Synthesis of p-coumaroylquinic acids and analysis of their interconversion

Article abstract of DOI:10.1016/j.tetasy.2017.01.015

The synthesis of four isomers of p-coumaroylquinic acids was performed by esterification of p-acetylcoumaroylchloride with a suitably protected (?)-quinic acid. All isomers have been characterized by means of NMR spectroscopy and circular dichroism. Acyl migration was observed in the synthesis of 3-O-p-coumaroylquinic acid and 4-O-p-coumaroylquinic acid. Calculations on the most stable conformations of all isomers have also been performed to explain the acyl migration observed during the synthesis procedure.

Full text of DOI:10.1016/j.tetasy.2017.01.015

Tetrahedron: Asymmetry 28 (2017) 419–427
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of p-coumaroylquinic acids and analysis of their
interconversion
Anggy Lusanna Gutiérrez Ortiz a, Federico Berti a, Luciano Navarini b, Angelo Monteiro c, Marina Resmini c,
Cristina Forzato a,
⇑
a Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, via L. Giorgieri 1, 34127 Trieste, Italy
b illycaffè S.p.A., via Flavia 143, 34100 Trieste, Italy
c School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of four isomers of p-coumaroylquinic acids was performed by esterification of p-acetyl-
coumaroylchloride with a suitably protected (ꢀ)-quinic acid. All isomers have been characterized by
means of NMR spectroscopy and circular dichroism. Acyl migration was observed in the synthesis of
3-O-p-coumaroylquinic acid and 4-O-p-coumaroylquinic acid. Calculations on the most stable conforma-
tions of all isomers have also been performed to explain the acyl migration observed during the synthesis
procedure.
Received 19 November 2016
Revised 19 January 2017
Accepted 26 January 2017
Available online 23 February 2017
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
tices as well as the soil composition.3 The most abundant CGA is
5-caffeoylquinic acid 2b (also called chlorogenic acid, Fig. 1), but
Chlorogenic acids belong to the family of phenolic compounds
often found in plants,1,2 that are secondary metabolites involved
in defense mechanisms against environmental stress.3 Although
chlorogenic acids are present in many vegetables4 and fruits, such
as potatoes, pears, apples and berries,5 green coffee beans are par-
ticularly rich in these compounds.6,2 Coffee is in fact the main
source of chlorogenic acids in the human diet.5 Moreover, chloro-
genic acids can be used as indicators of coffee quality,5,7 since
the final content of chlorogenic acids and their corresponding lac-
tones formed after roasting are responsible for the acidity and bit-
terness of the beverage.6,8 Over the last few years, some health
benefits have also been associated with chlorogenic acids and sev-
eral reports have claimed that chlorogenic acids can contribute to
the prevention of cardiovascular diseases and types 2 diabetes.5,9–
a total number of 76 chlorogenic acids have been isolated and
identified in the last few years.10 p-Coumaroylquinic acids are less
abundant and for this reason are the less studied10 so there is a lack
of information on their contribution to the aroma of coffee. The
experimental procedure for the quantification of chlorogenic acids
in coffee beans is relatively complex since it comprises of extrac-
tion, separation and purification processes and their identification
and quantification is usually carried out by HPLC coupled with
mass spectrometry.3,6,10,14 For this reason, it is important to have
analytical standards to unequivocally determine their presence in
coffee. Since Panizzi et al.15,16 reported the first synthesis of chloro-
genic acids, several literature reports have described the synthesis
of different isomers of caffeoylquinic acid (Sefkow et al.)17,18 and
feruloylquinic acid (Dokli et al.).19 In 1961 Haslam et al.20 synthe-
sized for the first time 5-O-p-coumaroylquinic acid using a conden-
sation reaction and subsequently in 196421 the same authors
synthesized the other three isomers using acyl migration as the
synthetic method. It is important to highlight that a different num-
bering system for the substituents on the cyclohexane ring was
adopted, resulting in different names.22 In the same way, Ma et al.23
carried out the synthesis of 5-O-p-coumaroylquinic acid by con-
densation between quinic acid bisacetonide and p-acetyl-
coumaroylchloride, in order to evaluate its potential antifungal
activity. Even though it seems that all the methods described in
the literature involve the esterification of the quinic acid with an
acyl chloride, to protect selectively the hydroxyl groups of the
11
Chlorogenic acids are esters formed between trans-cinnamic
acids (such as caffeic, ferulic and p-coumaric acid) and quinic
acid;12 therefore, depending on the type of cinnamic acid and on
which hydroxyl group of the cyclohexane ring in the quinic acid
is esterified, a great variety of chlorogenic acids can be formed,
not only as monoesters but also as di- and triesters.13 The total
content of chlorogenic acids in coffee depends on the coffee species
(Coffea arabica 4–8% and Coffea canephora 7–14% of the dry matter
basis),2,14 but also on the degree of roasting, the agriculture prac-
⇑
Corresponding author. Tel.: +39 0405583921.
E-mail address: cforzato@units.it (C. Forzato).
http://dx.doi.org/10.1016/j.tetasy.2017.01.015
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.

420
HO
A. L. Gutiérrez Ortiz et al. / Tetrahedron: Asymmetry 28 (2017) 419–427
Scheme 2. The ethyl carboxylate 719 was directly obtained by treat-
HO COOH
ment with sodium ethoxide in ethanol resulting in an opening of
the lactone ring of compound 5 and protection of the carboxylic
group. 1H NMR of the crude product revealed the presence of the
ethyl carboxylate 7, although in a mixture with lactone 5 in a
13:1 ratio. The crude product was esterified following the same
protocol as with 1 and purified by column chromatography to give
compound 8 in 48% yield. Protection of the hydroxyl group was not
necessary since Pooter et al. demonstrated that under mild condi-
tions, no esterification occurs at the axial C-1 hydroxyl group of
quinic acid.27 Deprotection was performed in 6 days in the pres-
ence of HCl (2 N)/THF to obtain 5-O-p-coumaroylquinic acid 2a in
77% from the protected ester 8.
COOH
O
O
1
5
O
R
O
HO
OH
HO
OH
OH
OH
1
1-O-p-coumaroylquinic acid
2a
5-O-p-coumaroylquinic acid , R = H
2b
5-O-caffeoylquinic acid , R = OH
COOH
HO
4
OH
COOH
HO
HO
3
1H NMR data are very similar to that of an authentic sample of
5-O-p-caffeoylquinic acid 2b except for the aromatic ring protons,
showing the same stereochemistry and conformation of the cyclo-
hexane ring. The most stable conformation of compound 2a, as
well as that of 2b, is the one with the ester and carboxylic groups
in equatorial positions, the hydroxyl group at C-4 equatorial and
hydroxyl group at C-3 axial. In compound 2b this is clearly evi-
denced by the coupling constants and WH of the proton signals
at C-3, C-4 and C-5 (see Table 1). H-5 resonates at 5.34 with a
WH of 23.2, indicating an axial position while H-3 resonates at
4.16 with a WH of 10.7 indicating an equatorial position. Com-
pound 2a had almost an identical spectra for the protons of the
quinic ring thus demonstrating that both have the same
conformation.
O
O
O
O
OH
OH
HO
R
R
OH
3-O-p-coumaroylquinic acid 3a, R = H
3b
4-O-p-coumaroylquinic acid 4a, R = H
4-O-caffeoylquinic acid 4b, R = OH
3-O-caffeoylquinic acid
, R = OH
Figure 1.
cyclohexane ring, there is still a lack of information about the syn-
thetic route and characterisation data of the different isomers of p-
coumaroylquinic acid.
3-p-Coumaroylquinic acid 3a was synthesized following
Scheme 3. The carboxyl group of (ꢀ)-quinic acid was protected
by esterification with MeOH, followed by protection of the hydro-
xyl groups at positions 4 and 5 using 2,2,3,3-tetramethoxybutane
to give the protected methyl quinate 1017,19,29 with 15% overall
yield from (ꢀ)-quinic acid. Coupling between p-acetyl-
coumaroylchloride and 10 under standard esterification conditions
gave the corresponding ester 11 in 74% yield, after purification by
column chromatography. Deprotection under acidic conditions by
HCl (2 M)/THF (3:1) for 6 days afforded a 4:1 mixture of 3-O-p-cou-
maroylquinic acid 3a and 4-O-p-coumaroylquinic acid 4a (62%
conversion yield) as determined by 1H NMR. It is necessary to mon-
itor the reaction by 1H NMR since after a prolonged time, the
hydrolysis reaction of the ester bond between quinic acid and p-
coumaroyl moiety occurs. Compound 4a could be recognized by
1H NMR since a double of doublet at lower field (4.81 ppm)
appeared, due to the presence of the acyl group at C-4, together
with an overlapped signal of two protons at C-3 and C-5 at
4.32 ppm. Also in this case, the 1H NMR spectrum of 3a is very sim-
ilar to the one of 3-O-caffeoylquinic acid 3b (see Table 1) with
respect to the most stable conformation. The WH 17.8 of H-5
clearly shows that it is an axial proton while H-3 is an equatorial
proton due to the lower WH (13.7).
Herein we report the synthesis and characterization of four
commercially unavailable isomers of p-coumaroylquinic acid: 1-
O-p-coumaroylquinic acid 1, 5-O-p-coumaroylquinic acid 2a, 3-O-
p-coumaroylquinic acid 3a, 4-O-p-coumaroylquinic acid 4a
(Fig. 1) that were carried out with some modifications of the syn-
thesis route proposed by Sefkow et al.17,18 and Dokli et al.19 The
work is complemented by a computational study, which provided
important evidence to explain the variations in outcome and
chemical yields of the different reactions, as a result of the relative
stability of the target products and their intermediates, together
with side products resulting from interconversions.
2. Results and discussion
All p-coumaroylquinic acids were synthesized by coupling p-
acetylcoumaroylchloride18,24 with the different targeted (ꢀ)-quinic
acids containing only one free hydroxyl group and all the other
hydroxyl groups protected in different ways. Although there is no
report in the literature of quinic acid rings esterified at position 1
occurring in coffee beans,25 this compound was identified as one
of the targets. It was envisaged that its availability would allow
it to be used as a standard to further confirm the absence of these
compounds in the natural source. The synthesis of 1-O-p-coumar-
oylquinic acid 1 was carried out according to Scheme 1. In the first
step, the protection of the hydroxyl groups in positions 3,4 and 5
was achieved by a modified literature procedure.19,26 Lactone 5
was synthesized in 72% yield and used in the next step without fur-
ther purification. The second step involved the condensation reac-
tion with p-acetylcoumaroylchloride, using DMAP with pyridine in
dichloromethane at room temperature. The protected ester 6 was
obtained in 57% yield after purification by column chromatogra-
phy. The deprotection of all hydroxyl groups was performed under
acidic conditions using HCl (2 M)/THF (4:1) with stirring for
4-O-p-Coumaroylquinic acid 4a was obtained after protection
at positions 5 and 3 of the quinic acid ring following Scheme 4.
1,5-c
-Quinide was synthesized from (ꢀ)-quinic acid through
dehydration in the absence of any solvent, as described by Wolin-
sky et al.30 and the crude product was purified by heating under
reflux in ethyl acetate as suggested by Raheem et al.31 Recrystal-
lizations of the brown sticky residue with EtOH or MeOH as sug-
gested by Wolinsky et al. and other literature procedures30,2
were not successful since compound 4 was obtained in less than
5% yield. Subsequently, protection with tert-butyldimethylsi-
lylchloride (TBS) following a literature procedure30,32 gave a mix-
ture of monosilylated isomers in positions
3 and 4 of the
11 days to give 1-O-p-coumaroylquinic acid
1 in 84% yield
cyclohexane ring in a 70:30 ratio (3-OTBDMS): (4-OTBDMS) with
the protection at position 3 in the major product, as determined
by 1H NMR spectroscopy. Although several eluents were tried in
order to separate the two isomers by flash chromatography, it
(Scheme 1).
The same lactone 5 was also used as the starting building block
for the synthesis of 5-O-p-coumaroylquinic acid 2a, following

A. L. Gutiérrez Ortiz et al. / Tetrahedron: Asymmetry 28 (2017) 419–427
421
O
HO
C
HO
COOH
2,2-dimethoxypropane
p-TsOH
O
acetone
reflux,4h
O
OH
HO
O
HO
(-)-quinic acid
72% yield
5
AcO
O
C
O
DMAP
pyridine
CH2Cl2
HO
C
O
COCl
1
O
O
O
AcO
+
5
24h, rt
3
4
O
57%
6
O
O
5
O
HCl(2M)
THF
HO
O
COOH
11 days, rt
84%
O
OH
HO
OH
1
Scheme 1. Synthesis of 1-O-p-coumaroylquinic acid 1.
O
HO
COOEt
OH
HO
C
i) NaOEt/EtOH, -20°C, 24h
ii) HOAc, rt
p-acetylcoumaroylchloride
O
DMAP, py, CH2Cl2
24h, rt
O
O
O
O
48% yield
7
5
HO
COOH
HO
3
COOEt
HCl(2M)/THF
O
O
5
4
6 days, rt
77% yield
HO
O
O
O
OH
O
OH
OAc
8
2a
Scheme 2. Synthesis of 5-O-p-coumaroylquinic acid 2a.
Table 1
1H NMR in CD3OD at 500 MHz
Compound Ar protons
Vinyl protons
H-3
H-4
H-5
H-2
H-6
2a
7.47 (d, J 8.5), 6.81 (d, J 8.5)
7.62 (d, J 16.0), 6.32
(d, J 16.0)
4.17 (m, WH
10.7)
4.16 (m, WH
10.7)
5.39 (m, WH
13.7)
5.35 (m, WH
11.9)
3.72 (dd, J1 3.6, J2
8.2)
3.72 (dd, J1 7.0, J2
3.6)
3.71 (dd, J1 7.6, J2
2.7)
3.65 (dd, J1 8.7, J2
4.3)
4.81 (dd, J110.0, J2 4.32 (m)
2.8)
4.80 (dd, J1 9.6, J2
3.8)
5.34 (dt, J1 8.9, J2 4.3,
WH 22.0)
5.34 (dt, J1 8.9, J2 5.3,
WH 23.2)
2.16–2.25 (2H, m), 2.01–
2.11 (2H,m)
2.16–2.24 (2H, m), 2.02–
2.10 (2H, m)
2.10–2.20 (3H, m), 1.93–
2.02 (1H, m)
2.11–2.22 (3H, m), 1.93–
1.99 (1H, m)
2.17–2.22 (2H, m), 2.00–
2.10 (2H, m)
2.16–2.22 (2H, m), 1.98–
2.08 (2H, m)
2b28
3a
7.05 (d, J 2.9), 6.96 (dd, J1 8.8, J2 2.9), 7.56 (d, J 14.7), 6.26
6.78 (d, J 8.8)
7.47 (d, J 8.5), 6.81 (d, J 8.5)
(d, J 14.7)
7.67 (d, J 15.9), 6.39
(d, J 15.9)
4.10 (m, WH 17.8)
3b28
4a
7.04 (d, J 2.4), 6.94 (dd, J1 8.8, J2 2.4), 7.58 (d, J 16.7), 6.31
6.78 (d, J 8.8)
7.49 (d, J 8.6), 6.82 (d, J 8.6)
4.14 (dt, J1 8.7, J2 4.3,
WH 21.7)
(d, J 16.7)
7.73 (d, J 15.9), 6.45
(d, J 15.9)
4.32 (m)
4b28
7.07 (d, J 3.1), 6.96 (dd, J1 9.4, J2 3.1), 7.64 (d, J 15.6), 6.37
6.78 (d, J 9.4) (d, J 15.6)
4.28 (m)
4.28 (m)
was not possible to isolate the 3-OTBDMS isomer as a pure com-
pound so the mixture of the two was used in the next step. Ester-
ification with p-acetylcoumaroylchloride, using pyridine as the
solvent, as suggested by Sefkow et al.17 and Dokli et al.,19 gave only
15 as a pure compound, while no esterification at position 3 was
observed as confirmed by 1H NMR analysis of the crude product.
Compound 15 was obtained in 41% yield after purification by col-
umn chromatography and subsequently deprotected under acidic

422
A. L. Gutiérrez Ortiz et al. / Tetrahedron: Asymmetry 28 (2017) 419–427
HO
HO
COOH
COOMe
OH
HO
COOMe
CSA,CH3OH
reflux, 24h
2,2,3,3-tetramethoxybutane
OH
CSA, trimethylorthoformate
CH3OH, reflux, 24h
HO
HO
HO
O
C
CH3
O
HO
(-)-quinic acid
HO
O
27% yield
CH3
C
9
O
H3C
CH3
10
HO
3
COOMe
1
4
O
p-acetylcoumaroylchloride
5
HCl (2M)/THF
6 days, rt
DMAP, py, CH2Cl2
O
O
CH3
O
C
24h, rt
O
AcO
CH3
C
74% yield
H3CO
CH3
11
HO
O
COOH
HO
COOH
+
O
OH
OH
HO
OH
OH
O
HO
O
3a
CSA: (-)-10-camphorsulfonic acid
Scheme 3. Synthesis of 3-O-p-coumaroylquinic acid 3a.
4a
4 : 1
conditions HCl (2 M)/THF (3:1) to give a mixture of isomers 3a and
4a in a 1:1 ratio (43% of conversion yield from the protected ester).
Since the starting compound was only isomer 15, an acyl migra-
tion from the C-4 to the C-3 of the cyclohexane ring occurred as
it was observed by 1H NMR spectroscopy. This kind of rearrange-
ment was already observed by Haslam et al. in 196421 when iso-
mers 3- and 5-O-p-coumaroylquinic acid were obtained from 4-
O-p-coumaroylquinic acid by treatment with sodium hydrogen
carbonate. Although in our case the deprotection reaction was car-
ried out under acidic conditions, it seems that the same acyl
migration occurs probably by the formation of the intermediate
orthoesters.
In order to explain the interconversions observed along the syn-
theses of the esters, we have carried out a computational analysis
on the end products and on the main intermediates leading to their
formation (Fig. 2).
O
C
O
O
HO
HO
COOH
p-TsOH, DMF
toluene
HO
HO
3
C
Imidazole, DMF
TBSiCl
C
O
+
O
O
reflux, 18h
85% yield
5
OH
HO
HO
0°C to rt, 1h
HO
TBSO
HO
HO
(-)-quinic acid
OH
OTBS
1,5-γ-quinide
13
14
O
70 : 30
HO
C
p-acetylcoumaroylchloride
1
DMAP, py
HCl (2M) / THF
O
5
3
4
OAc
24h, rt
TBSO
6 days, rt
84% yield
41% yield
O
O
15
HO
COOH
HO
COOH
O
+
OH
OH
HO
O
OH
O
OH
HO
O
3a
4a
1:1
Scheme 4. Synthesis of 4-O-p-coumaroylquinic acid 4a.

A. L. Gutiérrez Ortiz et al. / Tetrahedron: Asymmetry 28 (2017) 419–427
423
Figure 2. Computational analysis of the interconversions between products and between synthetic intermediates. The relative B3LYP/6.31G(d,p) energies are given in
Kcal/mol.
The geometries of the products and intermediates were opti-
mized first at the HF/6.31G(d) level, and then further refined with
a DFT calculation carried out at the B3LYP/6.31G(d,p) level. The end
products 2a, 4a and 3a showed slight differences in energy, with
the most stable being the 5-acyloyl derivative 2a. This explains
why its direct synthesis from compounds 7 and 8 is not affected
by any isomerization. Esters 4a and 3a are only 1.2 and 2.9 Kcal/-
mol less stable, respectively. The overall conformation of the three
compounds were very similar, with the carboxyl group at position
1 always found in an equatorial conformation. As a consequence,
ester 3a is the only product with the cumaroyl group in an axial
conformation, as experimentally observed in the NMR spectra.
The occurrence of a 20% 4a in the synthesis of 3a from the pro-
tected intermediate 9 (Scheme 3) can therefore be explained by
the thermodynamically favored intramolecular acyl transfer from
3a to 4a, starting upon deprotection of 9.
2.1. Circular dichroism
The Circular dichroism spectra of all isomers 1–4a were regis-
tered and a comparison with the those obtained for the commer-
cially available caffeoyl analogues 2b–4b was made to verify the
same absolute configuration of the stereocenters of the two series
of compounds. Additionally, two different solvents were used,
methanol and acetonitrile, in order to establish whether hydrogen
bonding can modify the spectra.
In Figure 3, the circular dichroism spectra of all compounds in
methanol are reported. The CD spectra of the p-coumaroylquinic
acids 2a–4a and those of the corresponding caffeoyl analogs 2b–
4b are very similar, indicating that they must have the same abso-
lute configuration of the stereogenic centers. Furthermore, the
same behavior is qualitatively observed for all compounds in both
solvents (methanol and acetonitrile) used as it can be noticed com-
paring Figure 3 with Figure 4 indicating that the distributions of
conformers are quite the same in both solvents.
The synthesis of 4a, as outlined in Scheme 4, involves more
complex interconversions. The protection of the starting 1,5-c-qui-
nide may lead to two different silylated compounds and the 3-pro-
tected derivatives are the most abundant in the reaction crude,
while compound 12 is the only product derived from the acylation
of this mixture. 3-OTBDMS is actually much more stable that its
isomer 4-OTBDMS, by 8.8 Kcal/mol. In quinides, at difference with
quinic derivatives, position 4 is in fact axial, and for this reason the
4-protected compound is strongly destabilized and the bulky pro-
tecting group forces the quinide to a boat-like conformations. Full
equilibration to the most stable 3-derivative is likely to occur
easily, via a pentacoordinate silicon intermediate, and this may
explain the fully selective transformation into compound 12,
which is even more stable than its isomer 120 (Scheme 4). In the
subsequent step of the synthesis, compound 12 was deprotected
and hydrolyzed, and a 1:1 mixture of products 4a and 3a was
obtained. Since 12 would lead directly to 4a, and this compound
is more stable than 3a, the only explanation for the observed result
may be if the deprotection occurs before the ring opening reaction
of quinides intermediates Q4a and Q3a (Fig. 2). The relative stabil-
ity of the two deprotected quinides is in fact reversed with respect
to the end products, and Q3a is more stable by over 10 Kcal/mol.
Interconversion thus happens at the quinide level and not at the
product level in this synthetic path, and its outcome is the result
of a complex competition between equilibria.
Compounds 2a,b–3a,b present a double Cotton effect, with a
positive band in the range 290–340 nm and a negative band in
the range 200–220 nm, while compounds 4a and 4b have both
bands negative. It should be noted that 3a and 3b present also a
third positive band in the range 220–260 nm.
3. Conclusion
In conclusion, all four isomers of p-coumaroylquinic acids were
synthesized and characterized. The quantification of these com-
pounds is very important in the area of coffee analysis and could
be used as standards to evaluate a range of coffee matrices of dif-
ferent origins. The interconversion occurring between the isomers
and during their synthesis have been explained on the basis of the
relative stability of the isomers and of the intermediates leading to
them.
4. Experimental
4.1. General
All reagents and solvents were purchased from Sigma–Aldrich
and used without further purification. Dichloromethane was dried

424
A. L. Gutiérrez Ortiz et al. / Tetrahedron: Asymmetry 28 (2017) 419–427
trometry measurements were performed with an Esquire 400
(Bruker-Daltonics) spectrometer. HRMS-ESI were obtained with a
Waters Xevo Q-Tof spectrometer in negative mode. Infrared spec-
tra (IR) were recorded with an Avatar 320-IR FTIR (ThermoNicolet).
Optical rotations were recorded on a Jasco P2000 polarimeter at
the wavelength of sodium D band (k = 589) using a quartz cell of
1 dm length. Circular dichroism spectra were recorded on a Jasco
J-710 spectropolarimeter. Melting points were measured with a
Sanyo Gallenkamp apparatus and were uncorrected.
4.2. p-Acetylcoumaroylchloride
Acetic anhydride was added (4.66 g, 45.69 mmol) at 0 °C to a
suspension of p-coumaric acid (5 g, 30.46 mmol) and DMAP
(93 mg, 0.76 mmol) in pyridine (10 mL). The reaction was stirred
for 3 h at room temperature and then poured onto crushed ice.
After acidification with aq. HCl (pH < 2) acetyl p-coumaric acid
was obtained as a white solid, which was filtered and washed with
water (93% yield). Oxalyl chloride was added at ꢀ5 °C, to a suspen-
sion of acetyl p-coumaric acid (1 g, 4.85 mmol) in toluene (17 mL)
containing two drops of DMF and the reaction was stirred at ꢀ5 °C
for 2 h and then overnight at room temperature. The solvent was
removed under reduced pressure to afford p-acetylcoumaroylchlo-
ride as a yellow solid in 95% yield. NMR data were in accordance
with the literature data.24
4.3. 3,4-O-Isopropylidene-1,5-quinic lactone 5
Figure 3. Circular dichroism spectra of compounds 1–4 in MeOH.
2,2-Dimethoxypropane (4.87 g, 46.83 mmol) was added to a
suspension of quinic acid (3 g, 15.61 mmol) and p-toluenesulfonic
acid (216 mg, 1.15 mmol) in acetone (60 mL) and the mixture was
heated at reflux for 2 h. After cooling, neutralization with NaHCO3
(5%) was performed and the mixture was stirred for 1 h at room
temperature. The reaction mixture was sequentially extracted with
CH2Cl2 (three times, 20 mL at time) and washed with water (two
times, 20 mL at time). The organic layer was dried over Na2SO4
and the solvent was removed under reduced pressure. Lactone 5
was obtained as a white solid in 72% yield and was used in the next
step without further purification. NMR data were in accordance
with the literature.26
over CaCl2. Caffeoylquinic acids 2b–4b were purchased from Phy-
tolab. Esterification reactions were performed under argon atmo-
sphere. Thin layer chromatography (TLC) was performed on
Merck silica gel 60 F254 silica gel plates. 1H and 13C NMR spectra
were recorded with a Varian 500 spectrometer (residual solvent
peaks, d = 7.26 ppm for CDCl3 and 3.31 ppm for CD3OD, were used
as the internal standard). Electrospray Ionization (ESI) mass spec-
4.4. 1-Acetyl p-coumaroyl-3,4-O-isopropylidene quinide 6
3,4-O-Isopropylidene-1,5-quinic lactone 5 (500 mg, 2.33 mmol)
was suspended in CH2Cl2 (20 mL), DMAP (86 mg, 0.7 mmol), pyri-
dine (0.47 mL, 4.66 mmol) and p-acetylcoumaroylchloride
(783 mg, 3.49 mmol) were added. The mixture was stirred 24 h
at room temperature. The reaction mixture was diluted with CH2-
Cl2, and sequentially extracted with 1 M aqueous HCl solution
(three times, 10 mL at time), NaHCO3 (5%) (10 mL) and brine
(10 mL). The organic layer was dried over Na2SO4, filtered and
the solvent was removed under reduced pressure. The residue
was purified by column chromatography on silica gel (diethyl
ether/CH2Cl2 = 1/1) to afford ester 6 (57%) as a colorless solid. 1H
NMR (500 MHz, CDCl3) d 7.72 (1H, d, J = 16.0 Hz, CH@CH), 7.55
(2H, d, J = 8.6 Hz, Ar), 7.14 (2H, d, J = 8.6 Hz, Ar), 6.41 (1H, d,
J = 16.0 Hz, CH@CH), 4.82 (1H, dd, J = 6.5, 2.5 Hz, H-4), 4.59 (1H,
dt, J = 2.19, 6.9, H-5), 4.36 (1H, m, H-3), 3.11 (1H, m, H-6), 2.65
(1H, apparent d, H-6), 2.53 (1H, ddd, J = 14.0, 6.5, 2.3 Hz, H-2ax),
2.45 (1H, dd, J = 14.5, 3.2 Hz, H-2 eq), 2.31 (3H, s, CH3CO), 1.54
(3H, s, CH3), 1.35 (3H, s, CH3); 13C NMR (500 MHz, CDCl3) d
173.65 (s, COO), 169.21 (s, COO), 164.99 (s, COO), 152.59 (s, Ar),
145.71 (d, CH@CH), 131.86 (s, Ar), 129.59 (d, Ar), 122.37 (d, Ar),
117.09 (d, CH@CH), 110.14 (s, C(CH3)2), 76.39 (s, C-1), 75.57 (d,
C-5), 72.64 (d, C-4), 71.33 (d, C-3), 35.82 (t, C-2), 30.87 (t, C-6),
27.15 C18 (q, C(CH3)2), 24.50 (q, C(CH3)2), 21.29 (q, CH3CO).
Figure 4. Circular dichroism spectra of compounds 1–4 in MeCN.

A. L. Gutiérrez Ortiz et al. / Tetrahedron: Asymmetry 28 (2017) 419–427
425
4.5. 1-O-p-Coumaroylquinic acid 1
4.8. 5-O-p-Coumaroylquinic acid 2a
Ester 6 (500 mg, 1.24 mmol) was dissolved in a mixture of THF
(10 mL) and aq. 2 M HCl (40 mL) and the yellowish solution formed
was stirred for 11 days at room temperature. The solution was sat-
urated with solid NaCl and then extracted with EtOAc (3 ꢁ 20 mL).
The organic layer was dried over Na2SO4, filtered and the solvent
was removed under reduced pressure. 1-p-coumaroylquinic acid
1 was obtained as a colorless solid in 84% from the corresponding
protected ester 6. Mp. 130–135 °C; 1H NMR (500 MHz, CD3OD) d
7.61 (1H, d, J = 15.9 Hz, CH@CH), 7.45 (2H, d, J = 8.6 Hz, Ar), 6.81
(2H, d, J = 8.6 Hz, Ar), 6.35 (1H, d, J = 15.9 Hz, CH@CH), 4.15 (1H,
q, J = 4.3, Hz, H-5), 4.06 (1H, dt, J = 9.1, 3.6 Hz, H-3), 3.48 (1H, dd,
J = 8.3, 3.3 Hz, H-4), 2.57 (1H, m, H-6), 2.44 (1H, m, H-2), 2.21
Ethyl 1-acetyl p-coumaroyl-3,4-O-isopropylidene quinate 12
(290 mg, 0.65 mmol) was dissolved in a mixture of THF (10 mL)
and aq. 2 M HCl (40 mL) and the solution was stirred for 6 days
at room temperature. After saturation with solid NaCl, the mixture
was extracted with EtOAc (3 * 30 mL) and the organic phase was
dried over anhydrous Na2SO4. Evaporation of the solvent gave 5-
O-p-coumaroylquinic acid as a colorless solid in 77% yield from
the corresponding protected ester 12.
Mp. 215–218 °C (lit.20 247–248 °C); IR (nujol): ṽ = 3582.67,
3302.38, 2917.48, 1687.13, 1633.37, 1170.30, 1080.85,
825.27 cmꢀ1 1H NMR is in accordance with literature data.23 13
; C
NMR (126 MHz, CD3OD): d 177.02 (s, C-7), 168.61 C8 (s), 161.28
(dd, J = 14.9, 3.5 Hz, H-6), 1.91 (1H, dd, J = 13.8, 8.5 Hz, H-2);13
C
C14 (s), 146.68 C10 (d), 131.18 C12,12 (d), 127.23 C11 (s), 116.80
0
0
NMR (500 MHz, CD3OD) d 174.91 (s, COO), 167.55 (s, COO),
160.79 (s, Ar), 146.40 (d, CH@CH), 130.67 (d, Ar), 126.73 (s, Ar),
116.30 (d, Ar), 114.97 (d, CH@CH), 80.95 (s, C-1), 75.77 (d, C-4),
69.13 (d, C-5), 67.40 (d, C-3), 39.40 (t, C-2), 35.38 (t, C-6); IR
(nujol): ṽ = 3582.61, 3358.97, 2950, 1693.99, 1631.07, 1170.67,
C13,13 (d), 115.33 C9 (d), 76.15 C1 (s), 73.41 C4 (d), 72.00 C5 (d),
71.15 C3 (d), 38.77 C2 (t), 38.22 C6 (t).; MS (ESI+): m/z [M+Na]:
361.4; [
a]
20 = ꢀ39.5 (c 0.79, MeOH).
D
4.9. 4,5-O-(20,30-Dimethoxybutane-20,30-dyil)-1,3-dihydroxycyclo
hexanecarboxylic acid methyl ester 10
1113.35, 831.61 cmꢀ1
.
MS (ESI+): m/z [M+Na] = 361.0; HRMS
(ESIꢀ): [MꢀH] = 337.092 (calculated: 337.092345); [
a]
20 = +5.1 (c
D
1.10, MeOH) (lit.21
[a
]
D
22 = ꢀ5.0 (c 2, MeOH)); UV (MeOH):
To a suspension of quinic acid (1 g, 5.20 mmol) in MeOH
(30 mL), (ꢀ)-10-camphorsulfonic acid (15 mg, 0.065 mmol) was
added and the mixture was refluxed for 15 h under an Ar atmo-
sphere. The methyl quinate 9 thus obtained was added with
2,2,3,3-tetramethoxybutane (1.01 g, 5.7 mmol), trimethylorthofor-
mate (2.6 mL, 0.024 mmol) and (ꢀ)-10-camphorsulfonic acid
(12 mg, 0.052 mmol) and the mixture was refluxed again. After
15 h the mixture was cooled and NaHCO3 (0.1 g) was added. Solu-
tion was concentrated under reduced pressure and the orange sus-
pension was partitioned between EtOAc (30 mL) and saturated
aqueous NaHCO3 (30 mL). The aqueous layer was extracted with
EtOAc (30 mL) and the organic layer was dried over Na2SO4, fil-
tered and the solvent was removed under reduced pressure.
Recrystallization of the brownish residue from EtOAc and hexane
(1:5, v/v) afforded 10 in 27% yield as an orange oil. NMR data were
in accordance with the literature.19,29
e
314 = 84200.
4.6. Ethyl 3,4-O-isopropylidene quinate 7
A suspension of crude lactone 5 (1 g, 4.67 mmol) in absolute
EtOH (30 mL) was treated with NaOEt (12.71 mg, 0.19 mmol)
dissolved in EtOH (160 lL). The brownish solution was stirred
at room temperature for 2 h and then stored at ꢀ20 °C for
24 h. After quenching the unreacted NaOEt by the addition of
acetic acid (13 lL) the solvent was removed under reduced
pressure at 30 °C. The residue was a mixture of lactone 5 and
ester 7 in a ratio 13:1 determined by 1H NMR analysis. This
crude mixture was used without further purification in the next
step.26,33
4.7. Ethyl 5-O-acetyl-p-coumaroyl-3,4-O-isopropylidene quinate
8
4.10. 3-Acetyl-p-coumaroyl-4,5-O-(20,30-dimethoxybutane-20,30-
diyl)-1-hydroxycyclohexanecarboxylic acid methyl ester 11
To a solution of ethyl-3,4-O-isopropylidene quinate 7 (500 mg,
1.92 mmol), DMAP (35 mg, 0.15 mmol) and pyridine (6 mL) in CH2-
Cl2 (25 mL), p-acetylcoumaroylchloride (645.18 mg, 2.88 mmol)
was added. The mixture was stirred for 24 h at room temperature
and acidified with aq. HCl 1 M (pH 2–3) and then extracted with
CH2Cl2 (three times, 50 mL at time). The organic layer was dried
over Na2SO4, filtered and the solvent was removed under reduced
pressure. The brownish residue was purified by column chro-
matography on silica gel (diethyl ether/CH2Cl2 = 1/1) to afford ester
8 in 48% yield as a colorless solid. 1H NMR (500 MHz, CDCl3) d 7.69
(1H, d, J = 15.9 Hz, CH@CH), 7.53 (2H, d, J = 8.6 Hz, Ar), 7.13 (2H, d,
J = 8.6 Hz, Ar), 6.40 (1H, d, J = 15.9 Hz, CH@CH), 5.49 (1H, dt,
J = 11.7, 4.5 Hz, H-5), 4.55 (1H, dt, J1 = 3.7, J2 = 5.6, H-3), 4.28–
4.20 (3H, m, OCH2+H-4), 2.31 (3H, CH3CO), 2.32–2.28 (2H, m, H-
2), 2.25 (1H, dd, J = 13.2, 4.4 Hz, H-6eq), 1.94 (1H, dd, J = 13.3,
11.3 Hz, H-6ax), 1.60 (s, C(CH3)2), 1.38 (s, C(CH3)2), 1.30 (3H, t,
J = 7.2 Hz, CH3CH2);13C NMR (500 MHz, CDCl3) d 174.48 (s, COO),
169.27 (s, COO), 166.03 (s, COO), 152.27 (s, Ar), 144.19 (d, CH@CH),
132.24 (s, Ar), 129.37 (d, Ar), 122.30 (d, Ar), 118.29 (d, CH@CH),
109.76 (s, C(CH3)2), 77.05 (d, C-3), 75.65 (s, C-1), 73.81(d, C-4),
71.11 (d, C-5), 62.36 (t, CH2CH3), 37.13 (t, C-6), 34.56 (t, C-2),
28.17 (q, C(CH3)2), 26.01 (q, C(CH3)2), 21.30 (q, CH3CO), 14.28 (q,
CH3CH2).
4,5-O-(20,30-Dimethoxybutane-20,30-diyl)-1,3-dihydroxycyclo-
hexanecarboxylic acid methyl ester 10 (122 mg, 0.38 mmol) was
suspended in CH2Cl2 (20 mL) and DMAP (4.17 mg, 0.034 mmol),
pyridine (320 lL, 4.03 mmol) and p-acetylcoumaroylchloride
(128 mg, 0.57 mmol) were added. The mixture was stirred 24 h
at room temperature and then acidified with aq. HCl 1 M (pH 2–
3). After extraction with CH2Cl2 (three times, 30 mL at time) the
organic layer was dried over Na2SO4, filtered and the solvent was
removed under reduced pressure. The brownish residue was puri-
fied by column chromatography on silica gel (diethyl ether/CH2-
Cl2 = 1/1) to afford ester 11 in 74% yield as a colorless solid. 1H
NMR (500 MHz, CDCl3) d 7.71 (1H, d, J = 15.8 Hz, CH@CH), 7.57
(2H, d, J = 8.6 Hz, Ar), 7.14 (2H, d, J = 8.6 Hz, Ar), 6.47 (1H, d,
J = 15.9 Hz, CH@CH), 5.38 (1H, q, J = 9.1 Hz, H-3), 4.45 (dt,
J = 10.2, 5.6 Hz, H-5), 3.79 (3H, s, COOCH3), 3.71 (1H, dd, J = 9.9,
3.2 Hz, H-4), 3.31 (3H, s, OCH3), 3.27 (3H, s, OCH3), 2.29 (3H, s, CH3-
CO), 2.28 (2H, m, H-2+H-6), 2.14 (1H, dd, J = 15.7, 3.2 Hz, H-2), 2.04
(1H, m, H-6); 13C NMR (500 MHz, CDCl3) d 175.62 (s, COO), 169.26
(s, COO), 166.61 (s, COO), 152.19 (s, Ar), 144.19 (d, CH@CH), 132.45
(s, Ar), 129.47 (d, Ar), 122.21 (d, Ar), 118.79 (d, CH@CH), 100.29 (s,
C(OCH3)), 99.73 (s, C(OCH3)), 74.78 (s, C-1), 71.38 (d, C-4), 70.02 (d,
C-3), 62.94 (d, C-5), 53.39 (q, CH3COO), 48.3 (q, OCH3), 48.14 (q,

426
A. L. Gutiérrez Ortiz et al. / Tetrahedron: Asymmetry 28 (2017) 419–427
OCH3), 38.91 (t, C-6), 36.81 (t, C-2), 21.3 (q, CH3CO), 18.03 (q, CH3C
(OCH3)), 17.81 (q, CH3C(OCH3)).
(15 mL), p-acetylcoumaroylchloride (700 mg, 3.12 mmol) was
added. The mixture was stirred for 24 h at room temperature and
then poured onto crushed ice, after which CH2Cl2 (20 mL) was
added. The mixture was acidified with aq. HCl 1 M (pH 2–3) and
then extracted with CH2Cl2 (three times, 30 mL at time). The
organic layer was dried over Na2SO4, filtered and the solvent was
removed under reduced pressure. The brownish residue was puri-
fied by column chromatography on silica gel (diethyl ether/CH2-
Cl2 = 1/1) to afford the only ester 15, in 41% yield, as a colorless
solid. 1H NMR (500 MHz, CDCl3) d 7.72 (1H, d, J = 15.9 Hz, CH@CH),
7.57 (2H, d, J = 8.6 Hz, Ar), 7.15 (2H, d, J = 8.6 Hz, Ar), 6.46 (1H, d,
J = 15.9 Hz, CH@CH), 5.43 (1H, t, J = 4.8 Hz, H-4), 4.88 (1H, dt,
J = 12.6, 5.3 Hz, H-5), 4.03 (1H, dt, J = 10.7, 4.6 Hz, H-3), 2.55 (1H,
d, J = 11.8 Hz, H-6), 2.43 (1H, dd, J = 11.8, 5.8 Hz, H-6), 2.32 (3H,
s, CH3CO), 2.11 (2H, apparent d, H-2), 0.81 (9H, s, C(CH3)3), 0.06
(3H, s, CH3Si), 0.03 (3H, s, CH3Si); 13C NMR (500 MHz, CDCl3) d
177.48 (s, COO), 169.27 (s, COO), 165.61 (s, COO), 152.50 (s, Ar),
145.15 (d, CH@CH), 131.98 (s, Ar), 129.53 (d, Ar), 122.38 (d, Ar),
117.40 (d, CH@CH), 74.42 (d, C-5), 72.15 (s, C-1), 66.68 (d, C-4),
66.06 (d, C-3), 41.14 (t, C-2), 37.64 (t, C-6), 25.71 (q, C(CH3)3),
21.28 (q, CH3CO), 18.05 (s, C(CH3)3), ꢀ4.92 (q, (CH3)2Si).
4.11. 3-O-p-Coumaroylquinic acid 3a
3-Acetyl-p-coumaroyl-4,5-O-(20,30-dimethoxybutane-20,30-dyil)-
1-hydroxycyclohexanecarboxylic acid methyl ester 11 (35 mg,
0.069 mmol) was dissolved in a mixture of THF (0.5 mL) and aq.
2 M HCl (1.5 mL) and the solution was stirred for 6 days at room
temperature. After saturation with solid NaCl, the mixture was
extracted with EtOAc (3 ꢁ 20 mL) and the organic phase dried over
anhydrous Na2SO4. Evaporation of the solvent gave a yellowish solid
(62% yield), which was defined to be a mixture of 3-p-coumaroylqui-
nic acid 3a and 4-p-coumaroylquinic acid 4a in a ratioof 8:2 as deter-
mined from 1H NMR. The crude was purified by semi-preparative
RP-HPLC on a Phenomenex Gemini C18 5
l
m 10 ꢁ 250 mm column,
using a gradient of H2O+0,1% formic acid (A) and MeOH+0,1% formic
acid (B), (20 min A 80% B 20%, from 20 to 90 min increase of B until A
40% B 60%, from 90 to 110 minA 5% B 95%, from 110 to 125 min A 95%
B 5%) at a flow rate of 2 mL/min. The elution was monitored with an
UV/vis detector k 325 nm and the fractions corresponding to each
peak were collected and keep at ꢀ80 °C and then freeze dried and
analyzed by 1H NMR. 3-O-p-coumaroylquinic acid 3a (3 mg) was
obtained as a white solid. Mp. 192–194 °C [lit.21 194 °C]; IR (nujol):
ṽ = 3582.64, 3381.37, 2921.16, 1694.22, 1631.26, 1171.87, 1019.74,
831.37 cmꢀ1; 1H NMR (500 MHz, CD3OD) d 7.67 (1H, d, J = 15.9 Hz,
H-10), 7.47 (2H, d, J = 8.5 Hz, H-12), 6.81 (2H, d, J = 8.3 Hz, H-13),
6.39 (1H, d, J = 15.9 Hz, H9), 5.39 (1H, m, WH 13.7, H-3), 4.10 (1H,
m, WH 17.8, H-5), 3.71 (1H, dd, J = 7.6, 2.7 Hz, H-4), 2.20–1.93 (4H,
m, H-2+H-6); 13C NMR (500 MHz, CD3OD) d 177.59 (s, COO),
168.91(s, COO), 161.15 (s, Ar), 146.43 (d, CH@CH), 131.09 (d, Ar),
127.39 (s, Ar), 116.79 (d, Ar), 115.85 (d, CH@CH), 76.42 (s, C-1),
74.22 (d, C-4), 72.61 (d, C-3), 68.93 (d, C-5), 36.93 (t, C-2), 36.22 (t,
4.15. 4-O-p-Coumaroylquinic acid 4a
4-O-Acetyl-p-coumaroyl-3-tert-butyldimethylsiloxy-1-hydrox-
ycyclohexane-1,5-carbolactone 15 (332 mg, 0.7 mmol) was dis-
solved in a mixture of THF (5 mL) and aq. 2 M HCl (15 mL) and
the solution was stirred for 6 days at room temperature. After sat-
uration with solid NaCl, the mixture was extracted with EtOAc (3 x
50 mL) and the organic phase was dried over Na2SO4. Evaporation
of the solvent gave a yellowish solid in 43% yield, which was a mix-
ture of 3-p-coumaroylquinic acid 3a and 4-p-coumaroylquinic acid
4a as determined by 1H NMR. The crude was purified by semi-
C-6). MS (ESI+): m/z [M+Na]: 361.0 [
a
]
D
20 = +2.2 (c 0.12 MeOH)
preparative RP-HPLC on a Phenomenex Gemini C18 5 lm 10 x
[lit.21
[
a]
20 = ꢀ5.6 (c 0.6, MeOH)]; UV (MeOH):
e
314 = 73,000.
250 mm column, using a gradient of H2O+0,1% formic acid (A)
and MeOH+0,1% formic acid (B) (20 min A 80% B 20%, from 20 to
90 min increase of B until A 40% B 60%, from 90 to 110 min A 5%
B 95%, from 110 to 125 min A 95% B 5%) at a flow rate of 2 mL/
min. A total of 4 runs were performed each one injecting 15 mg
of crude. The elution was monitored with UV/vis detector k
325 nm and the fractions corresponding to each peak were col-
lected and kept at ꢀ80 °C and then freeze dried and analyzed by
1H NMR. 4-p-coumaroylquinic acid 4a (5 mg) was obtained as a
white solid. Mp. 179–182 °C [lit.21 192–193 °C]; IR (nujol):
ṽ = 3580, 3382.60, 2952.03, 1689.11, 1604.93, 1172.21,
D
4.12. 1,5-c-Quinide
Quinic acid (3 g, 15.61 mmol) was heated in an open flask at
220 °C for 90 min. The brown sticky residue was refluxed with
EtOAc (60 mL) for 4 h and then the solution was cooled to room
temperature. The solvent was removed under pressure to give
1,5-c-quinide as a colorless solid in 85% yield. NMR data were in
accordance with the literature.28,29
4.13. 3-tert-Butyldimethylsiloxy-1,4-dihydroxy-cyclohexane-1,
1024.40.85, 830.63 cmꢀ1 1H NMR (500 MHz, CD3OD) d 7.73 (1H,
;
5-carbolactones 13 and 14
d, J = 15.9 Hz, CH@CH), 7.49 (2H, d, J = 8.6 Hz, Ar), 6.82 (2H, d,
J = 8.6 Hz, Ar), 6.45 (1H, d, J = 15.9 Hz, CH@CH), 4.81 (1H, dd,
J = 10.0, 2.8 Hz, H-4), 4.32 (2H, m, H-3+H-5), 2.22 (4H, m, H-2+H-
6); 13C NMR (126 MHz, CD3OD) d 177.97 (s, COO), 168.97 (s,
COO), 161.25 (s, Ar), 146.73 (d, CH@CH), 131.16 (d, Ar), 127.31
(s, Ar), 116.82 (d, Ar), 115.44 (d, CH@CH), 79.26 (d, C-4), 76.95 (s,
C-1), 69.65 (d, C-5), 65.69 (d, C-3), 42.64 (t, C-6), 38.49 (t, C-2).
TBSi-Cl (1.31 g, 8.68 mmol) was added to a stirred solution of
1,5-c-quinide (1.31 g, 7.55 mmol) and imidazole (1.9 g, 28 mmol)
in anhydrous DMF (14 mL) at 0 °C. The mixture was stirred at
0 °C for 30 min followed by 1 h at room temperature and then
poured into water (50 mL) and extracted with EtOAc (50 ml) and
diethyl ether (40 mL). The organic layer was washed with water
(3 ꢁ 100 mL), dried over Na2SO4 and concentrated under reduced
pressure to give a white solid in 57% yield containing esters 13
and 14 in a ratio of 7:3. The crude was used in the next step with-
out further purification. NMR data were in accordance with the
literature.31,32
MS (ESI+): m/z [M+Na]: 361.0 [
a]
20 = ꢀ28.3 (c 0.3, MeOH) [lit.21
D
[a]
20 = ꢀ47.3 (c 1.4, MeOH); UV (MeOH):
e316 = 63,200.
D
4.16. Calculations
Preliminary molecular mechanics calculations and HF optimiza-
tions were performed using the Spartan 14 package34 which was
installed on an Antec P193 V3, with two six core AMD opteron Pro-
cessor 2427 2.20 GHz, 4 GB RAM, 1 TB physical memory, and 64-bit
Windows 7 Enterprise as operating system. Convergence criteria
4.14. 4-Acetyl-p-coumaroyl-3-tert-butyldimethylsiloxy-1-hydro
xycyclohexane-1,5-carbolactone 15
To
cyclohexane-1,5-carbolactone, as
(500 mg, 1.74 mmol) and DMAP (32 mg, 0.26 mmol) in pyridine
a
solution of 3-tert-butyldimethylsiloxy-1,4-dihydroxy-
for geometry optimization were set as follows: energy 1.0 ꢁ 10ꢀ6
-
a
mixture of 13 and 14,
hartrees, gradient tolerance 3 ꢁ 10ꢀ4 hartrees, distance tolerance
1.2 ꢁ 10ꢀ3 Å. The DFT simulations were performed on the same

A. L. Gutiérrez Ortiz et al. / Tetrahedron: Asymmetry 28 (2017) 419–427
427
14. Ky, C.; Noirot, M.; Hamon, S. J. Agric. Food Chem. 1997, 45, 786–790.
machine with the Schrodinger suite of programmes using the
B3LYP functional35 and a localized 6-31G(d,p) basis set.
15. Panizzi, L.; Scarpati, M.; Oriente Gazz. Chim. Ital. 1956, 86, 913–922.
16. Panizzi, L.; Scarpati, M.; Oriente, G. Experientia 1955, 11, 383–384.
17. Sefkow, M.; Kelling, A.; Schilde, U. Eur. J. Org. Chem. 2001, 2735–2742.
18. Sefkow, M. Eur. J. Org. Chem. 2001, 1137–1141.
19. Dokli, I.; Navarini, L.; Hamersˆak, Z. Tetrahedron: Asymmetry 2013, 24, 785–790.
20. Haslam, E.; Haworth, R.; Makinson, G. J. Chem. Soc. 1961, 5153–5156.
21. Haslam, E.; Makinson, G.; Naumann, G.; Cunningham, J. J. Chem. Soc. 1964,
2137–2146.
22. In the present work the IUPAC numbering system is consistently applied (i.e. in
the cyclohexane ring the C atom bearing the OH on the same side as the
carboxylic acid, is identified as position 5) (IUPAC Commission on the
Nomenclature of Organic Chemistry (CNOC) and IUPAC-IUB Commission on
Biochemical Nomenclature (CBN), Biochem. J. 1976, 153, 23–31).
23. Ma, C.; Kully, M.; Khan, J.; Hattori, M.; Daneshtalab, M. Bioorg. Med. Chem. 2007,
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Acknowledgements
This project has received funding from the European Union’s
Horizon 2020 research and innovation programme under the
Marie Sklodowska-Curie grant agreement No 642014.
We are grateful to Dr. Luca Zuppiroli of the Dipartimento di
Chimica Industriale ‘‘Toso Montanari”, Università di Bologna, for
the HRMS analysis of compound 1.
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