Practical Synthesis of Chiral Sultam Auxiliaries: 3-Substituted-1,2-benzisothiazoline 1,1-Dioxides

Full text of DOI:10.1021/jo970917p

J . Org. Chem. 1997, 62, 7047-7048
7047
P r a ctica l Syn th esis of Ch ir a l Su lta m
Au xilia r ies: 3-Su bstitu ted -
1,2-ben zisoth ia zolin e 1,1-Dioxid es
Kyo Han Ahn,* Cheol Ham, Seung-Kee Kim, and
Chang-Woo Cho
Department of Chemistry and Center for Biofunctional
Molecules, Pohang University of Science & Technology
(POSTECH), San 31 Hyoja-dong, Pohang 790-784,
Republic of Korea
Received May 23, 1997
The sultam compounds 1 and 2 are an important class
of chiral auxiliaries, developed by Oppolzer and co-
workers.1 They are structurally simpler than the well-
known Oppolzer’s camphorsultam auxiliary2 and have a
benzene chromophore which makes their detection easier.
Sultam 1 has been shown to be a highly selective chiral
auxiliary in asymmetric alkylations, acylations, aldoliza-
tions, and Diels-Alder reactions.1b,c Both enantiomers
of sultam 1 are synthesized from an inexpensive starting
material, saccharin (4), in two steps:1a (1) methyllithium
addition to saccharin to give the corresponding N-
sulfonylimine 5a ; (2) asymmetric hydrogenation of the
sulfonylimine with a Ru-BINAP catalyst. Sultam 2 is
also an excellent chiral auxiliary, particularly for the 1,3-
dipolar cycloaddition of nitrile oxides, for which moderate
stereoselectivities were observed with sultam 1.1d In
spite of the excellent stereofacial discrimination of sultam
auxiliary 2, its usefulness as a chiral auxiliary has not
been explored fully, probably owing to its multistep
preparation. Each enantiomer of sultam 2 was prepared
by chemical resolution of the racemic mixture via N-(S)-
camphorsulfonylated sultams.1d Sultam 3 has been
briefly tested as an auxiliary in a racemic form in the
Diels-Alder reaction.1b Because it has a phenyl group
which could possibly participate in π-π interactions
during the cycloaddition stage, it would be of interest to
study it and its analogs as chiral auxiliaries further. As
a continuing project toward the development and utiliza-
tion of chiral auxiliaries in asymmetric reactions,3 we
have studied a more efficient synthesis of chiral 3-sub-
stituted sultam compounds. Here we report a practical
synthesis of the sultam auxiliaries 2 and 3 in high
enantiomeric excess which is also applicable to the
synthesis of other structural analogs.
with Noyori’s RuCl(TsDPEN)(benzene) catalyst6 pro-
duced desired sultams in high enantioselectivity. Thus,
the transfer hydrogenation of 5b1d in the presence of 0.5
mol % (S,S)-RuCl(TsDPEN)(benzene) afforded (S)-27 in
91% ee. The crude extracted product was crystallized,
providing optically pure compound in 75% isolated yield.
The enantiopurity was determined by 19F NMR and GC
analyses of the corresponding N-acylated derivative
prepared using (R)-Mosher’s acid chloride.8 For the
practical synthesis of chiral sultam 3, it was necessary
to improve the synthetic yield of N-sulfonylimine 5c from
saccharin. Addition of benzylmagnesium chloride to
saccharin in degassed THF at -78 to 25 °C gave 5c in
low yields (20-30%), as precedented in the literature.1b
However, by changing the solvent from THF to Et2O, the
yield could be increased to 67%.9 Then, subsequent
ruthenium-catalyzed transfer hydrogenation of 5c as
above gave (S)-3 in 93% ee. Recrystallization of the
extracted product gave essentially optically pure product.
The absolute configuration of (S)-3 was unambiguously
determined from the X-ray crystal structure of its N-
acryloylsultam derivative 6.10 Our results indicate that
the transfer hydrogenation method, which has been
demonstrated to be highly effective in the asymmetric
reduction of imines, can be equally extended to N-
sulfonylimines.11
In summary, we have developed an efficient synthesis
of chiral 3-substituted-1,2-benzisothiazoline 1,1-dioxides
2 and 3 which involves no chromatographic separation.
Because these sultam derivatives are excellent chiral
auxiliaries, their application in asymmetric syntheses
now becomes more feasible. An extension of the transfer
hydrogenation method to other N-sulfonylimine com-
We studied the asymmetric reduction of N-sulfo-
nylimine 5b using several ruthenium-BINAP catalysts
such as (R)-RuCl4(BINAP)2Et3N,1a (R)-Ru(OAc)2(BINAP),4
and (R)-RuCl2(BINAP)5 under ca. 5 atm of hydrogen
pressure but failed to reduce the imine bond. However,
we were pleased to find that the transfer hydrogenation
(6) (a) Hashiguchi, S.; Fujii, A.; Takehara, J .; Ikariya, T.; Noyori,
R. J . Am. Chem. Soc. 1995, 117, 7562. (b) Uematsu, N.; Fujii, A.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J . Am. Chem. Soc. 1996, 118,
4916.
(7) R-Description for this (-)-2 in the literature should be corrected
to S according to the sequence rule: Eliel, E. L.; Wilen, S. H.
Stereochemistry of Organic Compounds; J ohn Wiley & Sons, Inc.: New
York, 1994; pp 101-112.
(8) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
(9) The solvent must be degassed by flushing with an inert gas;
otherwise, the dimerization of benzyl Grignard reagent significantly
reduces the addition yield. For the addition of Grignard reagents to
saccharin, see: Abramovitch, R. A.; Smith, E. M.; Humber, M.;
Purtschert, B.; Srinivasan, P. C.; Singer, G. M. J . Chem. Soc., Perkin
Trans. I 1974, 2589.
(1) (a) Oppolzer, W.; Wills, M.; Starkemann, C.; Bernardinelli, G.
Tetrahedron Lett. 1990, 31, 4117. (b) Oppolzer, W.; Wills, M.; Kelly,
M. J .; Signer, M.; Blagg, J . Tetrahedron Lett. 1990, 31, 5015. (c)
Oppolzer, W.; Rodriguez, I.; Starkemann, C.; Walther, E. Tetrahedron
Lett. 1990, 31, 5019. (d) Oppolzer, W.; Kingma, A. J .; Pillai, S. K.
Tetrahedron Lett. 1991, 32, 4893. An attempted asymmetric hydro-
genation of 5b under the same conditions that were used for the
synthesis of 1 gave only traces of racemic sultam 2.
(2) (a) Oppolzer, W. Tetrahedron 1987, 43, 1969. (b) Oppolzer, W.
Pure Appl. Chem. 1990, 62, 1241.
(3) (a) Ahn, K. H.; Lee, S.; Lim, A. J . Org. Chem. 1992, 57, 5065.
(b) Ahn, K. H.; Yoo, D. J .; Kim, J . S. Tetrahedron Lett. 1992, 33, 6661.
(4) Kitamura, M.; Tokunaga, M.; Noyori, R. J . Org. Chem. 1992,
57, 4053.
(10) The authors have deposited atomic coordinates for 6 with the
Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.
(11) After completion of our work, asymmetric hydrogenation of
N-tosylimines, with low to moderate enantioselectivities, by RuII
-
(5) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Tetrahe-
dron Lett. 1991, 32, 4163.
BINAP complexes under high-H2 pressure has been reported; see:
Charette, A. B.; Giroux, A. Tetrahedron Lett. 1996, 37, 6669.
S0022-3263(97)00917-1 CCC: $14.00 © 1997 American Chemical Society

7048 J . Org. Chem., Vol. 62, No. 20, 1997
Notes
tiopurity of this crude product was determined by 19F NMR
analysis of its N-acylated derivative obtained with (R)-Mosher’s
acid chloride: 19F NMR (CDCl3) δ 10.37 (4.2%), 8.67 (95.6%);
91% ee. After a single crystallization from CHCl3-hexanes,
enantiopure (S)-(-)-2 was obtained in 75% yield (2.71 g). The
enantiopurity was confirmed by GC analysis of its (R)-Mosher’s
ester [conditions: flow rate, 1 mL/min; oven temperature, 225
°C; injector temperature, 250 °C; detector temperature, 280 °C;
tR ) 31.1 min (for comparison, an authentic sample of the
Mosher’s ester was synthesized from the racemic mixture of 2
which was prepared by the reduction of 5b with NaBH4; thus,
the corresponding (R)-Mosher’s ester of (R)-2 has tR ) 30.0 min;
this compound could not be detected in the once-crystallized
sample of (S)-(-)-2)]: Rf ) 0.23 (ethyl acetate/hexanes ) 1/2,
pounds and application of resulting sultams in asym-
metric syntheses are under investigation.
Exp er im en ta l Section
Gen er a l Meth od s. The tert-butyllithium and benzylmag-
nesium chloride used were from fresh bottles of commercial
products. THF and Et2O were purified from sodium-benzo-
phenone ketyl under nitrogen and degassed by flushing with
an inert atmosphere (Ar, N2) for the addition reaction of
benzylmagnesium chloride to saccharine. GC analysis was
carried out using a capillary column (HP-1, cross-linked methyl
silicone gum phase, 25 m × 0.2 mm × 0.33 µm) under the
conditions given below. Melting points are uncorrected. All
purification of reaction products was done by crystallization of
the extracted products, but purification by SiO2 column chro-
matography can be also used if necessary. HRMS data were
obtained from the Korea Basic Science Center, Seoul.
v/v); mp 128.5-129.5 °C (lit.1d mp 129-130 °C); [R]18 -54.0 (c
D
1.0, CHCl3) [lit.1d [R]20 -53.9 (c 1.0, CHCl3)]; IR (NaCl, cm-1
)
D
2953, 2352, 1545, 1474, 1336; 1H NMR (300 MHz, CDCl3) δ
7.94-7.68 (m, 4 H), 1.52 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ
181.8, 141.5, 133.8, 133.3, 130.2, 127.0, 123.1, 38.9, 28.7; HRMS
for C11H16NO2S (M + H)+ calcd 226.0902, found 226.0900.
3(S)-(P h en ylm eth yl)-1,2-ben zisoth ia zolin e 1,1-Dioxid e
(3). This compound was prepared from 5c (3.09 g) by a route
similar to that for 2. The enantiopurity of this product was
determined by 19F NMR analysis of its Mosher’s ester: (CDCl3)
δ 10.54 (96.7%), 8.35 (3.3%); 93% ee. One crystallization of the
extracted product from CH2Cl2 gave (-)-3 (1.82 g, 59%) with
95.8% ee. Recrystallization of the first crop from ethyl acetate
gave essentially optically pure compound (1.37 g, overall 44%
yield), whose optical purity was determined by GC analysis of
its (R)-Mosher’s ester [conditions: flow rate, 1 mL/min; oven
temperature, 250 f 290 °C (4 °C/min); injector temperature, 290
°C; detector temperature, 310 °C; tR ) 15.9 min ((R)-Mosher’s
ester of (S)-sultam 3), 15.5 min (authentic (R)-Mosher’s ester of
(R)-sultam 3): Rf ) 0.25 (ethyl acetate/hexanes ) 2/3, v/v); mp
3-(P h en ylm eth yl)-1,2-ben zisoth ia zole 1,1-Dioxid e (5c).
To a degassed diethyl ether (70 mL) solution of saccharin (5.21
g, 28.4 mmol) at 25 °C was added fresh benzylmagnesium
chloride (1.0 M in Et2O, 62.5 mL) dropwise. The resulting
mixture was further stirred at the same temperature for 6 h
before quenching with a saturated aqueous NH4Cl solution. The
aqueous layer was extracted further with Et2O (60 + 30 mL);
then the combined organic layer was washed with brine and
dried over MgSO4. Evaporation of the solvent and crystallization
from EtOAc-Et2O gave the desired sulfonylimine 5c in 67%
yield (first crop, 4.16 g; second crop, 0.73 g): Rf ) 0.36 (ethyl
acetate/hexanes ) 2/3, v/v); mp 142.7-143.5 °C (lit.1b mp 129-
131 °C); 1H NMR (300 MHz, CDCl3) δ 7.91-7.28 (m, 9 H), 4.32
(s, 2 H); 13C NMR (75 MHz, CDCl3) δ 174.2, 140.5, 134.3, 133.9,
133.3, 131.3, 129.6, 128.8, 128.3, 125.3, 122.9, 38.2; HRMS for
C
14H11NO2S (M+) calcd 257.0511, found 257.0512.
146.7-147.6 °C; [R]23 -64.4 (c 1.0, CHCl3); IR (NaCl, cm-1
)
D
3(S)-ter t-Bu tyl-1,2-ben zisoth ia zolin e 1,1-Dioxid e (2). To
3271, 3029, 1596, 1495, 1453, 1387, 1292, 1162, 1130, 1056; 1H
NMR (300 MHz, CDCl3) δ 7.79-7.28 (m, 9 H), 4.92 (dd, 1 H, J
) 4.7, 13.7 Hz), 4.83 (s, 1 H), 3.29 (dd, 1 H, J ) 4.7, 13.7 Hz),
3.06 (dd, 1 H, J ) 9.2, 13.7 Hz); 13C NMR (75 MHz, CDCl3) δ
139.8, 136.8, 133.4, 129.9, 129.8, 129.4, 127.8, 126.3, 124.8, 121.9,
59.2, 42.8; HRMS for C14H13NO2S (M+) calcd 259.0667, found
259.0663.
a CH2Cl2 solution (30 mL) of the catalyst RuCl(TsDPEN)(ben-
zene), prepared in situ by heating an acetonitrile solution (10
mL) of [RuCl2(benzene)]2 (20 mg, 0.040 mmol) and (1S,2S)-N-
(p-toluenesulfonyl)-1,2-diphenylethylenediamine (TsDPEN; 59
mg, 0.160 mmol) at 80 °C for 20 min according to the literature
procedure6b followed by solvent exchange (evaporation of aceto-
nitrile in vacuo, then addition of dichloromethane), were added
sequentially N-sulfonylimine 5b1d (3.57 g, 16.0 mmol) in CH2Cl2
(30 mL), formic acid (3.7 mL, 96.0 mmol), and triethylamine (5.6
mL, 40.0 mmol) dropwise at 0 °C. The reaction mixture was
stirred at 25 °C for 17 h before quenching with brine. After
extraction with CH2Cl2, the organic layer was dried over MgSO4
and concentrated in vacuo to give sultam (-)-2.7 The enan-
Ack n ow led gm en t. This work was financially sup-
ported by the Ministry of Education sponsoring the
Basic Science Research Center (BSRI-94/96-3437).
J O970917P