The first highly efficient asymmetric synthesis of α-substituted methyl sulfonates

Article abstract of DOI:10.1002/1521-3773(20020104)41:1<109::AID-ANIE109>3.0.CO;2-F

The right choice of sugar auxiliary led to a breakthrough in the first asymmetric α-alkylations of sulfonic acid esters (see scheme). The high asymmetric inductions were reached with 1,2:5,6-di-O-isopropyliden-α-D-allofuranose as the auxiliary group, whic

Full text of DOI:10.1002/1521-3773(20020104)41:1<109::AID-ANIE109>3.0.CO;2-F

COMMUNICATIONS
gradients with a strength of 56 GcmÀ1. All spectra were acquired with a
5 mm TBI probehead. For the DOSY experiments the BPPLED[3, 15] pulse
sequence or a modification of the INEPT DOSY sequence were used.[8]
The pulse-field gradients (g) were incremented in 32steps from 2% up to
95% of the maximum gradient strength in a linear ramp. Gradient lengths d
between 1.5 and 2.0 ms, diffusion times D between 90 and 200 ms, and an
eddy current delay (Te) of 5 ms were employed. After Fourier trans-
formation and baseline correction, the diffusion dimension was processed
by using the Bruker xwinnmr package (version 3.0) and the diffusion values
were read directly from the spectra.
The First Highly Efficient Asymmetric
Synthesis of a-Substituted Methyl Sulfonates**
Dieter Enders,* Nicola Vignola, Otto M. Berner,
and Jan W. Bats
Dedicated to Professor Dieter Hoppe
on the occasion of his 60th birthday
A number of a-substituted sulfonic acids with interesting
pharmacological properties is known, and numerous com-
pounds of this class have been isolated, synthesized, and
tested for their biological activity. For instance, 6-gingesul-
fonic acid, which shows anti-ulcer activity, was isolated from
Zingiberis Rhizoma.[1] Several a-substituted sulfonic acids,
which are known as semisynthetic b-lactam antibiotics, have
been examined with regard to their antibacterial activity.[2]
Cefsulodin, a representative compound of the semisynthetic
cephalosporins, shows potent in vivo antipseudomonal activ-
ity against Pseudomonas aeruginosa.[3] Other compounds such
as a-phosphonosulfonic acid derivatives are known as potent
squalene synthase inhibitors.[4]
Enantiopure a-substituted sulfonic acids are also employed
in synthesis as strongly acidic resolving agents, especially for
free neutral amino acids. For example, (S)-(À)-1-phenyletha-
nesulfonic acid ((À)-PES) was found to be an efficient
resolving agent for the optical resolution of dl-leucine.[5]
The related (‡)-2-(2,3,4-trichlorophenyl)ethanesulfonic acid
((‡)-TCPES) has been used as resolving agent for antifungal
sulfoximines.[6]
Considering their synthesis, enantiopure a-substituted
sulfonic acids are commonly obtained from the corresponding
racemates by resolution techniques with chiral amines.[7] To
the best of our knowledge, only two stereoselective methods
are known for the synthesis of optically active a-substituted
sulfonic acids. Corey et al. reported the conversion of
enantiopure (R)-1-phenylethanol to ((À)-PES) in a multistep
procedure.[8] For the synthesis of a squalene synthase inhib-
itor, the asymmetric a-alkylation of an a-phosphonosulfonate
bearing the chirality information within the phosphono
moiety was employed. To date this is the only known
auxiliary-controlled method for the asymmetric synthesis of
a-substituted sulfonates.[9]
For the experiment with a mixture of 4 and 6, a solution of 4 (0.013 mmol)
and 6 (0.041 mmol) in [D8]THF (400 mL) was prepared. For the monitoring
of the reaction of 1 with 13CO2, 1 (0.050 mmol) and [D8]THF (350 mL) were
placed in a pressure-stable NMR tube (Wilmad 522-PP), degassed, and
then frozen. 13CO2 (0.060 mmol) was condensed in vacuo on top of the
frozen mixture. The tube was sealed and transferred into the precooled
magnet.
Received: July 16, 2001 [Z17510]
[1] a) E. J. Cabrita, S. Berger, Magn. Reson. Chem. 2001, in press; b) G. S.
Kapur, E. J. Cabrita, S. Berger, Tetrahedron Lett. 2000, 41, 7181 7185;
c) M. D. DÌaz, S. Berger, Carbohydr. Res. 2000, 329, 1 5; d) review:
C. S. Johnson, Prog. NMRSpectrosc. 1999, 34, 203 256.
[2] a) A. Chen, M. J. Shapiro, Anal. Chem. 1999, 71, 669A 675A; b) J. S.
Gounarides, A. Chen, M. J. Shapiro, J. Chromatogr. B 1999, 725, 79
90.
[3] M. D. Pelta, H. Barjat, G. A. Morris, A. L. Davis, S. J. Hammond,
Magn. Reson. Chem. 1998, 36, 706 714.
[4] a) I. Kereztes, P. G. Williard, J. Am. Chem. Soc. 2000, 122, 102 2 8
10229. Diffusion studies without DOSY: b) M. Valentini, P. S.
Pregosin, H. R¸egger, J. Chem. Soc. Dalton Trans. 2000, 4507 4510,
and references therein; c) A. Pichota, P. S. Pregosin, M. Valentini, M.
Wˆrle, D. Seebach, Angew. Chem. 2000, 112, 157 160; Angew. Chem.
Int. Ed. 2000, 39, 153 156; d) S. Beck, A. Geyer, H. H. Brintzinger,
Chem. Commun. 1999, 2477 2478.
[5] G. Fachinetti, C. Floriani, A. Roselli, S. Pucci, J. Chem. Soc. Chem.
Commun. 1978, 269 270.
[6] N. E. Schlˆrer, S. Berger, Organometallics 2001, 20, 1703 1704.
[7] A. Cutler, M. Raja, A. Todaro, Inorg. Chem. 1987, 26, 2877 2881.
[8] D. Wu, A. Chen, C. S. Johnson, J. Magn. Reson. Ser. A 1996, 123, 215
218.
[9] The 13C INEPTexperiment was chosen because during the reaction of
[Cp2Zr(Cl)H] with CO2 the Cp region of the 1H NMR spectrum shows
a strong overlap of signals, which creates difficulties for processing 1H
DOSY spectra. The INEPT spectrum allows not only an easier
assignment of signals due to the broader dispersion of carbon chemical
shifts but has also the advantage of higher sensitivity than 13C DOSY
and an easier set-up because in the experiment the diffusion encoding
occurs in the proton frequency.
[10] C. S. Johnson in Encyclopedia of Nuclear Magnetic Resonance, Vol. 5
(Eds.: D. M. Grant, R. K. Harris), Wiley, New York, 1996, pp. 1626
1644.
[11] H. B. Bradley, L. G. Dowell, Anal. Chem. 1958, 30, 548; A. F. Reid,
J. S. Shanon, J. M. Swan, P. C. Wailes, Aust. J. Chem. 1965, 18, 173
181.
In contrast, no method is known to perform asymmetric a-
alkylations of metalated sulfonic esters prepared from enan-
tiopure alcohols as auxiliaries. A serious problem during
metalation of sulfonic esters could be b-elimination under
these basic conditions.
[12] Signal-to-noise ratio in the 13C INEPT spectrum: 20:1.
[13] The signal at d ˆ 114.6 arises from the overlapping Cp signals of the
complexes 3 and 4, which due to their almost identical molecular
weight cannot be resolved in the diffusion dimension. However, the
assignment of the Cp signal of 3 is clear since the CH2 signal can be
used as a reference for the self-diffusion coefficient.
[14] Geometries were optimized at the semiempirical PM3-level with
SPARTAN (Version 5.1.1, Wavefunction, Inc., 18401 Von Karman
Ave., Ste. 370, Irvine, CA 92612 USA). PM3: J. J. P. Stewart, J.
Comput. Chem. 1989, 10, 209 220; J. J. P. Stewart, J. Comput. Chem.
1989, 10, 221 264; SPARTAN 5.1.1: Wavefunction, Inc., 18401 Von
Karman Ave., Ste. 370, Irvine, CA 92612, USA.
[*] Prof. Dr. D. Enders, Dipl.-Chem. N. Vignola, Dr. O. M. Berner
Institut f¸r Organische Chemie der RWTH Aachen
Professor-Pirlet-Strasse 1, 52074 Aachen (Germany)
Fax : (‡49)241-80-92127
E-mail: enders@rwth-aachen.de
Dr. J. W. Bats
Institut f¸r Organische Chemie der Universit‰t Frankfurt
Marie-Curie-Strasse 11, 60439 Frankfurt am Main (Germany)
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 380) and the Fonds der Chemischen Industrie. We thank the
companies Degussa AG, BASF AG, Bayer AG, and Aventis for the
donation of chemicals.
[15] S. J. Gibbs, C. S. Johnson, J. Magn. Reson. 1991, 93, 395 402.
[16] T. E. Hogen-Esch, J. Smid, J. Am. Chem. Soc. 1966, 88, 318 324.
Angew. Chem. Int. Ed. 2002, 41, No. 1
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4101-0109 $ 17.50+.50/0
109

COMMUNICATIONS
Table 1. Asymmetric a-alkylation of sulfonates 1 to afford sulfonates 2.
We report here the first asymmetric a-alkylations of
lithiated sulfonic esters bearing a removable enantiopure
alcohol auxiliary. As chiral auxiliary 1,2:5,6-di-O-isopropyl-
idene-a-d-allofuranose was used, which was synthesized on a
30 g scale from inexpensive 1,2:5,6-di-O-isopropylidene-a-d-
glucose according to an improved and simple epimerization
procedure in 70% yield.[10] This sugar has also been used as a
chiral auxiliary in the alkylation of ester enolates,[11] but only
moderate diastereoselectivities were observed.
We obtained the sulfonates 1 by reaction of the allofur-
anose derivative with benzylic sulfonyl chlorides, which are
commercially available or can be easily prepared from the
corresponding sodium sulfonates[12] starting from the benzylic
bromides.[13] As shown in Scheme 1, the enantiopure sulfo-
nates 1 were metalated with one equivalent of n-butyllithium
[c]
2
R1
R2
Yield [%]
de[%][a,b]
[a]D
a
b
c
d
e
H
H
H
tBu
tBu
methyl
allyl
benzyl
benzyl
95
93
94
95
98
91 (ꢀ98)
90 (ꢀ98)
89 (ꢀ98)
91 (ꢀ98)
93 (ꢀ98)
‡ 91.3
‡ 77.0
‡ 34.4
‡ 22.6
‡ 3.8
(2-naphtyl)methyl
[a] Values in parentheses after recrystallization from 2-propanol. [b] De-
termined by 13C NMR spectroscopy. [c] All optical rotations were
measured in Uvasol grade CHCl3 with concentrations of 1.0 at room
temperature.
R2
SO3R*
SO3CH3
R1
R1
(R)-4a-e
ee ≥ 98%
1
a
94-98%
c
Figure 1. X-ray crystal structure of 2d.[14]
R2
R2
b
Finally, many procedures were screened for an efficient
racemization-free cleavage of the auxiliary. The best results
were achieved by refluxing the sulfonates 2 in an EtOH/H2O
solution containing 15 mol% Pd(OAc)2 for four days.[15] To
isolate the final products in a more accessible form, the
sulfonic acids 3 were directly converted with diazomethane to
the corresponding title methyl sulfonates (R)-4,[16] which were
obtained in very good yields and as pure stereoisomers
(Scheme 1, Table 2).
To explain the high diastereofacial selectivity of the
electrophilic substitutions in the a-position to the sulfonate
function, the solution structure and aggregation of the
lithiated chiral sulfonates remains to be determined.
In conclusion, the novel protocol provides an efficient and
first practical route to optically active a-substituted methyl
sulfonates. The asymmetric a-alkylation and the removal of
the auxiliary proceed in good overall yields and lead to the
final products in excellent enantiomeric excesses. The highly
enantioenriched title compounds are valuable substrates for
SO3R*
SO3H
86-98%
R1
R1
(R)-2a-e
de = 89-93% ( ≥ 98%)[a]
(R)-3
O
O
H3C
H3C
O
O
CH3
CH3
R* =
O
Scheme 1. Asymmetric synthesis of a-alkylated methyl sulfonates. a) 1.
nBuLi (1.0 equiv), THF, À(90 95)8C, 1 h; 2. R2X (1.5 equiv), À(90
95)8C, 1 h, À788C, 24 h; b) Pd(OAc)2 (15 mol%), EtOH/H2O, reflux,
4 d; c) CH2N2 (ethereal solution). [a] After recrystallization from 2-prop-
anol.
in tetrahydrofuran at À(90 95)8C. At low temperatures any
side reactions are minimized, such as the attack of n-
butyllithium on the sulfonate moiety or a b-elimination of
the lithium alcoholate of the sugar auxiliary. The lithiated
sulfonic esters are allowed to react with the electrophiles at
À(90 95)8C for one hour and then at À788C for 24 h. Work-
up and purification gave the a-substituted sulfonates 2 in
excellent yields (94 98%) and high diastereomeric excesses
of de ˆ 89 93% (Table 1). Virtually diastereomerically pure
sulfonates could be obtained by recrystallization from 2-prop-
anol (de ꢀ 98%).
Table 2. Removal of the chiral auxiliary to form the title methyl sulfonates
4.
[b]
(R)-4
R1
R2
Yield [%]
ee [%][a]
[a]D
a
b
c
d
e
H
H
H
tBu
tBu
methyl
allyl
benzyl
benzyl
98
90
94
88
86
ꢀ 98
ꢀ 98
ꢀ 98
ꢀ 98
ꢀ 98
‡ 25.6
À 6.3
À 77.4
À 92.8
À 108.2
(2-naphtyl)methyl
The configuration of the newly formed stereogenic center
was determined to be R through single-crystal X-ray structure
analysis in the case of product 2d (Figure 1).[14] Since we can
postulate a uniform reaction mechanism, all the described
examples should possess the same configuration.
[a] Determined by HPLC using a chiral stationary phase ((R)-4a: Daicel
OJ, n-heptane/2-propanol 85/15; (R)-4b: Whelk O1, n-heptane/2-propanol
95/5; (R)-4c e: Daicel OD 2, n-heptane/2-propanol 95/5). [b] All optical
rotations were measured in Uvasol grade CHCl3 with concentrations of 1.0
at room temperature.
110
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4101-0110 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 1

COMMUNICATIONS
[13] a) S. Otto, J. B. F. N. Engberts, J. C. T. Kwak, J. Am. Chem. Soc. 1998,
120, 9517 9525; b) H. Abdellaoui, P. Depreux, D. Lesieur, B. Pfeiffer,
P. Bontempelli, Synth. Commun. 1995, 25, 1303 1311.
further synthetic transformations, which are currently being
investigated in our laboratory.
[14] Crystal data for 2d: single crystals were obtained by recrystallization
from ethyl acetate. The substance (C30H40O8S, Mr ˆ 560.68) crystal-
lized in the monoclinic space group P21, a ˆ 17.624(2), b ˆ 18.704(2),
Experimental Section
c ˆ 26.905(5) ä, b ˆ 92.436(14)8, Vˆ 8861(2) ä3, Z ˆ 12, 1calcd
ˆ
1.216 gcmÀ3, F(000) ˆ 3600, Tˆ 173(2) K. Data collection: A single
crystal (colorless transparent block with dimensions 0.12 Â 0.2 Â
1.3 mm) was measured on a SIEMENS SMART diffractometer at a
temperature of about À1008C. Repeatedly measured reflections
remained stable. An empirical absorption correction was made by
using the program SADABS. The correction factor ranged from 0.950
to 1.000. Equivalent reflections were averaged. Friedel opposites were
not averaged. R(I)int ˆ 0.092. The structure was solved by direct
methods using the program SHELXS. The H atoms were placed at
calculated positions and were treated as riding atoms. The structure
was refined on F 2 values using the program SHELXL-97. Max./min.
resiual electron denisty À0.25/ ‡ 0.25 eäÀ3. The absolute configura-
tion of the structure was confirmed by the value of the Flack x
parameter (x ˆ À0.04(3)). Crystallographic data (excluding structure
factors) for the structures reported in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-168530. Copies of the data can be obtained free
of charge on application to CCDC, 12Union Road, Cambridge
CB21EZ, UK (fax: (‡44)1223-336-033; e-mail: deposit@ccdc.cam.
ac.uk).
Typical procedure for the a-alkylation: The enantiopure sulfonate 1
(1 mmol) was dissolved in dry THF (20 mL) and the solution cooled to
À(90 95)8C. After 30 min nBuLi (1.0 equiv) was added dropwise. The
solution was stirred for an additional hour after which the electrophile
(1.5 equiv in 5 mL THF) was added dropwise. The mixture was stirred for
1 h at À(90 95)8C, then at À788C. After 24 h the reaction was quenched
by adding pH 7 buffer (2mL). The mixture was partitioned between H 2O
and CH2Cl2 and washed with brine. The aqueous layer was then extracted
three times with CH2Cl2. The combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (SiO2, pentane/
diethyl ether).
Typical procedure for the removal of the chiral auxiliary: The sulfonate 2
(0.6 mmol) was dissolved in an EtOH/H2O solution (19 mL/1 mL).
Pd(OAc)2 (15 mol%) was added to the solution and the mixture was
refluxed for four days (TLC control). The palladium residues were
removed by filtration and washed twice with EtOH. The filtrate was
treated with an ethereal solution of diazomethane until the yellow color
persisted. The solvent was evaporated under reduced pressure and the
crude product purified by flash column chromatography (SiO2, pentane/
diethyl ether).
[15] As the sugar auxiliary is rather cheap, it is acceptable at the present
stage that the auxiliary cannot be recycled under these conditions.
[16] a) A. Windaus, E. Kuhr, Liebigs Ann. Chem. 1937, 532, 52 68; b) W.
Treibs, I. Lorenz, Chem. Ber. 1949, 82, 400 405; c) G. Geiseler, R.
Kuschmiers, Chem. Ber. 1958, 91, 1881 1891; d) H. C. Hansen, J. L.
Kice, J. Org. Chem. 1983, 48, 2943 2949; e) H. Ishiyama, M. Ishibashi,
A. Ogawa, S. Yoshida, J. Kobayashi, J. Org. Chem. 1997, 62, 3831
3836.
Received: August 10, 2001 [Z17705]
[1] M. Yoshikawa, S. Yamaguchi, K. Kunimi, H. Matsuda, Y. Kuno, J.
Yamahara, N. Murakami, Chem. Pharm. Bull. 1994, 42, 1226 1230.
[2] a) S. Morimoto, H. Nomura, T. Ishiguro, T. Fugono, K. Maeda, J. Med.
Chem. 1972, 15, 1105 1108; b) S. Morimoto, H. Nomura, T. Fugono,
T. Azuma, I. Minami, M. Hori, T. Masuda, J. Med. Chem. 1972, 15,
1108 1111.
[3] I. Minami, H. Akimoto, M. Kondo, H. Nomura, Chem. Pharm. Bull.
1983, 42, 482 489.
[4] a) D. R. Magnin, S. A. Biller, Y. Chen, J. K. Dickson, Jr., O. M.
Fryszman, R. M. Lawrence, J. V. H. Logan, E. S. Sieber-McMaster,
R. B. Sulsky, S. C. Traeger, D. C. Hsieh, S. Lan, J. K. Rinehart, T. W.
Harrity, K. G. Jolibois, L. K. Kunselmann, L. C. Rich, D. A. Slusarch-
yk, C. P. Ciosek, Jr., J. Med. Chem. 1996, 39, 657 660; b) J. K.
Dickson, Jr., S. A. Biller, D. R. Magnin, E. W. Petrillo, Jr., J. W.
Hillyer, D. C. Hsieh, S. Lan, K. Rinehart, R. E. Gregg, T. W. Harrity,
K. G. Jolibois, S. S. Kalinowski, L. K. Kunselman, K. A. Mookhtiar,
C. P. Ciosek, Jr., J. Med. Chem. 1996, 39, 661 664.
[5] R. Yoshioka, K. Okamura, S. Yamada, K. Aoe, T. Da-te, Bull. Chem.
Soc. Jpn. 1998, 71, 1109 1116.
[6] H. Kawanishi, H. Morimoto, T. Nakano, T. Watanabe, K. Oda, K.
Tsujihara, Heterocycles 1998, 49, 181 189.
Protonated Sulfuric Acid: Preparation of
Trihydroxyoxosulfonium
‡
À
Hexafluoroantimonate H3SO4 SbF6 **
Rolf Minkwitz,* Raphael Seelbinder, and
¬
Rene Schˆbel
Dedicated to Professor Karl Otto Christe
on the occasion of his 65th birthday
[7] E. B. Evans, E. E. Mabbott, E. E. Turner, J. Chem. Soc. 1927, 1159
1168.
One of the strongest acids is 100% sulfuric acid and this
marks per definition the border to the superacids. Among the
ions that are formed by the autoprotolysis of sulfuric acid
according to Equation (1), only the structure of the hydro-
gensulfate ion in solid salts and that of sulfuric acid itself is
known.[1, 2]
[8] E. J. Corey, K. A. Cimprich, Tetrahedron Lett. 1992, 33, 4099 4102.
[9] R. M. Lawrence, S. A. Biller, J. K. Dickson, J. V. H. Logan, D. R.
Mignin, R. B. Sulsky, J. D. DiMarco, J. Z. Gougoutas, B. D. Beyer,
S. C. Taylor, S. Lan, C. P. Ciosek, Jr., T. W. Harrity, K. G. Jolibois,
L. K. Kunselman, D. A. Slusarchyk, J. Am. Chem. Soc. 1996, 118,
11668 11669. For the asymmetric synthesis of sulfonic acid deriva-
tives see: a) M. H. H. Nkunya, B. Zwanenburg, Recl. Trav. Chim.
Pays-Bas 1985, 104, 253 259; b) F. A. Davis, P. Zhou, J. Org. Chem.
1993, 58, 4890 4896; c) D. Enders, C. R. Thomas, G. Raabe, J.
Runsink, Helv. Chim. Acta 1998, 81, 1329 1336; d) C. Huart, L.
Ghosez, Angew. Chem. 1997, 109, 627 629; Angew. Chem. Int. Ed.
Engl. 1997, 36, 634 636.
[10] W. Sowa, G. H. S. Thomas, Can. J. Chem. 1966, 44, 836 837.
[11] H. Kunz, J. Mohr, J. Chem. Soc. Chem. Commun. 1988, 19, 1315 1317.
[12] D. Brundish, A. Bull, V. Donovan, J. D. Fullerton, S. M. Garman, J. F.
Hayler, D. Janus, P. D. Kane, M. McDonell, G. P. Smith, R. Wakeford,
C. V. Walker, G. Howarth, W. Hoyle, M. C. Allen, J. Ambler, K.
Butler, M. D. Talbot, J. Med. Chem. 1999, 42, 4584 4603.
‡
À
2H2SO4 À! H3SO4 ‡ HSO4
(1)
[*] Prof. Dr. R. Minkwitz, Dipl.-Chem. R. Seelbinder, R. Schˆbel
Fachbereich Chemie, Anorganische Chemie
Universit‰t Dortmund
Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
Fax : (‡49) 231-755-5048
E-mail: minkwitz@citrin.chemie.uni-dortmund.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft.
Angew. Chem. Int. Ed. 2002, 41, No. 1
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4101-0111 $ 17.50+.50/0 111