Stereoisomerization of β-Hydroxy-α-sulfenyl-γ- butyrolactones controlled by two concomitant 1,4-type nonbonded sulfur-oxygen interactions as analyzed by X-ray crystallography

Article abstract of DOI:10.1021/jo1009454

We have synthesized nine β-hydroxy-α-sulfenyl-γ- butyrolactones having different substituents. The syn-anti or syn-syn lactones (or any mixture of both) invariably isomerized into syn-anti/syn-syn lactones in a ratio of ～6/4. The other two possible isomeric lactones (anti-syn or anti-anti) were never observed. The crystal structures of syn-syn lactones have been determined. We found sulfur-oxygen distances to be less than the sum of the van der Waals radii (3.3 A), with the angle formed among the hydroxylic oxygen, sulfur, and quaternary aromatic carbon being close to 180°. In addition, carbonylic oxygen-sulfur is directed <40° from the perpendicular to the C-S-C. Theoretical calculations were performed which emphasize the directionality of the sulfur-oxygen interaction. The X-ray and theoretical studies demonstrate that two concomitant, attractive 1,4 intramolecular interactions of divalent sulfur with both carbonyl and hydroxyl oxygens are the driving force for the aforementioned stereochemical preference. Then nonbonded sulfur-oxygen interactions would control the stereoselectivity of the reaction. The same features are observed in the X-ray structure of a β-hydroxy-α-sulfinyl-γ-butyrolactone.

Full text of DOI:10.1021/jo1009454

pubs.acs.org/joc
Stereoisomerization of β-Hydroxy-r-sulfenyl-γ-butyrolactones
Controlled by Two Concomitant 1,4-Type Nonbonded Sulfur-Oxygen
Interactions As Analyzed by X-ray Crystallography
ꢀ
ꢀ
Florenci V. Gonzalez,* Amit Jain, Santiago Rodrıguez,* Jose A. Saez,
ꢀ
Cristian Vicent, and Gabriel Peris
´ ꢁ ꢁ ꢀ ´
Departament de Quımica Inorganica i Organica and Serveis Centrals d’Instrumentacio Cientıfica,
ꢀ
Universitat Jaume I, 12080 Castello, Spain
fgonzale@qio.uji.es
Received May 19, 2010
We have synthesized nine β-hydroxy-R-sulfenyl-γ-butyrolactones having different substituents. The
syn-anti or syn-syn lactones (or any mixture of both) invariably isomerized into syn-anti/syn-syn
lactones in a ratio of ∼6/4. The other two possible isomeric lactones (anti-syn or anti-anti) were never
observed. The crystal structures of syn-syn lactones have been determined. We found sulfur-oxygen
˚
distances to be less than the sum of the van der Waals radii (3.3 A), with the angle formed among the
hydroxylic oxygen, sulfur, and quaternary aromatic carbon being close to 180°. In addition,
carbonylic oxygen-sulfur is directed <40° from the perpendicular to the C-S-C. Theoretical
calculations were performed which emphasize the directionality of the sulfur-oxygen interaction.
The X-ray and theoretical studies demonstrate that two concomitant, attractive 1,4 intramolecular
interactions of divalent sulfur with both carbonyl and hydroxyl oxygens are the driving force for the
aforementioned stereochemical preference. Then nonbonded sulfur-oxygen interactions would
control the stereoselectivity of the reaction. The same features are observed in the X-ray structure
of a β-hydroxy-R-sulfinyl-γ-butyrolactone.
Introduction
number of contributions such as nonbonded interactions.1
Attractive nonbonded interactions can play an important
role in determining the stereoselectivity of chemical pro-
cesses.2 Specifically, intramolecular reactions often benefit
from greater control of stereoselectivity relative to their
intermolecular counterparts.2
The steric energy of a molecule, which accounts for its
geometry at the energy minimum, is expressed in terms of a
(1) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds Ed.
John Wiley & Sons 1994, pp33.
ꢀ
(2) (a) Katz, C. E.; Aube, J. J. Am. Chem. Soc. 2003, 25, 13948. (b) Katz,
C. E.; Ribelin, T.; Withrow, D.; Basseri, Y.; Manukyan, A. K.; Bermudez,
ꢀ
A.; Nuera, C. G.; Day, V. W.; Powell, D. R.; Poutsma, J. L.; Aube, J. J. Org.
Chem. 2008, 73, 3318.
ꢀ
ꢀ
(3) Rodrıguez, S.; Kneeteman, M.; Izquierdo, J.; Lopez, I.; Gonzalez,
F. V.; Peris, G. Tetrahedron 2006, 62, 11112.
5888 J. Org. Chem. 2010, 75, 5888–5894
Published on Web 08/12/2010
DOI: 10.1021/jo1009454
r
2010 American Chemical Society

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Gonzalez et al.
JOCArticle
SCHEME 1. Isomerization of β-Hydroxy-R-sulfenyl Carbonyl
Compounds
FIGURE 1. Polar coordinates (polar θ and azimuthal φ angles) to
specify the direction of S O.
3 3 3
SCHEME 2. Syntheses of β-Hydroxy R-Sulfenyl γ-Butyrolactones
During the course of a preceding study related to the
synthesis of β-hydroxy-R-sulfenyl-γ-butyrolactones from
γ-hydroxy-R,β-epoxy esters,3 we made a curious observa-
tion: an approximately 6/4 ratio of a mixture of syn-anti/
syn-syn lactones was always obtained, regardless of the
stereoisomeric ratio of the starting epoxides (Scheme 1).
This tendency of R-sulfenyl carbonyl compounds to isomer-
ize into an isomer displaying a syn relative stereochemistry
has been reported previously by Silverman for dihydro-
naphthoquinones (Scheme 1).4
According to the seminal work by Parthasarathy and co-
workers,7 two types of sulfur-oxygen interactions can be
identified: nucleophilic oxygens, which tend to approach along
the extension of one of the covalent bonds to sulfur (60° < θ <
90°) (110° < φ < 150°), and electrophilic oxygens, which tend
to approach sulfur from the direction perpendicular to the plane
through the C-S-C atoms (θ <40°) (Figure 1).
Herein, we report a general study of the isomerization
process as applied to β-hydroxy-R-sulfenyl-γ-butyrolac-
tones. We have determined the crystal structures of syn-syn
β-hydroxy-R-sulfenyl-γ-butyrolactones 1-9. Both of the
aforementioned types of sulfur-oxygen contacts are ob-
served in lactones 1-9, with the sulfur atom in contact with
both the nucleophilic hydroxyl oxygen and with the electro-
philic carbonyl oxygen. We hypothesized these two conco-
mitant, attractive 1,4 intramolecular interactions of divalent
sulfur with both carbonyl and hydroxyl oxygens to be the
driving force for the aforementioned stereochemical prefer-
ence. Curiously, the same features are observed in the X-ray
structure of β-hydroxy-R-sulfinyl-γ-butyrolactone 11 read-
ily obtained by oxidation in a stereoselective fashion.
Weak nonbonding interactions between sulfur and oxygen
atoms have been invoked to explain the control of conforma-
tions in a large number of organosulfur compounds,5 in-
cluding molecules which play important roles in biological
systems.6 Usually, these interactions are based on the dis-
tances between sulfur and oxygen atoms being less than the
˚
sum of S and O van der Waals radii (3.3 A) as measured in
X-ray structures.
The sulfur-oxygen interactions in organic compounds are
usually formed between the nonbonding atoms separated
by three or four covalent bonds (1,4- or 1,5-type sulfur-
oxygen interactions, respectively), while those in proteins are
much more widely separated throughout the polypeptide
backbone.6h
(4) (a) Silverman, R. B. J. Org. Chem. 1981, 46, 4789. (b) Silverman, R. B.
J. Am. Chem. Soc. 1981, 103, 5941. (c) Caine, D.; Crews, E.; Salvino, J. M.
Tetrahedron Lett. 1983, 24, 2083.
(5) (a) Kucsman, A.; Kapovits, I. in Organic Sulfur Chemistry: Theore-
tical and Experimental Advances (Eds: Bernardi, F.; Csizmadia, I. G.;
Mangini, A.) Elsevier Scientific Publishing Co.: Amsterdam, 1985; pp
ꢀ
191-245. (b) Kucsman, A.; Kapovits, I. J. Mol. Str. 1986, 140, 141. (c)
Ohkata, K.; Ohsugi, M.; Yamamoto, K.; Ohsawa, M.; Akiba, K. J. Am.
Results and Discussion
ꢀ
Chem. Soc. 1996, 118, 6355. (d) Nagy, P.; Szabo, D.; Kapovits, I.; Kucsman,
A.; Argay, G.; Kalman, A. J. Mol. Str. 2002, 606, 61. (e) Fragoso-Serrano,
A series of β-hydroxy-R-sulfenyl-γ-butyrolactones having
different R1 and R2 substituents were prepared in order to study
the influence of these susbtituents on the isomerization process.
We also wanted to study how the sulfur-oxygen interactions
are influenced by different R2 substituents having an electron-
withdrawing group (fluorine) or an electron-donating group
(methoxy) in the aromatic ring.2 We have synthesized syn-syn
β-hydroxy-R-sulfenyl-γ-butyrolactones 1-9 from γ-hydroxy-
R,β-epoxy esters as previously reported (Scheme 2).3
These syn-syn lactones 1-9 (or syn-anti isomers, or any
mixture of both) invariably isomerized into syn-anti/syn-syn
lactones in a ratio of ∼6/4 (Scheme 3 and Table 1). The
isomerization occurred easily under basic conditions (stirring
at room temperature with triethylamine), neat upon heating, or
in a polar solvent like DMSO at room temperature (see the
Experimental Section).
ꢀ
ꢀ
ꢀ
ꢀ
M.; Guillen-Jaramillo, G.; Pereda-Miranda, R.; Cerda-Garcıa-Rojas, C. M.
J. Org. Chem. 2003, 68, 7167. (f ) Meyer, E.; Joussef, A. C.; Gallardo, H.;
Bortoluzzi, A. J.; Longo, R. L. Tetrahedron 2003, 59, 10187.
(6) (a) Goldstein, B. M.; Takusagawa, F.; Berman, H. M.; Srivastava,
P. C.; Robins, R. K. J. Am. Chem. Soc. 1983, 105, 7416. (b) Franchetti, P.;
Cappellacci, L.; Grifantini, M.; Barzi, A.; Nocentini, G.; Yang, H.; O’Connor,
A.; Jayaram, H. N.; Carrell, C.; Goldstein, B. M. J. Med. Chem. 1995, 38, 3829.
(c) Goldstein, B. M.; Li, H.; Hallows, W. H.; Langes, D. A.; Franchetti, P.;
Cappellacci, L.; Grifantini, M. J. Med. Chem. 1994, 37, 1684. (d) Li, H.;
Hallows, W. H.; Punzi, J. S.; Marquez, V. E.; Carrell, H. L.; Pankiewicz, K. W.;
Watanabe, K. A.;Goldstein, B. M. Biochemistry 1994, 33, 23. (e) Burling, F. T.;
Goldstein, B. M. J. Am. Chem. Soc. 1992, 114, 2313. (f) Goldstein, B. M.;
Takusagawa, F.; Berman, H. M.; Srivastava, P. C.; Robins, R. K. J. Am. Chem.
Soc. 1983, 105, 7416. (g) Wu, S.; Greer, A. J. Org. Chem. 2000, 65, 4883. (h)
Reznik, R.; Greer, A. Chem. Res. Toxicol. 2000, 13, 1193. (i) Pal, D.;
Chakrabartil, P. J. Biomol. Struct. Dyn. 2001, 19, 115. ( j) Iwaoka, M.;
Takemoto, S.; Okada, M.; Tomoda, S. Chem. Lett. 2001, 132. (k) Iwaoka,
M.; Takemoto, S.; Tomoda, S. J. Am. Chem. Soc. 2002, 124, 10613. (l) Iwaoka,
M.;Takemoto, S.; Okada, M.; Tomoda, S.Bull. Chem.Soc. Jpn.2002, 75, 1611.
(m) Iwaoka, M. Genome News 2003, 5, 29. (n) Iwaoka, M.; Isozumi, N.
Biophysics 2006, 2, 23.
The isomerization process can be rationalized through
a retroaldol-aldol sequence8 as previously reported by
(7) Rosenfield, R. E., Jr.; Partharasathy, R.; Dunitz, J. D. J. Am. Chem.
Soc. 1977, 99, 4860.
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SCHEME 3. Isomerization of β-Hydroxy R-Sulfenyl γ-Buty-
rolactones
TABLE 1. Ratio of Syn-Syn/Syn-Anti Lactones 1-9 Resulting from
Isomerization
basic conditions
syn-syn/syn-anti
neat upon heating
syn-syn/syn-anti
DMSO at rt
syn-syn/syn-anti
lactone
1
2
3
4
5
6
7
8
9
40/60
32/68
33/67
46/54
36/64
42/58
35/65
29/71
33/67
34/66
40/60
39/61
44/56
40/60
33/67
40/60
30/70
33/67
31/69
33/67
35/65
36/64
32/68
30/70
34/66
35/65
41/59
SCHEME 4. Retroaldol-Aldol Sequence
Silverman4a (Scheme 4). The other two possible isomeric
lactones (anti-syn or anti-anti) were never observed.
We hypothesized that the distinctive nonbonding sulfur-
oxygen contacts are at the origin of this phenomenon.9
In order to confirm it, the crystal structures of syn-syn
lactones (1-9) have been determined (Figure 2).10 Geo-
metric features were essentially similar for 1-9, with the
(8) Aldehyde 10 was trapped as an alkene when treated with a base in the
presence of a phosphonium salt. See also ref 3c
(9) We ruled out the intermediacy of hydrogen bonding between OH and
the sulfur atom as the driving force of the phenomenon under the reaction
conditions for several reasons: 1) The isomerization takes place in THF as
solvent which it is known to be a high hydrogen bonding acceptor.
2) Hydroxylic peak of the lactones in 1H NMR shifted considerably when
changing the solvent from CDCl3 to CD3CN (Δδ = 2.85 ppm in CDCl3 and
3.72 ppm in CD3CN for compound 2; Δδ = 2.74 ppm in CDCl3 and 3.73
ppm in CD3CN for compound 5).
(10) The crystal structures have been deposited at the CCDC and
allocated the deposition numbers: CCDC 603611, 293151, 293009, 714594,
714595, 714596, 714597, 714598 and 714599 for 1-9, respectively.
(11) It is well-known that different crystal ordering (and accordingly
intermolecular contacts) may affect intramolecular bond distances and
therefore comparisons between compounds with different crystal packing
must be undertaken with caution. This particularly holds for compound 6,
for which a different crystal packing is observed as compared with the rest of
FIGURE 2. X-ray structures of compounds 1-9.
the series. Consequently, intramolecular S O contacts in compound 6 fall
outside of the general trend determined for 1-5 and 7-9 as well as for the vast
majority of closely related compounds.
only exception being compound 6.11 The distances between
the hydroxyl oxygen and sulfur and between the carbonyl
3 3
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TABLE 2. Sulfur-Oxygen Distances (from Hydroxyl Groups) and
Polar and Azimuthal Angles in X-ray Structures of Lactones
lactone
S
Ohydroxyl
φhydroxylic (deg)
θhydroxylic (deg)
3 3 3
1
2
3
4
5
6
7
8
9
2.937
2.871
2.896
2.853
2.886
3.104
2.876
2.865
2.952
107.1
106.7
107.1
106.1
105.8
68.6
107.0
103.8
109.5
97.3
95.6
92.5
84.3
83.7
41.8
94.6
94.9
103.6
TABLE 3. Sulfur-Oxygen Distances (from Carbonyl Groups) and
Polar and Azimuthal Angles X-ray Structures of Lactones
lactone
S
Ocarbonyl
φcarbonylic (deg)
θ
carbonylic (deg)
3 3 3
1
2
3
4
5
6
7
8
9
3.197
3.178
3.214
3.202
3.165
3.054
3.211
3.213
3.200
33.6
39.9
38.0
35.5
40.7
98.3
41.8
30.7
60.2
42.7
41.0
42.6
40.7
40.7
63.8
41.1
42.1
40.7
FIGURE 3. 3D representation of S O distances and polar and
3 3
azimuthal angles for compounds 1-9. Red dots represent sulfur-
oxygen contacts from hydroxyl oxygens, and blue dots represent
sulfur-oxygen contacts from carbonyl oxygens.
oxygen and sulfur are less than the sum of S and O van der
˚
Waals radii (3.3 A) in all compounds (Tables 2 and 3).
The short atomic distances observed in syn-syn lactones
are interpreted as nonbonded interactions between oxygen
and sulfur atoms. For all structures, the distances between
the hydroxyl oxygen and sulfur atoms are less than the
distances between the carbonyl oxygen and sulfur atoms,
with the exception of compound 6.11
The distances between oxygen atoms (either carbonyl or
hydroxyl) and the sulfur atom depend on the substituent on
the aromatic ring.
FIGURE 4. Electron delocalization from the oxygen lone pair (nO)
to the antibonding orbital of a S-C bond (σ*) and from the sulfur
lone pair to the π* of the CdO bond.
Azimuthal angles for sulfur-hydroxyl oxygen contacts
are very similar, around 107° (Table 2), and polar angles for
sulfur-carbonyl oxygen contacts are also similar, being
around 41° (Table 3). Curiously, lactone 6 shows angles that
have a reversed relationship of magnitude (φcarbonyl = 98.3°
and θhydroxyl = 41.8°).
disulfide). The phenyl ring attached to the sulfur atom is
oriented in the direction opposite to the hydroxyl, permitting
the interaction to take place (see Figure 2). On the other
hand, the carbonyl oxygen is positioned ∼40° from the
perpendicular to the C-S-C plane and should allow orbital
interactions between π* of the CdO bond and the sulfur lone
pair electrons (see Figure 4). In the case of compound 6, the
phenyl ring attached to the sulfur atom is oriented in the
direction opposite to that of the carbonyl oxygen, permitting
an orbital interaction between the carbonyl oxygen lone pair
and σ* orbital of the S-C bond.
We performed theoretical calculations for the syn-syn and
syn-anti lactones 1. Their geometries were fully optimized in
vacuo using the B3LYP12 exchange-correlation functionals
together with the standard 6-31þG(d,p) basis set.13 The
electronic structures of the geometries associated with the
syn-syn and syn-anti lactones were analyzed using the Wiberg
bond order (BO)14 (Table 4). The BO values between the
sulfur atom and the hydroxyl oxygen are very similar in both
lactones, as are their interatomic distances. However, differ-
ences are evident when the BO between the sulfur and
Figure 3 shows a 3D representation of S O contacts, the
3 3 3
azimuthal and polar angles involving O atoms from the
carbonyl and hydroxyl groups (see also Tables 2 and 3). It
reflects graphically that the sulfur-oxygen contacts from the
hydroxyl oxygens have azimuthal and polar angles that are
very similar for all compounds and so is the case for the
sulfur-oxygen contacts from carbonyl oxygens.
Both types of sulfur-oxygen contacts are observed con-
comitantly in lactones 1-9, with the sulfur atom in contact
with both the nucleophilic hydroxyl oxygen and with the
electrophilic carbonyl oxygen. This configuration is reversed
in the case of compound 6, as illustrated by the outlying blue
and red dots midway between the other data points in
Figure 3. This is the first report of such a spatial disposition,
with both types of sulfur-oxygen interactions present at the
same time.
The linear alignment of the C-S covalent bond and the
coordinating hydroxyl oxygen should allow an effective
orbital interaction between the oxygen lone pair and σ*
orbital of the S-C bond (see Figure 4), which may elongate
(12) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang, W.;
Parr, R. G. Phys. Rev. B 1988, 37, 785.
(13) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab initio
Molecular Orbital Theory; Wiley: New York, 1986.
(14) Wiberg, K. B. Tetrahedron 1968, 24, 1083.
˚
˚
the S-C bond (1.76-1.78 A for 1-9, 1.75 A for the diphenyl
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TABLE 4. Theoretical Sulfur-Oxygen Distances and Bond Order (BO) (B3LYP/6-311þG**)
entrya
lactone
S
O hydroxyl
S
Ocarbonyl
BO (S OH)
3 3 3
BO (S OC)
3 3 3
3 3 3
3 3 3
1
2
a
syn-syn-1
syn-anti-1
3.093
3.010
3.429
3.248
0.014
0.014
0.023
0.009
˚
Sulfur-oxygen distances (A) and BO of the syn-syn- and syn-anti-1 B3LYP/6-311þG(d,p) geometries.
Experimental Section
General Experimental Methods. All solvents used in reactions
were freshly distilled from appropriate drying agents before use.
1H NMR spectra and 13C NMR spectra were measured in
CDCl3 (1H, 7.24 ppm; 13C 77.0 ppm) solution at 30 °C on a
300 MHz or a 500 MHz NMR spectrometer. Mass spectra were
measured in a hybrid quadrupole-t-TOF mass spectrometer
operating at a resolution ca. 15000 fwhm (W-mode) with an
orthogonal Z-spray-electrospray interface. The drying gas as
well as nebulizing gas was nitrogen at a flow of 400 and 60 L/h,
respectively. The temperature of the source block was set to
120 °C and the desolvation temperature to 150 °C. A capillary
voltage of 3 kV was used in the positive scan mode, and the cone
voltage was set to 15 V. Sample solutions were infused via
syringe pump directly connected to the ESI source at a flow
rate of 10 μL/min. ESI mass spectra were dominated by the
presence of sodium adducts of the target compound. For the
accurate mass measurements, a 2 mg/L standard solution of
leucine enkephalin was introduced via the lock spray needle at a
cone voltage set to 45 V and a flow rate of 30 μL/min. IR spectra
were recorded as oily films on NaCl plates on a FT-IR spectro-
meter. EM Science silica gel 60 was used for column chroma-
tography, while TLC was performed with precoated plates
(Kieselgel 60, F254, 0.25 mm). Unless otherwise specified, all
reactions were carried out under nitrogen atmosphere with
magnetic stirring.
General Procedure for the Syntheses of syn-syn-Lactones 1-9.
A -40 °C cold suspension of NaH (60% in mineral oil) (1.12
mmol) in THF (1 mL) was treated with thiophenol (2.25 mmol).
The mixture was stirred at -40 °C for 15 min, a solution of syn-
epoxy ester (0.75 mmol) in THF (1 mL) was added dropwise,
and the resulting mixture was stirred at -40 °C for 1.5 h. Brine
was added, the mixture was extracted with Et2O (3 ꢀ 20 mL),
and the organic layers were washed (brine), dried (Na2SO4), and
concentrated. The crude oil which contained the corresponding
diols was directly submitted for cyclization without further
purification.
FIGURE 5. X-ray structure of compound 11.
SCHEME 5. Synthesis of Sulfoxide 11
carbonyl oxygen are compared. Although the S O carbo-
3 3 3
˚
nyl bond of syn-anti 1 is ∼0.18 A shorter than that of the
corresponding syn-syn 1, the carbonyl BO of the syn-syn 1 is
2.5 times greater than syn-anti 1. This difference emphasizes
the directionality of the sulfur-oxygen interaction.
Interestingly, a very similar spatial disposition is also
observed in the structure of sulfoxide 11. Compound 11 is
an intermediate in the synthesis of the natural product 12
(Scheme 5).15 It is obtained through oxidation of the pre-
ceding sulfide as a single isomer (Scheme 5). It is well-known
that the oxidation of the thioether group is strongly influ-
enced by neighboring atoms.16
The X-ray crystal structure of sulfoxide 11 shows the
configuration of the sulfur atom to be R (Figure 5).17 The
˚
distance between the hydroxyl oxygen and sulfur is 2.734 A
˚
and between the carbonyl oxygen and sulfur is 3.177 A.
Azimuthal and polar angles are φ = 109.6° and θ = 96° for
the sulfur-hydroxyl oxygen contact and φ = 23.7° and θ =
38.3° for the sulfur-carbonyl oxygen contact, respectively.
These geometric features are similar to the ones depicted for
syn-syn lactones 1-9. The double sulfur-oxygen interaction
would stabilize the R configuration of the sulfur atom during
oxidation.
In summary, two attractive 1,4 intramolecular interac-
tions of divalent sulfur with both carbonyl and hydroxyl
oxygens are observed in the X-ray structures of β-hydroxy-R-
sulfenyl-γ-butyrolactones and a β-hydroxy-R-sulfinyl-γ-bu-
tyrolactone. Sulfur-oxygen interactions can be invoked to
account for the tendency of β-hydroxy R-sulfenyl γ-buty-
rolactones to assume the syn configuration. Our synthetic
R-sulfenyl carbonyl systems should contribute to the under-
standing of the role played by these subtle noncovalent
interactions in determining the preferred conformation in
biochemical and molecular recognition processes.
A solution of diol in CHCl3 (2 mL) was treated with
p-toluenesulfonic acid (catalytic amount). The resulting mixture
was stirred at room temperature for 1 h. NaHCO3 (saturated
aqueous solution) was added, and the mixture was extracted with
Et2O (3 ꢀ 20 mL), and the organic layers were washed (brine),
dried (Na2SO4), and concentrated. The crude was purified through
chromatography (silica gel, hexanes/EtOAc (7:3) and (6:4)).
Compound syn,syn-1: 1H NMR (CDCl3, 500 MHz) δ
7.50-7.53 (m, 2H), 7.35-7.45 (8H, m), 5.47 (1H, d, J = 3.0
Hz), 4.56 (1H, ddd, J = 4.0, 3.0, 2.0 Hz), 4.35 (1H, d, J = 4.0
Hz), 2.37 (1H,d, J = 2.0 Hz); 13C NMR (CDCl3, 125 MHz) δ
172.6, 133.0, 132.6, 129.6, 129.1, 128.7, 128.6, 126.5, 83.0, 71.4,
56.6; IR (NaCl) ν 3460, 3060, 2916, 1951, 1886, 1752, 1581, 1498,
1456, 1438, 1326, 1290, 1214, 1179, 1110, 1024, 994, 954, 942,
815, 790, 701, 634 cm-1; HRMS m/z calcd for C16H14O3SNa
[M þ Naþ] 309.0562, found 309.0580 (recrystallized from
hexanes/EtOAc, mp 151.5-154.5 °C).
Compound syn,syn-2: 1H NMR (CDCl3, 500 MHz) δ
7.33-7.57 (m, 5H), 4.51 (1H, dq, J = 6.5, 3 Hz), 4.24 (2H, m),
2.75 (1H, s), 1.50 (3H, d, J = 6.0 Hz); 13C NMR (CDCl3, 125
MHz) δ 172.9, 132.4, 129.7, 128.7, 79.0, 69.9, 57.3, 14.1; IR (NaCl)
ν 3381, 2921, 2860, 1752, 1630, 1436, 1174, 1113 cm-1; HRMS m/z
calcd for C11H12O3SNa [M þ Naþ] 247.0405, found 247.0376.
ꢀ
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(15) Lopez, I.; Rodrıguez, S.; Izquierdo, J.; Gonzalez, F. V. J. Org. Chem.
2007, 72, 6614.
(16) Musker, W. K. Acc. Chem. Res. 1980, 13, 200.
(17) The crystal structure has been deposited at the CCDC and allocated
the deposition number CCDC 752570.
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Gonzalez et al.
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Compound syn,syn-3: 1H NMR (CDCl3, 500 MHz) δ
7.52-7.54 (2H, m), 7.33-7.36 (3H, m), 4.31 (1H, m), 4.24
(1H, d, J = 4.0 Hz), 3.86 (1H, dd, J = 10.0, 2.5 Hz), 2.75
(1H,s), 2.27 (1H, m), 1.11 (3H, d, J = 7.0 Hz), 0.99 (3H, d, J =
6.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 172.2, 132.4, 132.0,
129.7, 128.7, 88.3, 68.6, 57.6, 27.6, 19.8, 17.5; IR (NaCl) ν 3423,
2965, 1760, 1471, 1440, 1392, 1339, 1171, 1072, 1026, 873, 778,
745, 690 cm-1; HRMS m/z calcd for C13H16O3SNa [M þ Naþ]
275.0718, found 275.0706 (recrystallized from hexanes/EtOAc,
mp 147.8-148.5 °C).
115.3, 88.3, 68.4, 58.8, 55.5, 27.7, 19.9, 17.5; IR (NaCl) ν 3480,
3068, 2965, 2923, 1753, 1591, 1494, 1459, 1337, 1284, 1247, 1201,
1172, 1078, 1035, 1004, 940, 818, 775, 734, 640, 516 cm-1
;
HRMS m/z calcd for C14H18O4SNa [M þ Naþ] 305.0818, found
305.0820 (recrystallized from hexanes/EtOAc, mp 148-150 °C).
General Procedure for the Isomerization of Lactones 1-9.
Method 1. A solution of syn-syn-lactone (0.25 mmol) in THF
(2 mL) was treated with Et3N (0.25 mmol). The reaction mixture
was stirred at room temperature for 12 h and then quenched
with 1 M HCl and extracted with Et2O (3 ꢀ 20 mL). The organic
layers were washed with saturated aqueous NaHCO3 solution
and brine and then dried (Na2SO4) and concentrated. Method 2.
A solution of syn-syn-lactone (0.25 mmol) in DMSO-d6 (2 mL)
was heated at 50 °C for 1 h. Method 3. Pure solid syn-syn-lactone
was heated to its melting point for 5 min and then cooled to
room temperature.
Compound syn,syn-4: 1H NMR (CDCl3, 500 MHz) δ
7.62-7.65 (2H, m), 7.37-7.45 (5H, m), 7.04-7.07 (2H, m),
5.45 (1H, d, J = 2.0 Hz), 4.55 (1H, ddd, J = 4.5, 3.0, 2.0 Hz),
4.22 (1H, d, J = 4.5 Hz), 2.26 (1H, br s); 13C NMR (CDCl3, 125
MHz) δ 172.7, 163.2 (J = 252.5 Hz), 135.6 (J = 8.4 Hz), 132.9,
129.2, 128.8, 127.7, 126.5, 116.7 (J = 22.0 Hz), 82.9, 71.6, 57.0;
IR (NaCl) ν 3483, 2925, 1951, 1758, 1590, 1498, 1456, 1492,
1456, 1363, 1398, 1320, 1234, 1172, 1093, 998, 932, 942, 843, 827,
817, 747, 697, 634, 508 cm-1; HRMS m/z calcd for C16H13O3S-
FNa [M þ Naþ] 327.0462, found 327.0471 (recrystallized from
hexanes/EtOAc, mp 176-178 °C).
Compound syn,anti-1: 1H NMR (CDCl3, 500 MHz) δ 7.48-7.50
(m, 2H), 7.24-7.35 (8H, m), 5.49 (1H, d, J = 4.0 Hz), 4.38 (1H, dd,
J = 4.0, 1.0 Hz), 3.89 (1H, d, J = 1.0 Hz), 2.20 (1H, s); 13C NMR
(CDCl3, 125 MHz) δ 173.1, 132.9, 132.5, 131.2, 129.5, 129.1, 129.0,
128.9, 126.3, 83.3, 75.5, 52.2; IR (NaCl) ν 3389, 3053, 2987, 1776,
1440, 1265, 1156, 1070, 1023, 909, 650 cm-1; HRMS m/z calcd for
C16H14O3SNa [M þ Naþ] 309.0562, found 309.0562 (recrystallized
from hexanes/EtOAc, mp 142.5-144.3 °C).
Compound syn,syn-5: 1H NMR (CDCl3, 500 MHz) δ
7.56-7.59 (2H, m), 7.04-7.07 (2H, m), 4.51 (1H, dq, J = 7.0,
3.5 Hz), 4.23 (1H, dd, J = 4.5, 3.0 Hz), 4.14 (1H, d, J = 4.5 Hz),
2.73 (1H, d, J = 2.5 Hz), 1.50 (3H, d, J = 6.0 Hz); 13C NMR
(CDCl3, 125 MHz) δ 172.2, 163.2 (J = 248.6 Hz), 135.4 (J = 8.3
Hz), 127.2 (J = 3.5 Hz), 116.9 (J = 22.0 Hz), 79.0, 70.0, 57.7,
14.1; IR (NaCl) ν 3487, 2908, 1755, 1589, 1491, 1340, 1232, 1186,
818 cm-1; HRMS m/z calcd for C11H11O3SFNa [M þ Naþ]
265.0305, found 265.0312 (recrystallized from hexanes/EtOAc,
mp 143-144 °C).
Compound syn,anti-2: 1H NMR (CDCl3, 500 MHz) δ
7.33-7.57 (m, 5H), 4.65 (1H, dq, J = 6.6, 4.4 Hz), 4.31 (1H,
dd, J = 4.4, 2.8 Hz), 3.81 (1H, d, J = 2.8 Hz), 1.40 (3H, d, J =
6.6 Hz); 13C NMR (CDCl3, 125 MHz) δ 172.9, 133.2, 132.3,
129.5, 129.5, 128.9, 78.7, 74.7, 53.0, 13.7; IR (NaCl) ν 3399,
2922, 2853, 1759, 1721, 1623, 1439, 1313, 1259, 1113, 1052 cm-1
;
HRMS m/z calcd. for C11H12O3SNa [M þ Naþ] 247.0405,
Compound syn,syn-6: 1H NMR (CDCl3, 500 MHz) δ
7.55-7.58 (2H, m), 7.05-7.08 (2H, m), 4.29 (1H, s), 4.14 (1H, d,
J = 4.0 Hz), 3.84 (1H, dd, J = 10.5, 3.0 Hz), 2.69 (1H, s),
2.24-2.29 (1H, m), 1.12 (3H, d, J = 7.0 Hz), 1.00 (3H, d, J = 6.5
Hz); 13C NMR (CDCl3, 125 MHz) δ 172.1, 163.2 (J = 248.5 Hz),
135.3 (J = 8.5 Hz), 127.0 (J = 3.6 Hz), 116.9 (J = 22.0 Hz), 88.3,
68.7, 58.2, 27.6, 19.8, 17.5; IR (NaCl) ν 3441, 2967, 1747, 1589,
1493, 1389, 1341, 1315, 1224, 1183, 1159, 1127, 1083, 988, 947, 826,
777, 734, 638, 616 cm-1; HRMS m/z calcd for C13H15O3SFNa
[M þ Naþ] 293.0618, found 293.0622. (Recrystallized from
hexanes/EtOAc, mp 173-174 °C).
found 247.0412.
Compound syn,anti-3: 1H NMR (CDCl3, 500 MHz) δ
7.52-7.54 (2H, m), 7.33-7.36 (3H, m), 4.35 (1H, m), 4.06
(1H, dd, J = 10.0, 3.0 Hz), 3.80 (1H, s), 2.42 (1H, d, J = 5.0
Hz), 2.15 (1H, m), 1.10 (3H, d, J = 6.5 Hz), 0.95 (3H, d, J = 7.0
Hz); 13C NMR (CDCl3, 125 MHz) δ 173.5, 132.8, 131.6, 129.5,
128.8, 88.4, 74.0, 53.5, 27.0, 19.9, 17.6; IR (NaCl) ν 3449, 3060,
2965, 2876, 1759, 1583, 1471, 1440, 1391, 1370, 1340, 1199, 1173,
1121, 1070, 1024, 955, 916, 821, 778, 747, 690 cm-1; HRMS m/z
calcd for C13H16O3SNa [M þ Naþ] 275.0718, found 275.0721.
Compound syn,anti-4 þ compound syn,syn-4: 1H NMR (CDCl3,
500 MHz) δ 7.58-7.63 (4H, m) (syn-syn and syn-anti), 7.34-7.45
(10H, m) (syn-syn and syn-anti), 7.03-7.09 (4H, m) (syn-syn and
syn-anti), 5.59 (1H, d, J=3.5 Hz) (syn-anti), 5.45 (1H, d, J=2.5 Hz)
(syn-syn), 4.55 (1H, t, J = 7.5) (syn-syn), 4.46 (1H, t, J = 4.0) (syn-
anti), 4.22 (1H, d, J=4.5Hz) (syn-syn), 3.87(1H, s) (syn-anti), 2.28
(1H, s) (syn-syn), 1.69 (1H, s) (syn-anti); 13C NMR (CDCl3, 125
MHz) δ 172.7 (syn-syn), 172.7 (syn-anti), 164.5 (syn-syn), 164.2
(syn-anti), 162.5 (syn-syn), 162.2 (syn-anti), 136.3 (syn-syn), 136.2
(syn-syn), 135.6 (syn-anti), 135.5 (syn-anti), 132.9 (syn-syn), 132.4
(syn-anti), 129.3 (syn-syn), 129.2 (syn-anti), 129.1 (syn-syn), 128.8
(syn-anti), 126.5 (syn-anti), 126.3 (syn-syn), 116.9 (syn-syn), 116.8
(syn-anti), 116.7 (syn-syn), 116.6 (syn-anti), 83.2 (syn-syn), 82.9
(syn-anti), 75.4 (syn-syn), 71.5 (syn-anti), 56.9 (syn-anti). 56.8 (syn-
syn).
Compound syn,syn-7: 1H NMR (CDCl3, 300 MHz) δ
7.54-7.57 (2H, m), 7.37-7.43 (5H, m), 6.87-6.90 (2H, m),
5.42 (1H, d, J = 3.0 Hz), 4.49 (1H, ddd, J = 4.5, 3.0, 1.8 Hz),
4.22 (1H, d, J = 4.5 Hz), 3.81 (3H, s), 2.49 (1H, d, J = 2.1 Hz);
13C NMR (CDCl3, 75 MHz) δ 172.5, 160.6, 135.7, 133.2, 129.0,
128.7, 126.5, 122.4, 115.2, 82.9, 71.2, 57.8, 55.5; IR (NaCl) ν
3369, 3064, 2914, 1864, 1770, 1595, 1494, 1451, 1408, 1321, 1282,
1239, 1181, 1158, 1148, 1123, 1084, 1008, 931, 847, 814, 742, 697,
642, 627, 544, 516 cm-1; HRMS m/z calcd for C17H16O4SNa
[M þ Naþ] 339.0662, found 339.0653 (recrystallized from
hexanes/EtOAc, mp 165-166 °C).
Compound syn,syn-8: 1H NMR (CDCl3, 500 MHz) δ 7.51
(2H, d, J = 8.0 Hz), 6.87 (2H, d, J = 8.5 Hz), 4.47 (1H, dq, J =
6.5 and 3.5 Hz), 4.16 (1H, s), 4.12 (1H, d, J = 4.5 Hz), 3.81 (3H,
s), 2.90 (1H, br s), 1.50 (3H, d, J = 6.5 Hz); 13C NMR (CDCl3,
125 MHz) δ 172.2, 160.6, 135.5, 122.0, 115.3, 78.9, 70.0, 58.4,
55.5, 14.1; IR (NaCl) ν 3482, 3028, 2978, 2935, 2896, 2836, 1750
1595, 1497, 1439, 1341, 1290, 1250, 1180, 1134, 1122, 1030, 1010,
944, 816 cm-1; HRMS m/z calcd for C12H14O4SNa [M þ Naþ]
277.0505, found 277.0501 (recrystallized from hexanes/EtOAc,
mp 133-135 °C).
Compound syn,anti-5 þ compound syn,syn-5: 1H NMR
(CDCl3, 500 MHz) δ 7.53-7.58 (2H, m) (syn-syn and syn-anti),
7.02-7.06 (2H, m) (syn-syn and syn-anti), 4.62 (1H, dq, J = 6.5,
5.0 Hz) (syn-anti), 4.52 (1H, dq, J = 7.0, 3.5 Hz) (syn-syn), 4.28
(1H, dd, J = 4.5, 3.0 Hz) (syn-anti), 4.25 (1H, dd, J = 4.5, 3.0
Hz) (syn-syn), 4.14 (1H, d, J = 4.5 Hz) (syn-syn), 3.72 (1H, d,
J = 3.0 Hz) (syn-anti), 2.89(1H, br s) (syn-anti), 2.78 (1H, br s) (syn-
syn), 1.49 (3H, d, J = 7.0 Hz) (syn-syn), 1.39 (3H, d, J = 6.5 Hz)
(syn-anti); 13C NMR (CDCl3, 125 MHz) δ 173.3 (syn-anti), 172.8
(syn-syn), 164.4 (syn anti), 164.1 (syn-syn), 162.4 (syn anti), 162.1
(syn-syn), 136.3 (syn-anti), 136.2 (syn-anti), 135.3 (syn-syn), 135.2
(syn-syn), 116.9 (syn-syn), 116.8 (syn-anti), 116.7 (syn-syn), 116.6
Compound syn,syn-9: 1H NMR (CDCl3, 500 MHz) δ
7.50-7.52 (2H, m), 6.88-6.90 (2H, m), 4.23 (1H, dq, J = 3.0
and 2.0 Hz), 4.12 (1H, d, J = 4.0 Hz), 3.81 (3H, s), 2.86 (1H, s),
2.25-2.29 (1H, m), 1.10 (3H, d, J = 7.0 Hz), 0.99 (3H, d, J = 7.0
Hz); 13C NMR (CDCl3, 125 MHz) δ 172.2, 160.6, 135.5, 121.9,
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(syn-anti), 79.2 (syn-syn), 79.0 (syn-anti), 74.4 (syn-anti), 70.1 (syn-
syn), 57.6 (syn-syn), 53.4 (syn-anti), 14.0 (syn-syn), 13.6 (syn-anti).
Compound syn,anti-6 þ compound syn,syn-6: 1H NMR
(CDCl3, 500 MHz) δ 7.53-7.58 (2H, m) (syn-syn and syn-anti),
7.04-7.08 (2H, m) (syn-syn and syn-anti), 4.35 (1H, d, J = 3.0
Hz) (syn-anti), 4.29(1H, s) (syn-syn), 4.14(1H, d, J = 4.5) (syn-
syn), 4.06 (1H, dd, J = 10.5, 3.5 Hz) (syn-anti), 3.85 (1H, dd, J =
10.5, 3.0) (syn-syn), 3.71(1H, s) (syn-anti), 2.72 (1H, s) (syn-syn),
2.24-2.29 (1H, m) (syn-syn), 2.10-2.18 (1H, m) (syn-anti), 1.11
(3H, d, J = 7.0 Hz) (syn-syn and syn-anti), 0.99 (3H, d, J = 6.5
Hz) (syn-syn), 0.97 (3H, d, J = 7.0 Hz) (syn-anti); 13C NMR
(CDCl3, 125 MHz) δ 173.5 (syn-anti), 172.5 (syn-syn), 164.4
(syn-anti), 164.2 (syn-syn), 162.4 (syn-anti), 162.2 (syn-syn),
136.0 (syn-anti), 136.0 (syn-anti), 135.3 (syn-syn), 135.2 (syn-
syn), 122.1 (syn-syn), 127.1 (syn-anti), 127.0 (syn-syn), 116.9
(syn-syn), 116.8 (syn-syn and syn-anti), 116.6 (syn-anti), 88.5
(syn-anti), 88.4 (syn syn), 73.7 (syn-anti), 68.7 (syn-syn), 58.1
(syn-syn), 53.9 (syn-anti), 27.6 (syn-syn), 27.0 (syn-anti), 19.9
(syn-anti), 19.8 (syn-syn), 17.6 (syn-anti), 17.5 (syn-syn).
(1H, t, J = 6.5 Hz) (syn-anti), 4.18 (1H, t, J = 8.0 Hz) (syn-syn),
4.11 (1H, d, J = 4.5 Hz) (syn-syn), 3.80 (3H, s) (syn-syn and syn-
anti), 3.65 (1H, d, J = 2.5 Hz) (syn-anti), 1.48 (3H, d, J = 6.5 Hz)
(syn-syn), 1.36 (3H, d, J = 6.5 Hz, (syn-anti); 13C NMR (CDCl3,
125 MHz) δ 173.9 (syn-anti), 173.0 (syn-syn), 160.7 (syn-anti),
160.4 (syn-syn), 136.5 (syn-anti), 135.3 (syn-syn), 122.1 (syn-syn),
121.0 (syn-anti), 115.2 (syn-syn), 115.0 (syn-anti), 79.2 (syn-syn
and syn-anti), 74.5 (syn-anti), 69.9 (syn-syn), 58.1 (syn-syn), 55.4
(syn-syn), 55.4 (syn-anti), 53.8 (syn-anti), 14.0 (syn-syn), 13.6
(syn-anti).
Compound syn,anti-9 þ compound syn,syn-9: 1H NMR
(CDCl3, 500 MHz) δ 7.46-7.50 (2H, m) (syn-syn and syn-anti),
6.85-6.89 (2H, m) (syn-syn and syn-anti), 4.32 (1H, s) (syn-anti),
4.23(1H, d, J = 3.5 Hz) (syn-syn), 4.11(1H, d, J = 4.5) (syn-syn),
3.99 (1H, dd, J = 9.5, 3.5 Hz) (syn-anti), 3.80 (3H, s) (syn-syn),
3.79(3H, s) (syn-anti), 2.94 (1H, s) (syn-syn), 2.68 (1H, s) (syn-
anti), 2.23-2.27 (1H, m) (syn-syn), 2.12-2.16 (1H, m) (syn-anti),
1.09 (3H, d, J = 6.5 Hz) (syn-syn), 1.07 (3H, d, J = 6.5 Hz) (syn-
anti), 0.97 (3H, d, J = 7.0 Hz) (syn-syn), 0.93 (3H, d, J = 7.0 Hz)
(syn-anti); 13C NMR (CDCl3, 125 MHz) δ 174.1 (syn-anti),
172.8 (syn-syn), 160.6 (syn-anti), 160.4 (syn-syn), 136.2 (syn-syn),
135.3 (syn-anti), 122.0 (syn-syn), 121.3 (syn-anti), 115.2 (syn-
syn), 115.0 (syn-anti), 88.6 (syn-syn), 88.4 (syn-anti), 73.6 (syn-
anti), 68.5 (syn-syn), 58.5 (syn-syn), 55.4 (syn-syn), 55.3 (syn-
anti), 54.4 (syn-anti), 27.5 (syn-syn), 26.9 (syn-anti), 19.8 (syn-
anti), 19.7 (syn-syn), 17.6 (syn-anti), 17.4 (syn-syn).
Compound syn,anti-7 þ compound syn,syn-7: 1H NMR
(CDCl3, 300 MHz) δ 7.54-7.57 (4H, m) (syn-syn and syn-anti),
7.31-7.43 (10H, m) (syn-syn and syn-anti), 6.89-6.92 (4H, m)
(syn-syn and syn-anti), 5.49 (1H, d, J=3.6 Hz) (syn-anti), 5.41
(1H, d, J=3.3 Hz) (syn-syn), 4.47 (1H, ddd, J = 1.2, 2.1, 3.9 Hz)
(syn-syn and syn-anti), 4.22 (1H, s) (syn-anti), 4.21 (1H, s) (syn-
syn), 3.81 (3H, s) (syn-anti), 3.81 (3H, s) (syn-syn), 2.51(1H, s)
(syn-anti), 2.27 (1H, s) (syn-syn); 13C NMR (CDCl3, 75 MHz) δ
173.2 (syn-anti), 172.7 (syn-syn), 160.9 (syn-anti), 160.5 (syn-
syn), 136.6 (syn-anti), 135.7 (syn-syn), 133.2 (syn-syn), 132.7
(syn-anti), 129.0 (syn-anti), 128.6 (syn-syn), 126.5 (syn-syn),
126.3 (syn-anti), 122.4 (syn-syn), 120.9 (syn-anti), 115.2 (syn-
syn and syn-anti), 83.2 (syn-anti), 82.9 (syn-syn), 75.5 (syn-anti),
71.2 (syn-syn), 57.7 (syn-syn), 55.4 (syn-syn and syn-anti), 53.1
(syn-anti).
Acknowledgment. This work was financed by the Bancaixa-
UJI foundation (P1 1B2008-31 and P1 1A2008-09). We thank
Prof. Karl A. Scheidt for helpful discussions. We also thank
ꢀ
Serveis Centrals d’Instrumentacio Cientıfica from Universitat
Jaume I for technical support.
Compound syn,anti-8 þ compound syn,syn-8: 1H NMR
(CDCl3, 500 MHz) δ 7.48-7.51 (2H, m) (syn-syn and syn-anti),
6.85-6.88 (2H, m) (syn-syn and syn-anti), 4.54 (1H, dq, J = 6.5,
5.0 Hz) (syn-anti), 4.47 (1H, dq, J = 7.0, 3.5 Hz) (syn-syn), 4.28
Supporting Information Available: Crystallographic data
(CIF), theoretical calculations, graphical NMR spectra of all
compounds, and ORTEP representations. This material is
available free of charge via the Internet at http://pubs.acs.org.
5894 J. Org. Chem. Vol. 75, No. 17, 2010