Stereoselective synthesis and application of isopulegol-based bi- And trifunctional chiral compounds

Article abstract of DOI:10.1039/d0ra07739a

A new family of isopulegol-based bi- and trifunctional chiral ligands was developed from commercially available (-)-isopulegol. Nucleophilic addition of primary amines towards (+)-α-methylene-γ-butyrolactone was accomplished, followed by reduction of the

Full text of DOI:10.1039/d0ra07739a

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Stereoselective synthesis and application of
isopulegol-based bi- and trifunctional chiral
Cite this: RSC Adv., 2020, 10, 38468
compounds†
ab
c
c
Tam Minh Le,
Ferenc Fulop
Thu Huynh,
Gabor Endre,c Andras Szekeres,
´ ´
ab
ad
*
and Zsolt Szakonyi
¨ ¨
A new family of isopulegol-based bi- and trifunctional chiral ligands was developed from commercially
available (ꢀ)-isopulegol. Nucleophilic addition of primary amines towards (+)-a-methylene-g-
butyrolactone was accomplished, followed by reduction of the obtained b-aminolactones to provide
aminodiols in highly stereoselective reactions. Epoxidation of (ꢀ)-isopulegol and subsequent oxirane ring
opening with primary amines resulted in N-substituted aminodiols. The regioselective ring closure of
these aminodiols with formaldehyde was also investigated. Benzylation of isopulegol furnished O-
benzyl-protected isopulegol, which was transformed into aminoalcohols via epoxidation and ring
opening of the corresponding epoxides. First benzyl-protected isopulegol was subjected to
hydroxylation and epoxidation, then aminolysis of the served oxiranes delivered aminodiols. On the other
hand, (ꢀ)-isopulegol was oxidised to diol, which was again converted into both dibenzyl- and
monobenzyl-protected diol derivatives. The products were transformed into aminoalcohols and
aminodiols, respectively, by aminolysis of their epoxides. The ring opening of epoxides, derived from
diols with primary amines was also performed producing aminotriols. Dihydroxylation of (ꢀ)-isopulegol
or derivatives with OsO4/NMO gave isopulegol-based di-, tri- and tetraols. The antimicrobial activity and
antioxidant property, measuring DPPHc free radical scavenging activity of aminodiol and aminotriol
derivatives as well as di-, tri- and tetraols were also explored. In addition, structure–activity relationships
were examined from the aspects of substituent effects and stereochemistry on the aminodiol and
aminotriol systems.
Received 9th September 2020
Accepted 10th October 2020
DOI: 10.1039/d0ra07739a
rsc.li/rsc-advances
anticholinesterase effects.7,8 In addition, some of these
compounds, such as 1,8-cineole, geraniol, linalool,9 thymol10
Introduction
along with limonene, a-pinene, b-pinene, g-terpinene and
linalyl acetate,8 as well as santolina alcohol, borneol, sabinol,
trans-sabinyl acetate and a-thujone,10 have been found to be
relatively potent DPPHc radical scavengers. This property is
directly related to their structures.11 It is worth pointing out that
essential oils also display excellent antimicrobial activity.12–14
For instance, linalool and a-terpineol exhibited strong activity
against periodontopathic and cariogenic bacteria,15 while citral,
linalool and b-pinene had an effect on Saccharomyces cer-
evisiae.16 Furthermore, linalyl acetate, (+)-menthol and thymol
were found to be efficient against Staphylococcus aureus and
Escherichia coli,17 while thymol, carvacrol, p-cymene and g-ter-
pinene showed inhibitory activity towards S. aureus and E. coli.18
Apart from proven properties, many monoterpenes exert anti-
biotic,19,20 nematicidal,21 anti-inammatory22,23 and analgesic24
inuences. Some monoterpenes are used as important avour
agents in foods, drinks, perfumes, cosmetics and tobacco,25
while others such as 1,8-cineole26 and pinene27 have been
considered as important biopesticides. Monoterpenes, there-
fore, are widely used in medicine, industry and agriculture.28–30
Monoterpenes constitute an interesting group of plant
secondary metabolites.1,2 They are readily available, relatively
nontoxic and inexpensive constituents. Moreover, mono-
terpenes possess many important pharmacological activities.3
For example, limonene and perillyl alcohol have chemo-
preventive activity against cancer,4–6 whereas linalool and
eucalyptol
exert
synergistic
antiproliferative
and
aInstitute of Pharmaceutical Chemistry, University of Szeged, Interdisciplinary
¨
¨
Excellence Centre, Eotvos utca 6, H-6720 Szeged, Hungary. E-mail: leminhtam@
pharm.u-szeged.hu; fulop@pharm.u-szeged.hu; szakonyi@pharm.u-szeged.hu; Fax:
+36-62-545705; Tel: +36-62-546809
b
¨
¨
Stereochemistry Research Group of the Hungarian Academy of Sciences, Eotvos utca 6,
H-6720 Szeged, Hungary
c
¨ ´
Department of Microbiology, University of Szeged, Kozep fasor 52, 6726 Szeged,
Hungary. E-mail: huynh_thu@hcmut.edu.vn; egabcy@gmail.com; andras.j.
szekeres@gmail.com
d
¨
¨
Interdisciplinary Centre of Natural Products, University of Szeged, Eotvos utca 6, H-
6720 Szeged, Hungary
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra07739a
38468 | RSC Adv., 2020, 10, 38468–38477
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
We have planned to combine aminodiol moieties of cardio-
RSC Advances
vascular, cytostatic and antiviral effectiveness with mono-
terpenic skeletons.31–33 Aristeromycin analogues, for example,
are widely used as effective agents against a range of viruses,
including the human immunodeciency, hepatitis B, herpes
simplex, varicella-zoster, inuenza and hepatitis C viruses.34–36
The Abbott aminodiol, found to be a useful building block for
the preparation of potent renin inhibitors Zankiren® and
Enalkiren®, was introduced into the therapy of hyperten-
sion.37,38 Aminodiols can also exert antidepressive activity. For
instance, (S,S)-reboxetine is a selective norepinephrine reuptake
inhibitor for the treatment of unipolar depression,39 while
others such as (2R,3R,7Z)-2-aminotetradec-7-ene-1,3-diol are
potent antimicrobial metabolites.40 Besides their varied, well-
known inuences, aminodiols may serve as starting materials
for the synthesis of biologically active natural compounds, e.g.
cytoxazone, a selective modulator of the secretion of TH2 cyto-
kine.41,42 Apart from their biological interest, monoterpene-
based aminodiols have been demonstrated to be excellent
chiral auxiliaries in a wide range of stereoselective trans-
formations including intramolecular radical cyclisation,43
intramolecular [2 + 2] photocycloaddition44 and Grignard
addition.45,46
In order to combine the properties of monoterpenes and
aminodiols as well as to develop new, efficient and commer-
cially available chiral ligands, naturally occurring chiral
monoterpenes such as (+)- and (ꢀ)-a-pinene,47–49 (+)-carene,50,51
(+)-camphor,52,53 (ꢀ)-fenchone,54 (ꢀ)-menthone,55 (ꢀ)-myrte-
nol,56,57 (+)-neoisopulegol,58,59 (S)-perillyl alcohol,60 (ꢀ)-pule-
gone,61 or (+)-sabinol62 have been widely used as key
intermediates for the synthesis of aminodiols.
Monoterpene-based diols also possess marked biological
properties, e.g. antiparkinsonian activity63 and skin microcir-
culatory improvement,64,65 whereas monoterpene-based triols
have been utilised as cytotoxic66,67 and anti-inammatory
agents.68
Fig.
1
Synthesis of (ꢀ)-isopulegol-based (+)-a-methylene-g-
butyrolactone.
8.58,75 Treatment of b-aminolactones with LiAlH4 resulted in
secondary aminodiols 9–12. Debenzylation via hydrogenolysis
of aminodiols 9–11 over Pd/C in MeOH gave primary aminodiol
13 in moderate yields. In order to study the regioselectivity of
ring closure of the aminodiol function, we attempted to incor-
porate one of the hydroxy groups of aminodiols into 1,3-oxazi-
nane or 1,3-oxazepinane ring.51,61,76 When aminodiols 9–12 were
reacted with HCHO under mild conditions, 1,3-oxazinane were
obtained in highly regioselective ring closure. Since either the
hydrogenolysis of N-benzyl analogues 9–11 or the formation of
the oxazine ring system (14–17) had no effect on the absolute
conguration, the relative conguration of the chiral centres of
13–17 is known to be the same as that of 9–12 (Scheme 1).51,76
Dihydroxylation of 4 with the OsO4/NMO system furnished
18 in low yield.51,61 The ring opening of a,b-dihydroxylactone 18
was performed by using 4 equivalents of primary amines under
reux conditions in anhydrous THF to form a,b-dihydrox-
yamides 19–21. It is important to mention that the ring opening
of lactones with (R)- and (S)-a-methylbenzylamine required
longer reactions than utilizing benzylamine. This is probably
due to steric hindrance exerted by the a-methyl group (Scheme
1). Note that the acylation of diols bearing an adjacent amide
function forms an important structural moiety with potential
biological applications.77 For example, asterobactin and vio-
prolide A have been identied as a new antibiotic and a new
antifungal peptolide, respectively.78,79
The relative conguration of compound 18 was determined
by means of NOESY experiments: clear NOE signals were
Therefore, our primary objective of the present research was
to prepare a new library of isopulegol-based bi-, tri- or even
tetrafunctionalised chiral synthons, such as aminodiols and
aminotriols as well as di-, tri- and tetraols, starting from
commercially available natural (ꢀ)-isopulegol and to evaluate
the inuence of these new isopulegol derivatives on antimi-
crobial attributes on multiple bacterial and yeast strains and
their DPPHc free-radical scavenging activity.
Results and discussion
The key intermediate (+)-a-methylene-g-butyrolactone 4 was
prepared from commercially available (ꢀ)-isopulegol 1. Acety-
lation of alcohol 1 to its acetate 2, followed by regioselective
oxidation of 2 gave diol 3, which was transformed to lactone 4 by
two-step oxidation and ring closure of obtained g-hydroxy-
substituted a,b-unsaturated carboxylic acid applying literature
methods (Fig. 1).69–74
Nucleophilic addition of primary amines to a-methylene-g-
butyrolactone 4 has proved to be an efficient method for the
preparation of a highly diversied library of b-aminolactones 5– equiv.), dry THF, 60 ꢁC, 24–72 h, 35–56%.
Scheme 1 Synthesis of (ꢀ)-isopulegol-based aminodiols. Reaction
conditions: (i) RNH2 (1 equiv.), dry EtOH, 25 ꢁC, 20 h, 65–75%; (ii) LiAlH4
(2 equiv.), dry Et2O, 25 ꢁC, 4 h, 50–70%; (iii) 5% Pd/C, H2 (1 atm), MeOH,
25 ꢁC, 24 h, 50–67%; (iv) 35% HCHO, Et2O, 25 ꢁC, 1 h, 64–74%; (v) 2%
OsO4/t-BuOH, 50% NMO/H2O, acetone, 25 ꢁC, 24 h, 28%; (vi) RNH2 (4
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 38468–38477 | 38469

View Article Online
RSC Advances
Paper
observed between the OH-8 and H-3 as well as OH-9 and H-4
protons (Fig. 2).
Homoallylic epoxidation of (ꢀ)-isopulegol 1 with m-CPBA
provided a 1 : 1 mixture of epoxides 23a and 23b in good yield.80
The two epoxides were separated by column chromatography to
give more polar isomer 23a and less polar isomer 23b. The ring
opening of epoxide 23a with different primary amines in the
presence of LiClO4 as catalyst delivered aminodiols 24a–27a.81,82
Debenzylation of 24a–26a by hydrogenolysis over Pd/C in MeOH
resulted in aminodiol 28a in excellent yields. When aminodiols
24a–27a were treated with HCHO at room temperature, oxazo-
lidines 29a–32a were obtained via highly regioselective ring
closures, similar to the regioisomeric 1,3-oxazinane analogues.
The other epoxide 23b underwent similar reactions to afford
24b–32b in excellent yields. Dihydroxylation of (ꢀ)-isopulegol 1
was performed with OsO4 in the presence of a stoichiometric
amount of co-oxidant NMO to afford a diastereoisomeric
mixture of 22a and 22b in a ratio of 1 : 1.83 The epimeric mixture
was puried by column chromatography followed by recrystal-
lisation to provide 22b in crystalline form and 22a as a colour-
less oil (Scheme 2).
Gram-scale separation of 23a and 23b turned out to be
difficult. In order to enhance the resolution by column chro-
matography, benzyl-protected isopulegol 33 was prepared.84,85
Epoxidation of 33 with mCPBA furnished a 1 : 1 mixture of
epoxides 34a and 34b. Aer separation by column chromatog-
raphy, they were subjected to aminolysis with primary amines.
Interestingly, epoxide 34b upon aminolysis was transformed
preferentially, while 34a did not react. This is probably due to
steric hindrance exerted by either the benzyl or the methyl
group at the a position in epoxide 34a. Consequently, the
mixture of 34a and 34b was used for the ring-opening reaction.
The resulting aminoalcohols (35b–38b) could be easily sepa-
rated from 34a on a gram scale by simple column chromatog-
raphy with good yields. The synthesis of primary aminodiol 28b
was accomplished by hydrogenolysis of 35b–37b over Pd/C in
high yields, while debenzylation of 34a provided 23a in
a moderate yield of 53% (Scheme 3).
Scheme 2 Synthesis of (ꢀ)-isopulegol-based aminodiols. Reaction
conditions: (i) 2% OsO4/t-BuOH, 50% NMO/H2O, acetone, 25 ꢁC, 24 h,
33% (22a), 33% (22b); (ii) mCPBA (2 equiv.), Na2HPO4$12H2O (3 equiv.),
CH2Cl2, 25 ꢁC, 2 h, 29% (23a), 43% (23b); (iii) RNH2 (2 equiv.), LiClO4 (1
equiv.), MeCN, 70–80 ꢁC, 8 h, 75–95% (23a), 50–90% (23b); (iv) 5% Pd/
C, H2 (1 atm), MeOH, 25 ꢁC, 24 h, 87–95% (28a), 85–90% (28b); (v) 35%
HCHO, Et2O, 25 ꢁC, 1 h, 89–97% (29a–32a), 85–90% (29b–32b).
conguration of the original diol.86,87 Accordingly, the reactions
of 39a and 39b with triphosgene successfully afforded 40a and
40b, respectively. Aer purication, carbonates 40a and 40b
were reduced by LiAlH4 (LAH). The reaction proceeded
smoothly giving the corresponding diols 39a and 39b in good
yields. It has been reported that reduction with LAH gives the
corresponding diol with the same stereochemical conguration
of the carbon atoms as of the original moiety.88,89 Debenzylation
syn-Selective dihydroxylation of compound 33 with OsO4 in
the presence of a stoichiometric amount of co-oxidant NMO
produced a 1 : 1.7 epimeric mixture of 39a and 39b in
a favourable yield. Our effort to separate the mixture failed.
Fortunately, their carbonates, obtained from the diols with tri-
phosgene, could be easily isolated. It is well known that this
carbonation
reaction
maintains
the
stereochemical
Scheme 3 Synthesis of (ꢀ)-isopulegol-based aminodiol derivatives.
Reaction conditions: (i) NaH (1.5 equiv.), BnBr (1.5 equiv.), KI (1.5 equiv.),
dry THF, 60 ꢁC, 12 h, 70%; (ii) mCPBA (2 equiv.), Na2HPO4$12H2O (3
equiv.), CH2Cl2, 25 ꢁC, 2 h, 43% (34a), 25% (34b); (iii) RNH2 (2 equiv.),
LiClO4 (1 equiv.), MeCN, 70–80 ꢁC, 20 h, 31–45%; (iv) 5% Pd/C, H2 (1
atm), MeOH, 25 ꢁC, 24 h, 65–70%; (v) 5% Pd/C, H2 (1 atm), n-hex-
ane : EtOAc ¼ 9 : 1, 25 ꢁC, 24 h, 53%.
Fig. 2 Determination of the structure of diol 18 by NOESY.
38470 | RSC Adv., 2020, 10, 38468–38477
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
of 39a and 39b by hydrogenolysis over Pd/C resulted in triols 22a
and 22b, respectively, with excellent yields (Scheme 4).
To extend the investigation of the substituent effects in the
ring opening of epoxide, 33 was oxidised to 41. The epoxidation
of 41 with mCPBA delivered a 4 : 1 mixture of epoxides 42a and
42b. The separation of 42a and 42b was not satisfactory on
a gram scale; therefore, the mixture was treated with different
primary amines in the presence of LiClO4 resulting in a library
of aminodiols. In our delight, aminodiols were well-separated
when chiral amines (R)- and (S)-methylbenzylamines were
applied, while in the case of benzylamine and isopropylamine,
only the major products were isolated. The debenzylation of
43a–45a by hydrogenolysis over Pd/C gave aminodiol 47a with
satisfactory yields. Tetraol 49 was prepared by dihydroxylation
of 41 with the OsO4/NMO system, followed by hydrogenolysis of
48 over Pd/C (Scheme 5).
During our attempt to improve the resolution of aminodiols
43b–46b, we realised that O-benzylation of 41 could serve this
purpose; however, the synthesis of 50b starting from 41 failed.
Fortunately, it was achieved by reacting 3 with benzyl bromide
under reux condition in dry THF. Besides expected product
50b, 50a also formed as a side product. Epoxidation of 50b with
mCPBA produced a 1 : 1 mixture of epoxides 51a and 51b. The
ring opening of the oxirane mixture was accomplished with
different primary amines resulting in a library of aminoalcohols
52a–55a and 52b–55b, respectively. The debenzylation of 52a–
54a and 52b–54b by hydrogenolysis over Pd/C gave, respectively,
aminotriols 47a and 47b with exceptional yields. Compound
50b was treated with the OsO4/NMO system providing a 3 : 1
mixture of diols 56a and 56b. Removal of the protecting group
of 56a gave tetraol 49 with good yield (Scheme 6).
Scheme 5 Synthesis of (ꢀ)-isopulegol-based aminotriol derivatives.
Reaction conditions: (i) SeO2 (0.24 equiv.), 70% t-BuOOH (4 equiv.),
CHCl3, 60 ꢁC, 20 h, then LiAlH4 (3 equiv.), dry Et2O, 0 ꢁC, 6 h, 60%; (ii)
mCPBA (2 equiv.), Na2HPO4$12H2O (3 equiv.), CH2Cl2, 25 ꢁC, 2 h, 64%
(42a), 15% (42b); (iii) RNH2 (2 equiv.), LiClO4 (1 equiv.), MeCN, 70–
80 ꢁC, 6 h, 46–58% (42a), 14% (42b); (iv) NMO/H2O, 2% OsO4/t-BuOH,
acetone, 25 ꢁC, 24 h, 60%; (v) 5% Pd/C, H2 (1 atm), MeOH, 25 ꢁC, 24 h,
87–95% (47a), 86% (48).
Debenzylation of 62a–b by hydrogenolysis over Pd/C resulted in
tetraol 49 with excellent yields (Scheme 7).
On the other hand, epoxidation of allylic diol 3 with mCPBA
was successfully applied to form the mixture of epoxy diols 63a
and 63b in a 3.5 : 1 ratio. Aer separation by chromatography,
the oxirane ring of 63a was opened with primary amines and
LiClO4 as catalyst to deliver aminotriol library 64a–67a. Primary
aminotriol 47a was obtained by debenzylation of the corre-
sponding aminotriols 64a–66a under standard conditions by
hydrogenation in the presence of a Pd/C catalyst. Diastereo-
isomeric aminotriols 65b–66b were prepared by ring opening of
63b with chiral amines (R)- and (S)-methylbenzylamine. The
synthesis of tetraol 49 was effectively performed by selective
dihydroxylation of 3 with the OsO4/NMO system (Scheme 8).
The relative conguration of primary aminotriol 47a was
determined through epoxide 63a. To this aim, epoxide 63a was
reduced with LiAlH4 (LAH) to the corresponding triol 22a (see
The epoxidation of 50a with mCPBA gave a 2 : 1 mixture of
epoxides 57a and 57b. The ring opening of this epoxide mixture
was carried out with different primary amines to form a library
of aminodiols 58a–61a and 58b–61b, respectively. Primary
aminotriols 47a and 47b were prepared via the usual way by
hydrogenolysis of aminodiols 58a–60a and 58b–60b over Pd/C.
Dihydroxylation of 50b with the OsO4/NMO system provided
triols 62a and 62b in a 2 : 1 ratio with an excellent yield of 90%.
Scheme 6 Synthesis of (ꢀ)-isopulegol-based aminotriol derivatives.
Reaction conditions: (i) NaH (1.5 equiv.), BnBr (3.0 equiv.), KI (1.5
Scheme 4 Synthesis of (ꢀ)-isopulegol-based diols. Reaction condi- equiv.), dry THF, 60 ꢁC, 12 h, 40% (50b), 19% (50a); (ii) mCPBA (2 equiv.),
tions: (i) 2% OsO4/t-BuOH, 50% NMO/H2O, acetone, 25 ꢁC, 24 h, 88%; Na2HPO4$12H2O (3 equiv.), CH2Cl2, 25 ꢁC, 2 h, 38% (51a), 28% (51b);
(ii) triphosgene (0.5 equiv.), pyridine (4 equiv.), dry CH2Cl2, 25 ꢁC, 2 h, (iii) RNH2 (2 equiv.), LiClO4 (1 equiv.), MeCN, 70–80 ꢁC, 6 h, 25–40%
36% (40a), 36% (40b); (iii) LiAlH4 (2 equiv.), dry Et2O, 0 ꢁC, 4 h, 95% (51a), 29–42% (51b); (iv) NMO/H2O, 2% OsO4/t-BuOH, acetone, 25 ꢁC,
(39a), 56% (39b); (iv) 5% Pd/C, H2 (1 atm), MeOH, 25 ꢁC, 24 h, 95% (39a), 24 h, 50% (56a), 15% (56b); (v) 5% Pd/C, H2 (1 atm), MeOH, 25 ꢁC, 24 h,
91% (39b).
95–98% (47a–b), 83% (56a).
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 38468–38477 | 38471

View Article Online
RSC Advances
Paper
Scheme 9 Determination of the structure of (ꢀ)-isopulegol-based
aminotriol as well as triol derivatives. Reaction conditions: LiAlH4 (2
Scheme 7 Synthesis of (ꢀ)-isopulegol-based aminotriol derivatives. equiv.), dry THF, 25 ꢁC, 6 h, 70%; (ii) 5% Pd/C, H2 (1 atm), n-hex-
Reaction conditions: (i) mCPBA (2 equiv.), Na2HPO4$12H2O (3 equiv.), ane : EtOAc ¼ 9 : 1, 25 ꢁC, 24 h, 90% (42a), 78% (51a), 90% (57a); (iii)
CH2Cl2, 25 ꢁC, 2 h, 38% (57a), 15% (57b); (ii) RNH2 (2 equiv.), LiClO4 (1 3 M NaOH, DMSO, 25 ꢁC, 2–24 h, 33% (56b), 57% (62b); (iv) LiAlH4 (2
equiv.), MeCN, 70–80 ꢁC, 6 h, 39–50% (57a), 16–21% (57b); (iii) 5% Pd/ equiv.), dry THF, 25 ꢁC, 6 h then 5% Pd/C, H2 (1 atm), n-hexane : EtOAc
C, H2 (1 atm), MeOH, 25 ꢁC, 24 h, 90–93% (47a–b), 97% (62a), 95% ¼ 9 : 1, 25 ꢁC, 24 h, 87%.
(62b); (iv) NMO/H2O, 2% OsO4/t-BuOH, acetone, 25 ꢁC, 24 h, 59%
(62a), 29% (62b).
Since several aminodiols as well as aminotriols exerted
antimicrobial activities on various microorganisms,91 antimi-
crobial activities of the prepared aminodiol and aminotriol
analogues were also explored against two yeasts as well as two
Gram-positive and two Gram-negative bacteria (Table 1, only the
best results are shown).
congurations in Scheme 9). It has been reported that reduction
with LAH gives the corresponding triol with the same stereo-
chemical conguration at the carbon atoms as of the original
moiety.88,89 The stereochemical structures of triol 22a is well-
known in the literature;83 therefore, the absolute conguration
of epoxide 63a could also be determined.
The absolute conguration of 42a, 51a and 57a was
conrmed by debenzylation via hydrogenolysis over Pd/C to
provide triol 22a with stereochemical retention. To prove that
the stereochemical conguration of the epoxide was main-
tained during reaction, 57a was reduced with LiAlH4 then
debenzylated applying the 5% Pd/C/H2 system to give 22a in
good yield. The stereostructure of 56b and 62b were assigned by
treatment of 51a and 57a with NaOH taking place with retention
of stereochemistry (Scheme 9).90
Our tests revealed that di-O-benzyl aminotriol derivatives
(52a–b) possess potential antimicrobial properties over 80%
against both the two Gram-positive and the yeast species. In the
case of B. subtilis, these compounds proved to be the most
effective agents even at a low concentration of 10 mg mLꢀ1, while
other derivatives (45a–b and 58a–b) showed lower activities.
Removal of one of the two benzyl protecting groups in aminotriol
derivatives (45a–b and 58a–b) led to improved selective inhibition
on B. subtilis. The almost complete loss of antibacterial activity
resulting from the replacement of all O-benzyloxy groups with
hydroxyl group as demonstrated with aminotriol derivatives 66a–
b suggests that the benzyl moiety is a key element to have satis-
factory antimicrobial activity in the case of aminotriols.
Among aminodiol derivatives, only O-benzyl aminodiol 35b
presented activity against B. subtilis, whereas debenzylated
derivative 9 had no effect. This result indicates that the O-ben-
zyloxy group attached to the cyclohexyl ring is responsible for
activity of the studied antibacterial agents.
The available data demonstrated that the O-benzyloxy group on
the cyclohexyl ring (41 and 50b) is much more effective to induce
antimicrobial activity than the 1-BnO-propen-2-yl group (50a).
In comparison, a-methylene-g-butyrolactone 4, the most
effective compound against C. albicans and C. krusei, was found
to possess highly selective effectiveness on the yeast species.
The synthetic aminodiol and aminotriol derivatives were
also evaluated for their antioxidant activity using DPPH assays
(Table 2, only the detected activities are shown).
In the DPPH study, aminodiol 9 displayed a potential anti-
oxidant effect, while the aminotriol derivatives (58a–b) had
only moderate effects. The results of this survey, namely
improvement of antioxidant activity alongside with the
Scheme 8 Synthesis of (ꢀ)-isopulegol-based aminotriols. Reaction
conditions: (i) mCPBA (2 equiv.), Na2HPO4$12H2O (3 equiv.), CH2Cl2,
25 ꢁC, 2 h, 33% (63a), 7% (63b); (ii) RNH2 (2 equiv.), LiClO4 (1 equiv.),
MeCN, 70–80 ꢁC, 6 h, 62–77% (63a), 87–93% (63b); (iii) 5% Pd/C, H2 (1
atm), MeOH, 25 ꢁC, 24 h, 67–75%; (iv) NMO/H2O, 2% OsO4/t-BuOH,
acetone, 25 ꢁC, 24 h, 53%.
38472 | RSC Adv., 2020, 10, 38468–38477
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Table 1 Antimicrobial activity of derivatives expressed in I% values
Inhibitory effecta (%) ꢂ RSD (%)
Gram positive
Gram negative
Yeast
Anal
4
Conc. (mg mLꢀ1
)
B. subtilis
S. aureus
E. coli
P. aeruginosa
C. albicans
C. krusei
100
10
100
10
100
10
100
10
100
10
100
10
100
10
100
10
100
10
100
10
100
10
100
10
100
10
100
10
100
10
31.51 ꢂ 4.58
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
94.30 ꢂ 5.46
88.22 ꢂ 5.36
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
30a
30b
35b
41
46.53 ꢂ 2.55
34.92 ꢂ 6.84
52.97 ꢂ 8.35
41.69 ꢂ 10.35
92.04 ꢂ 1.18
57.37 ꢂ 6.13
76.58 ꢂ 11.68
25.17 ꢂ 6.00
91.72 ꢂ 3.98
—
23.00 ꢂ 9.26
—
—
—
—
—
25.86 ꢂ 1.43
—
23.49 ꢂ 7.28
—
—
43a
45a
45b
50b
52a
52b
56a
58a
58b
66a
30.58 ꢂ 1.51
22.64 ꢂ 6.99
—
—
—
—
—
—
—
—
91.29 ꢂ 1.86
23.37 ꢂ 2.81
—
—
—
—
—
—
—
—
—
77.98 ꢂ 6.27
1.53 ꢂ 2.93
76.30 ꢂ 16.90
45.25 ꢂ 11.25
77.67 ꢂ 3.81
93.88 ꢂ 1.77
87.23 ꢂ 4.17
94.63 ꢂ 1.01
78.20 ꢂ 7.98
—
—
—
—
73.44 ꢂ 1.78
86.64 ꢂ 2.54
84.92 ꢂ 4.20
—
—
—
68.03 ꢂ 4.74
81.47 ꢂ 5.04
81.00 ꢂ 4.03
—
—
—
—
—
—
—
—
—
—
—
—
41.25 ꢂ 9.35
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
60.52 ꢂ 2.49
26.09 ꢂ 4.61
—
—
—
—
—
—
68.93 ꢂ 6.85
34.63 ꢂ 7.99
31.48 ꢂ 11.69
—
39.76 ꢂ 3.24
—
a
Inhibitory effect values less than 20% are considered negligible and not presented numerically. Compounds 1, 3, 9, 13, 14, 18, 19, 22a–b, 24a–b,
28a–b, 30a, 33, 39a–b, 47a–b, 48, 49, 50a, 56b, 62a–b, 64a and 66b were also examined but did not elicit 20% inhibitory effect even at 100 mg mLꢀ1
.
replacement of the O-benzyloxy moiety with a hydroxyl group, can act protectively. In the rst mechanism, the free radical (e.g.
show that efficiency depends on the hydroxyl function of DPPH) removes a hydrogen atom from the hydroxyl group that
the cyclohexyl ring more signicantly than on the 1- itself becomes a radical, in this way the functional group
hydroxypropen-2-yl group.
donates a proton to the free radicals and neutralise it (e.g.
The hydroxyl group of molecules play remarkable role in DPPH-H). In the second mechanism, called as one-electron
their antioxidant property.92 Recently, there are two proposed transfer, the hydroxyl group can give an electron to the free
mechanisms by which antioxidants containing hydroxyl group radical becoming itself a radical cation.93
Although aminotriol 58a was less active than aminodiols, its
antioxidant property is still considered to be notable compared
Table 2 Antioxidant effects of active synthetic derivatives expressed in
with aminotriol 45a. This result again demonstrates that the
IC50 values
hydroxyl group on the cyclohexyl ring is necessary for antioxi-
dant property.
DPPH antioxidant activity
Compound
(mmol mLꢀ1) ꢂ SD
9
24b
28a
30a
45a
58a
58b
Gallic acid
8.47 ꢂ 0.56
75.63 ꢂ 0.01
204.77 ꢂ 9.1
72.76 ꢂ 0.03
87.61 ꢂ 0.14
33.74 ꢂ 3.74
56.63 ꢂ 0.01
0.16 ꢂ 0.01
Conclusion
A new library of isopulegol-based chiral aminodiols and ami-
notriols was developed from commercially available (ꢀ)-iso-
pulegol. The isopulegol-based chiral di-, tri- and tetraols are
promising substrates for the preparation of chiral crown ethers.
a,b-Dihydroxyamides, accessed through the ring opening of a,b-
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 38468–38477 | 38473

View Article Online
RSC Advances
Paper
dihydroxylactones, are widely applicable in the synthesis of
natural products and in saccharide chemistry.
6 M. N. Gould, Prevention and therapy of mammary cancer by
monoterpenes, J. Cell. Biochem., 1995, 59, 139–144.
Our result proved again that steric hindrance exerted by both
benzyl and methyl groups at the a position in epoxide 34a
makes its conformationally constrained structure to restrict the
approach of nucleophiles in aminolysis.
O-Benzyl aminotriol and aminodiol derivatives exert mark-
edly selective antibacterial action on B. subtilis, while di-O-
benzyl aminotriols have also shown signicant effectiveness not
only against Gram-positive bacteria strains but also against
yeast species. Moreover, our result also indicated the potential
antifungal activity of a-methylene-g-butyrolactones.
7 B. Rodenak Kladniew, M. Polo, S. Montero Villegas, M. Galle,
´
R. Crespo and M. Garcıa de Bravo, Synergistic
antiproliferative and anticholesterogenic effects of linalool,
1,8-cineole, and simvastatin on human cell lines, Chem.-
Biol. Interact., 2014, 214, 57–68.
8 R. Tundis, M. R. Loizzo, M. Bonesi, F. Menichini,
V. Mastellone, C. Colica and F. Menichini, Comparative
study on the antioxidant capacity and Cholinesterase
inhibitory activity of Citrus aurantifolia Swingle, C.
aurantium L., and C. bergamia Risso and Poit. Peel
Essential Oils, J. Food Sci., 2012, 77, H40–H46.
In addition, aminodiol and aminotriol derivatives were
applied as antioxidant agents in DPPH assay. N-Benzyl amino-
diols are still considered to exert notable antioxidant property.
Finally, in vitro studies have clearly shown that the O-benzyl
9 G. Ruberto and M. T. Baratta, Antioxidant activity of selected
essential oil components in two lipid model systems, Food
Chem., 2000, 69, 167–174.
´
ˇ
substituent on the cyclohexyl ring in aminodiol and aminotriol 10 M. Nikolic, J. Glamoclija, I. C. F. R. Ferreira, R. C. Calhelha,
ˆ
´
´
derivatives is essential to have antimicrobial effect, whereas the
hydroxyl group on this ring is crucial on the antioxidant prop-
erty. The stereochemistry of the aminotriol and aminotriol
derivatives has no inuence on either effect.
A. Fernandes, T. Markovic, D. Markovic, A. Giweli and
´
M. Sokovic, Chemical composition, antimicrobial,
antioxidant and antitumor activity of Thymus serpyllum L.,
Thymus algeriensis Boiss. and Reut and Thymus
vulgaris L. essential oils, Ind. Crops Prod., 2014, 52, 183–190.
11 K. A. Wojtunik, L. M. Ciesla and M. Waksmundzka-Hajnos,
Model studies on the antioxidant activity of common
terpenoid constituents of essential oils by means of the
2,2-diphenyl-1-picrylhydrazyl method, J. Agric. Food Chem.,
2014, 62, 9088–9094.
Conflicts of interest
The authors declare no conict of interest.
Acknowledgements
12 A. Ahmad, S. van Vuuren and A. Viljoen, Unravelling the
complex antimicrobial interactions of essential oils -The
case of Thymus vulgaris (Thyme), Molecules, 2014, 19,
2896–2910.
13 A. C. R. da Silva, P. M. Lopes, M. M. B. de Azevedo,
D. C. M. Costa, C. S. Alviano and D. S. Alviano, Biological
activities of a-Pinene and b-Pinene enantiomers, Molecules,
2012, 17, 6305–6316.
We are grateful for nancial supports from the EU-funded
Hungarian grant GINOP-2.3.2-15-2016-00012, Ministry of
Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT,
Hungarian Research Foundation (OTKA No.
University of Szeged Open Access Fund (grant No. 4969) and
K 115731),
´
Tamas Szilasi for his experimental assistance.
14 J. Nguefack, O. Tamgue, J. B. L. Dongmo, C. D. Dakole,
V. Leth, H. F. Vismer, P. H. Amvam Zollo and
A. E. Nkengfack, Synergistic action between fractions of
essential oils from Cymbopogon citratus, Ocimum
gratissimum and Thymus vulgaris against Penicillium
expansum, Food Control, 2012, 23, 377–383.
References
1 L. M. Ciesla, K. A. Wojtunik-Kulesza, A. Oniszczuk and
M. Waksmundzka-Hajnos, Antioxidant synergism and
antagonism between selected monoterpenes using the 2,2-
diphenyl-1-picrylhydrazyl method: Antioxidant synergism 15 S.-N. Park, Y. K. Lim, M. O. Freire, E. Cho, D. Jin and
and antagonism between selected monoterpenes, Flavour
Fragrance J., 2016, 31, 412–419.
2 Y. Wen Xu, Effects of salicylic acid on monoterpene
J.-K. Kook, Antimicrobial effect of linalool and a-terpineol
against periodontopathic and cariogenic bacteria,
Anaerobe, 2012, 18, 369–372.
production and antioxidant systems in Houttuynia cordata, 16 N. Belletti, S. S. Kamdem, G. Tabanelli, R. Lanciotti and
Afr. J. Biotechnol., 2012, 11, 1364–1372.
F. Gardini, Modeling of combined effects of citral, linalool
and b-pinene used against Saccharomyces cerevisiae in
citrus-based beverages subjected to a mild heat treatment,
Int. J. Food Microbiol., 2010, 136, 283–289.
3 F. Bakkali, S. Averbeck, D. Averbeck and M. Idaomar,
Biological effects of essential oils – A review, Food Chem.
Toxicol., 2008, 46, 446–475.
4 N. L. S. Chan, H. Wang, Y. Wang, H. Y. Leung and 17 D. Trombetta, F. Castelli, M. G. Sarpietro, V. Venuti,
L. K. Leung, Polycyclic aromatic hydrocarbon-induced
CYP1B1 activity is suppressed by perillyl alcohol in MCF-7
cells, Toxicol. Appl. Pharmacol., 2006, 213, 98–104.
M. Cristani, C. Daniele, A. Saija, G. Mazzanti and
G. Bisignano, Mechanisms of antibacterial action of three
monoterpenes, Antimicrob. Agents Chemother., 2005, 49,
2474–2478.
5 P. L. Crowell, Monoterpenes in breast cancer
chemoprevention, Breast Cancer Res. Treat., 1997, 46, 191– 18 M. Cristani, M. D'Arrigo, G. Mandalari, F. Castelli,
197.
M. G. Sarpietro, D. Micieli, V. Venuti, G. Bisignano, A. Saija
38474 | RSC Adv., 2020, 10, 38468–38477
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
0
´
and D. Trombetta, Interaction of four monoterpenes 31 A. E. Wroblewski, I. E. Głowacka and D. G. Piotrowska, 1 -
contained in essential oils with model membranes:
implications for their antibacterial activity, J. Agric. Food
Chem., 2007, 55, 6300–6308.
Homonucleosides and their structural analogues: A review,
Eur. J. Med. Chem., 2016, 118, 121–142.
32 J. M. Sadler, S. L. Mosley, K. M. Dorgan, Z. S. Zhou and
K. L. Seley-Radtke, Synthetic strategies toward carbocyclic
purine–pyrimidine hybrid nucleosides, Bioorg. Med. Chem.,
2009, 17, 5520–5525.
19 W. T. Langeveld, E. J. A. Veldhuizen and S. A. Burt, Synergy
between essential oil components and antibiotics:
a review, Crit. Rev. Microbiol., 2014, 40, 76–94.
20 V. Pereira, C. Dias, M. C. Vasconcelos, E. Rosa and 33 K. A. Jacobson, D. K. Tosh, K. S. Toti and A. Ciancetta,
M. J. Saavedra, Antibacterial activity and synergistic effects
between Eucalyptus globulus leaf residues (essential oils
and extracts) and antibiotics against several isolates of
Polypharmacology
methanocarba nucleosides, Drug Discovery Today, 2017, 22,
1782–1791.
of
conformationally
locked
´
respiratory tract infections (Pseudomonas aeruginosa), Ind. 34 A. C. Allepuz, R. Badorrey, M. D. Dıaz-de-Villegas and
´
Crops Prod., 2014, 52, 1–7.
J. A. Galvez, Diastereoselective reduction of ketimines
21 N. G. Ntalli, F. Ferrari, I. Giannakou and U. Menkissoglu-
Spiroudi, Synergistic and antagonistic interactions of
terpenes against Meloidogyne incognita and the
derived from (R)-3,4-dihydroxybutan-2-one: an alternative
route to key intermediates for the synthesis of anticancer
agent ES-285, Tetrahedron: Asymmetry, 2010, 21, 503–506.
nematicidal activity of essential oils from seven plants 35 R. K. Mishra, C. M. Coates, K. D. Revell and E. Turos,
indigenous to Greece, Pest Manag. Sci., 2011, 67, 341–351.
22 K. R. Riella, R. R. Marinho, J. S. Santos, R. N. Pereira-Filho,
J. C. Cardoso, R. L. C. Albuquerque-Junior and
Synthesis
of
2-Oxazolidinones
from
b-Lactams:
stereospecic total synthesis of (ꢀ)-Cytoxazone and all of
Its stereoisomers, Org. Lett., 2007, 9, 575–578.
S. M. Thomazzi, Anti-inammatory and cicatrizing 36 A. Grajewska and M. D. Rozwadowska, Stereoselective
activities of thymol, a monoterpene of the essential oil
from Lippia gracilis, in rodents, J. Ethnopharmacol., 2012,
143, 656–663.
synthesis of cytoxazone and its analogues, Tetrahedron:
Asymmetry, 2007, 18, 803–813.
37 H. Kleinert, S. Rosenberg, W. Baker, H. Stein, V. Klinghofer,
J. Barlow, K. Spina, J. Polakowski, P. Kovar, J. Cohen, et al.,
Discovery of a peptide-based renin inhibitor with oral
bioavailability and efficacy, Science, 1992, 257, 1940–1943.
23 A. Djouahri, B. Saka, L. Boudarene, F. Benseradj,
S. Aberrane, S. Aitmoussa, C. Chelghoum, L. Lamari,
N. Sabaou and A. Baaliouamer, In vitro synergistic/
antagonistic antibacterial and anti-inammatory effect of 38 S. Chandrasekhar, S. Mohapatra and J. S. Yadav, Practical
various extracts/essential oil from cones of Tetraclinis
articulata (Vahl) Masters with antibiotic and anti-
inammatory agents, Ind. Crops Prod., 2014, 56, 60–66.
synthesis of Abbott aminodiol: A core unit of the potent
renin inhibitor Zankiren, Tetrahedron, 1999, 55, 4763–4768.
39 K. Toribatake, S. Miyata, Y. Naganawa and H. Nishiyama,
Asymmetric synthesis of optically active 3-amino-1,2-diols
from N-acyl-protected allylamines via catalytic diboration
with Rh[bis(oxazolinyl)phenyl] catalysts, Tetrahedron, 2015,
71, 3203–3208.
˜
´
24 A. G. Guimaraes, J. S. S. Quintans and L. J. Quintans-Junior,
Monoterpenes with analgesic activity-A systematic review,
Phytother. Res., 2013, 27, 1–15.
25 A. Aharoni, M. Jongsma and H. Bouwmeester, Volatile
science? Metabolic engineering of terpenoids in plants, 40 E. Richelle-Maurer, J.-C. Braekman, M. Kluijver, R. Gomez,
Trends Plant Sci., 2005, 10, 594–602.
G. de Vyver, R. Soest and C. Devijver, Cellular location of
(2R,3R,7Z)-2-aminotetradec-7-ene-1, 3-diol, potent
antimicrobial metabolite produced by the Caribbean
sponge Haliclona vansoesti, Cell Tissue Res., 2001, 306,
157–165.
26 H. T. Prates, J. P. Santos, J. M. Waquil, J. D. Fabris,
A. B. Oliveira and J. E. Foster, Insecticidal activity of
monoterpenes against Rhyzopertha dominica (F.) and
Tribolium castaneum (Herbst), J. Stored Prod. Res., 1998,
34, 243–249.
27 W.-S. Choi, B.-S. Park, Y.-H. Lee, D. Y. Jang, H. Y. Yoon and
S.-E. Lee, Fumigant toxicities of essential oils and
monoterpenes against Lycoriella mali adults, Crop Prot.,
2006, 25, 398–401.
a
41 H. Kakeya, M. Morishita, H. Koshino, T. Morita,
K. Kobayashi and H. Osada, Cytoxazone: A novel Cytokine
modulator containing a 2-Oxazolidinone ring produced by
Streptomyces sp., J. Org. Chem., 1999, 64, 1052–1053.
42 A. S. Paraskar and A. Sudalai, Enantioselective synthesis of
(ꢀ)-Cytoxazone and (+)-epi-Cytoxazone, novel cytokine
modulators via Sharpless asymmetric epoxidation and l-
proline catalyzed Mannich reaction, Tetrahedron, 2006, 62,
5756–5762.
28 B. A. Leita, A. C. Warden, N. Burke, M. S. O'Shea and
D. Trimm, Production of p-Cymene and hydrogen from
a
bio-renewable feedstock–1,8-cineole (Eucalyptus oil),
Green Chem., 2010, 12, 70–76.
´
´
29 W. Chen and A. M. Viljoen, Geraniol — A review of 43 R. Pedrosa, C. Andres, J. P. Duque-Soladana and C. D. Roson,
a commercially important fragrance material, South Afr. J.
Bot., 2010, 76, 643–651.
30 G. P. P. Kamatou, I. Vermaak, A. M. Viljoen and
B. M. Lawrence, Menthol: A simple monoterpene with
Regio- and stereoselective 6- exo - trig radical cyclisations
onto chiral perhydro-1,3-benzoxazines: synthesis of
enantiopure 3-alkylpiperidines, Tetrahedron: Asymmetry,
2000, 11, 2809–2821.
´
remarkable biological properties, Phytochemistry, 2013, 96, 44 R. Pedrosa, C. Andres, J. Nieto and S. del Pozo, Synthesis of
15–25.
enantiopure
3-Azabicyclo[3.2.0]heptanes
by
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 38468–38477 | 38475

View Article Online
RSC Advances
Paper
diastereoselective intramolecular [2+2] photocycloaddition
reactions on chiral perhydro-1,3-benzoxazines, J. Org.
Chem., 2003, 68, 4923–4931.
ketones and addition of diethylzinc to aldehydes, J. Org.
Chem., 1999, 64, 3207–3212.
´
´
¨
¨
58 T. Le, P. Berdi, I. Zupko, F. Fulop and Z. Szakonyi, Synthesis
and transformation of (-)-Isopulegol-based chiral b-
aminolactones and b-aminoamides, Int. J. Mol. Sci., 2018,
19, 3522.
´
˜´
45 C. Andres, J. Nieto, R. Pedrosa and N. Villamanan, Synthesis
of enantiopure primary amines by stereoselective ring
opening of chiral Octahydro-1,3-benzoxazines by Grignard
and Organoaluminum reagents, J. Org. Chem., 1996, 61, 59 F. Z. Bamou, T. M. Le, B. Volford, A. Szekeres and
4130–4135. Z. Szakonyi, Synthesis and application of 1,2-
aminoalcohols with neoisopulegol-based
octahydrobenzofuran core, Molecules, 2019, 25, 21.
´
46 A. Alberola, C. Andres and R. Pedrosa, Diastereoselective
ring opening of 2-substituted N-Benzyl-4,4, 7a-trimethyl-
trans-octahydro-1,3-benzoxazines by Grignard reagents. 60 R. Outouch, S. Oubaassine, M. Ait Ali, L. El Firdoussi and
Highly enantioselective synthesis of primary amines,
Synlett, 1990, 1990, 763–765.
47 Y.-J. Cherng, J.-M. Fang and T.-J. Lu, Pinane-type tridentate
reagents for enantioselective reactions: reduction of
A. Spannenberg, Crystal structure of (1S ,2R,4 S)-1-
[(morpholin-4-yl)methyl]-4-(prop-1-en-2-yl)cyclohexane-1,2-
diol, Acta Crystallogr., Sect. E: Crystallogr. Commun., 2015, 71,
79–81.
´
¨
¨
ketones and addition of Diethylzinc to aldehydes, J. Org. 61 T. Gonda, Z. Szakonyi, A. Csampai, M. Haukka and F. Fulop,
Chem., 1999, 64, 3207–3212.
48 Y.-J. Cherng, J.-M. Fang and T.-J. Lu, A new pinane-type
tridentate modier for asymmetric reduction of ketones
Stereoselective synthesis and application of tridentate
aminodiols derived from (+)-pulegone, Tetrahedron:
Asymmetry, 2016, 27, 480–486.
with lithium aluminum hydride, Tetrahedron: Asymmetry, 62 Y. Tashenov, M. Daniels, K. Robeyns, L. Van Meervelt,
1995, 6, 89–92.
W. Dehaen, Y. Suleimen and Z. Szakonyi, Stereoselective
syntheses and application of chiral bi- and tridentate
ligands derived from (+)-Sabinol, Molecules, 2018, 23, 771.
´
¨
¨
49 Z. Szakonyi, A. Hetenyi and F. Fulop, Synthesis of
enantiomeric spirooxazolines and spirooxazolidines by the
regioselective
ring
closure
of
(–)-a-pinene-based 63 O. V. Ardashov, A. V. Pavlova, I. V. Il’ina, E. A. Morozova,
aminodiols, Arkivoc, 2007, 2008, 33.
D. V. Korchagina, E. V. Karpova, K. P. Volcho,
¨
¨
50 Z. Szakonyi, K. Csillag and F. Fulop, Stereoselective synthesis
of carane-based aminodiols as chiral ligands for the catalytic
addition of diethylzinc to aldehydes, Tetrahedron:
Asymmetry, 2011, 22, 1021–1027.
T. G. Tolstikova and N. F. Salakhutdinov, Highly Potent
Activity of (1R,2R,6S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-3-
ene-1,2-diol in animal models of Parkinson's disease, J.
Med. Chem., 2011, 54, 3866–3874.
´
}
´
¨
¨
51 Z. Szakonyi, A. Csor, A. Csampai and F. Fulop, 64 D. A. Brown, M. T. Canning, S. L. Nay, A. V. Pena and
Stereoselective
synthesis
and
modelling-driven
D. B. Yarosh, Bicyclic monoterpene diols stimulate release
of nitric oxide from skin cells, increase microcirculation,
and elevate skin temperature, Nitric Oxide, 2006, 15, 70–76.
65 D. A. Brown, K. Lesiak, W.-Y. Ren, K. L. Strzelecki and
A. A. Khorlin, Bicyclic monoterpene diols induce
differentiation of S91 melanoma and PC 12
optimisation of Carane-based aminodiols and 1,3-Oxazines
as catalysts for the enantioselective addition of diethylzinc
to benzaldehyde, Chem.–Eur. J., 2016, 22, 7163–7173.
52 M. P. Stoyanova, B. L. Shivachev, R. P. Nikolova and
V. Dimitrov, Highly efficient synthesis of chiral
aminoalcohols and aminodiols with camphane skeleton,
Tetrahedron: Asymmetry, 2013, 24, 1426–1434.
pheochromocytoma cells by
a
cyclic Guanosine-
monophosphate-dependent pathway, Pigm. Cell Res., 1999,
12, 36–47.
53 D.-S. Lee, S.-M. Chang, C.-Y. Ho and T.-J. Lu,
Enantioselective addition of diethylzinc to aldehydes 66 S. Hammami, A. I. Elshamy, R. E. Mokni, A. Snene, K. Iseki,
catalyzed by chiral O, N, O-tridentate phenol ligands
derived from camphor, Chirality, 2016, 28, 65–71.
54 I. Philipova, V. Dimitrov and S. Simova, Synthesis of new
enantiopure aminodiols and their use as ligands for the
H. Dhaouadi, Y. Okamoto, M. Suenaga, M. Noji, A. Umeyama
and Y. Asakawa, Chemical Constituents of the Aerial Parts of
Daucus carota subsp. hispidus growing in Tunisia, Nat. Prod.
Commun., 2019, 14, 1934578X1986351.
addition of diethylzinc to benzaldehyde, Tetrahedron: 67 P. L. Crowell, Z. Ren, S. Lin, E. Vedejs and M. N. Gould,
Asymmetry, 1999, 10, 1381–1391.
55 S. Panev, A. Linden and V. Dimitrov, Chiral aminoalcohols
Structure-activity relationships among monoterpene
inhibitors of protein isoprenylation and cell proliferation,
Biochem. Pharmacol., 1994, 47, 1405–1415.
with
a
menthane skeleton as catalysts for the
enantioselective addition of diethylzinc to benzaldehyde, 68 A. E.-H. H. Mohamed, N. S. Mohamed, A. R. Hamed and
Tetrahedron: Asymmetry, 2001, 12, 1313–1321.
M.-E. F. Hegazy, Anti-inammatory activity of highly
oxygenated terpenoids from Achillea biebersteinii Afan, Z.
Naturforsch. C Biosci., 2016, 71, 429–432.
´
56 K. Csillag, L. Nemeth, T. A. Martinek, Z. Szakonyi and
¨
¨
F. Fulop, Stereoselective synthesis of pinane-type tridentate
aminodiols and their application in the enantioselective 69 T. J. Brocksom, R. B. dos Santos, N. A. Varanda and
addition of diethylzinc to benzaldehyde, Tetrahedron:
Asymmetry, 2012, 23, 144–150.
57 Y.-J. Cherng, J.-M. Fang and T.-J. Lu, Pinane-type tridentate
reagents for enantioselective reactions: reduction of
U. Brocksom, An efficient synthesis of monoterpene a-
methylene-g-butyrolactones, Synth. Commun., 1988, 18,
1403–1410.
38476 | RSC Adv., 2020, 10, 38468–38477
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
70 T. J. Brocksom, J. Tercio and B. Ferreira, A biomimetic 83 Y. Yuasa and Y. Yuasa, Synthesis and absolute conguration
synthesis
Commun., 1981, 11, 105–119.
of
a-methylene-g-butyrolactones,
Synth.
at C(8) of ‘p-Menthane-3,8,9-triol’ derived from
(-)-Isopulegol, Helv. Chim. Acta, 2004, 87, 2602–2607.
71 M. Carda and J. A. Marco, Total synthesis of the 84 B. R. Travis, R. S. Narayan and B. Borhan, Osmium tetroxide-
monoterpenes (ꢀ)-mintlactone and (+)-isomintlactone,
promoted catalytic oxidative cleavage of olens: An
organometallic ozonolysis, J. Am. Chem. Soc., 2002, 124,
3824–3825.
Tetrahedron, 1992, 48, 9789–9800.
72 D. Friedrich and F. Bohlmann, Total synthesis of various
elemanolides, Tetrahedron, 1988, 44, 1369–1392.
73 M. Schlosser and M. Kotthaus, Isopulegol as a model
compound: metalation and substitution of an allylic
position in the presence of an unprotected hydroxy
function, Eur. J. Org. Chem., 1999, 1999, 459–462.
85 G. N. Costa, R. M. B. Carrilho, L. D. Dias, J. C. Viana,
G. L. B. Aquino, M. Pineiro and M. M. Pereira, Highly
efficient Rh(I)/tris-binaphthyl monophosphite catalysts for
hydroformylation of sterically hindered alkyl olens, J.
Mol. Catal. A: Chem., 2016, 416, 73–80.
74 S. Serra and C. Fuganti, Enzyme-mediated preparation of 86 I. Paterson, E. A. Anderson, S. M. Dalby, J. H. Lim and
enantiomerically pure p-Menthan- 3,9-diols and their use
for the synthesis of natural p-menthane lactones and
ethers, Helv. Chim. Acta, 2002, 85, 2489–2502.
P. Maltas, The stereocontrolled total synthesis of
spirastrellolide A methyl ester. Fragment coupling studies
and completion of the synthesis, Org. Biomol. Chem., 2012,
10, 5873–5886.
75 N. J. Lawrence, A. T. McGown, J. Nduka, J. A. Hadeld and
R. G. Pritchard, Cytotoxic michael-type amine adducts of a- 87 S. Superchi, M. I. Donnoli, G. Proni, G. P. Spada and
methylene lactones alantolactone and isoalantolactone,
Bioorg. Med. Chem. Lett., 2001, 11, 429–431.
C. Rosini, Induction of cholesteric mesophases by simple
cyclic derivatives of p,p0-disubstituted 1,2-Diphenylethane-
1,2-diols: importance of shape and polarizability effects, J.
Org. Chem., 1999, 64, 4762–4767.
´
¨
¨
76 Z. Szakonyi, A. Hetenyi and F. Fulop, Synthesis and
application of monoterpene-based chiral aminodiols,
Tetrahedron, 2008, 64, 1034–1039.
˜
´
88 I. S. Marcos, L. Castaneda, P. Basabe, D. Dıez and
J. G. Urones, Synthesis of sibiricinone A, sibiricinone B
and leoheterin, Tetrahedron, 2008, 64, 10860–10866.
77 D. Wu, J. Li and W. Wang, Selective formation of
monoacylated diols through a mild Passerini reaction:
selective formation of monoacylated diols through a mild 89 P. A. Wender, N. Buschmann, N. B. Cardin, L. R. Jones,
Passerini reaction, Eur. J. Org. Chem., 2018, 2018, 3022–3030.
78 A. Nemoto, Y. Hoshino, K. Yazawa, A. Ando, Y. Mikami,
C. Kan, J.-M. Kee, J. A. Kowalski and K. E. Longcore,
Gateway synthesis of daphnane congeners and their
protein kinase C affinities and cell-growth activities, Nat.
Chem., 2011, 3, 615–619.
¨
H. Komaki, Y. Tanaka and U. Grafe, Asterobactin, a new
Siderophore group antibiotic from Nocardia asteroides, J.
Antibiot., 2002, 55, 593–597.
90 K. Chen and P. S. Baran, Total synthesis of eudesmane
terpenes by site-selective C–H oxidations, Nature, 2009,
459, 824–828.
¨
79 D. Schummer, G. Hoe, E. Forche, H. Reichenbach, V. Wray
and T. Domke, Antibiotics from Gliding bacteria, LXXVI.
¨
¨
Vioprolides: new antifungal and cytotoxic peptolides from 91 T. M. Le, T. Szilasi, B. Volford, A. Szekeres, F. Fulop and
Cystobacter violaceus, Liebigs Ann., 2006, 1996, 971–978.
80 J. H. Kim, H. J. Lim and S. H. Cheon, A facile synthesis of
(6S,10S)-(+)-hernandulcin and (6S,10R)-(+)-epihernandulcin,
Tetrahedron, 2003, 59, 7501–7507.
81 B. P. Shivani and A. K. Chakraborti, Zinc(II) perchlorate
hexahydrate catalyzed opening of epoxide ring by amines:
Z. Szakonyi, Stereoselective synthesis and investigation of
Isopulegol-based chiral ligands, Int. J. Mol. Sci., 2019, 20,
4050.
92 W. Brand-Williams, M. E. Cuvelier and C. Berset, Use of
a free radical method to evaluate antioxidant activity, LWT–
Food Sci. Technol., 1995, 28, 25–30.
applications to synthesis of (RS)/(R)-Propranolols and (RS)/ 93 E. Bendary, R. R. Francis, H. M. G. Ali, M. I. Sarwat and S. El
(R)/(S)-Naopidils, J. Org. Chem., 2007, 72, 3713–3722.
82 S. C. Bergmeier, The Synthesis of vicinal amino alcohols,
Tetrahedron, 2000, 56, 2561–2576.
Hady, Antioxidant and structure–activity relationships
(SARs) of some phenolic and anilines compounds, Ann.
Agric. Sci., 2013, 58, 173–181.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 38468–38477 | 38477