A Convenient Preparation of Carboxy-γ-pyrone Derivatives: Meconic Acid and Comenic Acid

Full text of DOI:10.1080/00304948.2018.1525990

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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A Convenient Preparation of Carboxy-γ-pyrone
Derivatives: Meconic Acid and Comenic Acid
Paul Güntzel, Leonard Forster, Curd Schollmayer & Ulrike Holzgrabe
To cite this article: Paul Güntzel, Leonard Forster, Curd Schollmayer & Ulrike Holzgrabe (2018) A
Convenient Preparation of Carboxy-γ-pyrone Derivatives: Meconic Acid and Comenic Acid, Organic
Preparations and Procedures International, 50:5, 512-516, DOI: 10.1080/00304948.2018.1525990
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Organic Preparations and Procedures International, 50:512–516, 2018
# 2018 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2018.1525990
OPPI BRIEF
A Convenient Preparation of Carboxy-c-pyrone
Derivatives: Meconic Acid and Comenic Acid
€
Paul Guntzel, Leonard Forster, Curd Schollmayer, and
Ulrike Holzgrabe
Department of Pharmaceutical and Medicinal Chemistry, Institute of
€
Pharmacy, University of Wurzburg, Am Hubland, DE-97074
€
Wurzburg, Germany
The dried milky sap from Papaver somniferum, known as opium, contains several alkaloids
with pharmacological activity. The major alkaloidal components are morphine (about 10%
by weight), noscapine (about 6%) and papaverine (about 1%); the major non-alkaloidal con-
stituents are water and organic acids, including lactic acid and meconic acid (1, 3-hydroxy-
2,6-dicarboxy-c-pyrone) (5%).1–8 In the 19th century Serturner isolated morphine as its mec-
€
onate salt from opium, an early indication of the importance of organic acid salts.9,10
Salt formation of poorly water soluble organic bases with acids leads to increased solu-
bility in an aqueous environment compared to the non-associated form, and this explains
the high concentration of acids in opium.1–3 Since large counterions are able to prevent
strong lattice forces within the crystals, it was desired to use those large natural acids,
within a comprehensive screening program, for salt formation of basic, poorly water soluble
active pharmaceutical ingredients (APIs), in order to enhance their solubility.11,12 Here, it
was intended to use the natural organic acids meconic acid (1) and comenic acid (2, 5-
hydroxy-2-carboxy-c-pyrone) for salt formation with alkaloids. Hence, a transition-metal
free short and simple synthesis of 1 and 2 was developed (Scheme 1), as the known proce-
dures were unable to produce these compounds on substantial scale.13,14 As well, develop-
ment of new methods would permit further structural modifications of both acids.
For the oxidation of the alcohol functions in 4 the procedure described by Lovell et al.
was applied first.13 However, in our hands the direct oxidation of the benzylic alcohol in 4 to
the corresponding carboxylic acid in 1 by means of palladium failed. Using stronger oxidants
such as chromate instead of palladium, similarly failed. A selective procedure described by
Pace et al. recommends the protection of the enolic function before oxidation of the benzylic
alcohols with manganese dioxide, but again, in our hands, no product was obtained.14
Compounds 1 and 2 had been prepared starting from kojic acid 3 as depicted in
Scheme 1. For the synthesis of meconic acid, the introduction of a second
Received October 19, 2017; in final form May 2, 2018.
€
Address correspondence to Paul Guntzel, Department of Pharmaceutical and Medicinal
€
€
Chemistry, Institute of Pharmacy, University of Wurzburg, Am Hubland, DE-97074 Wurzburg,
Germany. E-mail: paul.guentzel@uni-wuerzburg.de
512

Meconic Acid and Comenic Acid
513
Scheme 1. Synthetic route for meconic acid and comenic acid.
hydroxymethyl group in position 6 via reaction of 3 with formaldehyde in basic metha-
nol to 4 was performed as previously described.13 Next protection of the enolic function
of 4 and 3 with benzyl bromide was required in order to achieve 5 and 6, respectively.14
For the oxidation of 5 and 6 to the corresponding carboxylic acids 7 and 8 the radical
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) in the presence of bis(acetoxy)iodoben-
zene (BAIB) was used, following the protocol described by Epp et al. for similar reac-
tions.15,16 Subsequent deprotection of the enolic group with Me3SiCl and sodium iodide
gave 1 and 2 in almost quantitative yields.
Salt formation is indeed an attractive concept to improve the aqueous solubility of
poorly water soluble APIs.17,18 Nature often uses organic acids as counterions for basic
substances to obtain salts.1 Accordingly, in this work the natural organic acids meconic
acid and comenic acid were synthesized for salt formation with alkaloids. As the well-
known synthetic procedure did not lead to 1, a new 4-step synthesis was developed,
applying a transition-metal free oxidation with protection of the enolic function as the
crucial step. Further advantages are the low costs and ready availability of the starting
materials as well as the easy synthetic procedure. In a similar way, a novel total synthe-
sis of 2 was realized with a satisfactory yield. This opens a potential avenue for the syn-
thesis of further derivatives of both acids for subsequent studies, as well.
Experimental Section
Chemicals were purchased from Sigma-Aldrich (Schnelldorf, Germany) or TCI
Chemicals (Eschborn, Germany) and were used without further purification. Anhydrous
solvents were purified and/or dried by standard techniques prior to being used. Melting
points were measured with a MPM-H2 melting point meter from Coesfeld GmbH &
Co. KG (Dortmund, Germany). 1H (400.132 MHz) and 13C (100.613 MHz) NMR

514
G€untzel et al.
spectra were recorded on a Bruker AV 400 instrument (Bruker Biopsin). As an internal
1
standard, the signals of the deuterated solvents were used (DMSO-d6: H 2.5 ppm, 13C
1
39.52 ppm; CDCl3: H 7.26 ppm, 13C 77.16 ppm). IR measurements were conducted on
a Jasco FT/IR-6100 spectrometer (Gross-Umstadt, Germany) with a diamond total
reflection unit. ASAP mass spectra were recorded on an Exactive Plus instrument
(Therma Scientific) with an Orbitrap mass analyzer at the Institute of Inorganic
€
Chemistry of the University of Wurzburg. Complete characterization data are available
from the authors upon request.
3-Hydroxy-2,6-dihydroxymethyl-c-pyrone (4). Compound 4 was prepared as
described by Lovell et al. All characterization data matched the literature.13
3-Benzyloxy-2,6-dihydroxymethyl-c-pyrone (5). Cs2CO3 (13.85 g, 42.52 mmol)
and 4 (7.32 g, 42.52 mmol) were dissolved in DMF (130 mL) and treated with a-bromo-
toluene (5.05 mL, 42.52 mmol). The reaction mixture was heated to 70 ꢀC and stirred
for 1.5 h. Then, a saturated solution of sodium chloride (150 mL) was added and the
mixture was extracted with CHCl3 (8 x 50 mL). The organic layer was dried over
anhydrous MgSO4 and evaporated under reduced pressure. After drying in vacuo 5 was
collected as a brownish solid (8.07 g, 72% yield) and used without further purification.
mp 97 ꢀC; IR (ATR, cmꢁ1): 3319, 3104, 2875, 1642, 1604, 1581, 1239, 1195, 1151,
1
1074, 1041, 1017, 964, 915, 876, 748, 699; H NMR (CDCl3): d (ppm) ¼ 4.31 (s, 2H,
CH2OH), 4.41 (s, 2H, CH2OH), 5.12 (s, 2H, CH2Ph), 6.41 (s, 1H, H5), 7.34 (m, 5H,
C6H5); 13C NMR (CDCl3): d (ppm) ¼ 56.9 (CH2), 60.7 (CH2), 74.3 (CH2), 112.6 (C5),
127.1 (C2), 128.7 – 142.3 (6C, (phe)), 159.5 (C3), 167.5 (C6), 176.9 (C4). All charac-
terization data matched the literature.19
3-Benzyloxy-2,6-dicarboxy-c-pyrone (7). Compound 5 (8.07 g, 30.77 mmol),
BAIB (29.73 g, 92.31 mmol), NaHCO3 (2.59 g, 30.77 mmol), and TEMPO (2.40 g,
15.38 mmol) were dissolved in a mixture of H2O (100 mL) and CH2Cl2 (100 mL) and
stirred at 0 ꢀC for 24 h. After phase separation, the aqueous layer was washed with
CH2Cl2 (2 x 40 mL) and reduced by three-quarters in vacuo. The pH of the solution
was adjusted to 0.5 by adding concentrated HCl. The resulting colorless precipitate was
filtered, washed with cold H2O and dried under vacuum to give 7 as a solvate (5.21 g,
58%). mp 175 ꢀC; IR (ATR, cmꢁ1): 3558, 1717, 1660, 1619, 1591, 1415, 1293, 1261,
1
1223, 1182, 1009, 972, 914, 891, 729, 693; H NMR (DMSO-d6): d (ppm) ¼ 5.14 (s,
2H, CH2Ph), 7.05 (s, 1H, H5), 7.33 - 7.46 (m, 5H, C6H5); 13C NMR (DMSO-d6): d
(ppm) ¼ 73.7 (CH2), 118.3 (C5), 128.2 – 136.4 (6C, (phe)), 147.0 (C2), 147.8 (C3),
152.3 (C6), 160.4 (COOH), 160.5 (COOH), 176.2 (C4).
Anal. Calcd for C14H10O7x1.6H2O: C, 52.70; H, 4.17. Found: C, 52.54; H, 3.93.
3-Hydroxy-2,6-dicarboxy-c-pyrone (1). Compound 7 (1.00 g, 3.45 mmol) and
sodium iodide (0.775 g, 5.17 mmol) were dissolved in dry MeCN (50 mL) under argon,
trimethylsilyl chloride (880 mL, 6.90 mmol) was added. The solution was first stirred at
70 ꢀC for 4 h. Then, H2O (120 mL) was added and the mixture was extracted with
methyl tert-butyl ether (MTBE) (3 x 50 mL) and then with CHCl3 (3 x 50 mL). The
aqueous layer was concentrated by three-quarters under reduced pressure and the pH of
the solution was adjusted to 0.5 with concentrated HCl. The solution was left at room
temperature until crystals were formed. The brownish crystals were collected, recrystal-
lized from 50% aqueous ethanol and dried in vacuo to give compound 1 (0.527 g,
1
76%). mp 290 ꢀC; IR (ATR, cmꢁ1): 3344, 2974, 1727, 1629, 1482, 1217, 910, 775; H
NMR (DMSO-d6): d (ppm) ¼ 6.98 (s, 1H, H5); 13C NMR (DMSO-d6): d (ppm) ¼ 115.2
(C5), 135.9 (C3), 150.6 (C2), 151.9 (C6), 160.7 (COOH), 163.4 (COOH), 174.8 (C4);

Meconic Acid and Comenic Acid
515
ASAP (neg.) mass spectrum m/z 198.9877 (calculated for C7H4O7 198.9873). All char-
acterization data matched the literature.13
5-Benzyloxy-2-hydroxymethyl-c-pyrone (6). Kojic acid (3) (5.00 g, 35.18 mmol)
and Cs2CO3 (11.46 g, 35.18 mmol) were dissolved in DMF (150 mL), a-bromotoluene
(4.2 mL, 35.18 mmol) was added and the reaction mixture heated to 70 ꢀC and stirred
for 0.5 h. Then, a saturated solution of sodium chloride (100 mL) was added and the
mixture extracted with CHCl3 (10 x 50 mL). The combined organic layers were dried
over anhydrous MgSO4 and evaporated under reduced pressure. 6 was collected as a
brownish solid (7.37 g, 90% yield) and used without further purification. mp 137 ꢀC; IR
(ATR, cmꢁ1): 3302, 3261, 1643, 1601, 1586, 1455, 1442, 1256, 1233, 1197, 1147,
1077, 1017, 946, 865, 740, 694; 1H NMR (CDCl3): d (ppm) ¼ 4.44 (d, 2H,
4
4J ¼ 0.97 Hz, CH2OH), 5.05 (s, 2H, CH2Ph), 6.53 (t, 1H, J ¼ 0.79 Hz, H5), 7.31 - 7.34
(m, 5H, C6H5), 7.53 (s, 1H, H2); 13C NMR (CDCl3): d (ppm) ¼ 61.1 (CH2), 72.2
(CH2), 112.5 (C3), 128.0 (C6), 128.6 – 142.0 (6C, (phe)), 147.1 (C5), 167.2 (C2), 175.1
(C4). All characterization data matched the literature.19,20
5-Benzyloxy-2-carboxy-c-pyrone (8). In a mixture of H2O (50 mL) and CH2Cl2
(50 mL), 6 (4.51 g, 19.42 mmol), BAIB (12.51 g, 38.84 mmol), NaHCO3 (1.63 g,
19.42 mmol) and TEMPO (1.52 g, 9.71 mmol) were dissolved and stirred at 0 ꢀC for 2h.
After phase separation, the aqueous layer was washed with CH2Cl2 (2 x 40mL) and con-
centrated by three-quarters under reduced pressure. The pH of the solution was adjusted to
0.5 by adding concentrated HCl. The obtained slightly orange precipitate was filtered,
washed with cold H2O and dried in vacuo to give 8 (2.48 g, 52%). mp 200 ꢀC; IR (ATR,
cmꢁ1): 3542, 3179, 3003, 1734, 1645, 1603, 1577, 1249, 1206, 996, 940, 882, 741, 698;
1H NMR (DMSO-d6): d (ppm) ¼ 4.98 (s, 2H, CH2Ph), 6.94 (s, 1H, H5), 7.34 - 7.46 (m,
5H, C6H5), 8.36 (s, 1H, H2); 13C NMR (DMSO-d6): d (ppm) ¼ 70.7 (CH2), 117.1 (C3),
128.2 – 135.8 (6C, (phe)), 141.5 (C6), 148.2 (C5), 152.6 (C2), 160.8 (COOH), 173.0 (C4).
All characterization data matched the literature.20
5-Hydroxy-2-carboxy-c-pyrone (2). Compound 8 (0.50 g, 2.03 mmol) and sodium
iodide (0.457 g, 3.05 mmol) were dissolved in dry MeCN (40 mL) under argon and tri-
methylsilyl chloride (370 mL, 3.05 mmol) was added. The solution first stirred at 70 ꢀC
for 5.5 h. Then, H2O (100 mL) was added and the mixture was extracted with MTBE (2
x 20 mL) and then with CH2Cl2 (4 x 20 mL). The aqueous layer was concentrated by
three-quarters under reduced pressure and the pH of the solution was adjusted to 1 with
concentrated HCl. The solution was left at room temperature until crystals were formed.
The brownish crystals were collected, recrystallized from 50% aqueous ethanol and
dried in vacuo to give compound 2 (0.29 g, 92%). mp 286 ꢀC; IR (ATR, cmꢁ1): 3329,
1
3085, 2838, 2552, 1725, 1628, 1559, 1536, 1219, 1201, 1142, 1098, 936, 905, 760; H
NMR (DMSO-d6): d (ppm) ¼ 6.95 (s, 1H, H3), 8.19 (s, 1H, H6); 13C NMR (DMSO-
d6): d (ppm) ¼ 116.0 (C3), 140.3 (C5), 147.7 (C6), 152.4 (C2), 160.8 (COOH), 173.7
(C4); ASAP (neg.) mass spectrum m/z 154.9975 (calculated for C6H3O5 154.9975). All
characterization data matched the literature.21
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