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Absolute configuration of glycosyl sulfoxides
Tetrahedron: Asymmetry 21 (2010) 1830–1832
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Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Absolute configuration of glycosyl sulfoxides Carlos A. Sanhueza, Ander C. Arias, Rosa L. Dorta, Jesús T. Vázquez * Instituto Universitario de Bio-Orgánica ‘Antonio González’, Departamento de Química Orgánica, Universidad de La Laguna, 38206 La Laguna, Tenerife, Spain
a r t i c l e
i n f o
Article history: Received 4 May 2010 Accepted 15 June 2010 Available online 10 August 2010
a b s t r a c t A series of alkyl glycosyl sulfoxides were synthesized and analyzed by NMR and CD. The study of the configuration of the sulfur atom revealed several types of spectroscopic behavior that can be used as a criterion for this purpose. The study also pointed to CD as the preferential technique, showing clear advantages over NMR methods. A general rule for determining the absolute configuration of glycosyl sulfoxides by CD is proposed. Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction Over the years a variety of methods have been introduced for the construction of the interglycosidic bond. Among them Kahne’s sulfoxide glycosylation method1 has been shown to be one of the most powerful techniques for synthesizing biologically important glycosides.2 Glycosyl sulfoxides have thus become important intermediates for the synthesis of bioactive molecules. In addition, several glycosyl sulfoxides themselves show diverse biological activities, including antitumor, anti-infective, and antidiabetic actions.2,3 In addition to X-ray crystallography, general NMR methods for determining the configuration of sulfinyl glycosides have been proposed.4–7 One of them makes use of chiral shift reagents, but the small chemical shift differences achieved in the NMR spectra make this approach unattractive.4 Another, based on a series of correlations between 1H and 13C NMR chemical shifts and the absolute configuration of the sulfinyl group in several ethyl glycosyl sulfoxides,6 has the disadvantage of not considering aglycons other than the ethyl group, several exceptions to the method being found.7 Due to the drawbacks of these spectroscopic methods, a stereochemical study of the absolute configuration of glycosyl sulfoxides was undertaken. In this communication we report the stereochemical results on the absolute configuration of the sulfur atom in alkyl glycosyl sulfoxides by NMR and CD spectroscopic methods. A general rule for the direct determination of the absolute configuration of glycosyl sulfoxides by CD is proposed. 2. Results and discussion The most straightforward method for the synthesis of glycosyl sulfoxides is the oxidation of glycosyl sulfides. Since sulfide oxidation to sulfoxides by hydrogen peroxide has proved to be one of the most attractive methods,8 the electrophilic oxidation of thioglyco-
* Corresponding author. Tel.: +34 922318581; fax: +34 922318571. E-mail address: [email protected] (J.T. Vázquez). 0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2010.06.019
sides was carried out in good yields (80–95%) by using H2O2/Ac2O/ silica gel in CH2Cl2.9 A series of a- and b-thioglycosides were oxidized using the above-mentioned procedure and the corresponding alkyl glycosyl sulfoxides (Schemes 1 and 2) were characterized on the basis of their one- and two-dimensional NMR spectra. The anomeric configuration of the starting thioglycosides was retained in the glycosyl sulfoxides. The stereoselectivity of the oxidation was determined by 1H NMR analysis of the crude reaction products. It turned out to be strongly dependent on the anomeric configuration of the glycosyl moiety, high/low selectivity being observed for the a/b-anomers, respectively.10 OAc
OAc OO + AcO S+ R AcO R OAc OOAc SS (Major) RS (Minor) 1, R = Methyl; SS : R S = 3:1 2, R = Ethyl; SS : R S = 2:1 3, R = iso-Propyl; SS : R S = 1.4:1 4, R = Cyclohexyl;SS : R S = 1.2:1 5, R = tert -Butyl; SS : RS = 1.3:1
AcO AcO
O
AcO
OAc
AcO
O
S+
AcO S+
R OAc OSS (Major)
+
AcO
OAc O
O-
OAc
S+ R
R S (Minor)
6, R = Ethyl; SS : R S = 1.5:1 7, R = Cyclohexyl; SS : RS = 1.5:1 Scheme 1. Alkyl b-D-glycosyl sulfoxides 1–7.
On the basis of the chemical shift differences of the methylene protons a to the sulfinyl group and other correlations shown in Figure 1,6 analysis of the b ethyl sulfoxides 2 showed that the chemical shift difference for the methylenic H-proR and H-proS protons was 30 Hz for the major sulfoxide and 130 Hz for the minor.11
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C. A. Sanhueza et al. / Tetrahedron: Asymmetry 21 (2010) 1830–1832
OAc AcO AcO
OAc
O AcO
S+
H R
H AcO S+ R OS S (Minor)
O-
RS (Major)
O
+ AcO AcO
8, R = Ethyl; SS : RS = 1:6.5 9, R = iso-Propyl; SS : RS = 1:7 10, R = Cyclohexyl; S S : RS = 1:8 11, R = tert -Butyl; SS : R S = 1:5 AcO AcO
OAc
OAc
AcO
O
+
H AcO + R S
AcO
O AcO
S+
-
RS (Major) O
O
S S (Minor)
H R
12, R =Ethyl; SS : RS = 1:5 13, R = Cyclohexyl; SS : RS = 1:10 Scheme 2. Alkyl a-D-glycosyl sulfoxides 8–13.
deshielded H2 OΦ
S+
HproS CH3
H1 O- HproR
HproS CH3
S+
shielded H1
*
*exo-anomeric effect
SS
deshielded
O-
H2 O
difference of 98 Hz was observed for those of the minor one 3R (RS configuration). Analysis of the chemical shift of H2 for the b-glucopyranosides showed that RS sulfoxides (1R–5R, minor products) have a practically constant value of d 5.44 ppm independent of the structure of the aglycon. In contrast, d H2 for SS sulfoxides (1S–5S, major products) changes with the aglycon, from 5.07 ppm for the methyl sulfoxide to 5.56 ppm for the tert-butyl sulfoxide. Therefore, the chemical shifts of the H2 axial proton are more deshielded in RS sulfoxides than in SS ones (Fig. 1). This is only fulfilled for sulfoxides 1 (methyl) and 2 (ethyl). Sulfoxides 3 (isopropyl) and 4 (cyclohexyl) showed the same d values for H2, independent of the sulfinyl configuration. For the tert-butyl sulfoxide 5 the d value for H2 in the sulfoxide SS appeared to be more deshielded than the RS sulfoxide (d H2 (SS) = 5.56 ppm; d H2 (RS) = 5.43 ppm). Therefore, the chemical shift of H2 is not a valid criterion for determining the configuration of the sulfinyl group, given its variability with the structure of the aglycon. The chemical shifts of the axial protons H3 and H5 for the alkyl a-D-glycosyl sulfoxides (Fig. 2) revealed a clear deshielding of these protons in sulfoxides having the SS configuration, as a result of the strong anisotropic effect of the sulfinyl group, relative to those with the RS configuration. This effect was found to be stronger for H5 than H3.
HproR
shielded
strong nOe
deshielded
RS
Figure 1. NMR properties of ethyl b-D-glycosyl sulfoxides.6
O
H1 H5 R S+ H3 exo-anomeric OSS
Furthermore, the chemical shifts of H2 and C1 were d 5.24 and 5.45 ppm and d 89.9 and 86.6 ppm, for the major and minor sulfoxides, respectively. These results concur with those reported6 indicating that the major glucosyl sulfoxide 2S has the SS configuration and the minor sulfoxide 2R, the RS configuration. A similar analysis was carried out for the b isopropyl sulfoxides 3. For the major sulfoxide 3S a Dd of 17 Hz was observed for the methyls of the isopropyl group, pointing to an SS configuration, while a
effect
O H1 H5 R + S H3 RS
O-
Figure 2. NMR properties of alkyl a-D-glycosyl sulfoxides.
It seems to be a general fact for the b-anomers that the 13C NMR chemical shift of the anomeric carbon of RS sulfoxides is shielded with respect to the corresponding SS epimers. Table 1 shows higher d C1 values for the b-SS stereoisomers than for the b-RS ones (Fig. 1). However, the opposite behavior was observed for the aanomers, the a-SS stereoisomers showing a smaller chemical shift
Table 1 Optical activity (CHCl3), NMR data (CDCl3), and CD data (CH3CN) of the alkyl glycosyl sulfoxides 1–13
a
#
R
Config.a
d H2 (ppm)
d H3 (ppm)
d H5 (ppm)
d C1 (ppm)
k (nm)
1S 2S 3S 4S 5S 6S 7S 1R 2R 3R 4R 5R 6R
Methyl Ethyl iso-Propyl Cyclohexyl tert-Butyl Ethyl Cyclohexyl Methyl Ethyl iso-Propyl Cyclohexyl tert-Butyl Ethyl
b-glc b-glc b-glc b-glc b-glc b-gal b-gal b-glc b-glc b-glc b-glc b-glc b-gal
11.8 34.4 10.4 22.3 +36.9 12.0 10.1 65.9 51.0 56.8 55.3 59.4 36.9
5.07 5.24 5.46 5.45 5.56 5.40 5.65 5.43 5.45 5.44 5.45 5.43 5.49
5.31 5.30 5.29 5.29 5.27 5.12 5.10 5.36 5.36 5.36 5.36 5.32 5.40
3.84 3.80 3.77 3.77 3.74 4.02 3.99 3.82 3.80 3.78 3.78 3.78 4.05
90.7 89.9 88.6 88.3 86.5 90.4 88.7 87.4 86.6 85.6 85.3 85.4 87.1
222 226 230 231 229 226 231 217 220 221 222 223 220
+6.4 +7.1 +9.1 +8.0 +8.9 +6.7 +4.0 9.1 11.0 9.6 8.3 8.5 7.6
8S 9S 11S 12S 13S 8R 9R 10R 11R 13R
Ethyl iso-Propyl tert-Butyl Ethyl Cyclohexyl Ethyl iso-Propyl Cyclohexyl tert-Butyl Cyclohexyl
a-glc a-glc a-glc a-gal a-gal a-glc a-glc a-glc a-glc a-gal
+177.0 +157.1 +140.0 +192.9 +100.0 +116.0 +129.4 +150.4 +30.0 +127.1
5.36 5.34 5.20 5.58 5.58 5.34 5.34 5.33 5.35 5.52
6.14 6.07 6.07 6.00 6.05 5.58 5.58 5.60 5.41 5.50
5.20 5.15 5.31 5.25 5.31 3.95 3.92 3.96 4.26 4.06
84.5 82.9 81.6 85.1 83.2 87.2 85.0 84.3 83.4 84.8
227 227 231 228 227 233 236 237 233 237
+8.2 +26.3 +21.1 +7.9 +7.1 11.0 11.7 15.7 8.2 8.7
glc: glucopyranosides; gal: galactopyranosides.
[a]D
De
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than the a-RS ones (Fig. 2). This behavior was explained by a higher exo-anomeric effect for the RS than for the SS stereoisomers (b-anomers)6 and for the SS than for the RS stereoisomers (a-anomers).12 Therefore, 13C NMR comparison of the chemical shift of the anomeric carbon of both sulfoxides is a good criterion for determining the absolute configuration of the sulfur atom when both stereoisomers are available. According to the data shown in Table 1, the optical activity cannot be used as a criterion for the absolute configuration of the sulfinyl group. However, its sign indicates the anomeric configuration, negative [a]D for the b-anomers and positive [a]D for the a-anomers, with the sole exception of the tert-butyl derivative 5S. The absolute configuration of dialkyl and alkyl aryl sulfoxides was studied by Mislow13 using optical rotatory dispersion, in addition to NMR.14 Thus, methyl alkyl sulfoxides without any other strongly perturbing group and having an RS configuration exhibited negative Cotton effects centered at the strong absorption band near 200 nm (acetonitrile) in ord. Our model sulfoxides were also analyzed by CD in CH3CN. For the b-anomers, the spectra showed a positive first Cotton effect around 228 nm,15,16 for the major sulfoxides 1S–7S, corresponding to an SS absolute configuration, and a negative first Cotton effect around 220 nm for minor sulfoxides 1R–6R, corresponding to an RS configuration (Fig. 2). On the other hand, for the a-anomers the minor stereoisomers 8S, 9S, and 11S–13S show a positive first Cotton effect around 228 nm (SS absolute configuration) and the major ones 8R–11R, and 13R, a negative first Cotton effect around 235 nm (RS absolute configuration). The wavelength of the first Cotton effect undergoes a bathochromic shift as the alkyl group increases in size (Table 1), most likely as a result of steric effects. More interestingly, this CD wavelength is indicative of the absolute configuration of the sulfoxide. Thus, for the b-anomers, higher wavelengths were observed for the (S)-stereoisomers than for their corresponding (R) ones, while for the a-anomers, the opposite behavior was observed. These results, which are in agreement with the Mislow‘s antecedents,13 can be predicted according to the rule shown in Figure 3. The first Cotton effect is negative, therefore the absolute configuration of the sulfoxide is RS when the sugar ring is on the left side of the plane formed by the oxygen (top), the lone electron pair (bottom), and the sulfur atom (center). The opposite sign (positive) corresponds to the SS absolute configuration. We thus propose a rule for determining the absolute configuration of glycosyl sulfoxides by CD (on the basis of the sign of the first Cotton effect). 7
222 nm (−6.4)
Δε 0
217 nm (−9.1) −15
190
350 nm
Figure 3. CD spectra of the methyl derivatives 1S (blue) and 1R (red) (CH3CN).
3. Conclusions
13
In summary, the present study reveals that comparison of the C NMR chemical shift of the anomeric carbons of the two diaste-
reomeric sulfoxides is a convenient general method to determine the absolute configuration of the sulfur atom of alkyl glycosyl sulfoxides, regardless of the structural nature of the alkyl group. Thus, for the b-anomers the SS stereoisomers show d C1 at lower fields than RS ones, while for the a-anomers the SS stereoisomers show d C1 at higher fields than RS. Additionally, the wavelength of the first Cotton effect is also indicative of the absolute configuration of the sulfur atom. Higher wavelengths were therefore observed for the b-SS stereoisomers than for their corresponding b-RS ones, while the opposite was seen for the a-SS/RS isomers. More significantly, CD analysis shows itself to be a more straightforward way to determine the absolute configuration of the sulfur atom in alkyl glycosyl sulfoxides. Only one stereoisomer is needed which is an advantage since both stereoisomers are not always available, and the running two 13C NMR spectra are more time consuming than a simpler CD measurement. An empirical rule for determining the absolute configuration of glycosyl sulfoxides by CD is therefore established (Fig. 4).
O− (Sugar) R S+ (R) Sugar
CD
R
Sugar O
RS
+
R or
Sugar
O
SS
Figure 4. Rule for determining the absolute configuration of glycosyl sulfoxides by CD (sign of the first Cotton effect).
Acknowledgments This work was supported by the Ministerio de Ciencia e Innovación (MICINN, Spain), through grant CTQ2007-67532-C02-02/BQU. C.A.S. thanks the Consejería de Educación, Cultura y Deportes (Gobierno de Canarias) for a fellowship. References 1. Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111, 6881. 2. Review: Aversa, M. C.; Barattucci, A.; Bonaccorsi, P. Tetrahedron 2008, 64, 7659. 3. Goodwin, N. C.; Harrison, B. A.; Iimura, S.; Mabon, R.; Song, Q.; Wu, W.; Yan, J.; Zhang, H.; Zhao, M. M. PCT Int. Appl., 2009. 4. Buist, P. H.; Behrouzian, B.; MacIsaac, K. D.; Cassel, S.; Rollin, P.; Imberty, A.; Gautier, C.; Pérez, S.; Genix, P. Tetrahedron: Asymmetry 1999, 10, 2881. 5. Yabuuchi, T.; Kusumi, T. J. Am. Chem. Soc. 1999, 121, 10646. 6. Khiar, N. Tetrahedron Lett. 2000, 41, 9059. 7. Crich, D.; Mataka, J.; Zakharov, L. N.; Rheingold, A. L.; Wink, D. J. J. Am. Chem. Soc. 2002, 124, 6028. 8. Kaczorowska, K.; Kolarska, Z.; Mitka, K.; Kowalski, P. Tetrahedron 2005, 61, 8315. 9. Kakarla, R.; Dulina, R. G.; Hatzenbuhler, N. T.; Hui, Y. W.; Sofia, M. J. J. Org. Chem. 1996, 61, 8347. 10. a-Thioglycosides lead predominantly to sulfoxides having the RS absolute configuration, while their b-anomers lead to diastereomeric mixtures of SS (major) and RS (minor) sulfoxides. See Refs. 6,7. 11. This difference in the chemical shift was explained by the presence of the exoanomeric effect in the b-RS stereoisomer, which confers rigidity around the glucosidic linkage. Conversely, the substrate of b-SS configuration is more flexible, exhibiting a small difference in the chemical shift of these protons. See Ref. 6. 12. Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Bruno, G.; Giannetto, P.; Rollin, P. Lett. Org. Chem. 2004, 1, 376. 13. Mislow, K.; Green, M. M.; Laur, P.; Melillo, J. T.; Simmons, T.; Ternary, A. L., Jr. J. Am. Chem. Soc. 1965, 87, 1958. 14. (a) Coyle, T. D.; Stone, F. G. A. J. Am. Chem. Soc. 1961, 83, 4138; (b) Mislow, K.; Glass, M. A. W.; Hopps, H. B.; Simon, E.; Wahl, G. H. J. Am. Chem. Soc. 1964, 86, 1710. These authors also noted the magnetic nonequivalence of the methylene protons in diethyl and ethyl isopropyl sulfoxides. 15. Probably due to the (3sp3)2?(3sp3) (3d) transition of the sulfinyl group, suggestive of an n?p transition. See Ref. 13. 16. Acetates are considered ‘nonchromophoric’ groups since they give small Cotton effects at around 200 nm.
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Absolute configuration of glycosyl sulfoxides Carlos A. Sanhueza, Ander C. Arias, Rosa L. Dorta, Jesús T. Vázquez * Instituto Universitario de Bio-Orgánica ‘Antonio González’, Departamento de Química Orgánica, Universidad de La Laguna, 38206 La Laguna, Tenerife, Spain
a r t i c l e
i n f o
Article history: Received 4 May 2010 Accepted 15 June 2010 Available online 10 August 2010
a b s t r a c t A series of alkyl glycosyl sulfoxides were synthesized and analyzed by NMR and CD. The study of the configuration of the sulfur atom revealed several types of spectroscopic behavior that can be used as a criterion for this purpose. The study also pointed to CD as the preferential technique, showing clear advantages over NMR methods. A general rule for determining the absolute configuration of glycosyl sulfoxides by CD is proposed. Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction Over the years a variety of methods have been introduced for the construction of the interglycosidic bond. Among them Kahne’s sulfoxide glycosylation method1 has been shown to be one of the most powerful techniques for synthesizing biologically important glycosides.2 Glycosyl sulfoxides have thus become important intermediates for the synthesis of bioactive molecules. In addition, several glycosyl sulfoxides themselves show diverse biological activities, including antitumor, anti-infective, and antidiabetic actions.2,3 In addition to X-ray crystallography, general NMR methods for determining the configuration of sulfinyl glycosides have been proposed.4–7 One of them makes use of chiral shift reagents, but the small chemical shift differences achieved in the NMR spectra make this approach unattractive.4 Another, based on a series of correlations between 1H and 13C NMR chemical shifts and the absolute configuration of the sulfinyl group in several ethyl glycosyl sulfoxides,6 has the disadvantage of not considering aglycons other than the ethyl group, several exceptions to the method being found.7 Due to the drawbacks of these spectroscopic methods, a stereochemical study of the absolute configuration of glycosyl sulfoxides was undertaken. In this communication we report the stereochemical results on the absolute configuration of the sulfur atom in alkyl glycosyl sulfoxides by NMR and CD spectroscopic methods. A general rule for the direct determination of the absolute configuration of glycosyl sulfoxides by CD is proposed. 2. Results and discussion The most straightforward method for the synthesis of glycosyl sulfoxides is the oxidation of glycosyl sulfides. Since sulfide oxidation to sulfoxides by hydrogen peroxide has proved to be one of the most attractive methods,8 the electrophilic oxidation of thioglyco-
* Corresponding author. Tel.: +34 922318581; fax: +34 922318571. E-mail address: [email protected] (J.T. Vázquez). 0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2010.06.019
sides was carried out in good yields (80–95%) by using H2O2/Ac2O/ silica gel in CH2Cl2.9 A series of a- and b-thioglycosides were oxidized using the above-mentioned procedure and the corresponding alkyl glycosyl sulfoxides (Schemes 1 and 2) were characterized on the basis of their one- and two-dimensional NMR spectra. The anomeric configuration of the starting thioglycosides was retained in the glycosyl sulfoxides. The stereoselectivity of the oxidation was determined by 1H NMR analysis of the crude reaction products. It turned out to be strongly dependent on the anomeric configuration of the glycosyl moiety, high/low selectivity being observed for the a/b-anomers, respectively.10 OAc
OAc OO + AcO S+ R AcO R OAc OOAc SS (Major) RS (Minor) 1, R = Methyl; SS : R S = 3:1 2, R = Ethyl; SS : R S = 2:1 3, R = iso-Propyl; SS : R S = 1.4:1 4, R = Cyclohexyl;SS : R S = 1.2:1 5, R = tert -Butyl; SS : RS = 1.3:1
AcO AcO
O
AcO
OAc
AcO
O
S+
AcO S+
R OAc OSS (Major)
+
AcO
OAc O
O-
OAc
S+ R
R S (Minor)
6, R = Ethyl; SS : R S = 1.5:1 7, R = Cyclohexyl; SS : RS = 1.5:1 Scheme 1. Alkyl b-D-glycosyl sulfoxides 1–7.
On the basis of the chemical shift differences of the methylene protons a to the sulfinyl group and other correlations shown in Figure 1,6 analysis of the b ethyl sulfoxides 2 showed that the chemical shift difference for the methylenic H-proR and H-proS protons was 30 Hz for the major sulfoxide and 130 Hz for the minor.11
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C. A. Sanhueza et al. / Tetrahedron: Asymmetry 21 (2010) 1830–1832
OAc AcO AcO
OAc
O AcO
S+
H R
H AcO S+ R OS S (Minor)
O-
RS (Major)
O
+ AcO AcO
8, R = Ethyl; SS : RS = 1:6.5 9, R = iso-Propyl; SS : RS = 1:7 10, R = Cyclohexyl; S S : RS = 1:8 11, R = tert -Butyl; SS : R S = 1:5 AcO AcO
OAc
OAc
AcO
O
+
H AcO + R S
AcO
O AcO
S+
-
RS (Major) O
O
S S (Minor)
H R
12, R =Ethyl; SS : RS = 1:5 13, R = Cyclohexyl; SS : RS = 1:10 Scheme 2. Alkyl a-D-glycosyl sulfoxides 8–13.
deshielded H2 OΦ
S+
HproS CH3
H1 O- HproR
HproS CH3
S+
shielded H1
*
*exo-anomeric effect
SS
deshielded
O-
H2 O
difference of 98 Hz was observed for those of the minor one 3R (RS configuration). Analysis of the chemical shift of H2 for the b-glucopyranosides showed that RS sulfoxides (1R–5R, minor products) have a practically constant value of d 5.44 ppm independent of the structure of the aglycon. In contrast, d H2 for SS sulfoxides (1S–5S, major products) changes with the aglycon, from 5.07 ppm for the methyl sulfoxide to 5.56 ppm for the tert-butyl sulfoxide. Therefore, the chemical shifts of the H2 axial proton are more deshielded in RS sulfoxides than in SS ones (Fig. 1). This is only fulfilled for sulfoxides 1 (methyl) and 2 (ethyl). Sulfoxides 3 (isopropyl) and 4 (cyclohexyl) showed the same d values for H2, independent of the sulfinyl configuration. For the tert-butyl sulfoxide 5 the d value for H2 in the sulfoxide SS appeared to be more deshielded than the RS sulfoxide (d H2 (SS) = 5.56 ppm; d H2 (RS) = 5.43 ppm). Therefore, the chemical shift of H2 is not a valid criterion for determining the configuration of the sulfinyl group, given its variability with the structure of the aglycon. The chemical shifts of the axial protons H3 and H5 for the alkyl a-D-glycosyl sulfoxides (Fig. 2) revealed a clear deshielding of these protons in sulfoxides having the SS configuration, as a result of the strong anisotropic effect of the sulfinyl group, relative to those with the RS configuration. This effect was found to be stronger for H5 than H3.
HproR
shielded
strong nOe
deshielded
RS
Figure 1. NMR properties of ethyl b-D-glycosyl sulfoxides.6
O
H1 H5 R S+ H3 exo-anomeric OSS
Furthermore, the chemical shifts of H2 and C1 were d 5.24 and 5.45 ppm and d 89.9 and 86.6 ppm, for the major and minor sulfoxides, respectively. These results concur with those reported6 indicating that the major glucosyl sulfoxide 2S has the SS configuration and the minor sulfoxide 2R, the RS configuration. A similar analysis was carried out for the b isopropyl sulfoxides 3. For the major sulfoxide 3S a Dd of 17 Hz was observed for the methyls of the isopropyl group, pointing to an SS configuration, while a
effect
O H1 H5 R + S H3 RS
O-
Figure 2. NMR properties of alkyl a-D-glycosyl sulfoxides.
It seems to be a general fact for the b-anomers that the 13C NMR chemical shift of the anomeric carbon of RS sulfoxides is shielded with respect to the corresponding SS epimers. Table 1 shows higher d C1 values for the b-SS stereoisomers than for the b-RS ones (Fig. 1). However, the opposite behavior was observed for the aanomers, the a-SS stereoisomers showing a smaller chemical shift
Table 1 Optical activity (CHCl3), NMR data (CDCl3), and CD data (CH3CN) of the alkyl glycosyl sulfoxides 1–13
a
#
R
Config.a
d H2 (ppm)
d H3 (ppm)
d H5 (ppm)
d C1 (ppm)
k (nm)
1S 2S 3S 4S 5S 6S 7S 1R 2R 3R 4R 5R 6R
Methyl Ethyl iso-Propyl Cyclohexyl tert-Butyl Ethyl Cyclohexyl Methyl Ethyl iso-Propyl Cyclohexyl tert-Butyl Ethyl
b-glc b-glc b-glc b-glc b-glc b-gal b-gal b-glc b-glc b-glc b-glc b-glc b-gal
11.8 34.4 10.4 22.3 +36.9 12.0 10.1 65.9 51.0 56.8 55.3 59.4 36.9
5.07 5.24 5.46 5.45 5.56 5.40 5.65 5.43 5.45 5.44 5.45 5.43 5.49
5.31 5.30 5.29 5.29 5.27 5.12 5.10 5.36 5.36 5.36 5.36 5.32 5.40
3.84 3.80 3.77 3.77 3.74 4.02 3.99 3.82 3.80 3.78 3.78 3.78 4.05
90.7 89.9 88.6 88.3 86.5 90.4 88.7 87.4 86.6 85.6 85.3 85.4 87.1
222 226 230 231 229 226 231 217 220 221 222 223 220
+6.4 +7.1 +9.1 +8.0 +8.9 +6.7 +4.0 9.1 11.0 9.6 8.3 8.5 7.6
8S 9S 11S 12S 13S 8R 9R 10R 11R 13R
Ethyl iso-Propyl tert-Butyl Ethyl Cyclohexyl Ethyl iso-Propyl Cyclohexyl tert-Butyl Cyclohexyl
a-glc a-glc a-glc a-gal a-gal a-glc a-glc a-glc a-glc a-gal
+177.0 +157.1 +140.0 +192.9 +100.0 +116.0 +129.4 +150.4 +30.0 +127.1
5.36 5.34 5.20 5.58 5.58 5.34 5.34 5.33 5.35 5.52
6.14 6.07 6.07 6.00 6.05 5.58 5.58 5.60 5.41 5.50
5.20 5.15 5.31 5.25 5.31 3.95 3.92 3.96 4.26 4.06
84.5 82.9 81.6 85.1 83.2 87.2 85.0 84.3 83.4 84.8
227 227 231 228 227 233 236 237 233 237
+8.2 +26.3 +21.1 +7.9 +7.1 11.0 11.7 15.7 8.2 8.7
glc: glucopyranosides; gal: galactopyranosides.
[a]D
De
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than the a-RS ones (Fig. 2). This behavior was explained by a higher exo-anomeric effect for the RS than for the SS stereoisomers (b-anomers)6 and for the SS than for the RS stereoisomers (a-anomers).12 Therefore, 13C NMR comparison of the chemical shift of the anomeric carbon of both sulfoxides is a good criterion for determining the absolute configuration of the sulfur atom when both stereoisomers are available. According to the data shown in Table 1, the optical activity cannot be used as a criterion for the absolute configuration of the sulfinyl group. However, its sign indicates the anomeric configuration, negative [a]D for the b-anomers and positive [a]D for the a-anomers, with the sole exception of the tert-butyl derivative 5S. The absolute configuration of dialkyl and alkyl aryl sulfoxides was studied by Mislow13 using optical rotatory dispersion, in addition to NMR.14 Thus, methyl alkyl sulfoxides without any other strongly perturbing group and having an RS configuration exhibited negative Cotton effects centered at the strong absorption band near 200 nm (acetonitrile) in ord. Our model sulfoxides were also analyzed by CD in CH3CN. For the b-anomers, the spectra showed a positive first Cotton effect around 228 nm,15,16 for the major sulfoxides 1S–7S, corresponding to an SS absolute configuration, and a negative first Cotton effect around 220 nm for minor sulfoxides 1R–6R, corresponding to an RS configuration (Fig. 2). On the other hand, for the a-anomers the minor stereoisomers 8S, 9S, and 11S–13S show a positive first Cotton effect around 228 nm (SS absolute configuration) and the major ones 8R–11R, and 13R, a negative first Cotton effect around 235 nm (RS absolute configuration). The wavelength of the first Cotton effect undergoes a bathochromic shift as the alkyl group increases in size (Table 1), most likely as a result of steric effects. More interestingly, this CD wavelength is indicative of the absolute configuration of the sulfoxide. Thus, for the b-anomers, higher wavelengths were observed for the (S)-stereoisomers than for their corresponding (R) ones, while for the a-anomers, the opposite behavior was observed. These results, which are in agreement with the Mislow‘s antecedents,13 can be predicted according to the rule shown in Figure 3. The first Cotton effect is negative, therefore the absolute configuration of the sulfoxide is RS when the sugar ring is on the left side of the plane formed by the oxygen (top), the lone electron pair (bottom), and the sulfur atom (center). The opposite sign (positive) corresponds to the SS absolute configuration. We thus propose a rule for determining the absolute configuration of glycosyl sulfoxides by CD (on the basis of the sign of the first Cotton effect). 7
222 nm (−6.4)
Δε 0
217 nm (−9.1) −15
190
350 nm
Figure 3. CD spectra of the methyl derivatives 1S (blue) and 1R (red) (CH3CN).
3. Conclusions
13
In summary, the present study reveals that comparison of the C NMR chemical shift of the anomeric carbons of the two diaste-
reomeric sulfoxides is a convenient general method to determine the absolute configuration of the sulfur atom of alkyl glycosyl sulfoxides, regardless of the structural nature of the alkyl group. Thus, for the b-anomers the SS stereoisomers show d C1 at lower fields than RS ones, while for the a-anomers the SS stereoisomers show d C1 at higher fields than RS. Additionally, the wavelength of the first Cotton effect is also indicative of the absolute configuration of the sulfur atom. Higher wavelengths were therefore observed for the b-SS stereoisomers than for their corresponding b-RS ones, while the opposite was seen for the a-SS/RS isomers. More significantly, CD analysis shows itself to be a more straightforward way to determine the absolute configuration of the sulfur atom in alkyl glycosyl sulfoxides. Only one stereoisomer is needed which is an advantage since both stereoisomers are not always available, and the running two 13C NMR spectra are more time consuming than a simpler CD measurement. An empirical rule for determining the absolute configuration of glycosyl sulfoxides by CD is therefore established (Fig. 4).
O− (Sugar) R S+ (R) Sugar
CD
R
Sugar O
RS
+
R or
Sugar
O
SS
Figure 4. Rule for determining the absolute configuration of glycosyl sulfoxides by CD (sign of the first Cotton effect).
Acknowledgments This work was supported by the Ministerio de Ciencia e Innovación (MICINN, Spain), through grant CTQ2007-67532-C02-02/BQU. C.A.S. thanks the Consejería de Educación, Cultura y Deportes (Gobierno de Canarias) for a fellowship. References 1. Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111, 6881. 2. Review: Aversa, M. C.; Barattucci, A.; Bonaccorsi, P. Tetrahedron 2008, 64, 7659. 3. Goodwin, N. C.; Harrison, B. A.; Iimura, S.; Mabon, R.; Song, Q.; Wu, W.; Yan, J.; Zhang, H.; Zhao, M. M. PCT Int. Appl., 2009. 4. Buist, P. H.; Behrouzian, B.; MacIsaac, K. D.; Cassel, S.; Rollin, P.; Imberty, A.; Gautier, C.; Pérez, S.; Genix, P. Tetrahedron: Asymmetry 1999, 10, 2881. 5. Yabuuchi, T.; Kusumi, T. J. Am. Chem. Soc. 1999, 121, 10646. 6. Khiar, N. Tetrahedron Lett. 2000, 41, 9059. 7. Crich, D.; Mataka, J.; Zakharov, L. N.; Rheingold, A. L.; Wink, D. J. J. Am. Chem. Soc. 2002, 124, 6028. 8. Kaczorowska, K.; Kolarska, Z.; Mitka, K.; Kowalski, P. Tetrahedron 2005, 61, 8315. 9. Kakarla, R.; Dulina, R. G.; Hatzenbuhler, N. T.; Hui, Y. W.; Sofia, M. J. J. Org. Chem. 1996, 61, 8347. 10. a-Thioglycosides lead predominantly to sulfoxides having the RS absolute configuration, while their b-anomers lead to diastereomeric mixtures of SS (major) and RS (minor) sulfoxides. See Refs. 6,7. 11. This difference in the chemical shift was explained by the presence of the exoanomeric effect in the b-RS stereoisomer, which confers rigidity around the glucosidic linkage. Conversely, the substrate of b-SS configuration is more flexible, exhibiting a small difference in the chemical shift of these protons. See Ref. 6. 12. Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Bruno, G.; Giannetto, P.; Rollin, P. Lett. Org. Chem. 2004, 1, 376. 13. Mislow, K.; Green, M. M.; Laur, P.; Melillo, J. T.; Simmons, T.; Ternary, A. L., Jr. J. Am. Chem. Soc. 1965, 87, 1958. 14. (a) Coyle, T. D.; Stone, F. G. A. J. Am. Chem. Soc. 1961, 83, 4138; (b) Mislow, K.; Glass, M. A. W.; Hopps, H. B.; Simon, E.; Wahl, G. H. J. Am. Chem. Soc. 1964, 86, 1710. These authors also noted the magnetic nonequivalence of the methylene protons in diethyl and ethyl isopropyl sulfoxides. 15. Probably due to the (3sp3)2?(3sp3) (3d) transition of the sulfinyl group, suggestive of an n?p transition. See Ref. 13. 16. Acetates are considered ‘nonchromophoric’ groups since they give small Cotton effects at around 200 nm.