Synthesis of regioselectively protected protocatechuic acid derivatives by biomimetic transformation of quinic acid

Article abstract of DOI:10.3390/51001094

3- and 4-monoesterified protocatechuic acid methyl ester (5 and 7 respectively) have been synthesised from quinic acid by a high yields biomimetic rearrangement.

Full text of DOI:10.3390/51001094

Molecules 2000, 5, 1094–1100
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of Regioselectively Protected Protocatechuic Acid
Derivatives by Biomimetic Transformation of Quinic Acid.
Armandodoriano Bianco*, Francesco Bonadies, Cristiana Melchioni
Dipartimento di Chimica, Università “La Sapienza”, Piazzale Aldo Moro n. 5, I-00185, Roma, Italy
* Author to whom correspondence should be addressed. Fax: 39 06 490631; e-mail:
adbianco@axrma.uniroma1.it
Received: 7 Apr 2000; in revised form 11 Sep 2000 / Accepted: 19 Sep 2000 / Published: 31 Oct 2000
Abstract: 3- and 4-monoesterified protocatechuic acid methyl ester (5 and 7
respectively) have been synthesised from quinic acid by a high yields biomimetic
rearrangement.
Keywords: protocatechuic acid, quinic acid, diastereoselective synthesis
Introduction
The preparation of regioselectively protected protocatechuic acid derivatives has not been
previously described, owing to the difficulty of discriminating between the two very similar, from a
chemical reactivity point of view, phenolic hydroxyls. Ciamician et al. [1] described, for the first time,
the preparation, by partial esterification, of the mixture of the two monoacetyl derivatives of
protocatechuic acid. Later Fischer et al. [2] reported the preparation of 3-acetyl-protocatechuic acid by
partial alkaline hydrolysis of protocatechuic acid diacetate. A similar procedure was also reported by
Lesser et al. [3]. Chromatographic detection of 3-acetyl-protocatechuic acid in natural sources [4] or in
synthetic mixtures [5] has also been described.

Molecules 2000, 5
1095
4-acetyl-protocatechuic acid, on the contrary, was only detected in 1966 as a microbial degradation
metabolite of chloramphenicol [6].
Results and discussion
We obtained high yield transformations of the quinic acid skeleton, with formation of aromatic
protocatechuic acid derivatives, during the course of our research work to develop antiviral drugs
active against influenza viruses [7]. Compound 3, obtained from quinic acid 1, as described in Scheme
A, was a key intermediate in our synthetic strategy.
CO2CH3
CO2CH3
HO
CO2H
1
i, ii, iii, iv
v, vi, vii
6
2
5
HO
OH
HO
OH
3
HO
OAc
4
OH
OH
OH
1
2
3
Scheme A. Reagents and conditions: i, CH3OH, H2SO4; ii, Ac2O, pyr; iii, SOCl2, pyr; iv, CH3OH, H2SO4; v,
2,2-dimethoxypropane, acetone, Dowex-50 H+; vi, Ac2O, pyr; vii, AcOH/H2O,
.
The next step of our synthetic project made provision for the regioselective oxidation of the allylic
hydroxyl group with Jones’s reagent, to afford the keto derivative 4 (see scheme B). Nevertheless we
have not succeeded in obtaining significant amounts of compound 4. In fact, even when we utilised
oxidative conditions other than Jones’ reagent, the oxidation of 3 to 4 is always overcome by the quite
complete aromatization of ring, yielding 3-acetyl-protocatechuic acid methyl ester, 5 (scheme B).
CO2CH3
CO2CH3
CO2CH3
i
+
HO
OAc
OAc
O
OAc
OH
OH
OH
5, 92%
3
4, 8%
Scheme B. Reagents and conditions: i, Jones’s reagent, acetone
In our opinion this reaction route happens due to a fast 1,4-type elimination of a water molecule
from keto derivative 4, catalysed by the acidic medium. The mechanism of this aromatization,
proposed in Scheme C, is based on a series of keto-enol equilibria which, starting from the 3-keto-

Molecules 2000, 5
1096
derivative 4, with the catalysis of the strong acidic medium, gives rise to the formation of the 4-keto-
derivative 4’. From compound 4’ a molecule of water is irreversibly eliminated, with the formation of
the aromatic protocatechuic acid derivative 5. An aromatization process of other cyclohexene
derivatives that follows a different mechanism in which a lactone intermediate is involved has been
described [8].
CO2CH3
CO2CH3
CO2CH3
CO2CH3
H
CO2CH3
-H2O
O
OAc
HO
OAc
OAc
HO
OAc
HO
OAc
OH
O
OH
OH
OH
5
4
4'
Scheme C. Proposed rearrangement mechanism.
On the other hand, our result is not surprising because the biogenesis of protocatechuic acid starts
from quinic acid [9] and the key intermediates are keto derivatives, as described in Scheme D. Quinic
acid is in fact metabolised by initial conversion to 3-dehydroquinic acid and, after elimination of a
water molecule to form 3-dehydroshikimic acid, is then converted to protocatechuic acid by a 1,2 type
elimination of a proton and C-5 hydroxyl group induced by the enzyme 3-dehydroshikimate
dehydratase [10].
CO2H
CO2H
HO CO2H
HO CO2H
HO
OH
HO
O
OH
O
OH
OH
OH
OH
OH
protocatechuic acid
3-dehydroquinic acid
3-dehydroshikimic acid
quinic acid
Scheme D. Biosynthesis of protocatechuic acid.
At this point, we decided to verify the possibility of directing the reaction also towards the 1,2-type
elimination. In order to do that, the free 4-OH of compound 4 was protected with a different ester and
for this we chose the mesyl group. The hydroxyl at C-4 was esterified with methanesulfonyl chloride,
as depicted in Scheme E leading to the quantitative formation of product 6. Subsequent treatment of
o
compound 6 at moderately high temperature (80 C ) in dimethylformamide brought about the
predominant formation of the totally unsaturated product 7 (Scheme E) in 93% yield.

Molecules 2000, 5
1097
CO2CH3
CO2CH3
CO2CH3
i ii
iii
O
OAc
O
OAc
HO
OR
OH
OR
7 R=Ms
7' R=Ac
6 R=Ms
6' R=Ac
4
Scheme E. Reagents and conditions: i, CH3SO2Cl, Et3N, CH2Cl2, 0°C; ii, Ac2O, pyr; iii, DMF,
.
The same reaction, performed on the diacetyl derivative 6’, obtained from 4 by esterification with
acetic acid, afforded the monoacetate 7’, with comparable yields. In this case the proposed mechanism
(see Scheme F) is a 1,2-type elimination of acetic acid from the enolic form of the keto derivative 6.
CO2CH3
CO2CH3
CO2CH3
-AcOH
O
OAc
HO
OAc
HO
OR
OR
OR
6 R=Ms
6' R=Ac
7 R=Ms
7' R=Ac
Scheme F. Proposed rearrangement mechanism
Conclusions
In conclusion, it is possible to direct the dehydration of shikimic acid derivatives acid towards a
regioselective water elimination, which may be considered an acid catalysed aromatization, or towards
a type 1,2 thermal elimination, probably occurring with an Ei mechanism. These procedures afford
monoprotected protocatechuic acid methyl esters in very high yields. Even though these protocols do
not appear to be very short, owing to the interest of protocatechuic acid as antioxidants, the complete
regioselectivity observed in the preparation of monoprotected derivatives overcomes this
inconvenience.
Acknowledgements. This work is a part of a project supported by Istituto Pasteur - Fondazione Cenci
Bolognetti, Università di Roma “La Sapienza”.
Experimental

Molecules 2000, 5
1098
General
1H-NMR spectra were measured with a Varian Gemini 200 MHz spectrometer and chemical shifts are
expressed in ppm from TMS. Product purification was accomplished by solid-liquid column
chromatography on Merck 0.063 - 0.20 nm silica gel; using the elution mixtures listed under each
heading. Merck TLC plates coated with Kiesel-Gel 60 F254 were employed to monitor the reactions.
Detection was done using 2N H2SO4, heating at 120°C or 2,4-DNF for the carbonyl compounds.
Syntheses
Methyl 5-acetyl shikimate (3): Synthesis of compound 3 was described in ref. 11. 1H-NMR (200 MHz,
CDCl3), δ 2.09 (s, 3H, AcO), 2.25-2.35 (dd, 1H, H-6ax), 2.81-2.91 (dd, 1H, H-6eq), 3.73 (s, 3H,
CO2CH3), 3.85 (dd, 1H, H-4), 4.42 (m, 1H, H-3), 5.18 (m, 1H, H-5), 6.85 (m, 1H, H-2).
Methyl 5-acetyl-3-keto shikimate (4) and methyl 3-acetyl-protocatechuicate (5): compound 3 (200 mg)
was dissolved in acetone (10 mL) under stirring and, Jones’ reagent was added dropwise. When the
solution became persistent orange-brown coloured, the reaction was complete as the evidence by TLC.
Sodium tiosulphate was added until a green colour was observed, then the reaction mixture was
neutralised with barium carbonate and filtered through Celite. Volatile materials were evaporated in
vacuo and the residue purified by Si gel chromatography, eluting with ethyl acetate / chloroform (6:4)
1
to give 4 (15 mg, 8% yield) and compound 5 (166 mg, 92% yield), both as colourless oils. H-NMR
compound 4 (200 MHz, CDCl3): δ 2.15 (s, 3H, AcO), 2.60 (m, 1H, H-6ax), 3.30 (dd, 1H, H-6eq), 3.85
(s, 3H, CO2CH3), 4.30 (d, 1H, H-4), 5.10 (m, 1H, H-5), 6.90 (d, 1H, H-2). 1H-NMR compound 5 (200
MHz, CDCl3): δ 2.33 (s, 3H, AcO), 3.62 (s, 3H, CO2CH3), 6.3 (s, 1H, OH), 7.69 (d, 1H, J= .8 Hz),
7.82 (dd, 1H, J=1.8, 7.9 Hz), 8.12 (d, 1H, J=7.9 Hz).
Methyl 5-acetyl-3-keto-4-mesyl shikimate (6): Compound 4 (50 mg) was dissolved in dichloromethane
(2.5 mL) and the solution cooled at 0 °C. triethylamine (0.1 mL) was added, followed by dropwise
addition of methanesulfonyl chloride (0.05 ml). The reaction mixture was stirred at 0 °C for 2 h. The
mixture was then diluted with dichloromethane, the organic phase washed with water and dried over
anhydrous sodium sulphate. The volatile materials were removed in vacuo and the residue was purified
by Si gel chromatography, eluting with chloroform / ethyl acetate (7:3), to give 6 (58 mg, 86% yield) as
a colourless oil. 1H-NMR (200 MHz, CDCl3): δ 2.12 (s, 3H, AcO), 2.60 (m, 1H, H-6ax), 3.11 (s, 3H,
SO2CH3), 3.31 (m, 1H, H-6eq), 3.82 (s, 3H, CO2CH3), 4.81 (m, 1H, H-4), 5.05 (m, 1H, H-5), 6.91 (d,
1H, H-2).

Molecules 2000, 5
1099
Methyl 4,5-diacetyl-3-keto shikimate (6’): Compound 4 (50 mg) was dissolved in pyridine (0.1 mL)
and acetic anhydride (0.2 mL) was added. The reaction mixture was allowed to stand at room
temperature. After 1 h compound 6’ was formed, as shown by TLC using chloroform / ethyl acetate
(8:2) as eluent. Methanol was added to the reaction mixture and the volatile materials were removed in
vacuo. The residue was purified by chromatography eluting with chloroform / ethyl acetate (8:2) to
give 6’ (51 mg, 86% yield). 1H-NMR (200 MHz, CDCl3): δ 2.12, 2.14 (s, 2x3H, 2xAcO), 2.62 (m, 1H,
H-6ax), 3.28 (m, 1H, H-6eq), 3.78 (s, 3H, CO2CH3), 4.80 (m, 1H, H-4), 5.03 (m, 1H, H-5), 6.94 (d,
1H, H-2).
Methyl 4-mesyl-protocatechuicate (7): compound 6 (100 mg) was dissolved in anhydrous DMF (4 mL)
and the reaction mixture was heated at 80°C under stirring for 2 h. The reaction mixture was then
diluted with ethyl acetate, successively washed with saturated aqueous ammonium chloride, water and
brine, and dried over anhydrous sodium sulphate. The solvents were evaporated in vacuo and the
residue purified by Si gel chromatography, eluting with chloroform / ethyl acetate (6:4) to give
compound 7 (80 mg, 93% yield) as a yellow oil. 1H-NMR (200 MHz, CDCl3): δ 3.13 (s, 3H, SO2CH3)
3.70 (s, 3H, CO2CH3), 6.1 (s, 1H, OH), 7.67 (d, 1H, J=1.8 Hz), 7.91 (dd, 1H, J=1.8, 7.4 Hz), 8.10 (d,
1H, J=7.4 Hz).
Methyl 4-acetyl-protocatechuicate (7’): Compound 6’, under the same reaction conditions as described
for compound 6, afforded compound 7’, as a colourless viscous oil, in 94% yield. 1H-NMR (200 MHz,
CDCl3): δ 2.25 (s, 3H, AcO), 3.70 (s, 3H, CO2CH3), 6.1 (s, 1H, OH), 7.67 (d, 1H, J=1.8 Hz), 7.91 (dd,
1H, J=1.8, 7.4 Hz), 8.10 (d, 1H, J=7.4 Hz).
References and Notes
1. Ciamician, G; Silber, P. Chem. Ber., 1892, 25, 1470.
2. Fischer, E.; Bergman, M.; Lipschitz, W. Chem. Ber., 1918, 51, 74.
3. Lesser, R.; Gad, G. Chem. Ber., 1926, 59, 233
4. Schuster, B.; Winter, M.; Herrmann, K. Z. Naturforsh., C: Biosci. 1986, 41, 511.
5. Wagner, G.; Bohm, M. Pharm. Zentralhalle 1959, 98, 181.
6. Eberhardt, H.; Oltmanns, O. Biochim. Biophys. Acta 1966, 130, 245.
7. Bianco, A.; Brufani, M.; Ciabatti, R.; Melchioni, C.; Pasquali, V. Molecules Online 1998, 2, 129.
8. Palazzo, G.; Baiocchi, L. Tetrahedron Lett., 1968, 4739.

Molecules 2000, 5
1100
9. Sharf, K.H.; Zenk, M.H.; Onderka, D.K.; Carroll, M.; Floss, H.G. J. Chem. Soc. Chem. Comm.
1971, 765.
10. Knowles, P.F.; Haslam, E.; Haworth, R.D. J. Chem. Soc. 1961, 1854.
11. Bianco, A.; Brufani, M.; Manna, F.; Melchioni C., Carbohydr. Res., submitted.
Sample Availability: Samples are available from the authors
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes