Difficulties to Determine the Absolute Configuration of Guaiaretic Acid

Abstract

An account of the difficulties to determine the absolute configuration (AC) of guaiaretic acid (1a), using contemporary methodology, is described in commemoration of the century of its structure elucidation. In fact, the herein studied molecule was the derived diacetate 1b, since the natural lignan slowly decomposes upon manipulation. Single crystal X-ray diffraction of 1b demonstrated the structure, but calculation of Flack and Hooft parameters to know the AC was unsuccessful since the crystals were triclinic, P-1, which is a centro-symmetric space group. In turn, manual band to band comparison of experimental and DFT B3LYP/DGDZVP calculated VCD spectra of 1b allowed ascertaining its AC, although automatic comparison using the CompareVOA software was not very successful. This behavior is associated to the fact that the studied molecule has a sole stereogenic center located on the acyclic portion of a carbon chain possessing two quite similar substituents. The behavior is discussed in relation to cases where the molecular flexibility also generates a very large number of conformers.

Full text

Difficulties to Determine the Absolute Configuration of Guaiaretic
Acid
Alfredo R. Ortegaa, Eleuterio Burgueño-Tapiab and Pedro Joseph-Nathanc,*
aInstituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria,
Mexico City, 04510 Mexico
bDepartamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional,
Prolongación de Carpio y Plan de Ayala, Col. Santo Tomás, Mexico City, 11340 Mexico
cDepartamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional,
Apartado 14-740, Mexico City, 07000 Mexico
pjoseph@nathan.cinvestav.mx
Received: May 21st, 2018; Accepted: June 26th, 2018
An account of the difficulties to determine the absolute configuration (AC) of guaiaretic acid (1a), using contemporary methodology, is described in
commemoration of the century of its structure elucidation. In fact, the herein studied molecule was the derived diacetate 1b, since the natural lignan slowly
decomposes upon manipulation. Single crystal X-ray diffraction of 1b demonstrated the structure, but calculation of Flack and Hooft parameters to know the
AC was unsuccessful since the crystals were triclinic, P-1, which is a centro-symmetric space group. In turn, manual band to band comparison of experimental
and DFT B3LYP/DGDZVP calculated VCD spectra of 1b allowed ascertaining its AC, although automatic comparison using the CompareVOA software was
not very successful. This behavior is associated to the fact that the studied molecule has a sole stereogenic center located on the acyclic portion of a carbon
chain possessing two quite similar substituents. The behavior is discussed in relation to cases where the molecular flexibility also generates a very large
number of conformers.
Keywords: Guaiaretic acid, Absolute configuration, Lignan, Vibrational circular dichroism, X-Ray diffraction.
Guaiaretic acid (1a) is a lignan [1] which, rather than being a
carboxylic acid, derives its acidic properties from two phenol
groups, and is probably the emblematic 8,8’-lignan [2]. It is a
constituent of the resins of Guaiacum officinale and G. sanctum,
which was extensively studied in Germany during the nineteen
century [3,4] probably due to the wide use of the resin from the
former tree, growing in the island of Gonave in current Haiti, for the
treatment of syphilis (morbus gallicus) that Spanish people
confronted in Santo Domingo, current Dominican Republic, in the
sixteenth century [3]. Its structure was elucidated just a century ago
[5] and verified by synthesis of the racemic dimethylether
derivative [6], while its absolute configuration (AC) was originally
inferred from the specific rotation value [7] and later confirmed by
chemical correlation with L-dihydroxyphenylalanine [8].
Nowadays, the structure of guaiaretic acid (1a) is easily evidenced
using the 1H and 13C NMR data summarized in the experimental
section, which were secured by very detailed two-dimensional
gHSQC and gHMBC measurements since the task required the
distinction of several quite closely spaced signals owing to the two
aromatic ring systems. In turn, the E nature of the double bond is
evidenced by a NOESY plot which shows cross-peaks between the
vinyl methyl group signal at δ 1.82 and the multiplet at δ 6.65-6.70
corresponding to the four ortho hydrogen atoms of the two aromatic
rings, and between the vinyl hydrogen atom at δ 6.11 and the
multiplet at δ 2.49-2.53 corresponding to the H-8’ methine signal
overlapped with one of the methylene hydrogen atoms at C-7’. Of
relevance is to note the absence of a cross-peak for the signals
owing to the vinyl hydrogen and the vinyl methyl group, which
would be present in the Z double bond geometry.
Regarding the AC determination of the sole stereogenic center of
1a by comparison of the experimental and calculated VCD spectra,
experience dictates [9,10] that the study of molecules containing
alcohols of phenols is not the best idea due to the tendency of these
functional groups to associate at least to the solvent, thus providing
spectra that are difficult to compare with the calculated ones. An
alternative approach to the AC determination would be the study of
the molecule by single crystal X-ray diffraction to determine the
Flack and Hooft paramenters. This again resulted not quite feasible
since good quality crystals could not be generated.
Consequently, it was decided to attempt the AC determination with
either of the above methods using guaiaretic acid diacetate (1b)
which was easily won by acetylation. The molecule was quite
reluctant to provide suitable crystals for X-ray diffraction analysis,
but after many attempts reasonable crystals were obtained by slow
recrystallization from ethanol. The molecule crystallized in the
triclinic system and the crystal structure (Figure 1) could be solved
to a modest agreement factor R = 7.0%, the pertinent details being
summarized in the Experimental Section. Of course all hydrogen
atoms could be found in difference Fourier synthesis, but the crystal
resulted to have P-1 symmetry, which is a centrosymmetric space
group [11] thereby precluding the determination of Flack [12] or
Hooft [13,14] parameters to ascertain its AC.
Consequent to the X-ray results, the option for the AC
determination of 1b turned out to be a VCD study, a task that could
MeO
RO OR
OMe
1a R = H
1b R = Ac
2
4
6
7
9
8'
1'
3'
5'
9'
NPC Natural Product Communications 2018
Vol. 13
No. 8
981 - 986

982 Natural Product Communications Vol. 13 (8) 2018 Ortega et al.
Figure 1: PLUTO X-ray plot for guaiaretic acid diacetate (1b).
Figure 2: Starting models for the search of the complete conformational space of 1b.
be anticipated as quite laborious since the molecule has a sole
stereogenic center located on a carbon atoms chain, rather than
on a ring. In fact, assembly of a solid Dreiding stereomodel from
Büchi (Flawil, Switzerland) for (R)-1b revealed the molecule has a
significantly high conformational freedom. Thus a molecular model
was built using the Spartan 08 software which allowed preliminary
optimization using molecular mechanics to provide conformer A
shown in Figure 2. In order to cover the complete conformational
space, starting from conformer A, the sigma bonds between the two
aromatic rings were rotated 180 degrees to generate conformers B-
E. These five conformational arrangements, shown in Figure 2,
were used as individual starting points for molecular mechanics
conformational searches using the Monte Carlo protocol as
implemented in the Spartan 08 software package. This rendered 75
conformers starting from model A, 88 conformers starting from B,
73 conformers starting from C, 78 from D, and 87 form E, always
in 10 kcal/mol energy gaps. The five sets of conformers were
individually submitted to single point optimization using DFT at the
B3LYP/6-31G(d) level of theory with the same software. The
outcome of the five sets were combined and after elimination of
duplicate structures provided 73 conformers in a 5 kcal/mol energy
gap. The 16 conformers found in the initial 2.94 kcal/mol were
further optimized at the B3LYP/DGDZVP level of theory using the
Figure 3: Comparison of the experimental IR (b) and VCD (d) spectra of (+)-di-O-
acetylguaiaretic acid with the DFT B3LYP/DGDZVP calculated IR (a) and VCD (c)
spectra for (7E, 8’R)-guaiaretic acid diacetate (1b).
Gaussian 03 suit: The final conformational optimization, IR and
VCD calculations at the same level of theory were also performed
using the Gaussian 03 software and the pertinent thermochemical
parameters, summarized in Table 1, show 15 final conformers in a 3
kcal/mol energy gap, in agreement with the expectation that 1b is a
quite mobile molecule. These 15 conformers were weighted
according their Gibb free energies to generate the final calculated
IR and VCD spectra, which seems a quite secure calculation
methodology to find all conformers significantly populating the
conformational space. Comparison of the calculated and
experimental spectra with the CompareVOA software [15], provided
an anharmonicity factor of 0.971, which was used for further
evaluation of the vibrational data, since the overall comparison was
not very good due to the molecular flexibility which provides broad
IR and VCD absorption bands (Figure 3), thus complicating the
comparison procedures.
Visual inspection of the experimental VCD spectrum of 1b and the
calculated spectrum for the R enantiomer reveals that indeed there is
good phases agreement of the signals, thereby evidencing the R AC
for 1b. To further substantiate this it was decided to perform a peak
to peak evaluation of the experimental and calculated VCD spectra
of 1b. Consequently, the band assignment in the IR and VCD
P
0
400
800
1200
1600
000
9501100125014001550
0
200
400
600
800
1000
‐60
‐40
‐20
0
20
40
60
‐30
‐20
‐10
0
10
20
30
1
(a)
(c)
(b)
(d)


x

[M
‐1
cm
‐1
]
Molar absorptivity,

1
cm/ 

2
3
5
46
7
8
9
11
10
1213
14
15
16 17
18
110
12
1
235
46
78
9
11
10
12
13
14
15
16 17 18
1
23
5
4
6
78
911 14 15
16
17
18
13
23
5
46
8
11
12
13
15
16 17
18

Absolute configuration of guaiaretic acid Natural Product Communications Vol. 13 (8) 2018 983
Figure 4: Comparison of the experimental and selected DFT B3LYP/DGDZVP IR
(top) and VCD frequencies (center), as well as the rotational strengths (bottom) of 1b.
spectra (Figure 3) was made following a described methodology
[16] in which initially the vibrational normal modes are numbered
in the weighted calculated IR spectrum and are then assigned to the
experimental bands according the frequencies and relative
intensities. After that, the same numbers are used to correlate the
experimental and calculated VCD peaks. Wavenumber and
intensities of selected calculated and experimental bands are shown
in Table 2, together with some vibrational modes.
To further support the AC assignment we used a plot [17-19]
generated from a set of experimental and calculated rotational
strengths, is such a way that a fit in a line of slope +1 corresponds to
the correct enantiomer while for the opposite enantiomer the points
in the plot would lie along a line of slope 1. Considering sign and
Table 1: Thermochemical parameters of guaiaretic acid diacetate (1b).
Conformer

E
6-31G
(
d
)
a %
b

E
DGDZVPc %
b

G
DGDZVPd
%e
1 0.00 51.7 0.00 43.1 0.00 25.6
2 0.84 12.5 0.47 19.5 0.04 24.0
3 1.25 6.3 0.91 9.2 0.28 16.1
4 1.42 4.7 0.96 8.6 0.68 8.1
5 2.39 0.9 2.20 1.0 0.91 5.5
6 2.61 0.6 2.35 0.8 1.11 4.0
7 1.50 4.1 1.40 4.0 1.23 3.2
8 2.94 0.4 1.75 2.2 1.25 3.1
9 2.18 1.3 2.11 1.2 1.27 3.0
10 1.69 3.0 1.69 2.5 1.36 2.6
11 1.93 2.0 1.87 1.8 1.60 1.9
12 1.21 6.7 1.44 3.8 1.66 1.6
13 2.94 0.4 2.91 0.3 2.35 0.5
14 2.05 1.6 1.98 1.5 2.40 0.4
15 2.92 0.4 2.94 0.3 2.93 0.2
aRelative to 1 (867685.34 kcal/mol). bCalculated using

E   RT In K. cRelative to 1
(867791.07 kcal/mol). dRelative to 1 (867533.33 kcal/mol). eCalculated using

G =
 RT In K.
intensity of the VCD absorptions, as a measure of the average
rotational strengths, the 

experimental and calculated data were
compared using bands 1, 2, 5, 6, 8, 11-13, and 15-18 for (R)-1b
(Figure 4). In combination, the IR data whith a regression
coefficient of 0.9982, the VCD data with a regression coeficient of
0.9916, and the rotational strengths data with a regression coeficient
of 0.7500 clearly reveal the AC of the sole stereogenic center for
()-1b is 8'R.
The difficulties we experienced for the AC determination of
guaiaretic acid diacetate (1b) are in line with other difficult VCD
studied molecules in which a stereogenic center is found on a
carbon atoms chain. A good deal of difficulty occurred during the
determination of the AC of the sole stereogenic center of a
phloroglucinol derivative [20] possessing an α-methylbutyryl chain,
which was isolated from Achyrocline satureioides. The molecule is
relatively complex, C25H30O7, containing 236 electrons, and 180
vibrational frequency modes that are active in the VCD and IR
spectra. Furthermore, the molecule is highly unsaturated, the sole
stereogenic center is located two atoms away from a benzene ring
on a conformational flexible chain, and the stereogenic center has
two substituents with the minimum size difference (Me and Et
groups) in a molecule that possesses additional conformational
freedom. Similar situations became evident for the AC
determination of thymol derivatives, isolated from Ageratina
cylindrica [21] and A. glabrata [22], also caused by high
conformational flexibility of the studied molecules.
In the case of sapinofuranone C, isolated from Diplodia corticola,
which possesses a secondary hydroxy group on the carbon atoms
chain, the situation could satisfactorily be addressed [23] by
increasing the size of one of the sustituents on the stereogenic
center by preparation of the corresponding p-bromobenzoate, a
strategy which is not possible for the sole stereogenic center of 1b.
A general lack of VCD studies of acyclic monoterpenes like linalol,
citronellol, and citronellal is observed, although the ocimenes from
the essential oils of Artemisia absintium could be studied [24] since
a significant molecular portion is rigid due to the presence of a
conjugated diene. Of relevance is also to note that an AC study of
conformational very flexible citronellal by molecular rotational
resonance, using microwaves in the 2-8 GHz region, was reported
recently [25], also evidencing a very high number of relevant
conformers. Another interesting case of a molecule with high
flexibility is the hydrocarbon 4-ethyl-4-methyloctane [26] which,
despite of showing cryptochirality, could be studied by VCD.

R²= 0.9982
950
1050
1150
1250
1350
1450
1550
950 1050 1150 1250 1350 1450 1550
vCalculated(cm
‐1
)
vExperimental(cm
‐1
)

R²=0.9916
950
1050
1150
1250
1350
1450
1550
950 1050 1150 1250 1350 1450 1550
vCalculated(cm
‐1
)
vExperimental(cm
‐1
)

-60
-40
-20
0
20
40
60
-60 -40 -20 0 20 40 60


exp


cal
R
2
=0.7500

984 Natural Product Communications Vol. 13 (8) 2018 Ortega et al.
Table 2: Wavenumber (v), intensities (

and 

), and vibrational modes of selected bands of the experimental and calculated IR and VCD spectra of guaiaretic acid diacetate.
Ex
p
erimental Calculated
IR VCD IR VCD
Band va


b
va 

c va


b
va



c Vibrational modesd
1 1506 408.3 1504 9.5 1500 531.4 1501

4.4 (as) A and B rings
2 1462 207.2 1474 1.2 1472 253.6 1470 14.9 (b) Me-10 and Me-10’; (ab) Me-9, Me-9’, CH-8’ and CH2-7’
3 1448 133.8 - - 1443 142.1 - -
4 1414 154.6 1391 1.1 1406 210.0 1408 4.1
5 1389 39.7 1366 6.0 1379 102.4 1382

5.3 (b) Me-9; (ab) CH-8’ and CH2-7’
6 1367 255.0 1353 6.9 1365 289.8 1365 2.9
7 1329 56.1 - - 1312 115.4 - -
8 1304 126.4 1275 24.2 1300 137.5 1302

12.8 (as) A and B rings; (as) C-1–C-7, C-8–C-8’; (ab) CH-7, CH-8’ and
CH2-7’
9 1279 319.8 - - 1280 469.2 - -
10 1263 321.3 - - 1268 379.5 - -
11 1257 213.2 1242 6.9 1255 307.5 1254 9.6 (s) C-4–O-10; (as) B ring; (s) C-4’–O-10’; (as) A ring
12 1217 625.3 1221 38.9 1205 879.2 1200

22.8 (as) O-4–C-11 and C-11–C-12; (as) O-4’–C-11’ and C-11’–C-12’
13 1200 931.0 1200 45.7 1193 1503.6 1193

22.9 (as) C-4–O-4, O-4–C-11, C-11–C-12 and C-1–C-7; (as) C-4’–O-
14 1151 317.2 - - 1147 392.3 - -
15 1121 297.6 1134 8.6 1107 228.8 1118

1.8
16 1090 36.1 1067 12.8 1074 54.0 1076

4.5 (s) C-8’–C-7’; (ab) CH-8’, CH2-7’ and CH3-9’
17 1038 243.7 1042 5.6 1025 171.9 1036

4.9 (s) O-3’–C-10’; (as) B ring; (ab) CH2-7’, CH-8’, and CH3-9; (s) O-
3–C-10; (as) A ring; (ab) CH2-7’, CH-8’, and CH3-9
18 1009 108.1 1005 9.2 990 207.8 1008 14.3 (as) O-4’–C-11’, C-11’–C-12’; (b) CH3-12’; (as) O-4–C-11, C-11–
C-12; (b) CH3-12
aIn cm1. bIn M1cm1.cIn M1cm1(103). d(s) stretching, (as) asymmetric strectching. (ss) symmetric strectching. (b) bending. (ab) asymmetric bending. (sb) symmetric bending.
From our results on the study of guaiaretic acid diacetate (1b) by
VCD, and other results just summarized above, it can be concluded
the AC determination of stereogenic centers located on carbon atom
chains, or side chains in natural products, is much more demanding
than for cases where the sterogenic center is located on a cyclic
system, but at the end the VCD methodology turned out to be
capable providing the desired information.
Experimental
General: Optical rotations were measured in EtOH at 25 °C in a
Perkin-Elmer 341 polarimeter. IR and VCD measurements were
made on a BioTools dualPEM ChiralIR FT spectrophotometer.
NMR measurements were performed from CDCl3 solutions
containing TMS at 300 MHz for 1H and 75 MHz for 13C on a
Varian Mercury spectrometer. CC was carried out on Merck silica
gel 60 (230-400 mesh ASTM). TLC was developed on silica gel 60
F254 plates.
Compounds: Guaiaretic acid (1a) was isolated from Guaiacum
sanctum according to known procedures [3], while the diacetate
(1b) was obtained by routine acetylation using acetic anhydride and
sodium acetate [4].
Guaiaretic acid (1a)
White crystals that slowly turn slightly yellow (EtOH).
MP: 85-87°C.
[α]589 78.2, [α]578 82.2, [α]546 95.8, [α]436 190.2 (c 0.1, EtOH).
1H NMR (300 MHz, CDCl3) δ 6.85 (1H, d, J = 8.3 Hz, H-5), 6.82
(1H, d, J = 8.3 Hz, H-5'), 6.70 (1H, dd, J = 8.3, 1.9 Hz, H-6), 6.65
(3H, m, H-2, H-2' and H-6'), 6.11 (1H, br s, H-7), 5.60 (1H, s, OH-
4'), 5.52 (1H, s, OH-4), 3.85 (3H, s, OMe-3), 3.83 (3H, s, OMe-3),
2.74 (1H, m, H-7a'), 2.53 (1H, m, H-7b'), 2.49 (1H, m, H-8'), 1.81
(3H, br s, Me-9), 1.08 (3H, d, J = 6.6 Hz, Me-9').
13C NMR (75 MHz, CDCl3): δ 146.2 (C-3), 146.0 (C-3'), 143.8 (C-
4'), 143.6 (C-4), 141.0 (C-8), 133.1 (C-1'), 130.9 (C-1), 124.5 (C-7),
121.9 (C-6), 121.8 (C-6'), 114.0 (2C, C-5 and C-5'), 111.7 (C-2),
111.5 (C-5'), 55.9 (MeO), 55.8 (MeO), 45.6 (C-8'), 41.6 (C-7'), 18.9
(C-9'), 15.0 (C-9).
Guaiaretic acid diacetate (1b)
White needles (EtOH).
MP: 82-83°C.
[α]589 66.4, [α]578 69.1, [α]546 80.3, [α]436 156.5, [α]365 306.7
(c 0.66, EtOH).
1H NMR (300 MHz, CDCl3) δ 6.95 (1H, d, J = 8.2 Hz, H-5), 6.92
(1H, d, J = 8.4 Hz, H-5'), 6.75 (1H, m, H-6), 6.74 (1H, m, H-2'),
6.73 (1H, m, H-6'), 6.72 (1H, m, H-2), 6.14 (1H, br s, H-7), 3.80
(3H, s, OMe-3), 3.79 (3H, s, OMe-3'), 2.80 (1H, dd, J = 12.8, 6.6
Hz, H-7a'), 2.59 (1H, m, H-7b'), 2.53 (1H, m, H-8'), 2.31 (3H, s,
Ac), 2.30 (3H, s, Ac), 1.83 (3H, d, J = 1.4 Hz, Me-9), 1.11 (3H, d,
J = 6.6 Hz, Me-9').
13C NMR (75 MHz, CDCl3): δ 169.2 (2C, 2 Ac CO),150.6 (C-3'),
150.5 (C-3), 142.5 (C-8), 140.0 (C-1'), 137.8 (2C, C-4 and C-4'),
137.4 (C-1), 124.6 (C-7), 122.2 (2C, C-5 and C-5'), 121.3 (C-6'),
121.2 (C-6), 113.2 (C-2'), 113.0 (C-2), 55.8 (2C, 2MeO), 45.4
(C-8'), 41.8 (C-7'), 20.7 (2C, 2 Ac Me), 19.0 (C-9'), 15.0 (C-9).
Single crystal X-Ray diffraction analysis of guaiaretic acid
diacetate (1b): A crystal of the title compound, C24H28O6, M =
412.46 was mounted on an Agilent Xcalibur Atlas Gemini
diffractometer using the enhance Cu Kα X-ray source radiation (λ =
1.54184 Å) at 293(2) K in the  scan mode. Unit cell refinements
using 1600 machine detected reflections were done with the
CrysAlisPro, Agilent Technologies, Version 1.171.34.49 software.
The crystal was triclinic, space group P-1, a = 10.3460(6) Å, b =
10.3942(6) Å, c = 11.7217(7) Å,

= 71.992(3) deg,

= 89.300(3)
deg,

= 65.172(3) deg, V = 1077.8(1) Å3, Z = 2,

= 1.27 mg/mm3,
μ = 0.742 mm-1, total reflections = 51529, unique reflections 3132
(Rint 0.01%), observed reflections 2479. The structure was solved by
direct methods using the SHELXS-97. For the structural refinement,
the non-hydrogen atoms were treated anisotropically, and the

Absolute configuration of guaiaretic acid Natural Product Communications Vol. 13 (8) 2018 985
hydrogen atoms, included in the structure factor calculation, were
refined isotropically. The final R indices were [I > 2(I)] R1 = 7.0%
and wR2 = 14.8%. Largest difference peak and hole, 0.59 and 0.32
e/Å3. Crystallographic data (excluding structure factors) have been
deposited at the Cambridge Crystallographic Data Centre under
CCDC deposition number 1861855. Copies of the data can be
obtained free of charge on application to the CCDC, 12 Union
Road, Cambridge CB2 IEZ, UK. Fax: +44-(0)1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk.
VCD measurement: A sample of 6.6 mg of 1b was dissolved in
150 μL of 100% atom-D CDCl3 and placed in a BaF2 cell with a
path length of 100 μm. VCD data were acquired at a resolution of 4
cm-1 for 6 h, and the stability of the sample was verified by 1H
NMR measurements at 300 MHz immediately prior and after the
VCD determination.
VCD calculations: The conformational search for 1b was started
generating a molecular model of the R enantiomer, in the
arrangement shown in conformer A of Figure 2, using the
Spartan’08 software (Wavefunction, Inc., Irvine, CA 92612, USA).
After a preliminary optimization using the same software and
molecular mechanics at the MMFF94 level of theory, the C-2–C-
1/C-7–C-8, C-7–C-8/C-8’–C-2’, and C-8’–C-2’/C-1’–C-2’ bonds
had dihedral angles of 109, –58, and 105 degrees, respectively;
while Me-9’ and Me-9 had a dihedral angle of –115 degrees. Thus,
to cover the entire conformational space, starting from initial
conformation A, the C-1–C-7, C-8–C-8’, C-8’–C-7’, and C7’–C1’
bonds were rotated 180 degrees to generate conformations B-E,
respectively (Figure 2). Conformers A-E were then subjected to
conformational searches using the Monte Carlo protocol and the
MMFF94 force field to afford 75, 88, 73, 78, and 87 conformers,
respectively, in 10 kcal/mol energy windows. Each set of
conformers was then submitted to single point energy analysis using
DFT and the B3LYP/6-31G(d) functional and basis set. All
conformers were combined in a unique set, arranged according to
their energy values, and their conformations were evaluated. After
eliminating equals, 75 conformers remained in a 5 kcal/mol energy
gap. The 16 lower energy conformers which were found in a 3
kcal/mol gap were completely optimized using Gaussian 03W
(Gaussian, Inc., Wallingford, CT 06492, USA) at the DFT and
B3LYP/DGDZVP level of theory and their frequencies were
calculated at the same level of theory. After complete optimization,
an additional conformer was eliminated and the 15 conformers that
remained, having a Gibb free energies within a 2.93 kcal/mol gap
were used to generate the final calculated IR and VCD spectra
considering a Boltzmann distribution based on their G values. The
thermochemical analysis was made at 298 K and 1 atm, the VCD
and IR frequencies were plotted using Lorentzian bandshapes and
bandwidths of 6 cm1. Calculated vibrational frequencies were
obtained from the most stable conformer using the GaussView 4.1
software while DFT calculations required on average 12 h
computational time per conformer when using a PC operating at 3
GHz with 4 Gb RAM.
Acknowledgment - Partial financial support from CONACYT-
Mexico grant number 284194, and SIP-IPN grant 20181801 are
acknowledged.
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