Detailed 1H and 13C NMR spectral data assignment for two dihydrobenzofuran neolignans

Article abstract of DOI:10.5935/0103-5053.20150262

In this work we present a complete proton (¹H) and carbon 13(¹³C) nuclear magnetic resonance (NMR) spectral analysis of two synthetic dihydrofuran neolignans (±)-trans-dehydrodicoumarate dimethyl ester and (±)-trans-dehydrodiferulate

Full text of DOI:10.5935/0103-5053.20150262

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J. Braz. Chem. Soc., Vol. 27, No. 1, 136-143, 2016.
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Article
A
Detailed 1H and 13C NMR Spectral Data Assignment for Two
Dihydrobenzofuran Neolignans
Talita C. T. Medeiros,a,# Herbert J. Dias,a,# Eliane O. Silva,a Murilo J. Fukui,b
Ana Carolina F. Soares,b Tapas Kar,c Vladimir C. G. Heleno,b Paulo M. Donate,a
Renato L. T. Parreirab and Antônio E. M. Crotti*,a
aDepartamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto,
Universidade de São Paulo, 14040-901 Ribeirão Preto-SP, Brazil
bNúcleo de Pesquisas em Ciências Exatas e Tecnológicas, Universidade de Franca,
14404-600 Franca-SP, Brazil
cDepartment of Chemistry and Biochemistry, Utah State University,
84322-0300 Logan-UT, United States
In this work we present a complete proton (1H) and carbon 13 (13C) nuclear magnetic resonance
(NMR) spectral analysis of two synthetic dihydrofuran neolignans ( )-trans-dehydrodicoumarate
dimethyl ester and ( )-trans-dehydrodiferulate dimethyl ester. Unequivocal assignments were
achieved by 1H NMR, proton decoupled 13C (13C{1H}) NMR spectra, gradient-selected correlation
spectroscopy (gCOSY), J-resolved, gradient-selected heteronuclear multiple quantum coherence
(gHMQC), gradient-selected heteronuclear multiple bond coherence (gHMBC) and nuclear
Overhauser effect spectroscopy (NOESY) experiments. All hydrogen coupling constants were
measured, clarifying all the hydrogen signals multiplicities. Computational methods were also used
to simulate the 1H and 13C chemical shifts and showed good agreement with the trans configuration
of the substituents at C7 and C8.
Keywords: neolignans, oxidative coupling, J-resolved, benzofurans
Introduction
Because of these biological activities, several synthetic
methodologies have been proposed to build the basic
skeleton of dihydrobenzofuran neolignans (DBNL).10-12
However, the oxidative coupling of phenylpropanoids is so
far the most commonly reported synthetic route to obtain
DBNL, such as compounds ( )-trans-dehydrodicoumarate
dimethyl ester (2a) and ( )-trans-dehydrodiferulate
dimethyl ester (2b; Figure 1). Compound 2b is reported
to have antileishmanial,13 antiplasmodial,13 cytotoxic,13
antiangiogenic,14 antitumor,15 and antioxidant16 activities.
Despite of these biological activities, nuclear magnetic
resonance (NMR) data found in literature for both
Neolignans (NL) are a class of plant-derived natural
products which are produced from shikimic acid pathway.1
They differ from related lignans by the way the two
C6C3 units are joined by other bonds. According to the
International Union of Pure and Applied Chemistry
(IUPAC) recommendations, the term lignan refers to
structures where the two C6C3 units are β,β’ (8-8’)
linked, whereas the term neolignan must be used for
compounds that originate from coupling other than 8-8’
coupling.2
Among NL, compounds exhibiting a dihydrobenzofuran
moiety as structure feature have attracted special
attention because their wide range of biological activities,
such as antioxidant,3 antitumor,4 anti-inflammatory,5
antileishmanial,6 trypanocidal,7,8 insecticidal9 and cytotoxic.3
*e-mail: millercrotti@ffclrp.usp.br
#These authors contributed equally to this work.
Figure 1. Structures of dihydrobenzofuran neolignans 2a and 2b.

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Medeiros et al.
137
compounds are generally incomplete and, in some cases,
inaccurate.14,15,17,18
gHMQC; gradient-selected heteronuclear multiple bond
coherence, gHMBC; and nuclear Overhauser effect
spectroscopy, NOESY) for the same compounds are given
in Tables 2 and 4, respectively. Firstly, the 1H NMR spectra
were analyzed in detail, which made it possible to verify all
chemical shifts. Further analysis of 1H NMR spectra led to
the measurement of most homonuclear hydrogen coupling
constants. Some J values were measured only in J-resolved
spectrum and all couplings were confirmed by gCOSY
experiments. Then, most signals of the proton decoupled
13C (13C{1H}) NMR spectra were assigned through
gHMQC and distortionless enhancement by polarization
transfer (DEPT) 135 experiments. The assignment of non-
hydrogenated carbons was carried out by the use of gHMBC
information and by comparison with calculated spectra.
1H and 13C NMR data previously reported for
compound 2a and 2b were obtained in CDCl3 or acetone-d6.
Most of the signals in the 1H NMR spectrum were between
dH 6.0 and dH 8.0, but the hydrogen signal multiplicities are
ambiguous. In this work, we found that for compound 2a
in acetone-d6, the signals at dH 7.6-7.7 are referred to four
hydrogen atoms and their overlapping precluded their
correct assignment (Figure 2). Therefore, CDCl3 provided
much clearer spectra for 2a, but not for 2b, due to the
solvent influence on chemical shifts. For compound 2b,
three hydrogen atoms resonate at dH 6.91 in the 1H HMR
spectrum in CDCl3. On the other hand, the 1H NMR signals
of 2b were resolved by using acetone-d6 as solvent, which
allowed verification of the multiplicities, observation of the
chemical shifts and measurement of the coupling constants.
Owing to our interest in the detailed NMR study of
natural19-21 and synthetic22-25 compounds, in this study
we have performed a thorough assignment of all proton
(1H) and carbon 13 (13C) NMR data for the synthetic
dihydrobenzofuran neolignans 2a and 2b using one- (1D)
and two-dimensional (2D) NMR techniques.
Results and Discussion
The ( )-trans-dehydrodicoumaroate dimethyl ester (2a)
and ( )-trans-dehydrodiferulate dimethyl ester (2b) were
synthesized according to previous reported procedure,15,17,26
which was outlined in Scheme 1. The 1H and 13C NMR data
for these compounds were previously published14,15,17,18
but presented some imprecisions that should be corrected.
O
O
O
OCH
3
R
(i)
OCH
3
H CO
3
OH
HO
O
1a:
R
R = H
R
1b: R = OCH
3
2a: R = H
2b
: R = OCH
3
Scheme 1. (i) Ag2O, (CH3)2CO:C6H6 3:5, r.t., 20 h (2a: 36% yield; 2b:
43% yield).
1
The main H and 13C NMR data for ( )-trans-
dehydrodicoumaroate dimethyl ester (2a) and ( )-trans-
dehydrodiferulate dimethyl ester (2b) are presented in
Tables 1 and 3. Two-dimensional NMR data (gradient-
selected correlation spectroscopy, gCOSY; gradient-
selected heteronuclear multiple quantum coherence,
1
The H NMR (400 MHz, CDCl3) of compound 2a
(Table 1) showed resonances for one trans disubstituted
Figure 2. Expansions of the 1H NMR spectrum of compounds 2a and 2b obtained in CDCl3 and acetone-d6.

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138
Detailed 1H and 13C NMR Spectral Data Assignment for Two Dihydrobenzofuran Neolignans
J. Braz. Chem. Soc.
double bond at dH 6.32 (d, 1H, J 15.9 Hz) and dH 7.66 (ddd,
1H, J 0.6, 1.1, 15.9 Hz). The smaller coupling constant
values of the signal at dH 7.66 could be measured only
in the J-resolved spectrum. Analysis of the 1H-1H COSY
spectrum data (Table 2) revealed some long-range
couplings (4J): H7/H2, H7/H6, H7’/H2’, H7’/H6’. From 1H NMR
hydrogenated sp2-hybridized carbons C1’ (127.8), C4’ (161.2)
and C5’ (125.1) were unambiguously assigned to C1’, C4’
and C5’ on the basis of their long-range C−H correlations
in the gHMBC spectrum with dH 6.32 (H8’), 7.43 (H2’) and
6.09 (H7), respectively. Similarly, the assignment of C1 and
C4 to dC 132.0 and 156.1 was established on the basis of
the correlations with dH 7.27 (H2=H6) and 6.84 (H3=H5),
respectively. Considering that C4 is expected to be unshielded
when compared to C1 due to the inductive effect of the
oxygen hydroxyl, this corroborates the assignment.
1
and H-1H COSY spectra it was possible to establish
the spin systems corresponding to the C3’/C2’/C6’/C8 and
C2/C3/C5/C6/C7 portions of 2a.
Table 1. 1H and 13C NMR data assignments for compound 2a (400 MHz,
CDCl3)
Table 2. 2D NMR data for compound 2a (400 MHz, CDCl3)
a
dC
dH (integral, multiplicityb), J / Hz
a
C
H
–
gCOSY
gHMBCb
H3 =H5, H7, H8
H3 =H5, H7
H5
gHMQCc NOESYd
1
132.0 (C)
127.5 (CH)
−
1
–
–
H2=H6
H3=H5
–
–
2=6
7.27 (2H, ddd, J2,5 = J6,3 0.3, J2,7 = J6,7 0.6,
J2,3 = J6,5 8.3)
2=6
3=5
4
2=6
3=5
–
H3, H5, H7
H7, H8
3=5
4
115.7 (CH)
156.1 (C)
87.7 (CH)
55.1 (CH)
170.9 (C)
52.9 (CH3)
127.8 (C)
130.8 (CH)
110.3 (CH)
161.2 (C)
125.1 (C)
124.9 (CH)
6.84 (2H, dd, J3,6 = J5,2 0.3, J3,2 = J5,6 8.3)
H2, H6
–
−
–
H3 =H5, H2 =H6
H6, H8
–
7
6.09 (1H, dt, J7,2 = J7,6 0.6, J7,8 7.2)
7
7
H2=H6, H8
H7
H2=H6*
8
4.27 (1H, dd, J8,6’ 1.4, J8,7 7.2)
8
8
H7, H6’
H7, H6’
H8
H2=H6, H6’*
9
−
9
–
–
H7, H8, H10
–
–
10
1’
2’
3’
4’
5’
6’
3.83 (3H, s)
−
10
1’
2’
3’
4’
5’
6’
7’
8’
9’
10’
10
–
–
H10
–
–
−
7.43 (1H, ddd, J2’,7’ 1.1, J2’,6’ 2.0, J2’,3’ 8.3)
–
H3’, H8’
–
6.89 (1H, dd, J3’,6’ 0.4, J3’,2’8.3)
2’
3’
–
H3’, H6’, H7’
H6’, H7’
H2’
H3’
–
H7’, H8’*
−
−
−
H2’, H6’
–
–
–
H2’, H3’, H6’, H7, H8
H8, H3’
–
7.55 (1H, dddd, J6’,3’ 0.4, J6’,7’ 0.7, J6’,8 1.4,
J6’,2’2.0)
–
–
–
H8’, H7’, H8*
H6’*, H2’
H6’*, H2’
–
7’
144.7 (CH)
115.2 (CH)
167.9 (C)
7.66 (1H, ddd, J7’,6’ 0.7, J7’,2’ 1.1, J7’,8’ 15.9)
6’ H2’, H3’, H7’, H8
H2’, H7’, H8
H2’, H6’, H8’
H7’
H6’
H7’
H8’
–
8’
6.32 (1H, d, J8’,7’ 15.9)
7’
8’
H2’, H8’, H6’
9’
−
H7’
–
10’
51.7 (CH3)
3.81 (3H, s)
–
H7’, H8’, H10’
–
aMultiplicities assigned on the basis of distortionless enhancement
b
by polarization transfer (DEPT) 135 experiments; multiplicities and
10’
–
H10’
–
coupling constant values measured within 1H NMR and J-resolved spectra
with the help from 1H-1H correlation spectroscopy (COSY) results.
aGradient-selected correlation spectroscopy; bgradient-selected
heteronuclear multiple bond coherence; cgradient-selected heteronuclear
multiple quantum coherence; nuclear Overhauser effect spectroscopy.
d
*mean weak correlation.
Assignments of the carbonyl C9 and C9’ and methoxy
groups C10 and C10’are directly performed and those groups
can clearly be differentiated on the basis of the gHMBC
spectrum (Table 2). The gHMBC correlations are observed
between dC at 170.9 and the signals at dH 4.27 (H8), 6.09
(H7), and 3.83 (s, 3H); therefore, the dC at 170.9 is attributed
to C9, and dH at 3.83 is assigned to H10. On the other hand,
gHMBC correlations between dC at 167.9 and the signals at
dH 7.66 (H7’), 7.55 (H7’) and 3.81 (s, 3H) allowed to assign the
dC 167.9 to C9’, and the dH 3.81 to H10’. In addition, the dc 51.7
and dc 52.9 were assigned to C10’ and C10, respectively, on the
basis of the correlations observed in the gHMQC spectrum
with dH 3.81 (H10’) and dH 3.83 (H10). Finally, the non-
1
The H NMR (400 MHz, acetone-d6) data of
compound 2b are shown in Table 3 and their 2D NMR
data are compilated in Table 4.
The structure of compound 2b is related to the natural
dimer 3’,4-di-O-methylcedrusin, which is one of the active
compounds in dragon’s blood. This blood-red latex, produced
by some Croton species growing in the South America, is
employed in traditional medicine for wound-healing and
anticancer properties.27 Lemière et al.17 have previously
reported the synthesis of 3’,4-di-O-methylcedrusin and
other related neolignans, including compound 2b, and

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Vol. 27, No. 1, 2016
Medeiros et al.
139
Table 3. 1H and 13C NMR data assignments for compound 2b (400 MHz,
acetone-d6)
Table 4. 2D NMR data for compound 2b (400 MHz, acetone-d6)
a
C
H
–
gCOSY
gHMBCb
H2, H6, H7, H8
H5, H6, H7
H2, H5, H11
H2, H5, H6
H6
gHMQCc
–
NOESYd
a
dC
dH (integral, multiplicityb); J / Hz
1
–
–
1
132.5 (C)
111.2 (CH)
149.1 (C)
148.5 (C)
116.3 (CH)
120.7 (CH)
88.8 (CH)
57.0 (CH)
172.1 (C=O)
53.5 (CH3)
56.4 (CH3)
129.9 (C)
113.9 (CH)
146.3 (C)
151.5 (C)
127.8 (C)
119.5 (CH)
145.9 (CH)
116.8 (CH)
168.2 (C)
52.1 (CH3)
56.8 (CH3)
–
2
2
H5, H6, H7
H2
H3
–
H7, H8, H11
2
7.10 (1H, ddd, J2,5 0.3, J2,7 0.8, J2,6 2.1)
3
–
–
–
3
–
4
–
–
–
4
–
5
5
H2, H6
H5
H6
H7
H8
H9
H10
H11
H1’
H2’
–
–
5
6.84 (1H, dd, J5,2 0.3, J5,6 8.3)
6
6
H2, H5, H7
H2, H5
H7, H8
6
6.92 (1H, ddd, J6,7 0.6, J6,2 2.1, J6,5 8.3)
7
7
H2, H6, H8
H2, H6, H8
H2, H6’
H6*, H2
7
6.04 (1H, ddd, J7,6 0.6, J7,2 0.8, J7,8 7.3)
8
8
H6’, H7
H6’*, H2, H6
8
4.47 (1H, dd, J8,6’ 1.4, J8,7 7.3)
9
–
–
H7, H8, H10
–
9
–
−
10
11
1’
2’
3’
4’
5’
6’
7’
8’
9’
10’
11’
10
11
–
–
–
10
11
1’
2’
3’
4’
5’
6’
7’
8’
9’
10’
11’
3.81 (3H, s)
−
–
H2
3.84 (3H, s)
–
H7’, H8’
H6’, H7’
–
–
2’
–
H6’, H7’
H7’, H8’*, H11’
7.33 (1H, dd, J2’,7’ 0.4, J2’6’ 2.6)
–
–
–
H11’
–
–
–
H2’, H6’, H7, H8
H7, H8’
–
–
–
–
–
–
–
7.29 (1H, ddd, J6’,7’ 0.8, J6’,8 1.4, J6’,2’ 2.6)
7.63 (1H, ddd, J7’,2’ 0.4, J7’,6’ 0.8, J7’,8’ 15.8)
6.44 (1H, d, J8’,7’ 15.8)
–
6’
7’
8’
–
H7’, H2’, H8 H2’, H7’, H8
H2’, H6’, H8’ H2’, H6’, H8’
H6’
H7’
H8’
–
H8’, H7’, H8*
H6’, H2’,
H7’
–
H7’
H6’, H2’
H8’, H10’
–
–
10’
11’
–
–
–
H10’
H11’
3.73 (3H, s)
3.92 (3H, s)
–
H2’
aMultiplicities assigned on the basis of distortionless enhancement by
polarization transfer (DEPT) 135 experiments; bmultiplicities and coupling
constant values measured within 1H-NMR and J-resolved spectra with the
help from 1H-1H correlation spectroscopy (COSY) results.
aGradient-selected correlation spectroscopy; bgradient-selected
heteronuclear multiple bond coherence; cgradient-selected heteronuclear
multiple quantum coherence; nuclear Overhauser effect spectroscopy.
d
*mean weak correlation.
assigned the 13C NMR data of these compounds on the
basis of DEPT experiments and long-range of heteronuclear
correlation (HETCOR) correlations. In this work, we
found that the 13C NMR data assignment based on DEPT,
gHMQC and gHMBC were similar to that reported by
Lemière et al.17 and therefore, will not be discussed in
Similarly, the signal at H2’ (dd, dH 7.33) correlates with
dH 7.29 (H6’, J2’,6’ 2.6 Hz) and dH 7.63 (H7’). A long-range
coupling (4J) between H6’ and H8 was also deduced from the
correlations between dH 7.29 (ddd, H6’) and 4.47 (dd, H8’,
J7’,8 1.4 Hz) in the 1H-1H COSY spectrum. It was possible to
establish the spin systems corresponding to the C2’/C6’/C7’/C8
and C2/C3/C5/C6/C7 portions of 2b. The long-range coupling
(4J) of both H2 and H6 with H7 has not been previously
reported in the literature. In this work, we could measure
the scalar coupling constants J2,7 and J6,7 in the J-resolved
spectrum as being 0.8 and 0.6 Hz, respectively.
The relative stereochemistry of the substituents at
C7 and C8 in ( )-2a and ( )-2b, only the trans-(7R,8R)
stereoisomers, are reported in Figure 1 and Scheme 1 was
determined on the basis of the J7,8 value and some theoretical
calculations, all corroborated by nuclear Overhauser effect
(NOE) data (Figure 3).
1
details here. On the other hand, the H NMR data of
compound 2b available in the literature seems inaccurate.
1
Multiplicities of the signals of the H NMR spectrum of
2b are often reported as singlet (H10, H10’, H11 and H11’),
doublet (H2, H5, H7, H8, H7’ and H8’), doublet of doublets (H6)
or broad singlet (H2’ and H6’) and have not been previously
1
explored. In this work, H-1H COSY and 2D J-resolved
spectra were used to understand the multiplicity and to
measure the coupling constants.
Asreportedforcompound2a, analysisofthe1H-1HCOSY
spectrum of 2b (Table 4) revealed a long-range coupling (4J)
of H7’ (ddd, 1H, dH 7.63) with H2’ (dH 7.33) and H6’ (dH 7.29).
The coupling constant values J7’,6’ and J7’,2’ were measured in
the J-resolved spectrum to be 0.8 Hz and 0.4 Hz, respectively.
Firstly, a comparison of J7,8 values for 2a and 2b with J
values reported for other dihydrobenzofuran neolignans,28
showed a clear agreement with the trans configuration. It is