Biomimetic Transformation of p-Menthene Glucosides into p-Cymenes and Carvotanacetone

Article abstract of DOI:10.1021/acs.jnatprod.8b00855

A biomimetic transformation of p-menthene glucosides into aromatic monoterpenoids that alluded to mechanisms for essential oil metabolism, which lines up with the precepts of molecular economy, is described. Acid treatment of (-)-(3S,4S,6R)-3,6-dihydroxy-1-menthene 3-O-β-d-glucopyranoside (1) and (-)-(3S,4R,5R,6S)-3,5,6-trihydroxy-1-menthene 3-O-β-d-glucopyranoside (2), from Ageratina glabrata, yielded p-cymene (7) and carvacrol (9). The stable oxidized intermediates (+)-(3S,4S,6R)-3,6-dihydroxy-1-menthene (3), (+)-(1S,4S,6R)-1,6-dihydroxy-2-menthene (4), (+)-(1R,4S,6R)-1,6-dihydroxy-2-menthene (5), (+)-(4S,6R)-yabunikkeol (6), (+)-(4S)-carvotanacetone (8), (+)-(1S,4S,5R,6R)-1,5,6-trihydroxy-2-menthene (15), (+)-(1R,4S,5R,6R)-1,5,6-trihydroxy-2-menthene (16), and the new (+)-(4S,5R,6S)-1(7),2-menthadiene (17) permitted establishment of the reaction mechanisms. The reactivity of the hydroxy groups of 4 and 5, as well as those of 15 and 16, was compared by acetylation reactions and supported by DFT calculations, revealing diminished reactivity in 4 and 15 due to the cis configuration of their hydroxy groups at C-1 and C-6. In addition, p-cymene (7) was detected as one of the major constituents of the essential oil of A. glabrata, which matches well with the biomimetic study.

Full text of DOI:10.1021/acs.jnatprod.8b00855

Article
pubs.acs.org/jnp
Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
Biomimetic Transformation of p‑Menthene Glucosides into
p‑Cymenes and Carvotanacetone
‡
‡
Julio C. Pardo-Novoa,† Hector M. Arreaga-Gonzalez, Sinuhe Galvan-Gomez,
́
́
́
́
́
Gabriela Rodríguez-García,‡ Rosa E. del Río,‡ Carlos M. Cerda-García-Rojas,*,†
Pedro Joseph-Nathan,† and Mario A. Gomez-Hurtado*
,‡
́
†
́
́
Departamento de Química, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Apartado 14-740,
Mexico City 07000, Mexico
‡
́
́
Instituto de Investigaciones Químico-Biologicas, Universidad Michoacana de San Nicolas de Hidalgo, Ciudad Universitaria,
́
Morelia, Michoacan 58030, Mexico
S
* Supporting Information
ABSTRACT: A biomimetic transformation of p-menthene
glucosides into aromatic monoterpenoids that alluded to
mechanisms for essential oil metabolism, which lines up with
the precepts of molecular economy, is described. Acid
treatment of (−)-(3S,4S,6R)-3,6-dihydroxy-1-menthene 3-O-
β-D-glucopyranoside (1) and (−)-(3S,4R,5R,6S)-3,5,6-trihy-
droxy-1-menthene 3-O-β-D-glucopyranoside (2), from Ager-
atina glabrata, yielded p-cymene (7) and carvacrol (9). The
stable oxidized intermediates (+)-(3S,4S,6R)-3,6-dihydroxy-1-
menthene (3), (+)-(1S,4S,6R)-1,6-dihydroxy-2-menthene
(4), (+)-(1R,4S,6R)-1,6-dihydroxy-2-menthene (5),
(+)-(4S,6R)-yabunikkeol (6), (+)-(4S)-carvotanacetone (8), (+)-(1S,4S,5R,6R)-1,5,6-trihydroxy-2-menthene (15),
(+)-(1R,4S,5R,6R)-1,5,6-trihydroxy-2-menthene (16), and the new (+)-(4S,5R,6S)-1(7),2-menthadiene (17) permitted
establishment of the reaction mechanisms. The reactivity of the hydroxy groups of 4 and 5, as well as those of 15 and 16,
was compared by acetylation reactions and supported by DFT calculations, revealing diminished reactivity in 4 and 15 due to
the cis configuration of their hydroxy groups at C-1 and C-6. In addition, p-cymene (7) was detected as one of the major
constituents of the essential oil of A. glabrata, which matches well with the biomimetic study.
Previously we described the absolute configuration deter-
he biosynthetic pathway of p-menthenes assumes the
Tisomerization of geranyl diphosphate to neryl diphos- mination of (−)-(3S,4S,6R)-3,6-dihydroxy-1-menthene 3-O-β-
D-glucopyranoside (1) and (−)-(3S,4R,5R,6S)-3,5,6-trihy-
droxy-1-menthene 3-O-β-D-glucopyranoside (2), from Ager-
atina glabrata, and their derivatives (+)-(3S,4S,6R)-3,6-
dihydroxy-1-menthene (3), (+)-(1S,4S,6R)-1,6-dihydroxy-2-
menthene (4), (+)-(1R,4S,6R)-1,6-dihydroxy-2-menthene
(5), (+)-(1S,4S,5R,6R)-1,5,6-trihydroxy-2-menthene (15),
and (+)-(1R,4S,5R,6R)-1,5,6-trihydroxy-2-menthene (16), ob-
tained by acid hydrolysis.9
In this paper the biomimetic transformations of 1 and 2 into
aromatic monoterpene derivatives and other essential oil
constituents, by dehydration and oxidation processes, are
described. Dihydroxy-p-menthene derivatives 3−5,
(+)-(4S,6R)-yabunikkeol (6), 1,5,6-triols 15 and 16, and the
new (+)-(4S,5R,6S)-1(7),2-menthadiene (17), as reaction
intermediates in the formation of p-cymene (7) and carvacrol
phate, followed by cyclization through an allylic cation−
diphosphate ion-pair to afford an α-terpinyl cation, which is an
intermediate in the formation of several mono- and bicyclic
monoterpenes.1 Oxidation, isomerization, transposition, and
other reactions lead to an extensive variety of monoterpenes, of
which many are found in essential oils. The biosynthetic
pathway of aromatic monoterpenes is closely related to γ-
terpinene,2 limonene, menthene, and carvone through
dehydrogenation reactions,3 while the storage of volatile
compounds in plants proceeds through nonvolatile glycosides,
which after enzymatic glycolysis liberate the volatile aglycone
and the sugar residue.4−7 Nonetheless, due to the molecular
economy observed in cell metabolic processes, we can visualize
the relationship between the storage of volatile compounds
and the presence of a few strategic precursors capable of
providing essential oil constituents. Therefore, the under-
standing of anabolic and catabolic mechanisms, related to
volatile compounds, becomes relevant to the biosynthetic
pathways of these metabolites for subsequent chemical,
biological, biotechnological, and industrial applications.8
Special Issue: Special Issue in Honor of Drs. Rachel Mata and
Barbara Timmermann
Received: October 14, 2018
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.8b00855
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(9), were suggested. (+)-(4S)-Carvotanacetone (8) was also
observed as a dehydration product of 4 and 5, while oxidation
with iodine suggested that p-cymene (7) and carvacrol (9)
could arise from a common precursor, 4. The reactivity of the
tertiary hydroxy group of 4, 5, 15, and 16 was studied through
the preparation of their respective acetyl derivatives 10−13
and 18−21, determining that the trans-1,6-diol disposition
found in 5 and 16 was more reactive than the cis arrangement
found in 4 and 15 and that the steric effects of the isopropyl
group are insignificant, while fewer hydroxy group intra-
molecular interactions favor reactivity. All compounds were
characterized by physical and spectroscopic data, while GC-MS
analysis of the essential oil of the aerial parts from A. glabrata
revealed p-cymene (7) as a main constituent,10 supporting the
herein proposed chemical pathways.
Carbocation formation was induced by acid hydrolysis in a
polar protic medium. Dehydration of p-menthene 4 and/or 5
using 10% HCl yielded a mixture of (+)-yabunikkeol (6), p-
cymene (7), and (+)-(4S)-carvotanacetone (8) in a 1:4:10
ratio, establishing 8 as the most favored isomer. Furthermore,
acid hydrolysis of 6, under the same reaction conditions used
for 4 or 5, afforded p-cymene (7), suggesting that 6 is a
subsequent intermediate in the aromatization process from
glucoside 1 to 7. Thus, (Scheme 1), acid hydrolysis of 1
provides p-menthene 39 as the first intermediate, followed by
protonation of the C-3 hydroxy group and subsequent
dehydration to give allylic carbocation I, which is quenched
by addition of water at C-1, yielding 4 and 5 as the next diol
intermediates. Based on steric considerations a less probable
route for generating 4 and 5 would involve an allylic alcohol
exchange via hydroxylation at C-1 of 3. Activation of 4 or 5 via
protonation at the tertiary hydroxy group favors dehydration at
C-1 by proton loss from CH3-7 to give 6. Finally, loss of the C-
5 protonated hydroxy group from 6 to give II (path a) and
subsequent deprotonation at C-5 provides triene III, whose
acid-catalyzed rearrangement leads to p-cymene (7). The
aromatization could occur by a concerted mechanism or via a
carbocation pathway as depicted in Scheme 1.
For the generation of (+)-(4S)-carvotanacetone (8) from 1,
the aforementioned steps leading to the formation of 4 or 5
could afford the allylic carbocation IV, directly or through 6
followed by protonation of the Δ1(7) double bond (path b). A
subsequent 1,3-hydride shift from C-5 to C-3 would give V,
which would be susceptible to a 1,2-hydride shift from C-6 to
C-5 in concert with deprotonation of the 6-hydroxy group to
afford ketone 8. The above route is supported by density
functional theory (DFT) calculations at the B3LYP/6-31G(d)
level of theory of the reaction intermediates IV and V, as in
several mechanistic proposals for terpene syntheses, including
those for p-menthene derivatives.11−14 In the present case
98.6% of the population of IV showed an H-3−C-3−C-5−H-5
relative orientation of −75.5 4.7° and a C-3−C-5 distance of
2.47 0.008 Å to favor the 1,3-hydride shift. The measured
parameters for V (P = 97.7%) revealed a H-5−C-5−C-6−H-6
dihedral angle (θ = −71.5
3.9°) and a C-5−C-6 bond
distance (d = 1.47 Å) to permit the 1,2-hydride shift.
(+)-Yabunikkeol (6) was described as an oxidation
derivative of (−)-α-phellandrene,15 although the (4R,6S)
absolute configuration was wrongly assigned, while p-cymene
(7) and (+)-(4S)-carvotanacetone (8) are widely reported as
essential oil components. In addition, 7 has been considered a
good-quality essential oil ingredient in Origanum species16 or a
low-quality ingredient in lemon essential oil.17
Since allylic alcohol intermediates 4−6 lead to aromatic 7,
iodine was considered as the aromatization reagent.18,19 Thus,
p-menthenediol 4 was refluxed in the presence of iodine for 3 h
to yield 8 and 9 (1:2), while aromatization for 5 h only
provided carvacrol (9). Therefore, 8 is an intermediate in the
aromatization process as suggested in Scheme 1, where the
coordination of iodine to the tertiary hydroxy group of 4, as
depicted in IX, facilitates dehydration and formation of 6,
whose protonation at C-7 by HI favors allylic carbocation IV.
Subsequent 1,3-hydride shifts to V and 1,2-hydride shifts
afforded 8. Formation of the iodoiranium intermediate VI is
followed by rupture of the C-2−I bond to allow formation of
the Δ2 double bond in intermediate VII. Deiodination affords
carbocation VIII, which on deprotonation at C-4 and
spontaneous tautomerization would generate 9. Thus,
Figure 1. Formulas of p-Menthenes 1−21.
RESULTS AND DISCUSSION
■
Menthene glucosides 1 and 2 were individually hydrolyzed
using diluted HCl to generate hydroxy-p-menthenes 3−5 from
1, and 15 and 16 from 2.9 Considering 4, 5, 15, and 16 arise
from H2O trapping an allylic carbocation, induced by
elimination at C-3 in 2 or 3, these molecules were considered
as possible essential oil constituent intermediates. Such an idea
is in accord with several investigations where glycosides
function as a storage mechanism for volatile compounds.4−7
B
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Scheme 1. Putative Mechanism for the Aromatization of p-Menthenes 4 and 5
iodoiranium-assisted aromatization intermediates become
plausible since acid conditions deactivate the carbonyl moiety
in 8, via keto−enol tautomerism, which at the end may
contribute to the aromatization process, but avoiding
dehydration by acid catalysis as in the formation of p-cymene
(7). Consequently, (+)-(4S)-carvotanacetone (8) can be
considered as a common constituent in essential oils related
to the aromatic monoterpene biosynthesis. This mechanistic
proposal is based on those described for terpene aromatization
using iodine as a mild reagent.18,19
thus providing 29 conformers for 4 and 43 conformers for 5 in
10 kcal/mol energy gaps. Measurements of the O-1−H-1. . .O-
6, O-6−H-6. . .O-1, and O-1. . .O-6 bond lengths and angles
(Table S1, Supporting Information) suggested that 99.9% of
the conformational population of 4 favor weak hydrogen-
bonding interactions, while in 5 only 50% of the conforma-
tional population favor probable hydrogen-bonding interac-
tions.21,22 In turn, acetylation of 3 gave the expected diacetate
14.
Once the behavior of p-menthenediols 4 and 5 was studied
under acid- and iodine-catalyzed reaction conditions, glucoside
2 was evaluated under the same conditions. Acid hydrolysis of
2 yielded the triol epimers 15 and 16,9 which were individually
dissolved in tetrahydrofuran (THF) and treated with 10%
HCl. In either case two compounds were obtained and
separated by column chromatography, affording carvacrol (9)
Although 4 and 5 provided the same aromatization products,
their reactivity was assessed by acetylation of the C-1 hydroxy
group, since reactivity variations in the crude reaction
1
outcomes were observed by H NMR. A 25:1 mixture of 10
and 11 was obtained from 4, while 5 yielded the p-menthene
mixture of 12 and 13 in a 10:1 ratio. Thus, the 1-hydroxy
group in 5 is a more favorable nucleophile than that at 4,
perhaps due to a reduced hydroxy group interaction due to
their trans disposition. These results also discard possible steric
effects exerted by the isopropyl group, as revealed by 5. In
support of conformational preferences of 4 and 5, calculations
were done with the Monte Carlo protocol using a molecular
model force field (MMFF). All conformer energies were
optimized at the DFT B3LYP/6-31G(d) level of theory, a
methodology successfully employed for the conformational
analysis of aliphatic9 and aromatic p-menthene derivatives,20
1
and a sample of amorphous material, whose H NMR data
suggested the Δ2 endocyclic double bond conjugated with an
exocyclic Δ1(7) olefinic bond, whose signals were observed in
the δ 6.18−5.12 range. In addition, two hydrogen signals
geminal to hydroxy groups resonated at δ 4.33 (H-6) and 3.75
(H-5). The 13C NMR spectrum showed the expected 10
signals for a p-menthene skeleton, including four signals
assigned to the conjugated diene moiety in the δ 143.5−115.2
range and two signals at δ 71.6 and 71.4 attributed to C-6 and
C-5, respectively. The HRESIMS data confirmed the C10H16O2
C
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Scheme 2. Putative Mechanism for the Aromatization of p-Menthenes 15 and 16
composition showing the [M + NH4]+ molecular ion at m/z
186.1497 (calcd as C10H16O2 + NH4 , 186.1494), while the
directing regiospecificity toward formation of 9. In addition,
the polar reaction medium stabilizes the equatorial 6-hydroxy
group via a dipole−dipole interaction with the exocyclic
double bond.23 Coupling constant analysis was not used for
the conformational analysis since H-5 and H-6 resonated as
undefined broad signals.
+
specific rotation was dextrorotatory. These data suggested the
identity of the compound as the new p-menthene derivative
(+)-(4S,5R,6S)-5,6-dihydroxy-1(7),2-menthadiene (17). Un-
equivocal structure assignment of 17 was supported by
HETCOR, COSY, NOESY, and HMBC spectra. Treatment
of 17 with 10% HCl for 24 h yielded carvacrol (9).
A reactivity comparison of the hydroxy groups at C-1 in 15
and 16 was done as for 4 and 5. Acetylation of 15 gave a 10:1
mixture of 18 and 19. From the acetylation of 16 the formation
Based on the overall chemical transformations, an
aromatization reaction mechanism of 2, through 15−17 to
carvacrol (9), including stable reaction intermediates, is
suggested in Scheme 2, which involves protonation of the
allylic tertiary hydroxy group of 15 and/or 16 followed by
dehydration. The allylic carbocation intermediate X is
stabilized through deprotonation at C-7, yielding 17. This
stable diol has the potential to also undergo a dehydration at
C-5 affording conjugated diene carbocation XI, which can be
deprotonated at C-6 as shown in XI (shift a), followed by
protonation at C-7 and concomitant deprotonation at C-4 to
generate carvacrol (9). The other alternative, shown in XI
(shift b), involves deprotonation at C-4, providing a
conjugated triene, which aromatizes to 9. The possibility to
obtain thymol as the final aromatic compound, via dehydration
at C-6, was unsuccessfully searched.
To explain the regiospecific dehydration in 17, conforma-
tional population calculations were done by the Monte Carlo
protocol using MMFF. All conformer energies were optimized
at the DFT B3LYP/6-31G(d) level of theory as described
above. This procedure provided 22 conformers in a 10 kcal/
mol range, of which 74% of the conformer population revealed
the C-5 hydroxy group and the isopropyl group in a pseudo-
trans diaxial arrangement with a dihedral angle of 152 7.4°,
favoring σ−σ* conformational interactions, as depicted in
Scheme 2, increasing the reactivity of the 5-hydroxy group and
1
of compounds 20 and 21 was expected. However, the H
NMR spectrum revealed the presence of 20, a complex mixture
of acetylated compounds of undefined identity, and traces of
21, readily recognized by its typical H-2 signal at δ 6.13
(Figure S54, Supporting Information). It thus seems that 20
suffers degradation via reaction of the hydroxy group at C-1
since hydrogen atoms geminal to the C-5 and C-6 acetoxy
groups at δ 5.72−4.76 and acetoxy signals at δ 2.23−2.00 were
observed. This evidences a higher reactivity of the hydroxy
group at C-1 in 16 than in 15, which is similar to the case of 5.
As done for 4 and 5, DFT calculations for 15 and 16 were
performed, affording 37 conformers for 15 and 48 conformers
for 16 in 10 kcal/mol gaps. These calculations revealed
intramolecular hydrogen bonding interactions in 99.7% of the
conformational population of 15, of which essentially all
involve the oxygen atom at C-1. In turn, only 24% of the
conformational population of 16 shows this type of interaction,
thus inhibiting the tertiary hydroxy group from interacting, and
consequently the nucleophilicity of the hydroxy group at C-1
in 16 is higher than in 15. Modification of reaction conditions
for the acetylation permitted the preparation of 20 and 21 (see
Experimental Section).
The iodine aromatization reaction of 15 gave carvacrol (9)
as the regiospecific aromatization product. This reaction is
similar to the acid-catalyzed aromatization of 15, despite the
D
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chromatographed on silica gel using hexanes−CH2Cl2 mixtures as
eluent. Fractions 4−7 (hexanes−CH2Cl2, 4:1) afforded 8 (24 mg,
30%), fractions 8−12 (hexanes−CH2Cl2, 1:1) yielded 6 (11 mg,
12%), and fractions 15−17 (hexanes−CH2Cl2, 3:7) gave 7 (52 mg,
58%). Similarly, a solution of 15 and 16 (70 mg) was treated as above.
Column chromatography of the residue afforded 9 (19 mg, 34%) in
fractions 8−11 (hexanes−CH2Cl2, 3:2) and 17 (42 mg, 66%) in
fractions 15−19 (CH2Cl2−MeOH, 49:1). Acid treatment of 6 (20
mg), as above, yielded 7 (11 mg, 63%) in fractions 3−5 (hexanes−
CH2Cl2, 4:1), while 17 (40 mg) for 5 h afforded 9 (28 mg, 80%) in
fractions 5−7 (hexanes−CH2Cl2, 3:2).
Samples of 4 or 15 (40 mg each) were dissolved in toluene (10
mL), and iodine (40 mg) was added. Each reaction mixture was
stirred under reflux for 5 h. Each residue was washed with a saturated
Na2S2O3 solution, NaHCO3, and NaCl, poured over ice−H2O,
extracted with hexanes, dried over anhydrous Na2SO4, filtered, and
evaporated to yield 28 mg (80%) of 9 from 4 and 30 mg (94%) from
15. Similarly, a solution of 4 (30 mg) in toluene (10 mL) was treated
with iodine (30 mg) for 3 h. The residue was column chromato-
graphed on silica gel using hexanes−CH2Cl2. Fractions 3−5
(hexanes−CH2Cl2, 3:2) afforded 9 (17 mg, 64%), and fractions 5−
7 (hexanes−CH2Cl2, 3:7) gave 8 (7 mg, 26%).
fact that thymol and/or carvacrol (9) formation might be
possible. Thus, a plausible reaction mechanism (Scheme 2) for
the transformation of 15 involves the charged iodine-bonded
adduct at the tertiary hydroxy group in XII followed by
dehydration, yielding the Δ1(6) double bond in XIII. Since
keto−enol tautomerism of this intermediate is expected,
deactivation of the hydroxy group at C-6 leads to dehydration
at C-5 to yield 9, via adduct XIV. Alternatively, dehydration of
the hydroxy group at C-1, via iodine charged complex XII, to
form 17 followed by dehydration of the hydroxy group at C-5,
via XI (shift a or b), favors aromatization to 9. In the latter
alternative, regiospecificity could be induced by conforma-
tional effects, as well as dipole−dipole interactions in the
considered intermediate 17, since the polarity of the reaction
medium increases due to H2O and HI formation during the
reaction process.
Interestingly, NMR and GC-MS essential oil analysis of the
leaves revealed the presence of p-cymene (7) as a main
constituent in the mixture, thus supporting the present
biomimetic study. On the above basis it seems that several
biochemical processes may be related to laboratory studies,
under the principle that chemistry rules are applied in any
reaction system, but probably stereospecificity and reaction
rates are the most important differences between enzymatic
and chemical systems. In addition, biomimetic studies provide
chemical pathways applied to two targets: the synthesis of
organic molecules of interest24−26 and understanding the
observed biosynthetic pathways of natural products in living
systems.27 Moreover, glucosides 1 and 2 may favor the
formation of aromatic p-menthene derivatives 7 and 9 through
catabolic processes, which could be related to several anabolic
pathways providing multifunctionalized thymol derivatives,
similar to those reported from Ageratina glabrata.20,28,29 Other
relevant conclusions are the observation of precise chemical
routes for molecular transformations and the observation of
chemical economy during these processes.
Acetylation Reactions. Solutions of 3 (40 mg), 4, 5, 15, or 16
(30 mg each) were dissolved in pyridine (1 mL), and Ac2O (1 mL)
was added. Each reaction mixture was stirred at room temperature for
24 h, or 3 h for 3, poured over ice−H2O, and extracted with EtOAc.
Each organic layer was washed with aqueous 10% HCl, H2O, aqueous
NaHCO3, and H2O, dried over anhydrous Na2SO4, filtered, and
evaporated. The residue from the reaction of 3 was extracted to yield
14 (38 mg, 85%). Column chromatography of the reaction of 4
afforded 10 (18 mg, 48%) and 11 (11 mg, 25%), while that of 5
yielded 12 (26 mg, 70%) and 13 (3 mg, 7%). Chromatography of the
residue from 15 afforded 18 (25 mg, 57%) and 19 (3 mg, 6%), while
that from 16 yielded 20 (20 mg, 46%) and 21 (8 mg, 16%).
Reactivity Assay of 4, 5, 15, and 16. The studies were done by
acetylation using the above reaction conditions for 12 h, and the
1
crude reaction mixtures were analyzed by H NMR spectroscopy.
(+)-(4S,6R)-Yabunikkeol (6): colorless oil; [α]589 +5, [α]578 +5,
[α]546 +5, [α]436 +13, [α]365 +23 (c 0.1, CHCl3); lit.30 [α]589 +5.0 (c
0.8, CHCl3); lit.15 [α]589 +4.2 (c 3.1, CHCl3); IR (CHCl3) νmax cm−1
1
3411, 2957, 2925, 1675, 1464, 1038, 892; H NMR (CDCl3, 400
MHz) δ 6.14 (1H, dd, J = 10.1, 2.6 Hz, H-3), 5.83 (1H, dd, J = 10.1,
1.0 Hz, H-2), 5.06 (1H, br s, H-7), 4.96 (1H, br s, H-7′), 4.42 (1H,
m, H-6), 2.34 (1H, m, H-4), 1.91 (1H, m, H-5), 1.72 (1H, septd, J =
6.8, 1.1 Hz, H-8), 1.55 (1H, m, H-5′), 0.93 (6H, d, J = 6.8 Hz, CH3-9
and CH3-10); 13C NMR (CDCl3, 100 MHz) δ 145.3 (C, C-1), 134.0
(CH, C-2), 126.6 (CH, C-3), 112.9 (CH2, C-7), 69.4 (CH, C-6), 37.2
(CH, C-4), 32.5 (CH2, C-5), 31.5 (CH, C-8), 19.6 (CH3, C-9), 19.60
(CH3, C-10); IR and 1H and 13C NMR data in agreement with
published values.15,34,35
(+)-(1S,4S,6R)-6-Acetoxy-1-hydroxy-2-menthene (10): colorless
oil; [α]589 +9, [α]578 +9, [α]546 +12, [α]436 +28, [α]365 +64 (c 2.7,
CHCl3); IR (CHCl3) νmax 3582, 2959, 2870, 1727, 1464, 1375 cm−1;
1H NMR (400 MHz, CDCl3) δ 5.67 (1H, ddd, J = 10.4, 2.8, 1.2 Hz,
H-3), 5.59 (1H, ddd, J = 10.4, 2.4, 1.2 Hz, H-2), 4.94 (1H, ddd, J =
6.4, 2.4, 1.2 Hz, H-6), 2.10 (3H, s, Ac), 2.10 (1H, m, H-4), 2.02 (1H,
tdd, J = 13.0, 6.0, 1.2 Hz, H-5), 1.64 (1H, m, H-8), 1.58 (1H, ddd, J =
13.0, 8.8, 2.4 Hz, H-5′), 1.29 (3H, s, CH3-7), 0.89 (3H, d, J = 7.0 Hz,
CH3-9), 0.88 (3H, d, J = 7.0 Hz, CH3-10); 13C NMR (100 MHz,
CDCl3) δ 170.8 (C, Ac), 131.9 (CH, C-2), 131.2 (CH, C-3), 75.8
(CH, C-6), 69.0 (C, C-1), 38.1 (CH, C-4), 31.4 (CH, C-8), 26.9
(CH2, C-5), 21.3 (CH3, Ac) 27.0 (CH3, C-7), 19.5 (CH3, C-9), 19.4
(CH3, C-10); HRESIMS m/z 235.1312 [M + Na]+ (calcd for
C12H20O3 + Na+, 235.1308).
EXPERIMENTAL SECTION
■
General Experimental Procedures. Melting points (uncor-
rected) were determined on a Fisher−Johns apparatus. Optical
rotations were recorded in CHCl3 solutions at room temperature on a
PerkinElmer 341 polarimeter. 1D and 2D NMR spectra were
1
measured at 300 or 400 MHz for H and at 75.4 or 100 MHz for
13C on Varian Mercury 300 or 400 spectrometers from CDCl3
solutions using tetramethylsilane as the internal reference. Chemical
shift values are reported in parts per million, and coupling constants
(J) are in Hz. HRMS data were acquired on a Waters Synapt G2
spectrometer at the Department of Chemistry and Biochemistry,
University of Colorado, Boulder, CO, USA. Silica gel 230−400 mesh
(Merck) was used for column chromatography.
Compounds. Menthene derivatives 1−5, 15, and 16 were
obtained as described.9 A combination of vibrational circular
dichroism, single-crystal X-ray diffraction, and chemical correlations
allowed securing9 their absolute configuration (AC). Since all other
chiral molecules of the present study were also chemically correlated
with the above molecules, their AC is also fully substantiated. In turn,
monoterpenes 7−9 are known molecules.30−33 In cases when more
than one acetyl group was present, the signal distinction followed
from gHSQC and gHMBC NMR measurements.
Dehydration and Aromatization Reactions. Solutions of 4 or
5 (100 mg each) in THF (1 mL) were treated with aqueous 10% HCl
(5 mL) and stirred at room temperature for 5 h. Each reaction
mixture was washed with a saturated NaHCO3 solution, poured over
ice−H2O, extracted with CH2Cl2, dried over anhydrous Na2SO4,
filtered, and evaporated to dryness. Each residue was column
(+)-(1S,4S,6R)-1,6-Diacetoxy-2-menthene (11): colorless oil;
[α]589 +65, [α]578 +68, [α]546 +78, [α]436 +144, [α]365 +253 (c 1.2,
1
CHCl3); IR (CHCl3) νmax 2058, 1728, 1370 cm−1; H NMR (400
MHz, CDCl3) δ 6.01 (1H, ddd, J = 10.0, 2.4, 0.7 Hz, H-2), 5.73 (1H,
dd, J = 10.0, 2.8 Hz, H-3), 5.23 (1H, dd, J = 8.0, 2.8 Hz, H-6), 2.16
(1H, m, H-4), 2.10 (3H, s, Ac), 2.03 (1H, m, H-5), 2.01 (3H, s, Ac),
E
DOI: 10.1021/acs.jnatprod.8b00855
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
1.71 (1H, m, H-8), 1.65 (3H, s, CH3-7), 1.64 (1H, m, H-5′), 1.57
(3H, s, H-7), 0.92 (6H, d, J = 7.0 Hz, CH3-9, CH3-10); 13C NMR
(100 MHz, CDCl3) δ 170.5 (C, Ac), 170.1 (C, Ac), 132.5 (CH, C-3),
128.8 (CH, C-2), 78.3 (C, C-1), 73.4 (CH, C-6), 38.8 (CH, C-4),
31.7 (CH, C-8), 25.9 (CH2, C-5), 23.3 (CH3, C-7), 22.1 (CH3, Ac),
21.2 (CH3, Ac), 19.7 (CH3, C-9), 19.5 (CH3, C-10); HRESIMS m/z
277.1414 [M]+ (calcd for C14H22O4, 277.1410).
(C, Ac) 132.9 (CH, C-2), 126.1 (CH, C-3), 74.8 (CH, C-6), 70.7
(CH, C-5), 70.2 (C, C-1), 43.0 (CH, C-4), 27.5 (CH, C-8), 26.8
(CH3, C-7), 21.1 (CH3, Ac), 21.1 (CH3, Ac), 20.5 (CH3, C-10), 17.8
(CH3, C-9); HRESIMS m/z 293.1365 [M]+ (calcd for C14H22O5,
293.1359).
(+)-(1S,4S,5R,6R)-1,5,6-Triacetoxy-2-menthene (19): colorless oil;
[α]589 +96, [α]578 +103, [α]546 +116, [α]436 +204, [α]365 +333 (c 0.8,
1
CHCl3); IR (CHCl3) νmax 2954, 1731, 1369, 1053 cm−1; H NMR
(+)-(1R,4S,6R)-6-Acetoxy-1-hydroxy-2-menthene (12): colorless
oil; [α]589 +1, [α]578 +1, [α]546 +2, [α]436 +7, [α]365 +22 (c 0.8,
(400 MHz, CDCl3) δ 6.04 (1H, ddd, J = 10.4, 2.5, 1.6 Hz, H-2), 5.70
(1H, t, J = 2.0 Hz, H-6), 5.66 (1H, dd, J = 10.4, 2.2 Hz, H-3), 5.08
(1H, dd, J = 9.6, 2.0 Hz, H-5), 2.50 (1H, dq, J = 9.6, 2.9 Hz, H-4),
2.12 (3H, s, Ac), 2.05 (3H, s, Ac), 1.99 (3H, s, Ac), 1.84 (1H, septd, J
= 6.8, 2.9 Hz, H-8), 1.71 (3H, s, CH3-7), 1.02 (3H, d, J = 6.8 Hz,
CH3-10), 0.81 (3H, d, J = 6.8 Hz, CH3-9); 13C NMR (100 MHz,
CDCl3) δ 170.6 (C, Ac), 170.1 (C, Ac), 169.6 (C, Ac), 129.2 (CH, C-
2), 126.9 (CH, C-3), 79.8 (C, C-1), 72.7 (CH, C-6), 69.4 (CH, C-5),
42.0 (CH, C-4), 26.7 (CH, C-8), 24.7 (CH3, C-7), 22.0 (CH3, Ac),
20.9 (CH3, Ac), 20.9 (CH3, Ac), 20.3 (CH3, C-10), 19.3 (CH3, C-9);
HRESIMS m/z 335.1473 [M + Na]+ (calcd for C16H24O6 + Na+,
335.1465).
(+)-(1R,4S,5R,6R)-5,6-Diacetoxy-1-hydroxy-2-menthene (20):
colorless oil; [α]589 +47, [α]578 +49, [α]546 +56, [α]436 +97 (c 1.2,
CHCl3); IR (CHCl3) νmax 3594, 2964, 2875, 1734, 1600, 1370 cm−1;
1H NMR (400 MHz, CDCl3) δ 5.70 (1H, dd, J = 10.3, 2.2 Hz, H-3),
5.63 (1H, ddd, J = 10.3, 2.2, 1.3 Hz, H-2), 5.29 (1H, dd, J = 9.0, 2.5
Hz, H-5), 5.21 (1H, dd, J = 2.5, 1.3 Hz, H-6), 2.36 (1H, m, H-4), 2.09
(3H, s, Ac), 2.02 (3H, s, Ac), 1.84 (1H, septd, J = 7.0, 3.6 Hz, H-8),
1.27 (3H, s, CH3-7), 1.02 (3H, d, J = 7.0 Hz, CH3-10), 0.82 (3H, d, J
= 7.0 Hz, CH3-9); 13C NMR (100 MHz, CDCl3) δ 170.6 (C, Ac),
170.6 (C, Ac) 131.2 (CH, C-2), 128.7 (CH, C-3), 74.7 (CH, C-6),
70.4 (C, C-1), 69.5 (CH, C-5), 42.2 (CH, C-4), 27.0 (CH, C-8), 25.1
(CH3, C-7), 21.0 (CH3, Ac), 21.0 (CH3, Ac), 20.4 (CH3, C-10), 17.5
(CH3, C-9); HRESIMS m/z 293.1358 [M]+ (calcd for C14H22O5,
293.1359).
1
CHCl3); IR (CHCl3) νmax 3592, 2956, 1722, 1374, 1035 cm−1; H
NMR (400 MHz, CDCl3) δ 5.74 (1H, dd, J = 10.2, 2.7 Hz, H-3), 5.61
(1H, ddd, J = 10.2, 2.3, 1.0 Hz, H-2), 4.97 (1H, dd, J = 6.0, 3.8 Hz, H-
6), 2.08 (3H, s, Ac), 2.06 (1H, m, H-4), 1.81 (1H, m, H-8), 1.79 (1H,
m, H-5), 1.68 (1H, m, H-5′), 1.27 (3H, s, CH3-7), 0.91 (3H, d, J =
6.8 Hz, CH3-10), 0.92 (3H, d, J = 6.8 Hz, CH3-9); 13C NMR (100
MHz, CDCl3) δ 171.0 (C, Ac), 132.4 (CH, C-2), 131.6 (CH, C-3),
75.6 (CH, C-6), 69.3 (C, C-1), 38.4 (CH, C-4), 31.6 (CH, C-8), 26.4
(CH2, C-5), 24.3 (CH3, C-7), 21.3 (CH3, Ac), 19.8 (CH3, C-9), 19.7
(CH3, C-10); HRESIMS m/z 235.1310 [M]+ (calcd for C12H20O3,
235.1308).
(−)-(1R,4S,6R)-1,6-Diacetoxy-2-menthene (13): colorless oil;
[α]589 −77, [α]578 −80, [α]546 −92, [α]436 −164, [α]365 −275 (c
1
1.8, CHCl3); IR (CHCl3) νmax 1731, 1370, 1248, 1042 cm−1; H
NMR (400 MHz, CDCl3) δ 6.07 (1H, ddd, J = 10.3, 2.8, 1.0 Hz, H-
2), 5.80 (1H, ddd, J = 10.3, 2.8, 0.6 Hz, H-3), 5.21 (1H, ddd, J = 4.6,
3.1, 1.0 Hz, H-6), 2.08 (1H, m, H-4), 2.07 (3H, s, Ac), 1.95 (3H, s,
Ac), 1.83 (1H, m, H-5), 1.80 (1H, m, H-5′), 1.71 (1H, septd, J = 6.8,
1.3 Hz, H-8), 1.49 (3H, s, CH3-7), 0.90 (3H, d, J = 6.8 Hz, CH3-9),
0.89 (3H, d, J = 6.8 Hz, CH3-10); 13C NMR (100 MHz, CDCl3) δ
170.4 (C, Ac), 169.6 (C, Ac), 133.6 (CH, C-3), 128.4 (CH, C-2),
77.9 (C, C-1), 72.5 (CH, C-6), 37.7 (CH, C-4), 31.3 (CH, C-8), 25.5
(CH2, C-5), 22.1 (CH3, Ac), 21.2 (CH3, Ac), 21.1 (CH3, C-7), 19.5
(CH3, C-9), 19.2 (CH3, C-10); HRESIMS m/z 277.1418 [M + Na]+
(calcd for C14H22O4 + Na+, 277.1410).
(−)-(3S,4S,6R)-3,6-Diacetoxy-1-menthene (14): colorless oil;
(−)-(1R,4S,5R,6R)-1,5,6-Triacetoxy-2-menthene (21): colorless oil;
[α]589 −85, [α]578 −88, [α]546 −99, [α]436 −160, [α]365 −234 (c
[α]589 −35, [α]578 −36, [α]546 −43, [α]436 −80, [α]365 −145 (c 0.6,
1
2.6, CHCl3); IR (CHCl3) νmax 1721, 1466, 1371, 1022 cm−1; H
1
CHCl3); IR (CHCl3) νmax 2959, 1735, 1463, 1369, 1052 cm−1; H
NMR (400 MHz, CDCl3) δ 5.58 (1H, dd, J = 2.3, 1.5 Hz, H-2), 5.22
(1H, m, H-3), 5.20 (1H, m, H-6), 2.08 (3H, s, Ac), 2.07 (3H, s, Ac),
1.83 (1H, m, H-5), 1.78 (1H, m, H-8), 1.77 (1H, m, H-4), 1.71 (3H,
br t, J = 1.4, CH3-7), 1.58 (1H, m, H-5′), 0.92 (3H, d, J = 6.7, CH3-
9), 0.83 (3H, d, J = 6.7, CH3-10); 13C NMR (100 MHz, CDCl3) δ
170.7 (C, Ac), 170.6 (C, Ac), 135.3 (C, C-1), 127.4 (CH, C-2), 71.0
(CH, C-3), 69.2 (CH, C-6), 39.4 (CH, C-4), 26.9 (CH2, C-5), 26.4
(CH, C-8), 21.1 (CH3, Ac), 21.0 (CH3, Ac), 20.3 (CH3, C-9), 19.9
(CH3, C-7), 17.2 (CH3, C-10); HRESIMS m/z 277.1408 [M + Na]+
(calcd for C14H22O4 + Na+, 277.1410).
NMR (300 MHz, CDCl3) δ 6.14 (1H, ddd, J = 10.3, 2.4, 1.2 Hz, H-
2), 5.75 (1H, dd, J = 10.3, 2.7 Hz, H-3), 5.39 (1H, dd, J = 2.6, 1.2 Hz,
H-6), 5.30 (1H, dd, J = 9.0, 2.6 Hz, H-5), 2.35 (1H, ddd, J = 9.0, 3.0,
2.7 Hz, H-4), 2.10 (3H, s, Ac), 2.03 (3H, s, Ac), 2.00 (3H, s, Ac),
1.85 (1H, septd, J = 7.0, 3.0 Hz, H-8), 1.51 (3H, s, CH3-7), 1.01 (3H,
d, J = 7.0 Hz, CH3-10), 0.80 (3H, d, J = 7.0 Hz, CH3-9); 13C NMR
(75.4 MHz, CDCl3) δ 170.5 (C, Ac), 170.3 (C, Ac), 169.5 (C, Ac),
130.1 (CH, C-3), 128.6 (CH, C-2), 79.1 (C, C-1), 72.2 (CH, C-6),
68.9 (CH, C-5), 42.2 (CH, C-4), 27.1 (CH, C-8), 22.0 (CH3, Ac),
21.0 (CH3, Ac), 20.9 (2CH3, Ac and C-7), 20.8 (CH3, C-10), 20.3
(CH3, C-9); HRESIMS m/z 335.1479 [M + Na]+ (calcd for
C16H24O6 + Na+, 335.1465).
Conformational Calculations. Monte Carlo search protocols
using the Merck molecular force field (MMFF94) followed by single-
point energy calculations using DFT at the B3LYP/6-31G(d) level of
theory, both implemented in the Spartan’04 software, were carried
out. The MMFF step provided 29, 43, 37, 48, 22, six, and six
conformers for 4, 5, 15, 16, 17, IV, and V, respectively, in energy gaps
of 10 kcal/mol, while after single-point calculations these conformers
appeared in 8.79, 5.51, 8.53, 7.61, 5.68, 3.90, and 5.10 kcal/mol
energy gaps, respectively. Bond distances and dihedral angles of each
conformer were extracted using the Spartan’04 software. Averaged
and standard errors of these data were estimated using the Microsoft
Excel program. Calculations were performed using a laptop computer
operating at 2.20 GHz with 8 Gb RAM.
(+)-(4S,5R,6S)-5,6-Dihydroxy-1(7),2-menthadiene (17): white
solid; mp 86−88 °C (CHCl3); [α]589 +113, [α]578 +118, [α]546
+135, [α]436 +235, [α]365 +377 (c 1.1, CHCl3); IR νmax 3556, 2958,
1
1389 1056 cm−1; H NMR (400 MHz, CDCl3) δ 6.18 (1H, dd, J =
10.0, 2.1 Hz, H-2), 5.70 (1H, dd, J = 10.0, 2.6 Hz, H-3), 5.26 (1H, br
s, H-7), 5.12 (1H, br s, H-7’), 4.33 (1H, br s, H-6), 3.75 (1H, br s, H-
5), 2.25 (1H, m, H-4), 1.96 (1H, septd, J = 6.8, 1.7 Hz, H-8), 1.05
(3H, d, J = 6.8 Hz, CH3-9), 0.89 (3H, d, J = 6.8 Hz, CH3-10); 13C
NMR (100 MHz, CDCl3) δ 143.5 (C, C-1), 129.0 (CH, C-3), 127.3
(CH, C-2), 115.2 (CH2, C-7), 71.8 (CH, C-6), 71.4 (CH, C-5), 46.8
(CH, C-4), 28.3 (CH, C-8), 21.1 (CH3, C-9), 18.5 (CH3, C-10);
+
HRESIMS m/z 186.1497 [M + NH4]+ (calcd for C10H16O2 + NH4 ,
186.1489).
(+)-(1S,4S,5R,6R)-5,6-Diacetoxy-1-hydroxy-2-menthene (18):
white solid; mp 78−80 °C; [α]589 +113, [α]578 +118, [α]546 +134,
[α]436 +234, [α]365 +379 (c 0.1, CHCl3); IR (CHCl3) νmax 3584,
1
2963, 2875, 1743, 1371 cm−1; H NMR (400 MHz, CDCl3) δ 5.65
ASSOCIATED CONTENT
(1H, ddd, J = 10.4, 2.3, 1.1 Hz, H-2), 5.59 (1H, dd, J = 10.4, 2.5 Hz,
H-3), 5.20 (1H, dd, J = 2.2, 1.1 Hz, H-6), 5.11 (1H, dd, J = 8.3, 2.2
Hz, H-5), 2.38 (1H, ddt, J = 8.4, 3.6, 2.5 Hz, H-4), 2.15 (3H, s, Ac),
2.05 (3H, s, Ac), 1.80 (1H, septd, J = 6.8, 3.6 Hz, H-8), 1.38 (3H, d, J
= 1.0 Hz CH3-7), 1.02 (3H, d, J = 6.8 Hz, CH3-10), 0.83 (3H, d, J =
6.8 Hz, CH3-9); 13C NMR (100 MHz, CDCl3) δ 170.8 (C, Ac), 170.5
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.8b00855.
F
DOI: 10.1021/acs.jnatprod.8b00855
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
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AUTHOR INFORMATION
■
́
́
Corresponding Authors
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*(C. M. Cerda-Garcia-Rojas) E-mail: ccerda@cinvestav.mx.
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2018, 81, 630−633.
Tel: +52 55 5747 4035. Fax: +52 55 5747 7137.
́
*(Mario A. Gomez-Hurtado) E-mail: magomez@umich.mx.
Tel: +52 443 3265788. Fax: +52 443 326 5790.
ORCID
́
(20) Arreaga-Gonzalez, H. M.; Pardo-Novoa, J. C.; del Río, R. E.;
Julio C. Pardo-Novoa: 0000-0002-7807-1074
Rodríguez-García, G.; Torres-Valencia, J. M.; Manríquez-Torres, J. J.;
́
́
́
Hector M. Arreaga-Gonzalez: 0000-0002-3746-0137
Cerda-García-Rojas, C. M.; Joseph-Nathan, P.; Gomez-Hurtado, M.
A. J. Nat. Prod. 2018, 81, 63−71.
́
́
́
Sinuhe Galvan-Gomez: 0000-0001-6006-8523
Gabriela Rodríguez-García: 0000-0002-9840-9968
Rosa E. del Río: 0000-0001-8932-552X
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Carlos M. Cerda-García-Rojas: 0000-0002-5590-7908
Pedro Joseph-Nathan: 0000-0003-3347-3990
Mario A. Gomez-Hurtado: 0000-0002-2386-4819
́
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank CIC-UMSNH and CONACYT-Mexico (Grant No.
284194) for financial support. J.C.P.N., H.M.A.G., and S.G.G.
are grateful to CONACYT-Mexico for scholarships 446483,
295638, and 619406. We are grateful to Professor Jerzy
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Bajıo, Patzcuaro, Michoacan, Mexico, for identifying the plant
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DEDICATION
■
̧
Dedicated to Dr. Rachel Mata, Universidad Nacional
Autonoma de Mexico, Mexico City, Mexico, for her pioneering
work on bioactive natural products.
̧
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