The Dianion of Dehydroacetic Acid: A Direct Synthesis of Pogopyrone A

Article abstract of DOI:10.1055/s-0037-1610752

Dehydroacetic acid was converted into a silyl enol ether and titanium enolate. These reacted effectively with aldehydes and N -bromosuccinimide. Oxidation of the adduct with benzaldehyde afforded pogopyrone A in excellent overall yield.

Full text of DOI:10.1055/s-0037-1610752

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–C
paper
A
en
S. Wang, G. A. Kraus
Paper
Synthesis
The Dianion of Dehydroacetic Acid: A Direct Synthesis of
Pogopyrone A
Shuai Wang
O
O
O
OH
O
O
O
Si or Ti reagent
1) RCHO
2) DMP
George A. Kraus*
0
0
0
0-
0
0
0
2-3
0
3
7-8
4
1
3
O
O
O
R
X
HO
O
HO
Department of Chemistry, Iowa State University, Ames,
IA 50010, USA
gakraus@iastate.edu
X = Me2Si or Cl2Ti
Step 1)
6 Examples
Yield: 50–83%
R = Phenyl, Vinyl, Alkyl
Pogopyrone A (R = Phenyl)
Overall yield: 62%
Received: 07.01.2020
Accepted after revision: 28.01.2020
Published online: 12.02.2020
O
O
O
O
O
O
Si
DOI: 10.1055/s-0037-1610752; Art ID: ss-2020-m0015-op
O
HO
2
1
Abstract Dehydroacetic acid was converted into a silyl enol ether and
titanium enolate. These reacted effectively with aldehydes and N-bro-
mosuccinimide. Oxidation of the adduct with benzaldehyde afforded
pogopyrone A in excellent overall yield.
Figure 1 Structures of dehydroacetic acid and silyl enol ether 2
O
O
OH
O
O
Me2SiCl2
Et3N
Key words dianion, dehydroacetic acid, silyl enol ether, titanium eno-
late, pogopyrone A
O
R
O
then
HO
RCHO
HO
O
O
OH
O
O
OH
O
O
Dehydroacetic acid (1) is a readily available, biobased
pyrone. It has been employed in a number of condensations
including acylations, Mannich condensations and aldol
condensation–dehydrations mediated by secondary
amines. Its chemistry has been summarized in a recent re-
view.1 Metal complexes of 1 are also well documented.2
Harris and co-workers reported the preparation and use of
the trianion of 1, generated in ammonia using sodium
amide.3 Despite the extensive carbanion chemistry of 1, al-
kylation or aldol formation via the dianion of 1 does not ap-
pear to have been reported.4 When we attempted to depro-
tonate 1 using 2 equivalents of lithium diisopropylamide
followed by the addition of benzaldehyde, we obtained the
expected aldol product in only 27% yield. The majority of
the material was starting material. Reasoning that the cor-
responding silyl enol ether 2 might be more reactive, we re-
acted 1 with dichlorodimethylsilane and triethylamine in
dichloromethane at room temperature. This process afford-
ed the silane 2 in 99% yield (Figure 1).
Br
O
O
O
HO
HO
HO
3b 83%
3a
69%
4
72%
Scheme 1 Addition reactions via silyl enol ether 2
Although 2 made possible the synthesis of compounds
on millimole scales, its tendency to decompose during stor-
age prompted us to evaluate other dianion equivalents. Al-
though the boron or tin enolate was unreactive, the titani-
um enolate, generated via titanium tetrachloride and N,N-
diisopropylethylamine in dichloromethane at –78 °C, af-
forded an 80% yield of the aldol product 3a with benzalde-
hyde. Workup conditions at low temperature were essential
to minimize dehydration. The products and yields are
shown in Scheme 2. This chemistry was scalable and 3b
was synthesized on a 50 mmol scale.
Pogopyrone A (5) is a compound isolated from Pogoste-
mon heynianus Benth Syn.6 Although the acylation of either
silyl enol ether 2 or the titanium enolate of 1 with benzoyl
chloride gave no product, oxidation of 3a with Dess–Martin
periodinane (DMP) afforded a 78% yield of pogopyrone A
(enol/keto = 4:1) (Scheme 3).
Compound 2, which could be generated in situ, reacted
readily with a number of aldehydes and N-bromosuccinim-
ide.5 Boron trifluoride etherate was an effective Lewis acid
catalyst for the aldol reaction. The products and yields are
listed in Scheme 1.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–C
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Wang, G. A. Kraus
Paper
Synthesis
(10 mL) was added to quench the reaction, and the mixture was ex-
tracted with ethyl acetate (3 × 10 mL). The combined organic layers
were dried over sodium sulfate and concentrated. Purification by col-
umn chromatography on silica gel (hexane/ethyl acetate, 10:1 (v/v))
gave the product.
O
O
TiCl4
OH
O
O
N,N-diisopropylethylamine
O
O
R
O
RCHO
HO
HO
OH
O
O
OH
O
O
OH
O
O
O
O
4-Hydroxy-3-(3-hydroxy-3-phenylpropanoyl)-6-methyl-2H-
pyran-2-one (3a)
HO
HO
HO
3a 80%
3b 75%
3c 77%
Yellow oil; yield (Si method): 189 mg (69%); yield (Ti method): 219
mg (80%).
1H NMR (400 MHz, CDCl3):  = 7.44–7.42 (m, 2 H), 7.38–7.34 (m, 2 H),
7.30–7.26 (m, 1 H), 5.97 (s, 1 H), 5.26 (dd, J = 8.1, 3.9 Hz, 1 H), 3.59–
3.44 (m, 2 H), 3.12 (d, J = 3.9 Hz, 1 H), 2.28 (s, 3 H).
OH
O
O
OH
O
O
OH
O
O
O
O
O
HO
HO
HO
3d 67%
3e 50%
3f 74%
13C NMR (100 MHz, CDCl3):  = 205.8, 181.0, 169.6, 161.3, 142.9,
Scheme 2 Addition reactions via the titanium enolate
128.5, 127.7, 125.8, 101.5, 100.0, 70.3, 50.5, 20.8.
HRMS (ESI-TOF): m/z [M – H]– calcd for C15H13O5: 273.0768; found:
273.0771.
OH
O
O
OH
O
O
DMP
O
O
4-Hydroxy-3-(3-hydroxy-4-methylpentanoyl)-6-methyl-2H-
pyran-2-one (3b)
HO
HO
3a
5
78%
Colorless oil; yield (Si method): 199 mg (83%); yield (Ti method): 180
mg (75%).
Scheme 3 Synthesis of pogopyrone A
1H NMR (400 MHz, CDCl3):  = 5.96 (s, 1 H), 3.90 (ddd, J = 8.8, 5.5, 2.9
Hz, 1 H), 3.28–3.22 (m, 1 H), 3.17 (dd, J = 16.7, 9.3 Hz, 1 H), 2.70 (s, 1
H), 2.27 (s, 3 H), 1.78 (pd, J = 6.8, 5.6 Hz, 1 H), 0.98 (d, J = 4.5 Hz, 3 H),
0.97 (d, J = 4.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 207.5, 181.0, 169.3, 161.4, 101.5,
100.1, 72.9, 45.8, 33.6, 20.7, 18.5, 17.6.
Selective reactions at the acetyl group of 1 have been
achieved via either silyl enol ether 2 or the titanium enolate
of 1. The titanium chemistry can be scaled to make 3b on a
50 mmol scale. A direct synthesis of pogopyrone A was
achieved.
HRMS (ESI-TOF): m/z [M – H]– calcd for C12H15O5: 239.0925; found:
239.0925.
1H and 13C NMR spectra were recorded on Varian MR-400 M and
Bruker AV III 600 M spectrometers. Chemical shifts are reported in
3-(3-Cyclohexyl-3-hydroxypropanoyl)-4-hydroxy-6-methyl-2H-
pyran-2-one (3c)
ppm from the solvent resonance as the internal standard (CDCl3: H
=
White solid; mp 70–72 °C; yield (Ti method): 215 mg (77%).
7.26 ppm, C = 77.16 ppm). Multiplicity is indicated as follows: s (sin-
glet), d (doublet), t (triplet), q (quartet), p (pentet), m (multiplet).
High-resolution mass spectrometry (HRMS) data were obtained on
an Agilent QTOF 6540 instrument.
1H NMR (400 MHz, CDCl3):  = 5.96 (s, 1 H), 3.91 (ddd, J = 8.9, 5.8, 2.8
Hz, 1 H), 3.27 (dd, J = 16.7, 2.9 Hz, 1 H), 3.19 (dd, J = 16.7, 9.3 Hz, 1 H),
2.28 (s, 3 H), 1.91 (d, J = 12.8 Hz, 1 H), 1.82–1.62 (m, 4 H), 1.45 (dddt,
J = 11.6, 8.8, 6.0, 2.9 Hz, 1 H), 1.31–0.98 (m, 5 H).
13C NMR (100 MHz, CDCl3):  = 207.6, 181.0, 169.3, 161.4, 101.5,
Addition Reactions via Silyl Enol Ether 2; General Procedure
100.1, 72.4, 46.0, 43.5, 28.9, 28.1, 26.4, 26.2, 26.1, 20.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H21O5: 281.1384; found:
281.1385.
To a stirred solution of dehydroacetic acid (168 mg, 1.0 mmol) in di-
chloromethane (5.0 mL) was added dichlorodimethylsilane (129 mg,
1.0 mmol) followed by triethylamine (202 mg, 2.0 mmol) at 0 °C. The
mixture was stirred for 90 min at room temperature. Then, boron tri-
fluoride etherate (284 mg, 2.0 mmol) and aldehyde (2.0 mmol) were
added to the flask at 0 °C, and the mixture was stirred at 0 °C for 2 h.
Sat. ammonium chloride solution (10 mL) was added to quench the
reaction, and the mixture was extracted with ethyl acetate (3 × 10
mL). The combined organic layers were dried over sodium sulfate and
concentrated. Purification by column chromatography on silica gel
(hexane/ethyl acetate, 10:1 (v/v)) gave the product.
4-Hydroxy-3-(3-hydroxy-4,4-dimethylpentanoyl)-6-methyl-2H-
pyran-2-one (3d)
Colorless oil; yield (Ti method): 170 mg (67%).
1H NMR (400 MHz, CDCl3):  = 5.95 (s, 1 H), 3.79 (d, J = 10.2 Hz, 1 H),
3.47 (s, 1 H), 3.31–3.20 (m, 1 H), 3.15 (m, 1 H), 2.27 (s, 3 H), 0.97 (s, 9
H).
13C NMR (100 MHz, CDCl3):  = 207.8, 181.0, 169.3, 161.5, 101.5,
100.2, 75.9, 43.8, 34.9, 25.6, 20.7.
Addition Reactions via the Titanium Enolate; General Procedure
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H19O5: 255.1227; found:
255.1228.
To a stirred solution of dehydroacetic acid (168 mg, 1.0 mmol) in di-
chloromethane (5.0 mL) was added titanium tetrachloride (209 mg,
1.1 mmol) followed by N,N-diisopropylethylamine (284 mg, 2.2
mmol) at –78 °C. The mixture was stirred for 30 min at that tempera-
ture. Then, aldehyde (1.2 mmol) was added to the flask, and the mix-
ture was stirred at –78 °C for 2 h. Sat. ammonium chloride solution
4-Hydroxy-3-(3-hydroxy-4-methylpent-4-enoyl)-6-methyl-2H-
pyran-2-one (3e)
Yellow oil; yield (Ti method): 119 mg (50%).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–C

C
S. Wang, G. A. Kraus
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 5.97 (s, 1 H), 5.08–5.02 (m, 1 H), 4.89
(d, J = 1.7 Hz, 1 H), 4.64–4.56 (m, 1 H), 3.32 (d, J = 6.5 Hz, 2 H), 2.81 (d,
J = 4.0 Hz, 1 H), 2.28 (s, 3 H), 1.80 (s, 3 H).
overnight. After reaction completion, dichloromethane was removed
by rotary evaporation. Purification by column chromatography on sil-
ica gel (hexane/ethyl acetate, 10:1 (v/v)) gave 5.
13C NMR (100 MHz, CDCl3):  = 206.3, 181.0, 169.5, 161.4, 146.0,
Yellow solid; mp 138–140 °C; yield: 106 mg (78%).
111.2, 101.5, 100.0, 71.5, 47.2, 20.7, 18.4.
HRMS (ESI-TOF): m/z [M – H]– calcd for C12H13O5: 237.0757; found:
1H NMR (400 MHz, CDCl3):  = 8.12–7.91 (m, 2 H), 7.73 (s, 1 H), 7.54–
7.46 (m, 1 H), 7.46 (d, J = 7.8 Hz, 2 H), 5.93 (s, 1 H), 2.25 (s, 3 H).
237.0764.
13C NMR (100 MHz, CDCl3):  = 193.3, 180.0, 177.6, 167.8, 160.9,
133.5, 132.5, 128.7, 127.2, 101.8, 97.6, 95.6, 20.5.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H13O5: 273.0757; found:
273.0757.
4-Hydroxy-3-(3-hydroxy-5-methylhexanoyl)-6-methyl-2H-pyran-
2-one (3f)
Colorless oil; yield (Ti method): 188 mg (74%).
1H NMR (600 MHz, CDCl3):  = 5.97 (s, 1 H), 4.24 (ddt, J = 6.3, 4.4, 2.0
Hz, 1 H), 3.30–3.25 (m, 1 H), 3.21–3.14 (m, 1 H), 2.73 (s, 1 H), 2.29 (s, 3
H), 1.97–1.78 (m, 1 H), 1.62–1.53 (m, 1 H), 1.31 (ddd, J = 13.8, 6.7, 3.5
Hz, 1 H), 0.94 (d, J = 6.8 Hz, 6 H).
Funding Information
We thank KeyPlex for partial support of this work.()
13C NMR (150 MHz, CDCl3):  = 207.0, 181.0, 169.4, 161.3, 101.5,
100.0, 66.3, 49.2, 46.1, 24.5, 23.3, 22.1, 20.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H19O5: 255.1227; found:
Supporting Information
255.1225.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610752.
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3-(2-Bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one (4)
White solid; mp 114–116 °C; yield (Si method with NBS, boron triflu-
oride etherate not needed): 178 mg (72%).
References
1H NMR (600 MHz, CDCl3):  = 6.01 (s, 1 H), 4.70 (s, 2 H), 2.31 (s, 3 H).
13C NMR (150 MHz, CDCl3):  = 197.3, 181.0, 170.1, 160.6, 101.3, 98.4,
(1) Fadda, A. A.; Elattar, K. M. Synth. Commun. 2016, 46, 1.
(2) Chalaça, M. Z.; Figueroa-Villar, J. D.; Ellena, J. A.; Castellano, E. E.
Inorg. Chim. Acta 2002, 328, 45.
35.2, 20.8.
(3) Harris, T. M.; Harris, C. M. Chem. Commun. 1966, 699.
(4) Ricardo, L.; Konstantinos, A. A.; Doundoulakis, T.; Simonsen, K.
B.; Webber, S. E.; Xiang, A. X. Heterocycles 2006, 68, 1099.
(5) Lechani, N.; Hamdi, M.; Kheddis-Boutemeur, B.; Talhi, O.; Laichi,
Y.; Bachari, K.; Silva, A. M. S. Synlett 2018, 29, 1502.
(6) Thailambal, V. G.; Pattabhi, V.; Gabe, E. J. Acta Crystallogr., Sect. C
1986, 42, 1017.
HRMS (ESI-TOF): m/z [M – H]– calcd for C8H6BrO4: 244.9450; found:
244.9445.
4-Hydroxy-3-[(Z)-3-hydroxy-3-phenylacryloyl]-6-methyl-2H-
pyran-2-one (Pogopyrone A, 5)
To a stirred solution of 3a (137 mg, 0.5 mmol, 1.0 equiv) in dichloro-
methane (13 mL) was added Dess–Martin periodinane (318 mg, 0.75
mmol, 1.5 equiv), and the mixture was stirred at room temperature
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–C