A quantitative structure-reactivity relationship in N-acetyl oxazolidines: An electrostatic interaction controls rotamer population

Article abstract of DOI:10.1039/c0ob01039a

The conformational population of Z and E isomers of the amide bond in N-acetyl oxazolidines is dictated by the electronic nature of the vicinal aryl ring. Experimental and theoretical data support a rationale based on a strong and stereodirecting charge-c

Full text of DOI:10.1039/c0ob01039a

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PAPER
A quantitative structure-reactivity relationship in N-acetyl oxazolidines: an
electrostatic interaction controls rotamer population†
´
R. Fernando Mart´ınez,* Mart´ın Avalos, Reyes Babiano, Pedro Cintas, Jose´ L. Jime´nez,
Juan C. Palacios and Esther M. S. Pe´rez
Received 17th November 2010, Accepted 1st February 2011
DOI: 10.1039/c0ob01039a
The conformational population of Z and E isomers of the amide bond in N-acetyl oxazolidines is
dictated by the electronic nature of the vicinal aryl ring. Experimental and theoretical data support a
rationale based on a strong and stereodirecting charge–charge interaction that should be added to the
arsenal of non-covalent interactions and whose influence can be more important than once thought.
Introduction
Oxazolidines and N-acyloxazolidines constitute a family of im-
portant heterocycles found in bioactive natural products.1 N-
Acyloxazolidines can be considered as pseudo-prolines and exert a
pronounced effect upon backbone conformation in peptides due to
their structural similarity with proline itself.2 It is well established
that proline residues play a particular and often key role in peptide
and protein secondary structure formation.3 The prevalence of
proline residues in biological processes such as protein folding
and protein recognition4 has led to the development of numerous
mimetics5 and substituted-proline analogs.6 Therefore, pseudo-N-
acylprolines may offer new vistas and applications in peptide-
based drug and prodrug design, molecular recognition studies,
as well as in protein folding and self-aggregation processes.7
Likewise, DNA-templated syntheses of monocyclic and bicyclic
N-acyloxazolidines have also been reported and represent the
most complex architectures containing these heterocycles and
incorporating DNA sequences.2
Scheme 1
Remarkably, the rotameric ratio of polyol N-acyl oxazolidines
was found to be largely dependent on the substituent in the
aromatic ring. Thus, it was decided to explore whether a linear
relationship exists between the Z/E ratio and stereoelectronic
parameters of the substituents and, in such a case, to unravel
the nature of the associated electronic effect.
Results and discussion
Dependence on the substitution at the aromatic ring
During the course of our studies on chiral imines derived from
aminopolyols, we also found a facile and unexpected formation
of N-acyl-1,3-oxazolidines by simple acylation of such imines.8
Due to restricted rotation around the amide bond, the resulting
N-acyl oxazolidines show two sets of signals on the NMR
time scale, which correspond to Z and E rotamers (Scheme 1).
Z–E Isomerization constitutes a dynamic aspect of numerous
organic molecules and biomolecules with profound implications
and synthetic applications.9 The interconversion can be driven
by external stimuli, a fact that has been exploited for multiple
purposes including the design of atropisomeric substrates, chiral
switches, and molecular gears.10
To this end, representative series of trans-N-acetyl polyaceto-
xyalkyl-1,3-oxazolidines (1–10) having (2R,5S)-configurations,
the corresponding cis-(2S,5S) stereoisomers (13–22), and the O-
unprotected trans derivatives (25–34) have been evaluated.
Tables 1–3 collect the Z/E ratio of each N-acetyl oxazolidine,
which have been determined by 1H NMR spectroscopy in CDCl3
or DMSO-d6 (for O-unprotected compounds), and the corre-
sponding equilibrium constants (KZ/E = [E]/[Z]). The Hammett
plots (Fig. S1–S3, see Electronic Supplementary Information†)
for each series of diastereomeric oxazolidines show a good linear
relationship (eqn (1)–(3)).
For 1–10: log(Kx/K0)trans = -0.94sx - 0.03 (r = 0.99)
For 13–22: log(Kx/0)cis = -0.80sx - 0.02 (r = 0.99)
For 25–34: log(Kx/K0)trans = -0.64sx - 0.02 (r = 0.98)
(1)
(2)
(3)
Departamento de Qu´ımica Orga´nica e Inorga´nica, QUOREX Research
Group, Facultad de Ciencias-UEX, E-06006, Badajoz, Spain. E-mail:
rmarvaz@unex.es
† Electronic supplementary information (ESI) available: Syntheses of
compounds 3a, 4a, 3, 4, 27, 28, and 35, NMR spectra for all new
compounds, along with other graphical and computational data. See DOI:
10.1039/c0ob01039a
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Table 1 Z/E Ratios (CDCl3) and substituent effects in compounds 1–12 at 298 K
a
b
c
c
Compound
X Group
Z
E
KZ/E
K/K0
Log (K/K0)
sx
sx
sx
+
12
4-NHMe2
4-NO2
3-NO2
4-CN
4-CF3
3-Br
4-AcO
4-Cl
79.00
83.89
84.75
82.64
73.53
64.97
63.07
63.62
47.50
44.70
44.10
31.00
21.00
16.11
15.25
17.36
26.47
35.03
36.93
36.38
52.50
55.30
55.90
69.00
0.27
0.19
0.18
0.21
0.36
0.54
0.59
0.57
1.11
1.24
1.27
2.23
0.24
0.17
0.16
0.19
0.33
0.49
0.53
0.52
1.00
1.12
1.15
2.01
-0.62
-0.76
-0.79
-0.72
-0.49
-0.31
-0.28
-0.29
0.00
0.82d
0.81
0.71
0.70
0.53
0.37
0.31
0.24
0.00
-0.12
-0.14
-0.63d
-0.94
0.988
-0.79
0.975
0.82d
0.78
0.71
0.66
0.54
0.39
0.31
0.23
0.00
-0.27
-0.17
-0.63d
-0.87
0.974
-0.76
0.972
0.82d
0.78
0.71
0.66
0.54
0.39
0.31
0.23
0.00
1
2
3
4
5
6
7
8
H
9
4-MeO
4-Me
4-NMe2
r
0.05
0.06
0.30
-0.12b
-0.17
-0.63d
-0.94
0.983
-0.79
0.972
10
11
For 1–10
r
For 1–12
r
r
a KZ/E = [E]/[Z]. b Ref. 11a. c Ref. 11b. d Ref. 11c.
Table 2 Z/E Ratios (CDCl3) and substituent effects in compounds 13–24 at 298 K
a
b
c
c
Compounde
X Group
Z
E
KZ/E
K/K0
Log (K/K0)
sx
sx
sx
+
24
4-NHMe2
4-NO2
3-NO2
4-CN
4-CF3
3-Br
4-Cl
H
56.00
66.00
67.16
60.87
54.10
46.43
43.86
30.50
29.90
24.49
20.00
44.00
34.00
32.84
39.13
45.90
53.57
56.14
69.40
70.10
75.51
80.00
0.79
0.52
0.49
0.64
0.85
1.15
1.28
2.28
2.34
3.08
4.00
0.35
0.23
0.21
0.28
0.37
0.51
0.56
1.00
1.03
1.36
1.76
-0.46
-0.65
-0.67
-0.55
-0.43
-0.29
-0.25
0.00
0.82d
0.81
0.71
0.70
0.53
0.37
0.24
0.00
-0.12
-0.14
-0.63d
-0.80
0.989
-0.65
0.966
0.82d
0.78
0.71
0.66
0.54
0.39
0.23
0.00
-0.27
-0.17
-0.63d
-0.74
0.975
-0.63
0.962
0.82d
0.78
0.71
0.66
0.54
0.39
0.23
0.00
13
14
15
16
17
19
20
21
4-MeO
4-Me
4-NMe2
r
0.01
0.13
0.25
-0.12b
-0.17
-0.63d
-0.81
0.990
-0.64
0.959
22
23
For 13–22
r
For 13–24
r
r
a KZ/E = [E]/[Z]. b Ref. 11a. c Ref. 11b. d Ref. 11c. e For compound 18 the E/Z ratio could not be determined.
Table 3 Z/E Ratios (DMSO-d6) and substituent effects in compounds 25–35 at 298 K
Compounde
X Group
Z
E
KZ/E
K/K0
Log (K/K0)
sx
sx
sx
a
b
c
c
25
4-NO2
3-NO2
4-CN
4-CF3
3-Br
4-AcO
4-Cl
H
79.00
81.00
79.00
77.00
66.00
66.00
67.00
58.00
50.00
53.49
42.00
21.00
19.00
21.00
23.00
34.00
34.00
33.00
42.00
50.00
46.51
58.00
0.27
0.23
0.27
0.30
0.52
0.52
0.49
0.72
1.00
0.87
1.38
0.37
0.32
0.37
0.41
0.71
0.71
0.68
1.00
1.38
1.20
1.91
-0.44
-0.49
-0.44
-0.38
-0.15
-0.15
-0.17
0.00
0.81
0.71
0.70
0.53
0.37
0.31
0.24
0.00
-0.12
-0.14
-0.63d
-0.64
0.977
-0.58
0.977
0.78
0.71
0.66
0.54
0.39
0.31
0.23
0.00
-0.27
-0.17
-0.83
-0.61
0.978
-0.51
0.969
0.78
0.71
0.66
0.54
0.39
0.31
0.23
0.00
26
27
28
29
30
31
32
33
4-MeO
4-Me
4-NMe2
r
0.14
0.08
0.28
-0.12b
-0.17
-0.63d
-0.64
0.975
-0.52
0.959
34
35
For 25–34
r
For 25–35
r
r
a KZ/E = [E]/[Z]. b Ref. 11a. c Ref. 11b. d Ref. 11c. e For compound 36 the E/Z ratio could not be determined.
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For 25–35: log(Kx/K0)trans = -0.58sx - 0.01 (r = 0.98)
(6)
Fig. 1 Relationship between the E/Z ratio and the electron-withdrawing
ability of X groups in N-acetyl oxazolidines 1–11 and the protonated form
12.
The negative slope value is evidence that the electronic effect
of substituents in the aromatic ring largely dictates the Z/E
ratio. The lower magnitude for the O-unprotected derivatives
(25–34) is presumably due to solvent effects as the equilibrium
was determined in DMSO-d6 (e = 47) having a higher dielectric
constant than CDCl3 (e = 4.8). The choice of different sx
11
sets has little or no influence leading to similar correlations.
Clearly, electron-withdrawing groups favor the Z conformer,
whereas electron-releasing ones shift the equilibrium toward their
E counterparts.
The strong dependence of the Z/E equilibrium on the electronic
character of the substituent offers a potential means of controlling
this equilibrium by a judicious choice of substituent and substitu-
tion pattern. Thus pH-responsive systems can be envisaged and,
as a consequence, the Z/E ratio could be further fine-tuned. A
salient example is provided by an amino group acting as a strong
electron donor (sp ~ -0.6), while its protonated form behaves as a
good electron acceptor (sp ~ +0.8).11b,c To verify this hypothesis,
we have prepared an N-acetyl oxazolidine bearing such a func-
tionality, specifically the 4-dimethylamino group. Condensation
of D-glucamine with 4-dimethylamino benzaldehyde in benzene
with azeotropic removal of water led to imine 37. Its acetylation
not only produces the oxazolidine 11 (2R,5S-configured) but
also its 2S,5S isomer 23. The O-unprotected oxazolidine 35 was
isolated after deacetylation of 11 with ammonia in MeOH (see
Experimental). A CDCl3 solution of 11 shows an equilibrium Z/E
ratio = 31 : 69. Addition of an equimolar amount of CF3COOH
fully switches the ratio to 79 : 21 (i.e. protonated form 12). This
conformational inversion is consistent with a stereoelectronic
influence exerted by the substituents on the equilibrium (Scheme
2).
Fig. 2 Relationship between the E/Z ratio and the electron-withdrawing
ability of X groups in N-acetyl oxazolidines 13–23 and the protonated
form 24.
Fig. 3 Relationship between the E/Z ratio and the electron-withdrawing
ability of X groups in O-unprotected N-acetyl oxazolidines 25–35.
The above representations unambiguously show a stereoelec-
tronic effect, despite the fact that Z/E interconversion of the
amide function does not involve formal covalent bonds. This effect
cannot be steric in nature, because meta and para substituents are
far from the amide bond.
Inclusion of equilibria data corresponding to 11 and its proto-
nated form 12 into the Hammett representation led to a good linear
relationship (eqn (4), Fig. 1).12 Likewise, suitable correlations were
found for the series of (2R,5S)-oxazolidines, including 23 and the
protonated form 24 (eqn (5), Fig. 2). The oxazolidine derivative
35 shows in DMSO-d6 a Z/E rotamer population = 42 : 58. The
Hammett plot fitted well to eqn (6) (Fig. 3).
To confirm the existence of this electronic interaction, theo-
retical calculations at the B3LYP/6-31G* level of theory have
been undertaken.13,14 The structures of both Z and E isomers
of the oxazolidines 1–4 and 6–10 were evaluated, computing the
energies of both rotamers, their isomerization energy (DG◦), and
◦
the expected KZ/E value (KZ/E = e-DG /RT). The Hammett plot for
For 1–12: log(Kx/K0)trans = -0.79sx - 0.09 (r = 0.98)
For 13–24: log(Kx/K0)cis = -0.65sx - 0.07 (r = 0.97)
(4)
(5)
these derivatives gives a poor linear correlation (r = 0.805), which
could be substantially improved (r = 0.967), after removing the
proton and 4-methyl groups from this representation (see ESI†).
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Scheme 2
Given the disparate values found for DG◦ through this series of
oxazolidines, we thought of different geometric parameters to sat-
isfactorily represent the strength of the non-covalent interaction,
such as the distance between the carbonyl oxygen and the ipso
aromatic position linked to the oxazolidine moiety (d1), as well as
the distance between the carbonyl oxygen and the nearest ortho
carbon atom (d2) (Fig. 4 and Table 4).
equilibrium. The origin of such an interaction constitutes the
second and main part of this study.
On the nature of the electronic interaction
Recently, Raines and Hodges15 have reported a similar behavior
in phenyl esters derived from N-formylproline (Scheme 3), for
which the population of Z conformers increases with the electron-
withdrawing character of substituents at the aromatic ring. These
authors found a Hammett relationship with r = -0.26 and
attributed this effect to an n→p* electronic interaction involving
one lone pair on the amide carbonyl oxygen and the carbonyl
carbon at the ester bond.16 Due to structural similarities between
such proline esters and the N-acetyloxazolidines described herein,
we thought of the same effect; however, as we shall see this is not
the case.
Fig. 4 Schematic definition of d1 and d2 parameters in oxazolidines.
A plot of d1 versus sx for compounds 1–11 gives rise to a
good correlation (r = 0.956) because shorter distances should
be expected as the interaction increases. However, d1 varies
only slightly owing to the rigidity of the core framework. More
insightful should be a plot of d2 versus sx (as actually found,
r = 0.962) as rotation around the Chet–Carom bond causes greater
variations (see ESI†).
The above calculations clearly reproduce the experimental
results and support the working hypothesis that there should be
an electronic interaction involving the acetamido oxygen and the
aromatic ring, which controls the extent of the conformational
Scheme 3
To elucidate the origin of the electronic effect, four possibilities
have been scrutinized: (a) n→p* delocalization between one lone
pair on the carbonyl oxygen and one p* orbital of the aromatic
ring; (b) dipole–dipole interaction; (c) hydrogen bonding involving
the carbonyl oxygen and one ortho hydrogen at the aryl group, and
(d) charge–charge electrostatic interaction (Fig. 5).
Table 4 Calculated geometric parameters and Hammett parameters (for
X groups) according to Fig. 4
a
a
b
Compound
X group
d1
d2
sx
1
4-NO2
4-CN
4-CF3
4-AcO
4-Cl
3.5100
3.5138
3.5305
3.5298
3.5315
3.5617
3.5575
3.5629
3.5720
3.2943
3.3014
3.3279
3.3288
3.3311
3.3785
3.3776
3.3843
3.4000
0.81
0.7
0.53
0.31
0.24
2
Fig. 5 Possible electronic interactions involving the carbonyl group.
4
6
7
Dipole–dipole and n→p* interactions. Synthesis of N-thioacetyl
8
H
0.00
1,3-oxazolidines
9
4-MeO
4-Me
4-NMe2
-0.12
-0.14
-0.63
10
11
An n→p* interaction involves one lone pair on the carbonyl oxy-
gen and the lowest unoccupied orbital (LUMO, p*) of the aromatic
ring. According to the frontier orbital theory17 the stronger the
In A. b Ref. 11a
a
˚
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Table 5 Z/E Equilibria for compounds 1, 8, 20 and 38–40.a
interaction, the lower the energy difference between the above-
mentioned orbitals. This accounts for more intense interactions as
the electron-withdrawing character of the substituents increases,
thus lowering the LUMO energy.
b
Compound
Z
E
KZ/E
1
38
8
39
20
40
83.89
74.07
47.50
29.08
30.50
27.54
16.11
25.93
52.50
70.92
69.50
72.46
0.19
0.35
1.11
2.44
2.28
2.63
To verify the existence of an n→p* interaction, we have
employed the same strategy as Raines et al.18 On replacing the
amido group by its thio-counterpart, it should be possible to
distinguish between n→p* and charge–charge interactions. Such
a substitution would reinforce the former as the sulfur atom
represents a softer base than the oxygen, and hence a more suitable
donor atom. In contrast, the charge–charge interaction would
decrease because sulfur is less negatively polarized than oxygen.
To this end, the thio-analog 38 was obtained by treatment
of oxazolidine 1 with the Lawesson reagent; however a similar
reaction starting from 8 led to a mixture of compounds 39
and 40, the latter being isolated as a pure isomer by fractional
crystallization.
a In CDCl3. b KZ/E = [E]/[Z].
a thioamide function rather than its oxo-counterpart increases
markedly the magnitude of KZ/E, or in other words, a lower
proportion of Z rotamers. This result follows the opposite trend
to that observed by Raines and associates18 and would be more
consistent with a charge–charge interaction than stabilization via
n→p* interaction.
Furthermore, NBO (Natural Bond Orbital)19 analysis helped
to rule out the n→p* effect, because no appreciable interactions
between the amide oxygen and the aromatic ring could be
measured. Second-order interactions found for E and Z rotamers
were essentially identical. Results obtained by calculation using
the simplified model 41 at the B3LYP/6-311+G(2d,p) level were
similar to those found in 1, 8 and 9 at the B3LYP/6-31G*. From
such data, the anomeric effect, arising from the interaction of
the lone pair on the oxazolidine nitrogen with the s*C–O orbital
(<8.4 kJ mol-1), is much less than that shown by oxazolidines like
42 (~35.1 kJ mol-1).20 This fact can be attributed to delocalization
of the lone pair through the p* orbital of the acetyl C O bond
(~250 kJ mol-1). Such a delocalization implies an almost complete
planarity of the nitrogen atom, because the sum of bond angles
around this atom in question is close to 360◦ (41Z, 355.5◦; 41E,
356.5◦); which contrasts with the pyramidalization exhibited by
42 (320.3◦). As consequence of this nitrogen planarity, rotamers
E and Z adopt an E1 conformation, while that in 42 is E2. The E1
conformation is also responsible for the reduced anomeric effect
at the oxygen atom, varying from ~24.3 kJ mol-1 in 42 to <15.5 kJ
mol-1 in 41.
The structures attributed to 38–40 agree with their analytical
and spectroscopic data. FT-IR spectra show the stretching band of
the amide function at around 1650 cm-1. As expected NMR spectra
show two signal sets corresponding to both Z and E rotamers. The
oxazolidine ring remains unaffected as evidenced by resonances at
~6.8–6.0 ppm and ~92 ppm, which are typical of the H-2 and C-2
atoms at the heterocycle (Fig. 6).
Fig. 6 1H NMR spectrum of compound 38 in CDCl3.
The thiocarbonyl group causes a larger chemical shift between
the protons at C-2 and C-4 in each rotamer than the carbonyl
group does. Thus, for the H-2 atom, this difference between the
most and less populated rotamer is ~0.5 ppm (versus ~0.25 ppm
in the corresponding amides). Likewise, the shift difference for the
geminal protons at C-4 in the E rotamer is ~1.2 ppm and ~0.7 ppm
in its Z isomer (versus ~1.0 ppm and ~0.5 ppm, respectively, in
their oxo-analogs). For compounds 38–40 both rotamers can also
be easily differentiated on the basis of a significant downfield shift
(Dd ª 0.4 ppm) for the methyl protons of the thioamide function
in the Z rotamer. In addition, 13C NMR spectra show diagnostic
resonances for the thiocarbonyl function at ~196 ppm and its
methyl group at ~33 ppm.
A dipole–dipole interaction should likewise be discarded be-
cause thioamides usually exhibit larger dipole moments than
amides (e.g. for the two rotamers of 3: mZ = 5.85 D, mE = 1.46
D, whereas in their thio-analogs: mZ = 6.24 D, mE = 2.28 D). A
greater interaction would have been expected, which translates
into lower KE/Z values for 38–40, i.e. higher proportions of the Z
rotamer.
Intramolecular hydrogen-bonding interaction
Table 5 collects the data for Z/E equilibria in compounds
38–40 recorded in CDCl3. For comparative purposes, we have
also included data for compounds 1, 8 and 20. The presence of
An interaction involving the amide oxygen and a proximal
hydrogen atom at the phenyl ring cannot explain either the
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conformation behavior of N-acetyl and N-thioacetyl oxazolidines.
Although the conformational minimum shows that hydrogen close
to the carbonyl oxygen, the d2 distance between the latter and the
aromatic carbon (Table 4) invariably exceeds the sum of their van
In addition, this linear relationship suggests a similar influence,
though to a different extent, of solvents on the rotameric equilib-
rium. Solvents capable of participating in hydrogen bonding with
the amide carbonyl would disrupt the intramolecular hydrogen
bonding, thus altering the E/Z equilibrium. This effect should be
markedly different to that of solvents unable to engage in such
hydrogen bonding. The ability is well established in the case of
solvents like methanol; even chloroform may bind to the carbonyl
groups of peptide bonds, a fact often related to its anesthetic effect.
Overall, the whole range of solvents would not fit to a linear
correlation, while the empirical data collected in Fig. 8 prove
the opposite, thus ruling out any interaction by intramolecular
hydrogen bonding.
der Waals radii21 (rC + rO = 1.70 + 1.52 = 3.22 A < d2). Thus,
Fig. 7 depicts the optimized structures of 1Z and 13Z.
vdw
vdw
˚
Charge–charge interaction
Since the amount of Z rotamer in 3 decreases as the dielectric con-
stant of either solvent increases, one should reasonably conjecture
the existence of charge–charge interactions. On considering the
effective charge of all atoms close to the amide oxygen, which is
negatively charged, the most important and attractive electrostatic
interaction involves the C-1 atom of the aromatic ring that is
positively charged; in contrast, the vicinal atoms C-2 and C-6
show negative charges. The hydrogen atoms bound to C-2 and C-6
also possess positive charges, though free rotation of the aromatic
ring implies longer distances on average to the carbonyl oxygen,
thereby reducing the importance of such attractive interactions.
DFT calculations can be used to determine the total charges
on the amide oxygen and C-1 of the aromatic ring, from which
a further estimation of the charge–charge interaction can be
inferred.
Fig. 7 Optimized geometry for compounds 1Z and 13Z.
Moreover, a bonding interaction via a hydrogen bridge will also
hinder the free rotation of the aryl ring around the bond connected
to C-2, thereby altering the magnetic equivalence, in both 1H and
13C NMR spectra, of ortho hydrogen and carbon atoms on one
hand and of hydrogens and carbons located at the para position on
the other. However, all the N-acetyl and N-thioacetyl oxazolidines
reported in this work exhibit a complete magnetic equivalence of
their ortho and para positions, which agrees with free rotation of
the aryl rings.
Finally, the behavior of rotamers of compound 3 in different
solvents also disagrees with the existence of hydrogen bonds. The
rotamer population found in different solvent systems appears to
be linearly dependent on the corresponding dielectric constants.
The linear relationship in Fig. 8, obtained on plotting log KE/Z
against 1/e (Table 6), shows a very good correlation (r = 0.98). In
stark contrast, no significant correlations were obtained relative
to solvatochromic parameters Z and ET for the same solvents.22
According to Coulomb’s law, the electrostatic interaction be-
tween two charged particles, q1·e and q2·e, with a separation
distance r is given by:
q1.q2.e2
4pe0r2
F =
(7)
The stability resulting from such an interaction can be related to
work done in moving a positive charge from infinity to a distance
dr against the direction of electric field:
(8)
dW = -Fdr
And work done by moving the two charges from infinity to a
distance d will be obtained by integration of the above expression:
q1.q2.e2
W =
(9)
4pe0d
By replacing the magnitudes of e0 (= 8.8541878176 ¥ 10-12
F
m-1) and e (= 1.60217653 ¥ 10-19 C), the following equations can
Fig. 8 Plot of log KE/Z versus 1/e of a given solvent.
be obtained:
Table 6 Rotamer populations (%) of 3 in some deuterated solvents
q1.q2
d2
F = 2.307.10−8
(10)
Solvent
Z
E
KZ/E
log KZ/E
e
1/e
CDCl3
CD2Cl2
MeOD
DMF-d7
DMSO-d6
82.64
78.13
76.34
74.07
74.63
17.36
21.88
23.66
25.93
25.37
0.21
0.28
0.31
0.35
0.34
-0.68
-0.55
-0.51
-0.46
-0.47
4.8
9.1
33.0
38.0
47.0
0.21
0.11
0.03
0.03
0.02
q1.q2
E=W =2.307.10−18
(11)
d
˚
where q1 and q2 are given in atomic units and d in A, which results
in newtons for F and joules for E.
3284 | Org. Biomol. Chem., 2011, 9, 3279–3289
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Table 7 Electronic parameters calculated for compounds 1, 3, 4, 6–10
a
a
d
Comp.
X
qO
qC1
Fb (¥1010)
Ec (¥1020)
sx
1
4-NO2
4-CN
4-CF3
4-AcO
4-Cl
-0.509
-0.510
-0.511
-0.513
-0.512
-0.513
0.130
0.124
0.120
0.119
0.113
0.110
0.110
0.109
-1.239
-1.182
-1.135
-1.130
-1.070
-1.026
-1.033
-1.016
-4.349
-4.152
-4.007
-3.990
-3.780
-3.655
-3.674
-3.621
0.81
0.70
0.53
0.31
0.24
0.00
-0.12
-0.14
3
4
6
7
8
H
9
4-MeO -0.515
4-Me -0.513
10
a In atomic units. b In newtons. c In joules. d Ref. 11.
Fig. 11 Plot of log(K/K0) versus E for trans-N-acetyl oxazolidines.
Table 7 summarizes data for charges as well as calculated
values of F and E for diverse trans-N-acetyl polyacetoxyalkyl-
1,3-oxazolidines, i.e. those possessing the (2R, 5S) configuration.
The values of d were listed in Table 4 as d1.
is reached, the equilibrium constant is related to the Gibbs free
energy variation (DG◦) between both conformers by:
◦
/RT
KZ/E = [E]/[Z] = e-DG
(12)
Plots of F or E versus sx lead to essentially identical linear
relationships (Fig. 9) with good correlation coefficients (r = 0.97).
These results suggest that both F and E result from a direct
electronic effect of substituents.
or put in logarithmic form:
ln KZ/E = -DG◦/RT
On the other hand, DG◦ includes both one electrostatic term,
DGee◦, due to the interaction between charges, and a non-
electrostatic and independent term of the charges, DGnee◦, which
corresponds to the free energy variation to an infinite dielectric
constant:
(13)
◦
◦
DG◦ = DGnee + DGee
(14)
Therefore,
◦
◦
ln KZ/E = -(DGnee + DGee◦)/RT = ln KZ/E - DGee◦/RT
(15)
◦
where KZ/E is the equilibrium constant to an infinite dielectric
constant.
It is obvious that the charge–charge interaction between the
amide oxygen and C-1 on the aromatic ring for the Z isomer should
be larger than that of its E counterpart owing to a longer distance
for the latter, which results in a weaker electrostatic attraction.
Fig. 9 Plot of F versus sx for trans-N-acetyl oxazolidines.
Moreover, the values of log(K/K0), which account for ex-
perimental data of the E/Z equilibrium, also show a linear
relationship with F and E estimated by DFT calculations (Fig.
10 and 11).
◦
The term DGee equals to work done by moving the charges q1
and q2 from infinity to distance d1 for the Z rotamer minus work
done by moving q¢1 and q¢2 from infinity to d2 for the E rotamer.
The resulting expression per mole of substance is:
2
q1.q2.e2N A q1.q2.e N A
′ ′
DGee ° = DGee °(Z )− DGee °(E) =
−
(16)
ed1
ed2
Fig. 10 Plot of log(K/K0) versus F for trans-N-acetyl oxazolidines.
with NA denoting the Avogadro constant:
By combining eqn (15) and (16) one gets:
Analogous results could be obtained in the case of cis-N-acetyl
polyacetoxyalkyl-1,3-oxazolidines with (2S, 5S) configurations
(Table S1, Fig. S7–S9, see ESI†).
The linear relation between log KZ/E and 1/e in Fig. 8 is likewise
consistent with a charge–charge interaction as the dominant
effect. This dependence can be rationalized by means of a simple
model of electrostatic interaction.23 When the E/Z equilibrium
e2N A ⎜q1.q2 q1.q2
⎛
⎞
⎟
⎟
⎟
⎟
⎠
′ ′
lnKZ / E = InKZ / E °−
−
⎜
(17)
⎜
⎜
eRT d1
d2
⎝
A more accurate estimation, taking into account all the
electrostatic interactions, regardless of their magnitude, is given
by:
This journal is
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(400 MHz, DMSO-d6) d 8.12 (1H, s, CH N), 7.53 (2H, d, J =
8.8 Hz, H-arom), 6.73 (2H, d, J = 8.8 Hz, H-arom), 4.84 (1H, d,
JC2,OH = 2.8 Hz, OH-2), 4.65 (1H, d, J = 4.4 Hz, OH), 4.49 (1H, d,
J = 4.4 Hz, OH), 4.33 (1H, t, JC6,OH = 5.6 Hz, OH-6), 4.29 (1H, d,
J = 6.4 Hz, OH), 3.81 (1H, m, J1,2 = J2,3 = JC2,OH = 4.6 Hz, H-2),
3.71 (1H, t, H-3), 3.64 (1H, dd, J1,2 = 4.4 Hz, J1,1¢ = 12.0 Hz, H-1),
3.60 (1H, m, H-6), 3.53 (1H, dd, J1,2 = 5.6 Hz, J1,1¢ = 12.8 Hz,
e2N A
q1.q2
q1.q2
⎛
⎜
⎜
⎜
⎜
⎞
′ ′
⎟
⎟
⎟
⎟
⎟
⎠
(18)
lnKZ / E = lnKZ / E °−
−
∑
∑
eRT
d1
d2
⎜
⎝
Z
E
Eqn (17) and (18) are evidence of a linear correlation between log
KZ/E and 1/e with negative slope, because the term in parentheses
is always positive: d2 ꢀ d1, and agreeing with the plot of Fig. 8.
H-1¢), 3.50 (2H, m, H-5, H-4), 3.39 (1H, dt, J6,OH = 5.4 Hz, J6,6¢
=
10.6 Hz, H-6¢).13C NMR (100 MHz, DMSO-d6): 161.9 (C N),
152.2 (C-arom), 129.7 (2C, C-arom), 124.4 (C-arom), 111.9 (2C,
C-arom), 73.1 (C-2), 72.3 (C-4), 71.9 (C-5), 70.3 (C-3), 64.0 (C-6),
63.6 (C-1). Anal. calcd. for C15H24N2O5 (312.37): C, 57.68; H, 7.74;
N, 8.97. Found: C, 57.65; H, 7.86; N, 8.91%.
Conclusions
This investigation demonstrates the existence of a remarkable
stereoelectronic interaction that strongly influences the conforma-
tional equilibrium of the amide bond in N-acetyl oxazolidines
(chirality added in turn by an appended sugar chain). This
interaction is non-covalent in nature like others found in peptide
structures24 and should most likely have an impact on protein
folding. Dynamic control of this stereochemical motif through
external stimuli (e.g. pH) can also advance further possibilities
in nanomachinery. Current efforts are directed towards this
goal.
General procedure for the synthesis of N-acetyloxazolidines
To a solution of the corresponding 1-(arylmethylene)-amino-1-
deoxy-D-glucitol (5.0 mmol) in pyridine (6.7 mL) was added acetic
anhydride (6.5 mL). The reaction mixture was kept at 0 ◦C for 24 h,
and then it was poured into ice–water. If the resulting product was
an oil this was extracted with chloroform (3 ¥ 50 mL), and the
organic layer was sequentially washed with 1 N HCl (2 ¥ 50 mL),
a saturated solution of NaHCO3 (2 ¥ 50 mL), and distilled water
(2 ¥ 50 mL). The organic layer was dried (MgSO4) and evaporated.
If the resulting product was a solid this was separated by filtration
and washed with water.
Experimental
General procedures for the synthesis of Schiff bases
Method A. To a solution of D-glucamine (10.0 g, 55.2 mmol)
in water (70 mL) was slowly added a solution of the corresponding
aldehyde(55.0mmol)inasmallvolumeofmethanol(~30mL). The
mixture was stirred at room temperature, affording a precipitate
within a few minutes. The resulting product was collected by
filtration and successively washed with cold water, ethanol, and
diethyl ether and recrystallized from ethanol.
(2R,5S)-3-Acetyl-2-(3-nitrophenyl)-5-(1,2,3,4-tetra-O-acetyl-D-
arabino-tetrahydroxybutyl-1-yl)oxazolidine (2E,Z)
Method B. To a suspension of D-glucamine (0.91 g, 5.0 mmol)
in benzene (15 mL) was added the corresponding aldehyde (7.5
mmol). The mixture was refluxed for 5 h with concomitant water
removal (Dean–Stark). The product was filtered and washed with
cold benzene and recrystallized from ethanol.
◦
(92%). Recrystallized from ethanol, mp 145–146 C; [a]2D3 -12;
23
578
23
546
23
436
[a] -14; [a] -15; [a] -14 (c 0.5, chloroform); IR (KBr)
n
max/cm-1 1745 (C O), 1654 (C O, amide), 1215 (C–O–C, ester),
1081, 1051 (C–O); 1H NMR (400 MHz, CDCl3) d 8.36 (1H, s, H-
arom), 8.19 (1H, d, J 8.0 Hz, H-arom), 7.87 (1H, d, J 7.6 Hz,
H-arom), 7.53 (1H, t, J 7.8 Hz, H-arom), 6.29 (1H, s, H-2Z), 6.10
1-Deoxy-1-(3-nitrobenzylidene)amino-D-glucitol (2a)
(1H, s, H-2E), 5.46 (1H, d, J2¢,3¢ = 2.4 Hz, H-2¢Z), 5.43 (1H, d, J1¢,5
=
◦
Method A (66%); mp 137–138 C; [a]2D2 +3; [a] +4; [a] +4 (c
22
578
22
546
3.2 Hz, H-1¢Z), 5.33 (2H, m, H-1¢E, H-2¢E), 5.16 (1H, m, H-3¢Z),
5.09 (1H, m, H-3¢E), 4.38 (2H, m, H-5Z and H-5E), 4.27 (1H, dd,
J3¢,4¢ = 2.4 Hz, J4¢,4¢¢ = 12.8 Hz, H-4¢¢Z), 4.41–4.18 (3H, m, H-4a,E
H-4¢E, H-4¢¢E), 4.19 (1H, dd, J3¢,4¢¢ = 4.4 Hz, J4¢,4¢¢ = 12.8 Hz, H-
4¢¢Z), 3.97 (1H, dd, J4a,5 = 6.0 Hz, J4a,4b = 10.2 Hz, H-4a,Z), 3.43
(1H, t, J4b,4a = J4b,5 = 10.2 Hz, H-4b,Z), 3.28 (1H, t, J4b,4a = J4b,5
9.6 Hz, H-4b,E), 2.17, 2.15, 2.12, 2.10, 2.07 (8 ¥ 3H, s, CH3), 2.07
(3H, s, CH3, AcN Z isomer), 1.82 (3H, s, CH3, AcN E isomer). 13
NMR (100 MHz, CDCl3): 170.6, 170.5, 170.2, 169.8 (C O), 168.3
(N–C O, Z), 167.8 (N–C O, E), 148.6 (C-arom, E), 148.3 (C-
arom, Z), 141.0 (C-arom, Z), 140.9 (C-arom, E), 133.9 (C-arom,
Z), 132.8 (C-arom, E), 129.2 (C-arom, Z), 124.6 (C-arom, E),
123.9 (C-arom, Z), 122.1 (C-arom, E), 121.8 (C-arom, Z), 89.1
(C-2E), 88.3 (C-2Z), 77.4 (C-5Z), 77.3 (C-5E), 69.1 (C-2¢Z, C-2¢E),
68.3 (C-1¢Z, C-1¢E), 68.0 (C-3¢Z, C-3¢E), 61.5 (C-4¢Z and C-4¢E), 47.6
(C-4Z), 46.5 (C-4E), 23.2 (CH3, Ac–N Z isomer), 22.9 (CH3, Ac–N
E isomer), 20.9, 20.8, 20.7, 20.6 (CH3, acetates). Anal. calcd. for
C23H28N2O12 (524.47): C, 52.67; H, 5.38; N, 5.34. Found: C, 52.64;
H, 5.30; N, 5.60%.
0.5, pyridine); IR (KBr) nmax/cm-1 3400–3000 (OH), 1651 (C N),
1532 (arom), 1085, 1059, 1020 (C–O). 1H NMR (400 MHz,
DMSO-d6) d 8.56 (1H, s, CH N), 8.47 (1H, s, H-arom), 8.30
(1H, d, J = 7.6 Hz, H-arom), 8.17 (1H, d, J = 7.6 Hz, H-arom),
7.76 (1H, t, J = 8.0 Hz, H-arom), 4.76 (1H, d, JC2,OH = 4.4 Hz,
OH-2), 4.52 (1H, d, J = 4.8 Hz, OH), 4.50 (1H, d, J = 5.2 Hz,
OH), 4.36 (2H, m, OH), 3.89 (1H, m, H-2), 3.86 (1H, m, H-1),
3.71 (1H, m, H-3), 3.62–3.52 (3H, m, H-6¢, H-1¢, H-5, H-4), 3.40
(1H, dd, J6,OH = 5.6 Hz, J6,6¢ = 10.4 Hz, H-6¢).13C NMR (100 MHz,
DMSO-d6): 160.5 (C N), 148.6, 138.3, 134.6, 130.8, 125.4, 122.3
(C-arom), 72.8 (C-2), 72.4 (C-4), 72.0 (C-5), 70.4 (C-3), 63.9 (C-6,
C-1). Anal. calcd. for C13H18N2O7 (314.29): C, 49.68; H, 5.77; N,
8.91. Found: C, 49.47; H, 5.98; N, 8.83%.
,
=
C
1-Deoxy-1-(4-dimethylaminobenzylidene)amino-D-glucitol (37)
◦
Method B (66%); mp 188–189 C; [a]2D1 -23; [a] -25; [a] -30;
21
578
21
546
21
[a] -75 (c 0.5, DMSO); IR (KBr) nmax/cm-1 3300–2900 (OH),
436
1
1637 (C N), 1613 (arom), 1088, 1058, 1019 (C–O). H NMR
3286 | Org. Biomol. Chem., 2011, 9, 3279–3289
This journal is
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©

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(2R,5S)-3-Acetyl-2-(4-dimethylaminophenyl)-5-(1,2,3,4-tetra-O-
acetyl-D-arabino-tetrahydroxybutyl-1-yl)oxazolidine (11E,Z)
calcd. for C25H34N2O10 (522.54): C, 57.46; H, 6.56; N, 5.36. Found:
C, 57.30; H, 6.40; N, 5.42%.
To a solution of imine 37 (5.0 mmol) in pyridine (6.7 mL) was
added acetic anhydride (6.5 mL). Solvents were removed after 24 h,
and compounds 11 and 23 were purified b◦y crystallization. (55%);
General procedure for the synthesis of N - acetyl - polyhydro-
xyalkyl-1,3-oxazolidines
21
578
Recrystallized from ethanol, mp 168–169 C; [a]2D1 -36; [a] -38;
To a solution of the corresponding oxazolidine (0.98 mmol) in
methanol (16 mL) was added a saturated solution of ammonia
in methanol (16 mL). The transformation was monitored by
thin layer chromatography (benzene–methanol 9 : 1) and then the
mixture was filtered off and evaporated to dryness at a temperature
below 30 ◦C. The title compound was obtained as a solid.
21
546
21
436
[a] -43; [a] -89 (c 0.5, chloroform); IR (KBr) nmax/cm-1 1741
(C O), 1648 (C O, amide), 1629 (arom), 1221, 1207 (C–O–C,
ester), 1053, 1029 (C–O); 1H NMR (400 MHz, CDCl3) d 7.36 (2H,
d, J = 8.4 Hz, H-arom, Z), 7.18 (2H, d, J = 8.8 Hz, H-arom, E),
6.69 (4H, d, J = 8.8 Hz, H-arom, Z and E), 6.18 (1H, s, H-2Z),
5.83 (1H, s, H-2E), 5.43 (2H, m, H-2¢E and H-2¢Z), 5.37 (2H, m,
H-1¢E and H-1¢Z), 5.16 (1H, d, J2¢,3¢ = 3.8 Hz, J3¢,4¢ = 7.6 Hz, H-3¢Z),
5.10 (1H, dd, J2¢,3¢ = 3.6 Hz, J3¢,4¢ = 7.6 Hz, H-3¢E), 4.23 (6H, m,
H-4¢Z, H-4¢E, H-5Z, H-5E, H-4a,E, H-4¢¢Z), 4.15 (1H, dd, J4¢¢,5¢ = 4.2
(2R,5S)-3-Acetyl-2-(3-nitrophenyl)-5-(D-arabino-tetrahydroxy-
butyl-1-yl)oxazolidine (26E,Z)
◦
(83%); Recrystallized from ethanol, mp 142–143 C; [a]2D2 -27;
Hz, J4¢,4¢¢ = 12.6 Hz, H-4¢¢E), 3.86 (1H, dd, J4a,4b = 9.6 Hz, J4a,5
=
22
578
22
546
[a] -31; [a] -35 (c 0.5, pyridine); IR (KBr) nmax/cm-1 3500–
5.6 Hz, H-4a,Z), 3.37 (1H, t, J4b,4a = J4b,5 = 10.0 Hz, H-4b,Z), 3.29
(1H, t, J4b,4a = J4b,5 = 12.2 Hz, H-4b,E), 2.97 (6H, s, (CH3)2N, E),
2.95 (6H, s, (CH3)2N, Z), 2.14, 2.10, 2.09, 2.07, 2.03, (9 ¥ 3H, s,
CH3), 1.72 (3H, s, CH3, E AcN isomer). 13C NMR (100 MHz,
CDCl3): 170.6, 170.4, 170.3, 170.1, 170.0, 169.9 (C O), 168.4 (N-
3000 (OH), 1637 (C O), 1524 (arom), 1221 (C–N), 1100, 1079,
1034 (C–O); 1H NMR (400 MHz, CDCl3) d 8.30 (1H, s, H-arom,
E), 8.26 (1H, s, H-arom, Z), 8.20 (1H, d, J = 8.0 Hz, H-arom, E,
Z), 7.95 (1H, d, H-arom, E), 7.92 (1H, d, J = 7.6 Hz, H-arom,
Z), 7.75 (1H, t, J = 7.8 Hz, H-arom, E), 7.67 (1H, t, J = 7.8 Hz,
H-arom, Z), 6.32 (1H, s, H-2E), 6.13 (1H, s, H-2Z), 4.87 (1H, d,
JOH,1 = 6.4 Hz, OH-1Z), 4.78 (1H, d, JOH,1 = 6.8, Hz OH-1E), 4.57
(1H, d, J = 6.0 Hz, OH, E), 4.55 (1H, d, J = 6.0 Hz, OH, Z), 4.48
(1H, d, J = 6.0 Hz, OH, E), 4.40 (2H, t, JOH,4 = 5.6 Hz, OH-4Z and
OH-4E), 4.28 (1H, m, J4b,5 = 10.0 Hz, J5,1¢ = J4a,5 = 6.4 Hz, H-5Z),
4.17 (1H, m, H-4a,E, H-5E), 3.97 (1H, dd, J4a,5 = 5.6 Hz, J4a,4b = 9.6
Hz, H-4a,Z), 3.84 (1H, t, J1¢,5 = 6.8 Hz, J1¢,2¢ = 0 Hz, H-1¢Z), 3.79
(1H, t, J1¢,5 = 6.6 Hz, J1¢,2¢ = 0 Hz, H-1¢E), 3.61 (2H, m, H-4¢Z and
H-4¢E), 3.51 (2H, m, H-3¢Z and H-3¢E), 3.44 (4H, m, H-4¢Z and H-
4¢¢E, H-2¢Z and H-2¢E), 3.26 (2H, t, J4b,5 = J4b,4a = 7.8 Hz, H-4b,E and
H-4b,Z), 2.03 (3H, s, CH3, Z), 1.66 (3H, s, CH3, E). 13C NMR (100
MHz, CDCl3): 167.7 (C O, E), 167.1 (C O, Z), 147.9, 147.5,
142.1, 141.9, 134.0, 133.9, 130.4, 129.6, 124.1, 123.3, 122.1, 121.9
(C-arom), 88.0 (C-2E), 87.8 (C-2Z), 80.7 (C-5Z), 80.1 (C-5E), 71.2,
71.1, 70.8, 70.5, 70.3 (C-1¢Z and C-1¢E, C-2¢Z and C-2¢E, C-3¢Z and
C-3¢E), 63.2 (C-4¢Z and C-4¢E), 47.7 (C-4Z), 46.6 (C-4E), 23.0 (CH3,
Z), 22.5 (CH3, E). Anal. calcd. for C15H20N2O8 (356.33): C, 50.56;
H, 5.66; N, 7.86. Found: C, 50.47; H, 5.60; N, 7.84%.
C
O, E), 167.9 (N–C O, Z), 151.3 (C-arom, E), 150.8 (C-arom,
Z), 128,4 (C-arom, Z), 128.2 (C-arom, E, Z), 127.9 (C-arom, Z),
126.5 (C-arom, Z), 125.1 (C-arom, E), 112.1 (C-arom, E), 111.9
(C-arom, E), 90.7 (C-2E), 89.5 (C-2Z), 76.4 (C-5Z), 75.7 (C-5E),
69.1 (C-2¢E), 69.0 (C-2¢Z), 68.7 (C-1¢Z), 68.5 (C-1¢E), 68.2 (C-3¢Z
and C-3E), 61.5 (C-4¢Z and C-4¢E), 47.7 (C-4Z), 47.0 (C-4E), 40.5
(2C, (CH3)2N, Z), 40.3 (2C, (CH3)2N, E), 23.4 (CH3, Ac–N Z
isomer), 22.8 (CH3, Ac–N E isomer), 20.9, 20.8, 20.7, 20.6 (CH3,
acetates). Anal. calcd. for C25H34N2O10 (522.54): C, 57.46; H, 6.56;
N, 5.36. Found: C, 57.39; H, 6.44; N, 5.37%.
(2S,5S)-3-Acetyl-2-(4-dimethylaminophenyl)-5-(1,2,3,4-tetra-O-
acetyl-D-arabino-tetrahydroxybutyl-1-yl)oxazolidine (23E,Z)
See compound 11 (31%); Recrystallized from ethanol, mp 188–
◦
21
578
21
546
21
21
436
189 C; [a]2D1 +72; [a] +77; [a]
+89; [a] +165 (c 0.5,
546
chloroform); IR (KBr) nmax/cm-1 1741 (C O), 1648 (C O,
amide), 1629 (arom), 1221, 1207 (C–O–C, ester), 1053, 1029 (C–
O); 1H NMR (400 MHz, CDCl3) d 7.21 (2H, d, J = 8.4 Hz, H-arom,
Z), 7.16 (2H, d, J = 8.4 Hz, H-arom, E), 6.69 (4H, d, J = 8.4 Hz,
H-arom, Z and E), 6.39 (1H, s, H-2Z), 6.05 (1H, s, H-2E), 5.43 (1H,
m, H-2¢Z), 5.39 (1H, dd, J2¢,3¢ = 5.2 Hz, J2¢,1¢ = 1.6 Hz, H-2¢E), 5.33
(1H, m, H-1¢Z), 5.26 (1H, dd, J1¢,5¢ = 7.6 Hz, J1¢,2¢ = 1.6 Hz, H-2¢E),
5.16 (1H, m, H-3¢Z), 5.13 (1H, m, H-3¢E), 4.44 (1H, m, H-5Z) 4.26
(4H, m, H-4¢E, H-5E, H-4¢Z, H-4¢¢Z), 4.16 (1H, dd, J4¢¢,5¢ = 4.0 Hz,
Synthesis of (2R,5S)-2-(4-nitrophenyl)-5-(1,2,3,4-tetra-O-acetyl-
D-arabino - tetrahydroxybutyl - 1 - yl) - 3 - thioacetyloxazolidine
(38E,Z)
To a solution of the oxazolidine 1 (0.11 mmol) in dry toluene
(0.8 mL) was added Lawesson reagent (45 mg, 0.11 mmol) and the
mixture was refluxed for 24 h. The reaction mixture was cooled at
4 ◦C and the resulting product was collected by filtration. (49%);
mp 170–171 ◦C; IR (KBr) nmax/cm-1 1747 (C O), 1610, 1530,
J
4¢,4¢¢ = 11.4 Hz, H-4¢¢E), 3.98 (1H, dd, J4a,4b = 12.0 Hz, J4a,5 = 4.8 Hz,
H-4a,E), 3.79 (1H, m, H-4a,Z), 3.75 (1H, dd, J4b,4a = 11.8 Hz, J4b,5
7.0 Hz, H-4b,E), 3.63 (1H, dd, J4b,4a = 10.0 Hz, J4b,5 = 5.6 Hz, H-4b,Z
=
)
1
2.98 (6H, s, (CH3)2N, E), 2.95 (6H, s, (CH3)2N, Z), 2.14, 2.11,
2.10, 2.09, 2.08 (9 ¥ 3H, s, CH3), 1.87 (3H, s, CH3, AcN E isomer).
13C NMR (100 MHz, CDCl3): 170.7, 170.6, 170.5, 170.1 (C O),
168.3 (N–C O, E), 167.8 (N–C O, Z), 151.2 (C-arom, E, Z),
127.6, 127.3, 125.3, 112.1 (C-arom), 90.1 (C-2E), 89.6 (C-2Z), 75.7
(C-5Z), 74.4 (C-5E), 69.1 (C-2¢E, C-2¢Z, C-1¢E), 68.3, 68.0 (C-3¢Z and
C-3¢E), 61.6 (C-4¢Z), 61.4 (C-4¢E), 47.9 (C-4E), 46.4 (C-4Z), 40.5 (2C,
(CH3)2N, Z), 40.4 (2C, (CH3)2N, E), 23.1 (CH3, Ac–N Z isomer),
22.8 (CH3, Ac–N E isomer), 20.9, 20.8, 20.7 (CH3, acetates). Anal.
1460 (arom), 1209 (C S); H NMR (400 MHz, CDCl3) d 8.28
(2H, d, J 8.8 Hz, H-aromE), 8.19 (2H, d, J 8.8 Hz, H-aromZ), 7.57
(2H, t, J 8.8 Hz, H-aromZ), 7.47 (2H, t, J 8.8 Hz, H-aromE), 6.60
(1H, s, H-2Z), 6.21 (1H, s, H-2E), 5.39 (1H, m, H-2¢E), 5.37 (2H,
m, H-2¢Z, H-1¢Z), 5.33 (1H, m, H-1¢E), 5.11 (1H, m, H-3¢Z), 5.07
(1H, m, H-3¢E), 4.85 (1H, dd, 1H, dd, J4a,5 = 6.0 Hz, J4a,4b = 12.8
Hz, H-4a,E), 4.47 (1H, m, H-5E), 4.41 (1H, m, H-5Z), 4.28 (1H, m,
H-4a,Z), 4.24 (2H, m, H-4¢Z, H-4¢E), 4.17 (1H, dd, J3¢,4¢¢ = 4.4 Hz,
J4¢,4¢¢ = 12.4 Hz, H-4¢¢Z), 4.14 (1H, dd, J3¢,4¢¢ = 4.4 Hz, J4¢,4¢¢ = 12.4
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Hz, H-4¢¢E), 3.64 (1H, dd, J4b,4a = 12.8 Hz, J4b,5 = 10.0 Hz, H-4b,E),
3.59 (1H, t, J4b,4a = J4b,5 = 10.6 Hz, H-4b,Z), 2.64 (3H, s, CH3C
66641/BQU, and CTQ2010-18938/BQU). R. F. M. thanks the
Junta de Extremadura for a fellowship.
S
Z isomer), 2.26 (3H, s, CH3C S E isomer), 2.08–2.02 (8 ¥ 3H,
s, CH3). 13C NMR (100 MHz, CDCl3): 197.9 (C S), 170.5–169.7
(8C, C O), 149.0–123.5 (C-arom), 92.1 (C-2Z), 91.1 (C-2E), 76.8
(C-5Z), 76.5 (C-5E), 69.0 (C-2¢E), 68.9 (C-2¢Z), 68.4 (C-1¢Z, C-1¢E),
68.1 (C-3¢Z, C-3¢E), 61.4 (C-4¢Z and C-4¢E), 53.9 (C-4E), 51.6 (C-4Z),
34.3 (CH3C S Z isomer), 32.8 (CH3C S E isomer), 20.9–20.5
(CH3, acetates). Anal. calcd. for C23H28N2O11S (540.54): C, 51.11;
H, 5.22; N, 5.18; S, 5.93. Found: C, 51.33; H, 4.95; N, 5.27; S,
5.84%.
References
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Synthesis of (2R,5S)-2-(phenyl)-5-(1,2,3,4-tetra-O -acetyl-D-
arabino-tetrahydroxybutyl-1-yl)-3-thioacetyloxazolidine (39E,Z)
and (2S,5S) - 2 - (phenyl) - 5 - (1,2,3,4 - tetra -O - acetyl - D- arabino-
tetrahydroxybutyl - 1 - yl) - 3 - thioacetyloxazolidine (40E,Z)
To a solution of the oxazolidine 8 (1.04 mmol) in dry toluene
(7 mL) was added Lawesson’s reagent (0.46 g, 1.13 mmol) and the
mixture was refluxed for 24 h. Solvent was removed under vacuum
and the resulting mixture was purified by flash chromatography
(hexane–ethyl acetate, 3 : 1), giving a mixture of 39 and 40 (68%).
Compound 40 was isolated by recrystallization, (44%); mp 141–
142 ◦C; IR (KBr) nmax/cm-1 1742 (C O), 1593, 1478 (arom),
1218 (C S); 1H NMR (400 MHz, CDCl3) d 7.41–7.21 (10H, m,
H-arom), 6.84 (1H, s, H-2Z), 6.31 (1H, s, H-2E), 5.38 (2H, dd,
7 X. Li, Z. J. Gartner, B. N. Tse and D. R. Liu, J. Am. Chem. Soc., 2004,
126, 5090.
´
8 M. Avalos, R. Babiano, P. Cintas, J. L. Jime´nez, M. E. Light, J. C.
J2¢,1¢ = 2.4 Hz, J2¢,3¢ = 8.8 Hz, H-2¢Z, H-2¢E), 5.33 (2H, dd, J1¢,2¢
=
Palacios and E. M. S. Pe´rez, J. Org. Chem., 2008, 73, 661.
9 C. Dugave and L. Demange, Chem. Rev., 2003, 103, 2475.
10 C. Wolf, Dynamic Stereochemistry of Chiral Compounds. Principles and
Applications, Royal Society of Chemistry, Cambridge, 2008, pp. 47–52,
94–99, 423–432.
2.4 Hz, J1¢,5 = 6.4 Hz, H-1¢Z, H-1¢E), 5.11 (2H, m, H-3¢Z, H-3¢E),
4.47 (1H, m, H-5¢Z), 4.34 (1H, m, H-5¢E), 4.78 (1H, dd, 1H, dd,
J4a,5 = 6.0 Hz, J4a,4b = 12.4 Hz, H-4a,E), 4.41 (2H, m, H-5E, H-5Z),
4.23–3.88 (8H, H-4a,Z, H-4a,E, H-4¢E, H-4¢Z, H-4¢¢Z, H-4¢¢E, H-4b,E
,
11 (a) F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry,
Plenum Press, New York, 1990, p. 201; (b) C. Hansch, A. Leo
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12 We were unable to find any reliable sx value for the dimethylammonium
group, NH+Me2, in the bibliography. Due to its structural similarity,
the latter was replaced by the trimethylammonium group, N+Me3; see
ref. 11c.
13 Gaussian 03, Revision C.02, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr.,
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Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V.
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Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov,
G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J.
Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M.
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H-4b,Z), 2.63 (3H, s, CH3C S Z isomer), 2.37 (3H, s, CH3C S E
isomer), 2.10–2.03 (8 ¥ 3H, s, CH3). 13C NMR (100 MHz, CDCl3):
196.8 (C S), 170.9–169.7 (8C, C O), 136.2–126.4 (C-arom), 93.6
(C-2Z), 92.1 (C-2E), 75.9 (C-5Z), 74.5 (C-5E), 69.7 (C-2¢Z), 69.1 (C-
2¢E), 69.0 (C-1¢Z), 68.5 (C-1¢E), 68.0 (C-3¢Z, C-3¢E), 61.5 (C-4¢Z and
C-4¢E), 53.4 (C-4E), 51.4 (C-4Z), 33.8 (CH3C S Z isomer), 32.6
(CH3C S E isomer), 20.9–20.7 (CH3, acetates). Anal. calcd. for
C23H29NO9S (495.54): C, 55.75; H, 5.90; N, 2.83; S, 6.47. Found:
C, 55.72; H, 5.83; N, 2.84; S, 6.53. Spectroscopic data for compound
1
39: H NMR (400 MHz, CDCl3) d 7.36 (10H, m, H-arom), 6.58
(1H, s, H-2Z), 6.07 (1H, s, H-2E), 5.38 (4H, m, H-2¢E, H-2¢Z, H-1¢Z,
H-1¢E), 5.09 (2H, m, H-3¢Z, H-3¢E), 4.78 (1H, dd, 1H, dd, J4a,5 = 6.0
Hz, J4a,4b = 12.4 Hz, H-4a,E), 4.41 (2H, m, H-5E, H-5Z), 4.25 (3H,
m, H-4a,Z, H-4¢E, H-4¢Z), 4.17 (2H, m, H-4¢¢Z, H-4¢¢E), 3.62 (1H,
dd, J4b,4a = 12.0 Hz, J4b,5 = 10.8 Hz, H-4b,E), 3.55 (1H, t, J4b,4a
=
J4b,5 = 10.6 Hz, H-4b,Z), 2.64 (3H, s, CH3C S Z isomer), 2.22
(3H, s, CH3C S E isomer), 2.07–2.01 (8 ¥ 3H, s, CH3). 13C NMR
(100 MHz, CDCl3): 192.4 (C S), 170.6–169.7 (8C, C O), 136.8–
126.4 (C-arom), 93.2 (C-2Z), 92.7 (C-2E), 76.4 (C-5Z), 76.0 (C-5E),
69.1 (C-2¢E), 69.0 (C-2¢Z), 68.9 (C-1¢Z, C-1¢E), 68.1 (C-3¢Z, C-3¢E),
61.4 (C-4¢Z and C-4¢E), 54.1 (C-4E), 51.5 (C-4Z), 34.2 (CH3C S Z
isomer), 32.7 (CH3C S E isomer), 20.9–20.7 (CH3, acetates).
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Acknowledgements
This work has been supported by the Junta de Extremadura, the
Ministerio de Educacio´n y Ciencia (MEC) and Fondos Europeos
para el Desarrollo Regional (FEDER) (PRI08A032, CTQ2007-
3288 | Org. Biomol. Chem., 2011, 9, 3279–3289
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The Royal Society of Chemistry 2011
©

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