NMR spectroscopic determination of the absolute configuration of chiral sulfoxides via N-(methoxyphenylacetyl)sulfoximines [11]

Full text of DOI:10.1021/ja992730g

10646
J. Am. Chem. Soc. 1999, 121, 10646-10647
Scheme 1
NMR Spectroscopic Determination of the Absolute
Configuration of Chiral Sulfoxides via
N-(Methoxyphenylacetyl)sulfoximines
Tetsuya Yabuuchi and Takenori Kusumi*
Faculty of Pharmaceutical Sciences
Tokushima UniVersity, Tokushima 770-8505, Japan
ReceiVed August 2, 1999
An increasing number of reports is being published on the
NMR methods that enable the elucidation of the absolute
configuration of chiral secondary alcohols,1 amines,2 and car-
boxylic acids.3 In respect to chiral sulfoxides, however, there have
been very few methods to determine their absolute configuration
except for X-ray crystallography, although the sulfinyl moiety is
an important functional group that is frequently found in biologi-
cally active natural products and synthetic drugs. 9-Anthryl-1,1,1-
trifluoroethanol,4 R-methoxyphenylacetic acid,5 and (R)-(-)-N-
(3,5-dinitrobenzoyl)-R-phenylethylamine6 have been developed
as the NMR reagents for deducing the absolute configuration of
sulfoxides. These reagents form complexes by hydrogen bonds
between their acidic OH groups and the oxygen atom of the
sulfoxide, and because of the instability of the complexes, the
chemical shift differences between the diastereomeric complexes
are usually very small or in some cases nonsystematic, which
makes these methods somewhat uncertain. Difficulty in assuming
the stable conformation of the fragile complexes may also be an
intrinsic drawback of these methods.
We considered that, if a certain chiral anisotropic reagent7 could
be covalently bonded to the stereogenic sulfur or the sulfoxide
oxygen, the anisotropic effect from the aromatic ring of the chiral
auxiliary would be more significant than the conventional
hydrogen-bonded complexes. Introduction of a chiral anisotropic
moiety at the sulfoxide oxygen seems less promising because the
Pummerer rearrangement8 would occur on acylation, and the
information on the chirality would thus be lost. Therefore, we
focused on amination of sulfoxide with O-mesitylsulfonylhy-
droxylamine9 which proceeded with complete retention of chirality
at the sulfur atom.10 The strategy of our method is outlined in
Scheme 1.
When an amino group is introduced at the stereogenic sulfur
atom, (R)- and (S)-methoxyphenylacetic acids can be introduced
specifically at the nitrogen atom. The stable conformation of the
resulting N-(methoxyphenylacetyl)sulfoximine is easily deduced
to be [I],11 because the alternative conformations [II] and [III]
will be destablized by the serious dipole-dipole repulsion between
the electronegative atoms. The absolute configurations will be
determined by the “Sulfoximine Model” in an analogous way to
the modified Mosher’s method.1
To see if this strategy works as expected, racemic sulfoxides
1-4 were prepared by reaction of methyl alkylsulfinates12 with
Grignard reagents as shown in Scheme 2. The racemic sulfoxides
were treated with O-mesitylsulfonylhydroxylamine in dichlo-
romethane to give the corresponding sulfoximines 1a-4a in 60-
80% yields. Each product was condensed with rac-methoxyphe-
nylacetic acid (PyBOP/HOBT),13 affording the respective
N-(methoxyphenylacetyl)sulfoximines 1b-4b in 50-80% yields.
The enantiomeric pairs of diastereomers were separated by flash
chromatography, and the “apparent” ∆δ values were calculated
by subtracting the proton chemical shifts of the fast-eluting
N-(methoxyphenylacetyl)sulfoximine from those of the slow-
eluting one. The results are shown in Scheme 2. The apparent
∆δ values with opposite signs are arranged systematically on both
sides of the methoxyphenylacetyl plane (Scheme 2).
(1) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 4929. (c) Ohtani, I.;
Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
(d) Latypov, S.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 1995, 60, 504. (e)
Seco, J. M.; Latypov, S.; Quin˜oa´, E.; Riguera, R. Tetrahedron Asymmetry
1995, 6, 107.
This new methodology was applied to chiral sulfoxides
5-15.14,15 These optically active sulfoxides were prepared by the
diacetone-D-glucose method,16 which can produce the chiral
sulfoxides with predictable absolute configurations (Scheme 3).
The chiral sulfoxides were aminated with O-mesitylsulfonylhy-
(2) Kusumi, T.; Fukushima, T.; Ohtani, I.; Kakisawa, H. Tetrahedron Lett.
1991, 32, 2939.
(3) Nagai, Y.; Kusumi, T. Tetrahedron Lett. 1995, 36, 1853.
(4) Pirkle, W. H.; Sikkenga, D. L. J. Chromatogr. 1976, 123, 400.
(5) Gautier, N.; Noiret, N.; Nugier, C. C.; Patin, H. Tetrahedron Asymmetry
1997, 8, 501.
(11) An X-ray analysis of S,S-dimethyl N-(methoxyphenylacetyl)sulfox-
imine indicated that its methoxyphenylacetyl part existed in the expected
conformation whereas the dimethylsulfoximine moiety rotates in 30° from
the supposed one. This deviation may have been caused by the stacking effect;
a neighboring molecule was found to be located very close to the questioning
molecule. The verification of conformation [I] by ab initio MO calculation is
in progress.
(12) (a) Andersen, K. K. Tetrahedron Lett. 1962, 18, 93. (b) Andersen, K.
K.; Gaffield, W.; Papanikolaou, N. E.; Foley, J. W.; Perkins, R. I. J. Am.
Chem. Soc. 1964, 88, 5637.
(6) Deshmukh, M.; Dunach, E.; Kagan, H. B. Tetrahedron Lett. 1984, 25,
3467.
(7) Kusumi, T.; Takahashi, H.; Ping, X.; Fukushima,T.; Asakawa, Y.;
Hashimoto, T.; Kan, Y. Tetrahedron Lett. 1994, 35, 4397.
(8) (a) Pummerer, R. Chem. Ber. 1910, 43, 1401. (b) Horner, L.; Kaiser,
L. Liebig’s Ann. Chem. 1959, 19, 626. (c) Oae, S.; Kise, H. Tetrahedron Lett.
1986, 2261. (d) Boyle, R. E. J. Org. Chem. 1966, 31, 83.
(9) (a) Tamura, Y.; Minamikawa, J.; Sumoto, K. J. Org. Chem. 1973, 38,
1239. (b) Tamura, Y.; Sumoto, K.; Minamikawa, J.; Ikeda, M. Tetrahedron
Lett. 1972, 40, 4137.
(13) (a) Coste, J.; Le-Nguyen, D.; Castro, B. Tetrahedron Lett. 1990, 31,
205. (b) Jensen, T. H.; Jakobsen, M. H.; Olsen, C. E. Tetrahedron Lett. 1991,
32, 7617.
(10) Johnson, C. R.; Kirchhoff, R. A.; Corkins, H. G. J. Org. Chem. 1974,
39, 2458.
10.1021/ja992730g CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/30/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 45, 1999 10647
Scheme 2
Scheme 3
Figure 1. The ∆δ values [∆δ ) δ[(S)-amide] - δ[(R)-amide]] obtained for
1
N-MPA-sulfoximides 5a-15a. The H-NMR spectra were recorded at
400 MHz (CDCl3).
The absolute configurations, determined by the present method,
of these sulfoxides are in complete accord with those of the known
ones (1217 and 1417) and as predicted by the literature (5-11,
13).16 The ∆δ values of the protons are much larger than those
observed in the conventional methods such as those using
methoxytrifluoromethylphenylacetic acid (MTPA) for secondary
alcohols, which indicates that the presumed conformation of the
N-(methoxyphenylacetyl)sulfoximine (Scheme 1) is quite pre-
dominant.
We later found that N-(methoxyphenylacetyl)sulfoximine (7a)
was obtained from sulfoxide (7) in 61% yield by a one-pot
reaction (7/O-mesitylsulfonylhydroxylamine/CH2Cl2 then meth-
oxyphenylacetic acid/PyBOP/HOBT/pyridine), without isolation
of the sulfoximine. This finding may greatly contribute to the
expediency of the present methodology.
droxylamine followed by acylation with (R)- and (S)-methoxy-
phenylacetic acids to give a single diastereomer in each case. The
∆δ values were calculated according to the equation ∆δ ) δS-amide
- δR-amide. The results are shown in structures 5a-15a (Figure
1).
(14) The enantiomeric excess (ee) values of the synthesized sulfoxides are
as follow: 5, 99%; 6, 98%; 7, 98%; 8, 94%; 9, 98%; 10, 95%; 11, 94%; 12,
67%; 13, 45%; 14, 96%; 15, 46%. These ee’s were determined by comparing
the chiroptical properties with those reported (12 and 14), or integration of
the proton signals observed for the corresponding S,S-dimethyl N-(methoxy-
phenylacetyl)sulfoximine diastereomers. Alternation of stereochemistry in the
amination reaction of the chiral sulfoxides or the epimerization of the
methoxyphenylacetyl moiety did not occur at all, because (i) the ee’s observed
for 12a and 14a were exactly the same as those for 12 and 14 and (ii) the
ee’s obtained by analyzing the 1H NMR spectra of 5a-15a were identical
between their (R)- and (S)-N-(methoxyphenylacetyl) derivatives.
(15) The 1H NMR spectra were recorded at 32 °C for the 6 mM CDCl3
solutions.
(16) (a) Ferna´ndez, I.; Khiar, N.; Llera, J. M.; Alcudia, F. J. Org. Chem.
1992, 57, 6789. (b) Khiar, N.; Ferna´ndez, I.; Alcudia, F. Tetrahedron Lett.
1994, 35, 5719. (c) Gautier, N.; Noiret, N.; Nugier, C. C.; Patin, H. Tetrahedron
Asymmetry 1997, 8, 501.
(17) Drabowicz, J.; Bujnicki, B.; Mikolajczyk, M. J. Org. Chem. 1981,
46, 2788.
Supporting Information Available: Procedure of the one-pot reaction
from (R)-(ethyl 2-phenylethyl sulfoxide) to the corresponding (S)-N-
(methoxyphenylacetyl)sulfoximine and the 1H and 13C NMR data of (R)-
and (S)-N-(methoxyphenylacetyl)sulfoximines (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA992730G