An improved aldol protocol for the preparation of 6-styrenylpyrones

Article abstract of DOI:10.1016/j.tetlet.2015.11.021

An improved aldol protocol for the synthesis of 6-styrenylpyrones is reported. The first synthesis of PTP1B inhibitor 1 and 4 has been described.

Full text of DOI:10.1016/j.tetlet.2015.11.021

Tetrahedron Letters 56 (2015) 7112–7114
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An improved aldol protocol for the preparation of 6-styrenylpyrones
⇑
George A. Kraus , Umayangani K. Wanninayake
Department of Chemistry, Iowa State University, Ames, IA 50011, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An improved aldol protocol for the synthesis of 6-styrenylpyrones is reported. The first synthesis of
PTP1B inhibitor 1 and 4 has been described.
Received 23 October 2015
Revised 3 November 2015
Accepted 8 November 2015
Available online 10 November 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
2-Pyrone
Triacetic acid lactone
Aldol reaction
Aldehydes
Styrenylpyrones
O
O
Styrenylpyrones are an emerging class of natural products. Rep-
resentative examples include penstyrylpyrone (1),1 5,6-dehy-
drokawain (2),2 11-methoxy yangonin (3),3 and pyrone 4.4 They
exhibit anti-obesity effects,5 collagenase inhibition,6 anti-influenza
activity,7 PTP1B inhibitory activity,1 and HIV neuraminidase inhibi-
tion.8 (Fig. 1).
Me
O
O
R3
R2
MeO
MeO
R1
2: R1 = R2 = R3 = H
1
3: R1 = H, R2= R3 = OMe
These compounds have been synthesized from pyrones by Wit-
tig reactions,9 Heck reactions,10 Suziki–Miyaura reactions,11 and
aldol reactions.12 The aldol reaction is the most commonly used
strategy for preparing styrenylpyrones. Typical conditions for the
aldol reaction of 5 with aromatic aldehydes involve the reaction
of 5 and the aromatic aldehyde with excess magnesium methoxide
in boiling methanol. Yields typically range from 20% to 40%
(Scheme 1).
4: R1 = OMe, R2, R3 = OCH2O
Figure 1. Representative styrylpyrones.
of 5 at À78 °C with n-butyl lithium also produced the C-3
lithiated pyrone.15
We prepared pyrone 2 from 512 using this method and
obtained a yield of only 29%. Evaluation of the co-products
showed that a Meerwein–Pondorf–Verley reduction of benzalde-
hyde to benzyl alcohol was a significant side reaction. However,
even with 3 equiv of benzaldehyde, the yield of 2 was not signif-
icantly improved. Deprotonation of 5 with stronger bases has
been reported and the results vary with the substitution pattern
on pyrone. Lyga had reported that the reaction of pyrone 5 with
lithium diisopropylamide (LDA) furnished the aldol adduct at
C-3 of pyrone.13 Interestingly, 4-methoxypyrones substituted
with alkyl groups at both C-5 and C-6 afforded the deprotona-
tion product at the methyl group at C-6.14 Additionally, reaction
Because we needed multigram quantities of styrenylpyrones,
we sought alternate conditions. Pyrones 5 and 6 (prepared from
commercially available 4-hydroxy-3,6-dimethylpyrone by
O-methylation) were used. Commercially available bases that
might reversibly deprotonate the methyl group at C-6 along with
a range of dipolar aprotic solvents were evaluated. The reaction
of 5 and benzaldehyde with anhydrous potassium carbonate in
DMF at 25 °C or P4-tBu in DMF gave complicated product mix-
tures. The reaction with potassium tert-butoxide at 25 °C
afforded adduct 2 in 53% yield. Lowering the reaction tempera-
ture to 0 °C resulted in the yield of 31%. The reaction of 5 with
potassium tert-butoxide in dry DMSO afforded the styrenylpy-
rone in low yield. Optimal reaction conditions involved adding
solid potassium tert-butoxide in portions to a solution of the
aromatic aldehyde and 5 in DMF at ambient temperature.16
⇑
Corresponding author. Tel.: +1 515 294 7794; fax: +1 515 294 0105.
E-mail address: gakraus@iastate.edu (G.A. Kraus).
http://dx.doi.org/10.1016/j.tetlet.2015.11.021
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

G. A. Kraus, U. K. Wanninayake / Tetrahedron Letters 56 (2015) 7112–7114
7113
O
O
O
Aldol
Pd(2)
O
O
O
MeO
MeO
MeO
5
Wittig
O
O
H
MeO
O
Scheme 1. Synthesis of 6-styrenylpyrones.
O
Acknowledgments
O
Aromatic aldehyde
t-BuOK, DMF 25 ºC
R
O
O
We thank the NSF Engineering Center for Biorenewable
Chemicals which was awarded NSF grant EEC-0813570 for support
of this research.
MeO
MeO
Ar
5: R = H
6: R = Me
References and notes
Scheme 2. Improves aldol conditions.
1. Lee, D.-S.; Jang, J.-H.; Ko, W.; Kim, K.-S.; Sohn, J. K.; Kanf, M.-S.; Ahn, J. S.; Kim,
J.-C’.; Oh, H. Mar. Drugs 2013, 11, 1409–1426.
2. Beak, P.; Abelson, H. J. Org. Chem. 1962, 27, 3715–3716.
3. Haensel, R.; Klaproth, L. Arch. Pharm. Ber. Deutsch. Pharm. Ges. 1966, 299, 503–
506.
4. Pizzolatti, M. G.; Luciano, C.; Monache, F. D. Phytochem 2000, 55, 819–822.
5. Tu, P. T. B.; Tawata, S. Molecules 2014, 19, 16656–16671.
6. Tawada, S.; Chompoo, J. Jpn. Kokai Tokkyo Koho 2014, 10.
7. Iwai, Y.; Murakami, K.; Gomi, Y.; Hashimoto, T.; Asakawa, Y.; Okuno, Y.;
Ishikawa, T.; Hatakeyama, D.; Echigo, N.; Kuzuhara, T. PLoS One 2011, 6,
e19825.
8. Upadhyay, A.; Chompoo, J.; Kishimoto, W.; Makise, T.; Tawata, S. J. Agric. Food
Chem. 2011, 59, 2857–2862.
9. Suzuki, E.; Hamajima, R.; Inoue, S. Synthesis 1975, 192–194.
10. Moro, A. V.; Cardoso, F. S. P.; Correia, C. R. D. Org. Lett. 2009, 11, 3642–3645.
11. Soldi, C.; Moro, A. V.; Pizzolatti, M. G.; Correia, C. R. D. Eur. J. Org. Chem. 2012,
2012, 3607–3616.
The use of a commercial solution of 1 M potassium tert-butoxide
in THF afforded a yield of 30% (Scheme 2).
Results from a series of aldol reactions are shown below in
Figure 2. Functional groups such as ethers, alkenes, and acetals
are compatible with our reaction conditions. Nitro substituted
aldehydes afforded adducts in poor yields. Adducts derived from
pyrone 6 afforded slightly better yields, presumably due to the
absence of the acidic hydrogen atom at C-3.18
In summary, an improved preparation of 6-styrenylpyrones has
been developed. The reaction proceeds in good yields, is opera-
tionally convenient, and is compatible with a variety of functional
groups. This reaction has been conducted on gram scale.
12. McCracken, S. T.; Kaiser, M.; Boshoff, H. I.; Boyd, P. D. W.; Copp, B. R. Bioorg.
Med. Chem. 2012, 20, 1482–1493.
(1)
(2)
(3)
O
O
O
O
O
O
OCH
OCH
H3CO
H3CO
3
3
H3CO
53 %
46 %
84%
O
O
(7)
(4)
(8)
O
O
O
O
O
O
H3 CO
H3CO
H3CO
H3 CO
OCH 3
OCH 3
61 %
61 %
63 %
(11)
(9)
(10)
O
O
O
O
O
O
O
O
H3CO
H3 CO
H3CO
NO 2
39 %
33 %
32 %
Figure 2. Aldol products.

7114
G. A. Kraus, U. K. Wanninayake / Tetrahedron Letters 56 (2015) 7112–7114
13. Lyga, J. W. J. Heterocyc. Chem. 1995, 32, 515–518.
(E)-4-methoxy-6-styryl-2H-pyran-2-one (5, 6-dehydrokawain) (2) (53%) Yellow
solid: mp 131–133 °C (Lit. 16 134–136 °C); 1H NMR (300 MHz, CDCl3) d 7.52
(d, 2H), 7.48(d, J = 16 Hz, 1H), 7.37 (d, 2H), 7.35 (t, 1H), 6.60 (d, J = 16 Hz, 1H),
5.94 (d, 1H), 5.50 (d, 1H) 3.82 (s, 3H) ppm. HRMS (ESI-QTOF) calcd for C14H13O3
[M+H]+ 229.0859, found 229.0861. 13C NMR data agreed with the literature.16
(E)-4-methoxy-6-(2-(6-methoxybenzo[1,3]dioxol-5-yl)vinyl)-2H-pyran-2-one (4)
(61%) brown solid: mp 187–189 °C (Lit. 4 189–191 °C); 1H NMR (300 MHz,
CDCl3) d 7.74 (d, J = 16 Hz, 1H), 6.96 (s, 1H), 6.52 (s, 1H), 6.47(d, J = 16 Hz, 1H),
5.94 (s, 2H), 5.91 (d, 1H), 5.45 (d, 1H) 3.84 (s, 3H), 3.82 (s, 3H) ppm. HRMS (ESI-
QTOF) calcd for C16H15O6 [M+H]+ 303.0863, found 303.0867. 13C NMR data
agreed with the literature.4
(E)-4-methoxy-6-(4-methoxystyryl)-2H-pyran-2-one (Yangonin) (8) (61%) yellow
solid: mp 146–148 °C (Lit. 16 148–150 °C); 1H NMR (300 MHz, CDCl3) d 7.47
(d, 2H), 7.46(d, J = 16 Hz, 1H), 6.91 (d, 2H), 6.46 (d, J = 16 Hz, 1H), 5.88 (d, 1H),
5.46 (d, 1H) 3.89 (s, 3H) ppm. HRMS (ESI-QTOF) calcd for C15H15O4 [M+H]+
259.0892, found 259.0965. 13C NMR data agreed with the literature.16
(E)-4-methoxy-6-(4-nitrostyryl)-2H-pyran-2-one (10) (33%) yellow solid: mp
209–211 °C (Lit. 17 211.5–214 °C); 1H NMR (300 MHz, CDCl3) d 8.25 (d, 2H),
7.62 (d, 2H), 7.57 (d, J = 16 Hz, 1H), 6.73 (d, J = 16 Hz, 1H), 6.04 (d, 1H), 5.54 (d,
1H), 3.85 (s, 3H) ppm. HRMS (ESI-QTOF) calcd for C14H12NO5 [M+H]+ 274.0637,
found 274.0714. 13C NMR data agreed with the literature.12
14. Schreiber, S. L.; Satake, K. J. Am. Chem. Soc. 1984, 106, 4186–4188.
15. Carpenter, T. A.; Jenner, P. J.; Leeper, F. J.; Staunton, J. J. Chem. Soc., Chem. Comm.
1980, 1227.
16. Amaral, P. A.; Gouault, N.; Le Roch, M.; Eifler-Lima, V. L.; David, M. Tetrahedron
Lett. 2008, 49, 6607–6609.
17. Fujita, T.; Nishimura, H.; Kaburagi, K.; Mizutani, J. Phytochemistry 1994, 36, 23.
18. Representative procedure: To a stirred solution of 4-methoxy-6-methyl-2-
pyrone (0.067 g, 0.47 mmol) in DMF (1 mL) at room temperature was added
benzaldehyde (0.1 mL, 0.95 mmol). Potassium tert-butoxide solid (0.1 g,
0.95 mmol) was then added portionwise to it and stirred for 2 days at room
temperature. Solution became dark red in color. This was extracted with
diethyl ether (3 Â 10 mL). For the compounds 3, 4, 8, 9, 10 methylene chloride
was used for the extraction. The organic layer was washed with brine
(3 Â 20 mL), water (5 Â 20 mL), dried over MgSO4, and concentrated in vacuo.
The crude product was purified by preparative thin layer chromatography
(EtOAc/hexanes) to afford the product.
(E)-4-Methoxy-3-methyl-6-styryl-2H-pyran-2-one (Penstyrylpyrone) (1) (84%)
Bright yellow solid: mp 197–199 °C; 1H NMR (300 MHz, CDCl3) d 7.53 (d,
2H), 7.49 (d, J = 16 Hz, 1H), 7.40 (d, 2H), 7.35(t, 1H), 6.65 (d, J = 16 Hz, 1H), 6.17
(s, 1H), 3.91 (s, 3H), 1.97 (s, 3H) ppm. HRMS (ESI-QTOF) calcd for C15H15O3 [M
+H]+ 243.0943, found 243.1016. 13C NMR data agreed with the literature.1