolecular interaction between a TBDPS group and
carbonyl oxygen. In the case of 1c, the TBDPS group would
interact with the C-3 carbonyl oxygen (Scheme 4). This
interaction might preclude enol formation at the C-3 carbonyl
group and decrease its basicity and nucleophilicity. The low
nucleophilicity of the C-3 carbonyl oxygen would decrease
the rate of cyclization of 1c.
In conclusion, we found a rate-accelerating effect in the
Brønsted acid-catalyzed dehydrative cyclization of 1,3,5-
triketones by the neighboring-group participation of acyl
protecting groups. This rate-accelerating effect provided 2d
in high yield, which could be easily converted to a common
synthetic intermediate for γ-pyrone-containing bioactive
natural products. Furthermore, the Tf2NH-catalyzed dehy-
drative cyclization of 1,3,5,7-tetraketone 4b preferentially
gave γ-pyrone 5b with the aid of the acyloxy group.
Table 3. 13C NMR Data of 5-Substituted 2-Pentanones 8 and
2-Hexanone (9)
To explore the effect of TBDPS group on the reactivity
of 1,3,5-triketones 1 and 1,3,5,7-tetraketones 5, we compared
the 13C NMR data of 5-substituted 2-pentanones 8 and
2-hexanone (9) in C6D12 (Table 3). All compounds we
Scheme 4
.
Proposed Mechanism for the Rate-Decelerating
Effect of TBDPS Group in 1c
Acknowledgment.ThisprojectwassupportedbyJSPS.KAK-
ENHI (Grant No. 20245022), the Toray Science Foundation,
and the G-COE in Chemistry, Nagoya.
Supporting Information Available: Experimental details,
1
spectroscopic data for all new compounds, and H and 13C
NMR charts of products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL800860P
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Org. Lett., Vol. 10, No. 12, 2008