1. Journal of Molecular Structure 827 (2007) 121–125
www.elsevier.com/locate/molstruc
Conformational characterization of a camphor-based chiral
c-amino alcohol
Erika M. de Carvalho a, Jose D. Figueroa Villar a, Sandro J. Greco b, Sergio Pinheiro b,
´
Jose Walkimar de M. Carneiro c,*
´
a
´ ´
Departamento de Quımica, Instituto Militar de Engenharia, Praca General Tiburcio, 20 — Urca, Rio de Janeiro-RJ 22290-270, Brazil
¸
b
ˆ
Departamento de Quımica Organica, Instituto de Quımica, Universidade Federal Fluminense, Niteroi, RJ 24210-150, Brazil
´ ´ ´
c
ˆ
Departamento de Quımica Inorganica, Instituto de Quımica, Universidade Federal Fluminense, Niteroi, RJ 24020-150, Brazil
´ ´ ´
Received 30 March 2006; received in revised form 9 May 2006; accepted 11 May 2006
Available online 7 July 2006
Abstract
Experimental 1H chemical shift analysis for the camphor-based chiral c-amino alcohol 2 shows a difference of 0.9 ppm for the two
diastereotopic hydrogens H11a and H11b. In contrast, for the exo adduct (1) and its acetate (3) these hydrogens have very similar chemical
shifts. DFT calculations followed by NBO analysis show that these differences in chemical shifts arise as a consequence of an intramo-
lecular hydrogen bond OAHÁ Á ÁN in 2, which restricts its conformational mobility. In the most stable conformer of 2, the interaction of
the nitrogen lone-pair with the vicinal r*(CAH11a) antibonding orbital shifts that hydrogen downfield by 0.9 ppm. This is confirmed by
experimental NMR studies based on NULL.
Ó 2006 Elsevier B.V. All rights reserved.
Keywords: Camphor; Amino alcohol; Intramolecular hydrogen bond; NULL
1. Introduction
The synthesis of stereochemically defined c-amino alco- OH
hols merits considerable attention since they play an N
important role in medicinal chemistry as well as in asym- n
metric synthesis. For example, both the c-amino alcohols n=1 (R)-procyclidine
R-procyclidine and R-trihexyphenidyl are among the most n=2 (R)-trihexyphenidyl
effective anticholinergic agents used for the treatment of
Parkinson’s disease in which the absolute configuration is
essential for their pharmacological activities [1]. Also, tra- Some conformationally restricted c-amino alcohols are
damol, which is a cis-c-amino alcohol, possesses important widely employed in the preparation of attractive chiral aux-
analgesic activity [2]. iliaries [3] as well as chiral ligands, which are very useful in
asymmetric catalysis in organic synthesis [4]. Since the con-
formational rigidity in the structures of chiral c-amino
alcohols could be essential for both the pharmacological
activity and the efficiency of these ligands in asymmetric
* synthesis, we have focused our attention on the preparation
Corresponding author. Tel.: +55 02126292174; fax: +55 02126292129.
E-mail addresses: spin@rmn.uff.br (S. Pinheiro), walk@vm.uff.br of new conformationally restricted camphor-based chiral
(J. W. de M. Carneiro). c-amino alcohols.
0022-2860/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2006.05.023

2. 122 E.M. de Carvalho et al. / Journal of Molecular Structure 827 (2007) 121–125
Some time ago we reported the stereoselective access to pling constants for H11a in 2, as compared with 1, suggest
the exo adduct 1 in a very attractive procedure [5]. In this that compound 2 is a c-amino alcohol conformationally
work we used theoretical calculations and NULL to study restricted around the C3–C11 bond, possibly due to an
the differences in chemical shifts and coupling constants for intramolecular OAHAN hydrogen bond. Indeed, in ace-
the diastereotopic hydrogens at C11 of the corresponding tate 3, where such hydrogen bond cannot occur, H11a
amino alcohol 2, when compared with ketone 1 and the was observed as a doublet of doublets at 2.67 ppm, and
acetate 3. Our results show that compound 2 is a c-amino H11b appears as another doublet of doublets at 2.87 ppm,
alcohol conformationally restricted around the C3–C11 both partially overlapped with H12 (2.76 ppm).
bond due to an intramolecular hydrogen bond OAHÁ Á ÁN. In order to obtain more evidence to support the exis-
tence of the hydrogen bond, we carried out a computation-
11 11 11
3
3 3 al approach using DFT calculations and NBO analysis,
N N N
H OH OAc and an experimental determination of the inter-hydrogen
O H2 H2 distances using the NMR NULL method.
1 2 3
3. Computational analysis
2. Results and discussion
The role of the intramolecular OAHÁ Á ÁN hydrogen
The highly stereoselective Mannich reaction of D(+)- bond in the conformational behavior of the c-amino alco-
camphor titanium enolate was employed to reach preferen- hol 2 was assessed by means of molecular orbital calcula-
tially the exo adduct 1 (Scheme 1) [5]. This compound was tions. To compare with a similar system where there is
treated with LiAlH4 to yield the corresponding amino alco- no possibility of forming an intramolecular hydrogen
hol 2 as a pale yellow solid, which was obtained as a sole bond, the exo adduct 1 was also calculated.
diastereomer. Indeed, in the 1H NMR spectrum of the Both structures, that of the c-amino alcohol 2 and of the
crude product (2) no duplicities of signals that could be exo adduct 1, were fully optimized with the semi-empirical
attributed to diastereomers at positions 2 and 3 were PM3 method using the Titan package of molecular orbital
observed. This result is in good agreement with the highly calculation [7]. After this initial geometry optimization,
stereoselective reduction of the carbonyl group at position starting from a reasonable conformation, the conformer
2 of camphor derivatives reported in the literature [6]. The distribution subroutine of the Titan package was employed
subsequent treatment of compound 2 with Ac2O in DMAP to identify additional conformations with possible lower
furnished the corresponding acetate 3 as a light yellow oil energy. While this procedure does not allow us to definitely
after flash chromatography on silica gel. locate the global minimum energy conformer, for these rel-
The stereochemical assignment of the position 2 at the atively small, restricted systems we assume that the most
amino alcohol 2 was made on the basis of NOE NMR relevant conformations are actually identified. The semi-
spectra. For H2 a significant NOE value was observed with empirical PM3 method was again employed to search for
H3 (4.1%) suggesting an exo configuration for the hydroxyl the conformer distribution. For each of the systems, the
group in 2. In fact, NOE effect was not observed neither for three most stable, nonidentical conformations were select-
H8 with the signal of H3 or for H2 with the signals attrib- ed for further calculations.
uted to H11a and H11b. After identifying the three most stable conformers for
In the stereoselective reduction of the amino ketone 1 to both systems at the semi-empirical level, they were submit-
the amino alcohol 2 a significant change in the chemical ted to a new full geometry optimization, now using the
shifts and coupling constants of the diastereotopic hydro- more rigorous DFT (B3LYP) methodology [8], with the
gens H11a and H11b was observed (Table 1). Indeed, for 6-31G(d) basis set, in the G03W package of molecular orbi-
compound 1 H11b was observed at 2.61 ppm as a doublet tal calculation (Fig. 1) [9]. For the c-amino alcohol 2 the
of doublets and partially overlapped with H12 (2.63 ppm), above procedure clearly indicates the conformer with an
while H11a was found at 2.86 ppm (dd, J = 12.5 and intramolecular OAHÁ Á ÁN hydrogen bond as the most sta-
4.5 Hz). In 2 H11b was observed upfield, at 2.39 ppm (dd, ble, 6.86 kcal/mol below the next lower in stability. In
J = 12.0 and 6.6 Hz) while H11a was found downfield, at order to verify the effect of a low polarity solvent on the rel-
3.29 ppm (dd, J = 13.1 and 11.9 Hz). Also, the greater cou- ative stabilities of the most stable conformers we recalcu-
i N ii N iii N
H OH OAc
O O H H
D-(+)-camphor 1 2 3
Scheme 1. (i) 1 M TiCl4, i-Pr2NEt, CH2Cl2, À10 °C, 1 h then 1-methoxymethyl-pyrrolidine, 50%, exo:endo = 92: 8. (ii) LiAlH4, THF, r. t., 96 h, 71%. (iii)
Ac2O, cat. DMAP, r. t., 6 h, 65%.

3. E.M. de Carvalho et al. / Journal of Molecular Structure 827 (2007) 121–125 123
Table 1
Selected 1H NMR data for compounds 1–3
H H H H H H
7 8 11a 11b 7 8 11a 11b 7 8 11a 11b
9 12 9 12 9 12
4 4 4
5 N 5 N 5 N
13 OH 13 OAc 13
6 1
H3 6 1 6 1
10 O 10 H2 10 H2
1 2 3
Hydrogen 1 (d, ppm) 2 (d, ppm) 3 (d, ppm)
11a 2.86 (dd) J = 12.5 and 4.5 Hz 3.29 (dd) J = 13.1 and 11.9 Hz 2.67 (dd) J = 12.6 and 5.1 Hz
11b 2.61 (dd) J = 12.5 and 7.5 Hz 2.39 (dd) J = 12.0 and 6.6 Hz 2.87 (dd) J = 12.6 and 7.5 Hz
12a 2.63 (m) 2.52–2.44 (m) 2.76 (m)
12b 2.63 (m) 2.70–2.61 (m) 2.76 (m)
1 2
Fig. 1. Calculated most stable conformers for the exo adduct 1 and the c-amino alcohol 2.
lated their energies at the B3LYP/6-31G(d) level using the shifts for the diastereotopic hydrogens H11a and H11b of
COSMO solvation procedure [10]. This calculation con- 1 and 2. The agreement between the experimental and the
firmed for compound 2 the hydrogen bonded conformer calculated values is excellent. The most relevant aspect,
as the most stable, now 7.5 kcal/mol more stable than the however, is the systematic chemical shift differences
next one. observed between the two diastereotopic hydrogens. For
These results indicate that to a certain degree, the intra- the nonrestricted exo adduct 1 both hydrogens have chem-
molecular hydrogen bond restricts the conformational ical shifts that diverge by no more than 0.2 ppm. For the
mobility of the c-amino alcohol 2. Following a Boltzman conformationally restricted c amino alcohol 2, however,
distribution law, the next populated conformers should the difference in chemical shift between those two hydro-
only marginally contribute to the complete description of gens amounts to 0.9 ppm. This chemical shift difference
this alcohol. may be attributed to the differential interaction of both
For the most stable conformers of each the c-amino hydrogens with the vicinal nitrogen lone pair. This interac-
alcohol 2 and the exo adduct 1 we calculated the chemical tion may be quantified by the NBO analysis in terms of
shift and the degree of hyperconjugation involving the hyperconjugation between the nitrogen lone pair and the
nitrogen lone pair. Calculation of chemical shifts for indi- antibonding vicinal r*(CAH) orbital. In this context hyper-
vidual conformers has the advantage of detecting effects conjugation is quantified in terms of the second order per-
that otherwise would appear as averages in observed spec- turbation interaction energy obtained from the NBO
tra. Similarly, calculations of interactions between individ-
ual orbitals (hyperconjugation) may help understand the Table 2
phenomena responsible for stability and properties [11]. Experimental versus theoretical chemical shifts for H11a and H11b in 1 and 2
In this work we used the Gauge-included atomic orbital d (ppm) H11a and H11b d (ppm) H11a and H11b
(GIAO) [12] approach and the natural bond orbital analy- experimental calculated
sis (NBO) [13] to study the effect of conformation on the H11a H11b
chemical shifts of the diastereotopic hydrogens H11a and N H11a: 2.86 (dd) H11a: 2.65
H11b for the c-amino alcohol 2 and the exo adduct 1. 1 H3 H11b: 2.64–2.56 (m) H11b: 2.60
The GIAO chemical shifts were calculated with the O
B3LYP method using the 6-311 + G(d) basis set. The rela- H11a H11b
tive values given in Table 2 were obtained after subtraction
of the absolute values from the corresponding ones with 2 N H11a: 3.29 (dd) H11a: 3.27
OH H11b: 2.39 (dd) H11b: 2.60
TMS, calculated at the same theoretical level. In Table 2
H2
we compare experimental versus theoretical 1H chemical

4. 124 E.M. de Carvalho et al. / Journal of Molecular Structure 827 (2007) 121–125
analysis, and represents the estimate of the second order Table 3
interaction energy (E(2)) between orbitals in vicinal centers. Calculated and experimental H11a–HO and H11b–HO distances for 2
This was also calculated at the B3LYP/6–311+G(d) level. ˚
Experimental distance (A) ˚
Calculated distance (A)a
The interaction energy between the nitrogen lone pair H11a–HO 2.75 2.54
and the parallel antibonding r*(CAH11a) orbital is H11b–HO 3.37 3.47
1.59 kcal/mol, while for the other orbital r* of CAH11b, a
Calculated for the most stable hydrogen bonded conformation for 2.
which does not interact with the nitrogen lone pair due
to its orientation, it is essentially zero. Although the value
where qij is the cross relaxation term for hydrogens i and j.
for the interaction energy is small, it is enough to clearly
The correlation time is calculated by carrying out determi-
differentiate between the two hydrogens. Both the experi-
nations for selective and nonselective T1 [16].
mental and the calculated chemical shifts for the interact-
This method allows for the experimental determination
ing hydrogen are deshielded by about 0.9 ppm as
of H–H distances in solution with a precision of a hun-
compared to the chemical shift of the hydrogen that does
dredth of Angstrom [14,15]. The experimental and the cal-
not interact with the nitrogen lone pair. In contrast, for
culated distances for the hydroxyl hydrogen with H11a and
the nonrestricted exo adduct 1 both hydrogens have essen-
H11b are shown in Table 3.
tially the same chemical shift.
From the data in Table 3 it is clear that there is a good
These results clearly indicate that the hydrogen bond in
agreement between the calculated and the experimental dis-
the c amino alcohol 2 restricts its conformational mobility,
tances, with a difference of only 8% and 3% for H11a and
leading to a conformer where the two diastereotopic hydro-
H11b, respectively. In the absence of the OAHÁ Á ÁN hydro-
gens H11a and H11b may be distinguished by their differen-
gen bond, the average distance for both hydrogens would
tial interaction with the vicinal nitrogen lone pair, what
be quite similar, thus confirming the existence of the
reflects in their different chemical shifts. Both the experi-
OAHÁ Á ÁN hydrogen bond in compound 2. In fact, the
mental and the calculated chemical shifts confirm these
intramolecular nature of the hydrogen bond was confirmed
conclusions.
by the execution of several NMR experiments varying sol-
vent (CDCl3, acetone-d6, acetonitrile-d3, CH3OD and
4. NMR studies
DMSO-d6) and temperature (25–40 °C). In those experi-
ments it was observed that the major chemical shift change
In order to confirm the formation of the OAHÁ Á ÁN
for the OH was only 0.005 ppm, and that the shape of its
hydrogen bond for compound 2, we carried out experi-
signal remained unchanged. Those results are only in
mental measurements of the distance between the
agreement with an intramolecular hydrogen bond.
hydroxyl hydrogen with H11a and H11b using the NULL
method [14,15]. NULL allows for a more precise deter-
5. Conclusions
mination of interproton distances when compared to
methods based on NOE [15], as it minimizes spin diffu-
Molecular modelling using the DFT methodology and
sion effects. The NULL pulse sequence starts with a
the COSMO procedure in connection with NMR theoreti-
selective composite 180° hydrogen pulse, which inverts
cal and experimental studies based on NULL pulse
the magnetization of only the hydrogen of interest for
sequence proved the existence of an OAHÁ Á ÁN intramolec-
the desired distance determination. In the present case,
ular hydrogen bond in the c-amino alcohol 2. This hydro-
it was decided to invert either H11a or H11b, as it has
gen bond restricts the conformational mobility of 2,
been shown that selective excitation of hydroxyl hydro-
allowing for the diastereotopic hydrogens at C11 to be dis-
gens may lead to greater errors. The NULL experiment
criminated due to their differential interactions with the
continues with a nonselective 180° pulse, which resets
nitrogen lone pairs, as determined by GIAO and NBO
the selected hydrogen magnetization back to the z-axis
methods.
while inverting all other hydrogens. The experiment con-
tinues with a variable delay followed by a 90° pulse and
6. Experimental
detection, thus allowing for the determination of the
longitudinal relaxation times of all hydrogens without
The simple 1H and 13C NMR spectra were determined
the cross relaxation to the initially selected hydrogen.
in CDCl3 using TMS as internal reference in a Varian Uni-
If the molecular correlation time (sc) is known it is pos-
ty-300 (300 MHz) NMR spectrometer at 19 ± 0.1 °C, using
sible to use the cross relaxation value to calculate the
45 °C RF pulses (11.3 ls for 1H and 15.8 ls for 13C).
distance between the selectively excited hydrogen with
Chemical shifts are given in the d-scale and J-values are
any one of the other hydrogens, as shown in Eq. (1)
given in Hertz. Nonselective T1 values were measured using
[14,15]
the standard inversion-recovery program. For the selective
quot; #1=6
3 l0 2 c4 hsc experiments, the 180 °C selective inversion pulse was
rij ¼ ð1Þ achieved by replacement of the hard 180 °C pulse of the
8 4p 4pqij
inversion-recovery sequence by a DANTE train (75 pulses,

5. E.M. de Carvalho et al. / Journal of Molecular Structure 827 (2007) 121–125 125
s = 40 ls) with the transmitter power attenuation adjusted 7.5 Hz, H11b), 2.76 (m, H12ab), 2.67 (dd, J = 12.6 and
to 40 dB (15 dB attenuation in relation to the nonselective 5.1 Hz, H11a), 2.07 (s, H14), 1.98–1.94 (m, H3), 1.93–1.87
pulse) [14]. The selective 180 °C pulse for the NULL (m, H13), 1.93–1.73 (m, H4), 1.56 (td, J = 12.9 and
sequence was obtained using the composite pulse, p/2x _ 3.3 Hz, H5), 1.28–1.15 (m, H6), 1.03 (s, H10), 0.83 and
py _ p/2x [15], where each part of the composite pulse 0.82 (s, H8 and H9). 13C NMR (CDCl3, 75 MHz, APT,
was made up of a DANTE sequence (75 pulses, ppm): d 170.8 (C15), 82.1 (C2), 56.3 and 54.2 (C11 and
s = 40 ls). This method gave better selectivity that a single C12), 50.3 (C14), 49.8 and 47.7 (C1 and C7), 47.2 and
180 °C DANTE pulses train. 47.0 (C3 and C4), 33.6 (C5), 29.8 (C6), 23.8 (C13), 21.8
(C10), 21.6 (C9), 11.6 (C8).
6.1. Synthesis of amino alcohol 2
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