Aldol-type reaction of a 4-pyrone: a straightforward approach to 4-pyrone-containing natural products

Article abstract of DOI:10.1016/j.tetlet.2008.11.017

A straightforward approach to 4-pyrone-containing natural products has been developed, which includes an aldol-type reaction between 2,6-diethyl-3,5-dimethyl-4-pyrone and aldehydes. The counter cation of the carbanion of the pyrone was found to play an im

Full text of DOI:10.1016/j.tetlet.2008.11.017

Tetrahedron Letters 50 (2009) 325–328
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Aldol-type reaction of a 4-pyrone: a straightforward
approach to 4-pyrone-containing natural products
*
Tetsuya Sengoku , Takuma Takemura, Emi Fukasawa, Ichiro Hayakawa, Hideo Kigoshi
Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward approach to 4-pyrone-containing natural products has been developed, which includes
an aldol-type reaction between 2,6-diethyl-3,5-dimethyl-4-pyrone and aldehydes. The counter cation of
the carbanion of the pyrone was found to play an important role in this reaction.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 15 September 2008
Revised 28 October 2008
Accepted 4 November 2008
Available online 11 November 2008
Keywords:
4-Pyrone-containing natural product
Aldol-type reaction
Counter cation
Polyketide compounds with 4-pyrone moieties have been iso-
lated from marine natural sources. These compounds show valu-
able biological activities represented by cytotoxic activity
(Fig. 1).1 Their structures and bioactivities have attracted the inter-
est of synthetic chemists, and total synthesis has been achieved for
some of them.2
Generally, the synthesis of 4-pyrone-containing natural
products is achieved via the dehydrative cyclization of long-chain
triketones 1 as a precursor of the 4-pyrone moiety with a stoichi-
ometric amount of reagents (Scheme 1, Eq. 1). Although this meth-
od has been well established3 and a successful catalytic system has
recently been reported,4 the requirement of multisteps in linear
synthetic sequence remains a significant problem.
Another approach is the installation of a side-chain into a 4-pyr-
one (Scheme 1, Eq. 2). This approach has the benefit of straightfor-
ward access even to complex molecules and the construction of
two stereogenic centers at once. Although examples of alkylation
O
R
O
O
O
O
R =
R =
O
O
O
O
at the c
-position of 4-pyrones have been reported,5 to the best of
O
OH
(auripyrone A)
O
O
our knowledge, aldol-type reactions have been demonstrated only
for the simple 4-pyrone, 2,6-di-substituted-4-pyrone.6 We now re-
port an aldol-type reaction of the polypropionate-derived 4-pyr-
one, 2,6-diethyl-3,5-dimethyl-4-pyrone (2), as a substrate, which
O
OR
OH
R = Me (siphonarin A)
R = Et (siphonarin B)
(auripyrone B)
R
H
H
O
O
O
O
O
O
O
O
O
OP
OH OH
OH
O
OP
R
(eq 1)
(eq 2)
O
O
O
O
R
1
ilikonapyrone
R = Me (vallartanone A)
R = H (vallartanone B)
O
Figure 1. Natural products containing 4-pyrone.1
O
OH
+
5
3
H
R
O
R
O
6
2
γ
* Corresponding author. Tel./fax: +81 29 853 4313.
E-mail address: kigoshi@chem.tsukuba.ac.jp (H. Kigoshi).
Present address: Department of Materials Science, Faculty of Engineering,
Shizuoka University, Hamamatsu 432-8561, Japan.
2
Scheme 1. Approach to polypropionate-derived 4-pyrone.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.017

326
T. Sengoku et al. / Tetrahedron Letters 50 (2009) 325–328
Table 1
Aldol-type reaction with 2,6-diethyl-3,5-dimethyl-4-pyrone 2 and propionaldehyde 3aa
O
O
O
O
base (1.2 eq), additive
3a
propionaldehyde
(1.5 eq)
OH
Et
OH
Et
+
°
C
THF, -78
O
O
2
anti-4a
syn-4a
Entry
Base
Additive (equiv)
Yield of 4ab (%)
anti-4a:syn-4ac
Recovery of 2 (%)
1
2d
3
4
5
6
7
8
9
LDA
LDA
LDA
LTMP
LiHMDS
LiHMDS
KHMDS
NaHMDS
NaHMDS
NaHMDS
—
45
53
16
9
69
38
15
76
56
9
3.1:1
3.7:1
0.6:1
1.5:1
2.9:1
3.2:1
2.8:1
2.8:1
2.5:1
1.3:1
11
14
62
Trace
17
39
62
12
10
LiCl (8.0)
HMPA (8.6)
—
—
LiCl (8.0)
—
—
NaCl (8.0)
15-Crown-5 (1.2)
10
69
a
Experimental conditions: After treatment of 2 (0.20 mmol) with base (0.24 mmol) in THF (1.0 ml) for 2 h at À78 °C, propionaldehyde (0.30 mmol) was added to the
mixture, and the mixture was stirred for 3 h at the same temperature. The additive was added to the reaction mixture concurrently with corresponding base. Spectral data for
4a are shown in Ref. 8.
b
Combined yield of isolated anti- and syn-4a.
The ratio was calculated from respective yields of anti- and syn-4a.
The conditions described in Ref. 5 were applied.
c
d
will be applicable to the synthesis of naturally occurring 4-pyrone
compounds, as shown in Figure 1.
carried out with lithium dialkylamide, pyrone 2 was decomposed
and recovered in poor yield (trace-14%) except for the case of
entry 3.
We initially screened an assortment of bases and additives
(Table 1). The configuration of diastereomers was determined by
J-based configuration analysis.7 Under the simple condition with
lithium diisopropylamide (LDA), aldol adducts were obtained in
moderate yield (entry 1), but this result was not reproducible.
The addition of LiCl6 or hexamethyl phosphoramide (HMPA) did
not give improved results (entries 2 and 3). When the reaction
was carried out with lithium tetramethylpiperidide (LTMP), 4a
was produced in only 9% yield (entry 4). When the reaction was
On the other hand, an appropriate amount of 2 was recovered in
each reaction with metal bis(trimethylsilyl)amides. The reaction
with lithium bis(trimethylsilyl)amide (LiHMDS) or potassium
bis(trimethylsilyl)amide (KHMDS) gave the desired adduct in 69%
or 15% yield, respectively (entries 5 and 7). The addition of LiCl
did not give improved yield, but slightly advanced in diastereose-
lectivity (entry 6). The reaction with sodium bis(trimethyl-
silyl)amide (NaHMDS), which was revealed to be the most
Table 2
Aldol-type reaction with 2,6-diethyl-3,5-dimethyl-4-pyrone 2 and aldehydes 3a,b
O
O
O
NaHMDS (1.6 eq)
O
OH
OH
+
+
°
C
THF, -78
H
R
O
R
O
R
O
3b-p
(1.0 eq)
2
anti-4b-p
syn-4b-p
(1.4 eq)
Entry
R
Yieldc (%)
anti-4:syn-4d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
n-Pr (3b)
i-Pr (3c)
C6H11 (3d)
t-Bu (3e)
trans-CH3CH@CH (3f)
CH2@CCH3 (3g)
Ph (3h)
p-CH3C6H4 (3i)
p-CH3OC6H4 (3j)
p-BrC6H4 (3k)
p-NO2C6H4 (3l)
m-CH3C6H4 (3m)
o-CH3C6H4 (3n)
o-BrC6H4 (3o)
Mesityl (3p)
76 (4b)
57 (4c)
64 (4d)
36 (4e)
2.9:1
2.8:1
2.1:1
2.6:1e
—
f
—
—
f
—
95 (4h)
92 (4i)
94 (4j)
86 (4k)
30 (4l)
85 (4m)
92 (4n)
99 (4o)
93 (4p)
2.4:1
2.1:1
2.5:1
1.9:1
1.9:1
2.7:1
1.2:1
0.5:1
0.5:1
a
All reactions were carried out with NaHMDS (0.29 mmol), 2 (0.27 mmol), and aldehyde (0.18 mmol).
See experimental procedure in Ref. 9.
Combined yield of isolated anti- and syn-4.
The ratio was calculated from respective yields of anti- and syn-4.
The ratio of anti- and syn-4e was calculated from 1H NMR.
1,4-Adduts were obtained.
b
c
d
e
f

T. Sengoku et al. / Tetrahedron Letters 50 (2009) 325–328
327
Table 3
Reaction with 2 and nucleophiles
O
O
base (1.2 eq)
nucleophile
R
THF, temp, time
O
O
R = D (5)
R = CH3 (6)
2
Entry
Base
Nucleophile (equiv)
Temperature
Time (h)
Yield (%)
34a (59)b
1
2
3
4
5
6
7
8
LDA
D2O (excess)
D2O (excess)
D2O (excess)
D2O (excess)
CH3I (1.5)
CH3I (1.5)
CH3I (1.5)
CH3I (1.5)
À78 °C to rt
À78 °C to rt
À78 °C to rt
À78 °C to rt
À78 °C
0.5
0.5
0.5
0.5
3
3
3
3
LiHMDS
KHMDS
NaHMDS
LDA
LiHMDS
KHMDS
NaHMDS
Quant.a (>95)b
Quant.a (>95)b
Quant.a (>95)b
10c
26c
75c
79c
À78 °C
À78 °C
À78 °C
a
Combined yield of isolated 2 and 5.
b
c
The percentage of deuterated compound 5 was determined by 1H NMR.
Isolated yield.
suitable base for this reaction, afforded 4a in 76% yield with mod-
erate diastereoselectivity (2.8:1) (entry 8), while the addition of
NaCl had little effect (entry 9). The addition of 15-crown-5
disturbed the reaction and afforded 4a in 9% yield (entry 10).
The generality of this reaction was then evaluated (Table 2). The
configuration of the aliphatic adducts 4b–e was determined by a
comparison of spectral data with those of 4a, and the configuration
of aromatic adducts 4i–p was determined by comparison with 4h,
whose structure was confirmed by X-ray crystallographic analysis.
Saturated alkylaldehydes 3b–d gave aldol adducts 4b–d in moder-
ate to good yields (57–76%) (entries 1–3). Pivalaldehyde 3e showed
somewhat lower reactivity and afforded 4e in 36% yield (entry 4).
The diastereomeric ratios of adducts were in the 2:1 to 3:1 range.
In contrast, the reaction with unsaturated alkylaldehydes 3f and 3g
predominantly afforded 1,4-adducts (entries 5 and 6). Among the
aromatic aldehydes, both para- and meta-substituents did not
affect the reaction (entries 7–10 and 12). When the reaction was
carried out with p-nitrobenzene 3l, decomposition of materials
was observed on TLC, and adduct 4l was obtained in only 30% yield
(entry 11). The reaction with ortho-substituted aromatic aldehydes
3n–p gave adducts 4n–p in excellent yield (92–99%), whereas the
diastereoselectivity varied widely depending on the ortho-substit-
uents (entries 13–15). A sterically hindered substituent at the
ortho-position tended to give adducts with syn selectivity.
It is conceivable that the counter cation would affect deprotona-
tion from 2 and/or activation of aldehydes. To probe the role of the
counter cations in this aldol-type reaction, 2 was allowed to react
with other nucleophiles (Table 3). D2O and CH3I, respectively, were
employed as nucleophiles to obtain information about the degree
of deprotonation and the nucleophilicity of the enolates. When
the reaction was carried out with D2O, the enolate generated from
2 and LDA was deuterated only in low yield (entry 1). However,
each enolate prepared from 2 and metal bis(trimethylsilyl)amide
gave 5 in nearly quantitative yields (entries 2–4). In the nucleo-
philic addition toward CH3I, the reactions with KHMDS and NaH-
MDS gave mono-methylated compound 6 in good yields (entries
7 and 8), while the enolates generated with LDA and LiHMDS gave
6 in poor yields (entries 5 and 6). As expected from the results in
Table 1, the reactions of the enolate generated with LDA gave the
products in lower yields than those generated with bis(trimethyl-
silyl)amides due to the decomposition of the anion species. It is
interesting that the reactivity of metal enolates of 6 prepared with
bis(trimethylsilyl)amides was changed significantly depending on
the nature of the metal counterion and electrophile (see also Table
1, entries 5–7).
H
O
O
M
O
The results shown in Table 3 indicate that counter cations will
not participate in the deprotonation step, but in the activation of
aldehydes. From these results, we suggest two plausible transition
states (Fig. 2). Both involved the coordination of the aldehyde to
the metal ion.10
O
M
R
O
R
O
H
n
A
B
Finally, we applied this aldol-type reaction to an optically active
aldehyde 711 for the preliminary study of natural product synthesis
(Scheme 2). The adduct was obtained as a mixture of diastereo-
mers in 68% yield. After purification via silica gel column chroma-
tography, an adduct 8,12 the building block of auripyrones and
ilikonapyrone shown in Figure 1, was obtained in 47% yield, and
the other adducts were obtained as the inseparable mixture in
21% yield.
In conclusion, we have demonstrated an efficient aldol-type
reaction with 2,6-diethyl-3,5-dimethyl-4-pyrone. The diastereo-
meric ratio of adducts was influenced by steric factors around
the aldehyde, especially on ortho-substituted benzaldehydes. We
expect that this reaction may be potentially applicable to the
synthesis of 4-pyrone-containing natural products.
Figure 2. Plausible transition state model.
O
O
OTr
NaHMDS (1.2 eq)
OH OTr
2
+
(1.3 eq)
H
THF, -78 °C, 2 h
O
7
8
(1.0 eq)
(47%)
Scheme 2. Application to an optically active substrate 7.

328
T. Sengoku et al. / Tetrahedron Letters 50 (2009) 325–328
179.8, 164.7, 164.2, 118.6, 117.9, 75.4, 41.4, 27.8, 24.7, 14.1, 11.3, 10.1, 9.7, 9.5;
Acknowledgments
IR (neat) 3400, 1650, 1592 cmÀ1; HRMS (ESI) calcd for C14H22O3Na (M+Na)+
261.1467, found 261.1462.
This study was supported in part by a Grant-in-Aid for Scientific
Research (B) (No. 20310129) and Scientific Research on Priority
Area ‘Creation of Biologically Functional Molecules’ from the Min-
istry of Education, Culture, Sports, Science and Technology, Japan.
We would like to thank Professors Akira Sekiguchi and Masaaki
Ichinohe (University of Tsukuba) for their help with the X-ray
crystallographic analysis and for their helpful discussion. We thank
9. Typical procedure for aldol-type reaction: After treatment of 2 (0.27 mmol) with
NaHMDS (0.29 mmol) in THF (1.0 ml) for 2 h at À78 °C, aldehyde (0.18 mmol)
was added to the mixture, and the mixture was stirred for 3 h at the same
temperature. The reaction mixture was quenched with saturated aqueous
NH4Cl. The aqueous layer was extracted with EtOAc. Combined organic
extracts were washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. Purification by silica gel column chromatography
(hexane–EtOAc) afforded anti-4 and syn-4.
Selected spectral data: anti-4h: 1H NMR (270 MHz, CDCl3) d 7.29–7.36 (m, 5H),
4.79 (br d, J = 8.6 Hz, 1H), 3.30 (dq, J = 8.6 Hz, 7.0 Hz, 1H), 2.60 (q, J = 7.6 Hz,
2H), 1.96 (s, 3H), 1.91 (s, 3H), 1.20 (t, J = 7.6 Hz, 3H), 1.00 (d, J = 7.3 Hz, 3H); 13C
NMR (68 MHz, CDCl3) d 179.7, 164.1, 163.4, 142.1, 128.6, 128.2, 126.7, 119.9,
118.0, 76.8, 43.1, 24.8, 14.5, 11.3, 9.6, 9.5; IR (neat) 3369, 1653, 1589, 762,
Kaneka Corporation for their gift of methyl
hydroxyisobutanoate.
D-(R)-b-
; HRMS (ESI) calcd for C18H22O3Na (M +
702 cmÀ1 Na)+ 309.1467, found
Supplementary data
309.1474.
syn-4h: 1H NMR (270 MHz, CDCl3) d 7.18–7.23 (m, 5H), 4.82 (br d, J = 8.1 Hz,
1H), 3.30 (dq, J = 8.1 Hz, 6.8 Hz, 1H), 2.58 (q, J = 7.6 Hz, 2H), 1.87 (s, 3H), 1.68 (s,
3H), 1.41 (d, J = 6.8 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H); 13C NMR (68 MHz, CDCl3) d
179.6, 164.0, 163.4, 142.2, 128.3, 128.1, 125.8, 119.0, 117.8, 77.0, 43.4, 24.7,
14.6, 11.3, 9.5, 9.3; IR (neat) 3369, 1651, 1589, 760, 702 cmÀ1; HRMS (ESI) calcd
for C18H22O3Na (M+Na)+ 309.1467, found 309.1469.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.017.
References and notes
10. To provide further insight into the reaction, we tried to trap the enolate as the
corresponding silyl ether. However, this attempt resulted in failure,
presumably due to the instability of the silyl ethers
1. (a) Hochlowski, J. E.; Coll, J. C.; Faulkner, D. J.; Biskupiak, J. E.; Ireland, C. M.;
Zheng, Q.; He, C.; Clardy, J. J. Am. Chem. Soc. 1984, 106, 6748; (b) Suenaga, K.;
Kigoshi, H.; Yamada, K. Tetrahedron Lett. 1996, 37, 5151; (c) Ireland, C. M.;
Biskupiak, J. E.; Hite, G. J.; Rapposch, M.; Scheuer, P. J.; Ruble, J. R. J. Org. Chem.
1984, 49, 559; (d) Manker, D. C.; Faulkner, D. J. J. Org. Chem. 1989, 54, 5374.
2. (a) Paterson, I.; Chen, D. Y.; Franklin, A. S. Org. Lett. 2002, 4, 391; (b) Linter, P.;
Perkins, M. V. Angew. Chem., Int. Ed. 2006, 45, 2560; (c) Arimoto, H.; Cheng, J.;
Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1993, 34, 5781; (d) Arimoto, H.;
Yokoyama, R.; Nakamura, K.; Okumura, Y.; Uemura, D. Tetrahedron 1996, 52,
13901.
O
OSiR3
NaHMDS, R3SiX
R3SiX = TMSCl, TESCl
TBSCl, TBSOTf
O
O
2
11. Gaunt, M. J.; Jessiman, A. S.; Orsini, P.; Huw, R. T.; Hook, D. F.; Ley, S. V. Org. Lett.
2003, 5, 4819.
3. Arimoto, H.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1990, 39, 5619; For a
review of the synthesis of 4-pyrone-containing marine natural products, see:
Yamamura, S.; Nishiyama, S. Bull. Chem. Soc. Jpn. 1997, 70, 2025.
12. The configuration of 8 was determined by 1H NMR and NOESY correlations
with the corresponding acetonide derivative
4. (a) Sakakura, A.; Watanabe, H.; Nakagawa, S.; Ishihara, K. Chem. Asian J. 2007, 2,
477; (b) Sakakura, A.; Watanabe, H.; Ishihara, K. Org. Lett. 2008, 10, 2569.
5. (a) Yamamoto, M.; Sugiyama, N. Bull. Chem. Soc. Jpn. 1975, 48, 508; (b) Smith, A.
B., III; Scarborough, R. M., Jr. Tetrahedron Lett. 1978, 19, 4193; (c) Yamamoto,
M.; Iwasa, S.; Takatsuki, K.; Yamada, K. J. Org. Chem. 1986, 51, 346; (d) West, F.
G.; Fisher, P. V.; Arif, A. M. J. Am. Chem. Soc. 1993, 115, 1595; (e) West, F. G.;
Amann, C. M.; Fisher, P. V. Tetrahedron Lett. 1994, 35, 9653.
O
O
O
O
1) HCOOH/EtOAc (2/3)
2) 25% NH3 aq., MeOH
3) Me2C(OMe)2, PPTS
OH OTr
O
O
85%
6. Crimmins, M. T.; Katz, J. D. Org. Lett. 2000, 2, 957.
8
7. Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana, K. J. Org.
Chem. 1999, 64, 866.
8. Spectral data: anti-4a: 1H NMR (270 MHz, CDCl3) d 3.72 (br m, 1H), 3.04 (quint,
J = 7.2 Hz, 1H), 2.62 (q, J = 7.6 Hz, 2H), 1.98 (s, 3H), 1.95 (s, 3H), 1.60–1.72 (m,
1H), 1.32–1.51 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H), 1.22 (d, J = 7.0 Hz, 3H), 1.02 (t,
J = 7.3 Hz, 3H); 13C NMR (68 MHz, CDCl3) d 179.8, 164.4, 164.2, 119.5, 117.9,
10.8 Hz
O
Me
Me
H
O
coupling constant
(500 MHz, CDCl3)
H
R
Me
75.2, 41.3, 27.3, 24.7, 14.4, 11.2, 10.1, 9.7; IR (neat) 3392, 1653, 1593 cmÀ1
;
Me
H
H
H
HRMS (ESI) calcd for C14H22O3Na (M+Na)+ 261.1467, found 261.1471. syn-4a:
1H NMR (270 MHz, CDCl3) d 3.73 (br m, 1H), 2.98 (quint, J = 7.0 Hz, 1H), 2.60 (q,
J = 7.6 Hz, 2H), 1.97 (s, 3H), 1.94 (s, 3H), 1.35–1.55 (m, 2H), 1.31 (d, J = 6.8 Hz,
3H), 1.21 (t, J = 7.4 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (68 MHz, CDCl3) d
NOE
1.6 Hz
(500 MHz, CDCl3)
2.4 Hz
2.8 Hz