Synthesis of Chiral Benzosultams: 3-Functionalized 1,2-Benzisothiazoline 1,1-Dioxides

Full text of DOI:10.1021/jo000952n

7690
J . Org. Chem. 2000, 65, 7690-7696
sultams.5 Although the direct nucleophilic addition ap-
Syn th esis of Ch ir a l Ben zosu lta m s:
proaches are useful for the synthesis of 3-alkyl- or 3-aryl-
substituted derivatives, we were unsuccessful in introduc-
ing directly a functional moiety such as cyano group.6 To
synthesize 3-functionalized saccharin derivatives, par-
ticularly 3-carboxy analogues 5 and 6, we have studied
two indirect approaches, an asymmetric approach and a
racemic synthesis followed by chemical resolution ap-
proach. Herein, we report the synthetic results which
provide some useful chemistry on the C-3 functionaliza-
tion of saccharin and 3-carboxybenzosultams.
3-F u n ction a lized 1,2-Ben zisoth ia zolin e
1,1-Dioxid es
Kyo Han Ahn,* Hyon-Ho Baek,† Seok J ong Lee,‡ and
Chang-Woo Cho†
Department of Chemistry and Center for Integrated
Molecular Systems, Division of Molecular and Life Sciences,
Pohang University of Science & Technology, San 31
Hyoja-dong, Pohang, 790-784 Republic of Korea
ahn@postech.ac.kr
Received J une 26, 2000
In tr od u ction
1,2-Benzisothiazoline-3-one 1,1-dioxide (1), known as
saccharin, has been frequently used as a key component
of biologically active compounds.1 Also, it is a cheap and
versatile starting material for the synthesis of related
heterocyclic derivatives. Among those derivatives, 3-sub-
stituted ones are readily accessible through direct nu-
cleophilic additions to the carbonyl carbon using strong
nucleophiles such as alkyl- and aryllithium reagents or
corresponding Grignard reagents.2 The substitution reac-
tions proceed at monoaddition or diaddition stage de-
pending on the reagents and reaction conditions. The
monoaddition reactions lead to 3-substituted saccharins
2, while the diadditions provide benzosultam analogues
3.3 Recently, we have devised an efficient and practical
synthetic route to various enantiomeric 3-substituted
benzosultams such as 4 starting from saccharin via the
nucleophilic addition and subsequent catalytic reduction
steps.4 As a continuing study on the synthesis and
application of chiral benzosultam derivatives, we have
been interested in chiral 3-carboxy-substituted benzo-
Resu lts a n d Discu ssion
An Asym m etr ic Ap p r oa ch to 3-Ca r boxysu lta m 5
a n d Its Der iva tives. The asymmetric route to sultam
5 was studied using an inexpensive starting material,
sodium o-formylbenzenesulfonate (7). The results are
depicted in Scheme 1. The key steps are the Sharpless
asymmetric epoxidation7 of o-(aminosulfonyl)-trans-cin-
namyl alcohol (10) and a subsequent intramolecular
epoxide opening by the sulfonamide group. An aqueous
Wittig-Horner-Emmons reaction8 of aldehyde 7 with
triethyl phosphonoacetate readily afforded cinnamate 8.
After the azeotropic removal of water, 8 was directly
converted to sulfonamide 9 in overall 45% yield by
treatment with thionyl chloride followed by an aqueous
ammonium hydroxide solution.9 Reduction of the ester
group of 9 was done with excess DIBALH, affording
allylic alcohol 10 in 86% yield. Asymmetric epoxidation
of allylic alcohol 10 was then carried out according to the
Sharpless protocol.7 Employing (+)-diisopropyl tartrate,
tert-butyl hydroperoxide, titanium isopropoxide, and 4 Å
activated molecular sieve at -15 to -20 °C, we were able
to obtain the corresponding epoxy-alcohol 11 in 90% yield.
Enantiopurity of the epoxide was determined to be 91%
† Samsung Fine Chemicals Co., Ltd., 103-1, Moonji-dong, Yusong-
gu, Taejeon, 305-380 Republic of Korea.
‡ Department of Chemistry, McGill University 801 Sherbrooke
Street West, Montreal, Quebec H3A 2K6, Canada.
(1) (a) Lombardino, J . G.; Wiseman, E. H.; Mclamore, W. M. J . Med.
Chem. 1971, 14, 1171. (b) Sunkel, C. E.; de Casa-J uana, M. F.; Cillero,
F. J .; Priego, J . G.; Ortega, M. P. J . Med. Chem. 1988, 31, 1886. (c) As
a part of a 5-HT1A ligand, ipsapirone, see: Hibert, M. F.; Mir, A. K.;
Fozard, J . R.: serotonin (5-HT) receptors. In Comprehensive Medicinal
Chemistry; Sammes, P. G., Taylor, J . B., Eds.; Pergamon Press: Oxford,
1990; Vol. 3, pp 578-580. (d) Nagasawa, H. T.; Kawle, S. P.; Elberling,
J . A.; DeMaster, E. G.; Fukuto, J . M. J . Med. Chem. 1995, 38, 1865.
(e) Zimmerman, M.; Morman, H.; Mulvey, D.; J ones, H.; Frankshun,
R.; Ashe, B. M. J . Biol. Chem. 1980, 255, 9848. (f) Ahn, K. H.; Lee, S.
J .; Lee, C.-H.; Hong, C. Y.; Park, T. K. Bioorg. Med. Chem. Lett. 1999,
9, 1379.
(2) (a) Abramovitch, R. A.; Smith, E. M.; Humber, M.; Purtschert,
B.; Srinivasan, P. C.; Singer, G. M. J . Chem. Soc., Perkin Trans. 1
1974, 22, 2589. (b) Teeninga, H.; Engberts, J . B. F. N. J . Org. Chem.
1983, 48, 537. (c) Abramovitch, R. A.; Azogu, C. I.; McMaster, I. T.;
Vanderpool, D. P. J . Org. Chem. 1978, 43, 1218. (d) For other
approaches, see: Hermann, C. K. F.; Campbell, J . A.; Greenwood, T.
D.; Lewis, J . A.; Wolfe, J . F. J . Org. Chem. 1992, 57, 5328 and
references therein.
(5) One of possible applications of 3-carboxy-substituted benzosul-
tams is in catalytic asymmetric reactions via boron complexes. For
selected examples, see: (a) Takasu, M.; Yamamoto, H. Synlett. 1990,
194. (b) Sartor, D.; Saffrich, J .; Helmchen, G. Synlett. 1990, 197. (c)
Corey, E. J .; Loh, T.-P. J . Am. Chem. Soc. 1991, 113, 8966. (d) Parmee,
E. R.; Tempkin, O.; Masamune, S. J . Am. Chem. Soc. 1991, 113, 9365.
(e) Kiyooka, S.-I.; Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano, M. J .
Org. Chem. 1991, 56, 2276. (f) Corey, E. J .; Loh, T.-P.; Roper, T. D.;
Azimioara, M. D.; Noe, M. C. J . Am. Chem. Soc. 1992, 114, 8290. (g)
Seerden, J .-P. G.; Scheeren, H. W. Tetrahedron Lett. 1993, 34, 2669.
(6) Attempt at the preparation of 3-cyano-1,2-benzisothiazole 1,1-
dioxide from 3-chloro-1,2-benzisothiazole 1,1-dioxide under various
conditions was not successful.
(3) Kakuda, H.; Suzuki, T.; Takeuchi, Y.; Shiro, M. Chem. Commun.
1997, 85.
(4) (a) Ahn, K. H.; Ham, C.; Kim, S.-K.; Cho, C.-W. J . Org. Chem.
1997, 62, 7047. (b) Ahn, K. H.; Kim, S.-K.; Ham, C. Tetrahedron Lett.
1998, 39, 6321. For other previos syntheses, see: (c) Oppolzer, W.;
Wills, M.; Starkemann, C.; Bernardinelli, G. Tetrahedron Lett. 1990,
31, 4117. (d) Oppolzer, W.; Kingma, A. J .; Pillai, S. K. Tetrahedron
Lett. 1991, 32, 4893.
(7) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(8) Villieras, J .; Rambaud, M.; Graff, M. Tetrahedron Lett. 1985, 26,
53.
(9) During the drying stage of
8 with methanol by a rotary
evaporator, transesterification was occurred to give the methyl ester.
10.1021/jo000952n CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/05/2000

Notes
J . Org. Chem., Vol. 65, No. 22, 2000 7691
Sch em e 1a
Sch em e 2a
a
Reagents and conditions: (a) (CH3)2C(OCH3)2, PPTS cat,
CH3CN, 25 °C; (b) MPMCl, NaH, DMF, 0 °C; (c) 2 N HCl, THF,
25 °C; (d) NalO4, RuCl3(H2O), CCl4-CH3CN-H2O, 25 °C.
diol 12 was treated with sodium periodate followed by
sodium borohydride, alcohol 15 was obtained in 96%
yield. However, all attempts to oxidize alcohol 15 to
3-carboxysultam 5 with PDC, KMnO4, or Ru(IV) re-
agents15 did not give an appreciable amount of the
desired product but instead produced decomposed com-
pounds. During the preparation of alcohol 15 from diol
12, we could observe an intermediate on TLC, which was
believed to be 14. However, the intermediate decomposed
during the subsequent oxidation stage. When N-protected
diol 18, prepared from 12 in three steps, was subjected
to the RuCl3-NaIO4 oxidation, the major product was
not the desired carboxylic acid 19 (27%) but saccharine
derivative 20 (50%) (Scheme 2). These results indicate
that 3-formylsultam 14 and its N-protected derivatives
have limited stability and may undergo deformylation
under the oxidation conditions. Because we were not
successful in converting diol 12 or alcohol 15 into the
corresponding carboxylic acid, we turned our attention
to a racemic route.
Ra cem ic Rou tes to 3-Su bstitu ted Ben zosu lta m s
5 a n d 6. The introduction of a carboxy group at the
3-position of saccharin was carried out according to
Scheme 3. The p-methoxyphenylmethyl (MPM) group
was chosen as a protecting group for the sulfonamide of
saccharin, because it can be deprotected under mild
conditions. N-Protected saccharin 20 was treated with
DIBALH to give semi aminal 21 in 88% yield. Conversion
of the hydroxy group of 21 to the cyano group of 22 was
cleanly done with TMSCN in the presence of BF3‚OEt2
in 92% yield. Nitrile 22 was hydrolyzed to the corre-
sponding methyl ester 23 in a methanolic hydrogen
chloride solution in a quantitative yield. Deprotection of
the MPM group of 23 with ceric ammonium nitrate
(CAN) gave sultam 24 in 95% yield. Finally, hydrolysis
of the ester group of 24 with LiOH in THF-water
produced racemic 3-carboxysultam 5 in 80% yield. This
racemic route from saccharin to 3-carboxysultam 5
involves six steps with an overall yield of 55%.
a
Reagents and conditions: (a) (EtO)2P(O)CH2CO2Et, aq K2CO3,
25 °C; (b) DMF, SOCl2, reflux; aq NH4OH, 0 °C; (c) DlBAL, THF,
-78 °C; (d) tBuOOH, Ti(OiPr)4, (+)-DlPT, 4 Å molecular sieve, -10
°C; (e) Ti(OiPr)4, Et3N, CH2Cl2, rt; (f) NalO4, aq MeOH, 0 °C; (g)
NaBH4, 0 °C.
ee by 19F NMR analysis of its Mosher ester.10 Thus, the
presence of the sufonamide substituent in allylic alcohol
10 resulted in a slight decrease in the chiral induction
of the epoxidation, compared to the case of cinnamyl
alcohol.7 The next key step, an intramolecular epoxide
opening reaction of epoxy-alcohol 11, was studied under
several reaction conditions. The selectivity between the
5-exo-type opening (leading to diol 12) and the 6-endo-
type opening (leading to diol 13) was ∼1:1 when K2CO3
in DMF was used as the base system. The regioselectivity
was increased to 3.5:1 when the base system was changed
to 5 mol % NaOMe in MeOH.11 The observed 6-endo-type
opening might be caused by a ring strain, which would
develop at the transition state of the 5-exo-type opening
due to the benzene ring.12 A complete regioselectivity was
achieved by using the Ti(OiPr)4-Et3N system.13 Under
these conditions, the desired diol 12 was obtained in 83%
yield, together with 12% yield of a side product after
column chromatography. The enantiopurity of this diol
12 was determined to be 96% ee by 19F NMR analysis of
its Mosher ester, which excludes a possibility of epimer-
ization during the ring opening. The side product was
identified to be the C-3-opened diol by the isopropyloxy
ion that must be transferred from the titanium reagent.
The final step, oxidative conversion of the diol functional-
ity in 12 to the carboxy group, was found to be difficult
due to the instability of the reaction intermediate.
Treatment of diol 12 with sodium periodate produced the
corresponding aldehyde, and subsequent in situ oxidation
with potassium permaganate14 produced decomposed
products instead of the desired 3-carboxysultam 5. When
(10) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
Similarly, we have studied the synthesis of (()-3-
benzyl-3-carboxysultam 6, starting from ester 23. The
results of the synthesis are depicted in Scheme 4.
Treatment of ester 23 with NaH in DMF followed by
benzyl bromide gave 3-benzylated sultam 25 in 96% yield.
Deprotection of the MPM group of 25 with CAN produced
ester 26 in 95% yield. Finally, hydrolysis of the ester
(11) The selectivity was determined by the analysis of 1H NMR
spectrum of the crude products. Because two products (12 and 13) were
not easily separable by column chromatography, the mixture was
treated in situ with sodium periodate to give chromatographically
separable aldehyde 14 and unreacted 13.
(12) It was originally suggested by Baldwin that the 5-exo-type
opening of an unrestricted epoxide would be more favorable than the
6-endo-type opening, see: Baldwin, J . E. J . Chem. Soc., Chem.
Commun. 1976, 734.
(13) Caron, M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1557.
(14) Abiko, A.; Roberts, J . C.; Takemasa, T.; Masamune, S. Tetra-
hedron Lett. 1986, 27, 4537.
(15) Carlsen, P. H. J .; Katsuki, T.; Martin, V. C.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.

7692 J . Org. Chem., Vol. 65, No. 22, 2000
Notes
Sch em e 3a
Sch em e 5
a
Reagents and conditions: (a) MPMCl, NaH, DMF, 110 °C, 5
h, 89%; (b) DlBALH, CH2Cl2, -78 °C, 1 h, 88%; (c) TMSCN,
BF3‚OEt2, CH2Cl2, -78 °C, 1 h, 92%; (d) HCl-MeOH, 1,4-dioxane,
25 °C, 3 d, 100%; (e) CAN, CH3CN-H2O (3:1), 25 °C, 1 h, 95%; (f)
LiOH, THF-H2O (1:1), 25 °C, 10 min, 80%.
Sch em e 6a
Sch em e 4a
a
Reagents and conditions: (a) LiOH, THF-H2O (1:1), 25 °C,
a
Reagents and conditions: (a) BnBr, NaH, DMF, 0 °C, 2 h, 96%;
77%; (b) i-BuOCOCl, 4-methylmorpholine, (S)-(-)-R-methylben-
zylamine, CH2Cl2, -10 f 25 °C, 5 h, 90% (c) CAN, CH3CN-H2O
(3:1), 25 °C, 1 h, 80%.
(b) CAN, CH3CN-H2O (3:1), 25 °C, 2 h, 95%; (c) LiOH, THF-
H2O (1:1), 25 °C, 20 min, 96%.
group of 26 produced the desired sultam 6 in 96% yield.
Overall, our synthesis of racemic sultam 6 from saccharin
involves seven steps with an overall yield of 63%.
X-r a y Cr ysta llogr a p h ic Stu d ies on th e Ben zosu l-
ta m s. To confirm the absolute stereochemistry of product
12, we made an effort and could get the single crystals
suitable for X-ray crystallography in the case of its der-
ivative 16. The crystal structure of 16 confirms the ab-
solute stereochemistries of diol 12 as (R,R),16 which is
also inferred from the chiral induction mechanism of the
Sharpless epoxidation process.17 In the case of 3-benzyl-
substituted carboxylic acid 6, we could not get crystals
suitable for X-ray crystallography. However, finally we
succeeded in obtaining single crystals from its amide der-
ivative (-)-29, which was prepared by treatment with
ethyl chloroformate followed by an ammonium hydroxide
solution. The X-ray crystallography of (-)-29 provided
its absolute stereochemistry as (S).16 In the case of amides
(-)-28 and (+)-28, we have not succeeded in getting suit-
able single crystals, and their absolute stereochemistries
are not known at present.
With racemic 3-carboxysultams 5 and 6 at hand, we
studied their chemical resolution. We have found that
3-benzyl-3-carboxysultam 6 can be efficiently resolved
with a readily available resolving agent (-)-brucine, as
described in Scheme 5. Two diastereomeric salts were
separated into a white salt and an ethanol solution. The
sultams regenerated from both the white salt and the
ethanol solution, when treated with concentrated HCl,
exhibited almost the same specific rotation but of opposite
sign.
In contrast to the successful resolution of benzyl-
substituted carboxylic acid 6, we were unable to resolve
3-carboxysultam 5 using (-)-brucine or (-)-R-methyl-
benzylamine as the resolving agent. Therefore, we stud-
ied a derivatization approach, as depicted in Scheme 6.
3-Carboxysultam 19, prepared from ester 23 in 77% yield
by hydrolysis with aqueous LiOH, was coupled with (S)-
(-)-R-methylbenzylamine by a mixed anhydride method
to give a 1:1 mixture of diastereomeric amide 27 in 90%
yield. The two diastereomers of amide 27 were not
separable on SiO2. However, after deprotecting the MPM
group, we could readily separate both diastereomeric (+)-
28 and (-)-28 by SiO2 column chromatography.
(16) The authors have deposited atomic coordinates for (R,R)-16
(CCDC 149844) and (S)-29 (CCDC 149893) with the Cambridge
Crystallographic Data Centre. The coordination can be obtained, on
request, from the Director, Cambridge Crystallographic Data Centre,
12Union Road,Cambridge,CB21EZ,UK;e-mail: deposit@ccdc.cam.ac.uk.
For ORTEP plots of (R,R)-16 and (S)-29, see the Supporting Informa-
tion.
(17) Finn, M. G.; Sharpless, K. B. In Asymmetric Synthesis; Morri-
son, J . D., Ed.; Academic Press: New York, 1985; Vol. 5, Chapter 8, p
247.

Notes
In summary, we have established an asymmetric and
J . Org. Chem., Vol. 65, No. 22, 2000 7693
concentrated under reduced pressure. The residue was purified
by recrystallization from CH2Cl2 to afford the allylic alcohol 10
as a white solid (6.8 g, 86%). 10: Rf ) 0.42 (ethyl acetate/hexanes
) 4/1); mp 125.3-126.1 °C; IR (KBr pellet, cm-1) 3344, 3243,
2862, 1531, 1466, 1301, 1153, 1122; 1H NMR (300 MHz, acetone-
d6) δ 7.92 (d, 1H, J ) 7.9 Hz), 7.58 (d, 1H, J ) 7.9 Hz), 7.49-
7.38 (m, 2H), 7.30 (t, 1H, J ) 6.6 Hz), 6.37-6.28 (m, 1H), 4.26
(dd, 2H, J ) 1.8, 5.0 Hz), 6.18 and 3.14 (each br s, 3H, SO2NH2
and OH); 13C NMR (75 MHz, acetone-d6) δ 140.7, 136.3, 135.3,
132.4, 128.2, 127.7, 127.3, 126.2, 62.8; MS (EI) m/z (rel intensity)
213 (M+, 22); Anal. Calcd for C9H11NO4S: C, 50.69; H, 5.20; N,
6.57. Found: C, 50.45; H, 5.25; N, 6.41.
racemic routes to 3-functionalized 1,2-benzisothiazoline
1,1-dioxides. Both routes consist of all high-yielding steps
amenable to a large scale. Racemic benzosultam 6 has
been efficiently resolved with (-)-brucine, while benzo-
sultam 5 can be separated after derivatization to a
diastereomeric mixture. Single-crystal X-ray crystal-
lography for benzosultams 16 and 29 established their
absolute stereochemistries. The established chemistry
throughout the syntheses would be useful for the syn-
thesis of related benzosultam derivatives, which are
important heterocyclic compounds in pharmaceutical
research and asymmetric synthesis.
(1S ,2S )-o-(3-H yd r oxy-1,2-e p oxyp r op a n -1-yl)b e n ze n e -
su lfon a m id e (11). An oven-dried flask was charged with 1.5 g
of 4 Å powdered, activated molecular sieves and 350 mL of dry
CH2Cl2. After being cooled to -25 °C, to the mixture were added
L-(+)-diisopropyl tartrate (0.408 mL, 2.1 mmol) and Ti(O-i-Pr)4
(0.524 mL, 1.76 mmol) sequentially by a hypodermic syringe
with stirring. The reaction mixture was stirred at -25 °C for
10 min, and t-BuOOH (77.6 mmol, 13.0 mL, 5,97 M in toluene)
was added at a moderate rate (over ca. 3 min). The resulting
mixture was stirred at -20 °C for 30 min. The allylic alcohol 10
(7.49 g, 35.1 mmol), dissolved in 18 mL of THF, was then added
dropwise over a period of 10 min, being careful to maintain the
reaction temperature between -20 to -15 °C. The mixture was
stirred for an additional 1 h at -20 °C, and the reaction
temperature was slowly raised to -15 °C and stirred for 4 h.
When the reaction was complete, to the reaction mixture was
added 370 mg (1.76 mmol) of citric acid monohydrate dissolved
in 48 mL of 10% acetone in ethyl ether. The cooling bath was
removed, and the mixture was stirred for 20 min before filtering
through a pad of Celite. The filtrate was concentrated under
reduced pressure, and the residue was subjected to column
chromatography (eluant: 50% ethyl acetate in hexanes) to give
the epoxy alcohol 11 (7.24 g, 90%). The enantiopurity of this
compound was determined to be 91% ee by 1H and 19F NMR
analysis of the corresponding Mosher ester prepared with (+)-
Mosher’s acid chloride. 11: Rf ) 0.45 (ethyl acetate/hexanes )
Exp er im en ta l Section
Gen er a l P r oced u r es. All reagents were commercial products
and were used without further purification. All reactions involv-
ing air-sensitive agents were conducted under an argon atmo-
sphere. Column chromatography was performed on Merck silica
gel 60 (230-400 mesh). Melting points are uncorrected. Elemen-
tal and high-resolution mass analyses were performed by Seoul
Branch Analytical Laboratory of Korea Basic Science Institute.
NMR spectral data are reported as follows: chemical shift in
ppm from internal Me4Si on the delta scale, multiplicity (s )
singlet, d ) doublet, t ) triplet, m ) multiplet, dd ) doublet of
doublet, br s ) broad singlet), integration, and coupling constant.
Meth yl o-Am in osu lfon yl-tr a n s-cin n a m a te (9). A solution
of 2-formylbenzenesulfonic acid sodium salt dihydrate (7, 75%
purity, 50.0 g, 180 mmol), K2CO3 (49.8 g, 360 mmol), and
(EtO)2P(O)CH2COOEt (35.7 mL, 180 mmol) in water (120 mL)
was stirred at 25 °C for 6 h. MeOH (120 mL) was added to the
reaction mixture, and it was further stirred for 30 min. The
reaction mixture was filtered through a Bu¨chner funnel to
remove precipitates, and the filtrate was concentrated under
reduced pressure to remove most of MeOH and water (at this
stage, transesterification from ethyl ester to methyl ester
occurred), and the remaining solvent was thoroughly dried using
a freeze-drying apparatus to give a white solid. To this hygro-
scopic Wittig-Horner-Emmons reaction product (8) was added
dropwise SOCl2 (120 mL) at 0 °C using a dropping funnel,
followed by DMF (5 mL). The resulting mixture was refluxed at
80 °C for 2 h. (The evolved gas was trapped by an aqueous KOH
solution). The heterogeneous mixture was cooled to 25 °C, and
excess SOCl2 was distilled off using an aspirator pump. The
resulting mixture was diluted with CH2Cl2 and was stirred for
30 min, and the precipitates were filtered off. The filtrate was
concentrated, redissolved in THF (120 mL), and was treated
slowly with an aqueous ammonium hydroxide solution (60 mL)
at 0 °C. After being stirred for 10 min, the mixture was first
acidified to pH ) 7 with concentrated HCl and then to pH ) 2
with 2 N aqueous HCl. The organic layer was separated, and
the aqueous layer was extracted with ethyl acetate three times.
The combined organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product
was purified first by passing through a short pad of silica gel
(eluant: 30% ethyl acetate in hexanes) and then by recrystal-
lizing from ethyl acetate-hexanes to give cinnamate 9 (19.5 g,
45% yield): Rf ) 0.63 (ethyl acetate/hexanes ) 1/1); mp 138.1-
139.2 °C; IR (KBr pellet, cm-1) 3330, 3248, 1697, 1633, 1344,
4/1); mp 125.3-126.1 °C; [R]24 -69.7 (c 1.01, MeOH); IR (KBr
D
pellet, cm-1) 3344, 3259, 1557, 1448, 1329, 1156; 1H NMR (300
MHz, acetone-d6) δ 7.96-7.93 (m, 1H), 7.63-7.56 (m, 1H), 7.49-
7.44 (m, 2H), 6.79 (br s, 2H), 4.50 (s, 1H), 4.37-4.33 (m, 1H),
3.88-3.83 (m, 1H), 3.76-3.69 (m, 1H), 3.01-2.97 (m, 1H), 2.85-
2.83 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 140.7, 134.7, 131.4,
126.7, 126.5, 124.7, 61.3, 61.0, 52.8; MS (FAB) m/z (rel intensity)
252 (MNa+, 12).
3(R)-{1(R),2-Dih yd r oxyet h a n -1-yl}-1,2-b en zisot h ia zo-
lin e 1,1-Dioxid e (12). To a suspension of epoxy-alcohol 11 (6.15
g, 26.8 mmol) in dichloromethane (134 mL) was added titanium-
(IV) isopropoxide (8.8 mL, 29.5 mmol). When the mixture became
a
solution, triethylamine (4.1 mL, 29.5 mmol) was added
dropwise under an argon atmosphere at the same temperature.
The reaction temperature was raised to 25 °C and stirred for 1
h. The mixture was cooled to 0 °C and acidified to pH ) 2 with
1 M aqueous HCl. After being stirred vigorously for 1 h, the
mixture was extracted with ethyl acetate five times, and the
extracts were dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by column chromatography
(ethyl acetate/hexane ) 1:1) to give the diol 12 (5.12 g, 83%) as
a white solid and the side product (see the text, 947 mg, 12%)
as an oil. The enantiopurity of the major product was determined
1
to be 96% ee by H NMR analysis of the corresponding Mosher
ester prepared with (+)-Mosher’s acid chloride. 12: Rf ) 0.38
1
(ethyl acetate); mp (CH2Cl2-MeOH, 20:1) 130-131 °C; [R]24
1205, 1159; H NMR (300 MHz, acetone-d6) δ 8.48 (d, 1H, J )
D
+24.7 (c 1.0, MeOH); IR (KBr pellet, cm-1) 3471, 3228, 1619,
1474, 1398, 1280, 1161; 1H NMR (300 MHz, CD3OD) δ 7.76-
7.55 (m, 4H), 4.76 (s, 3H, OH and NH), 4.65 (d, 1H, J ) 6.2 Hz),
3.74-3.64 (m, 3H); 13C NMR (75 MHz, CH3OH-d4) δ 140.3, 137.5,
133.7, 130.4, 127.8, 121.6, 75.4, 64.6, 59.8; MS (FAB) m/z (rel
intensity) 252 (MNa+, 22), 230 (M + 1, 48).
15.7 Hz), 8.00 (d, 1H, J ) 6.4 Hz), 7.7 (d, 1H, J ) 7.2 Hz), 7.58-
7.43 (m, 2H), 6.35 (d, 1H, J ) 15.7 Hz), 3.72 (s, 3H), 6.43 and
2.73 (br s and s, 2H, -SO2NH2); 13C NMR (75 MHz, acetone-d6)
δ 166.5, 142.0, 141.4, 133.4, 132.6, 128.8, 128.6, 128.2, 122.2,
51.6; MS (EI) m/z (rel intensity) 241 (M+, 12).
o-Am in osu lfon yl-tr a n s-cin n a m yl Alcoh ol (10). To a solu-
tion of ester 9 (9.3 g, 38.6 mmol) in THF (130 mL) at -78 °C
was added dropwise neat DIBALH (31 mL, 174 mmol) under
an argon atmosphere, and the reaction mixture was stirred for
1 h. The reaction was carefully quenched with an aqueous
sodium potassium tartrate solution (30%, 150 mL), and the
resulting mixture was vigorously stirred at 25 °C overnight. The
mixture was extracted with ethyl acetate, dried over MgSO4,
4(S)-H yd r oxy-3(R)-h yd r oxym et h yl-3,4-d ih yd r o-2H -1,2-
ben zth ia zin e 1,1-Dioxid e (13). This compound was Isolated
as a byproduct during the epoxide opening (11 f 12, see the
text): mp 201.5-202.5 °C; [R]20D +20.1 (c 1.02, MeOH); IR (KBr
pellet, cm-1) 3518, 3218, 2934, 1420, 1342, 1311, 1260, 1171;
1H NMR (300 MHz, DMSO-d6) δ 7.71-7.59 and 7.48-7.43 (m,
4H), 5.94 (d, 1H, J ) 8.1 Hz, NH), 4.82 (br s, OH), 4.61 (dd, 1H,

7694 J . Org. Chem., Vol. 65, No. 22, 2000
Notes
J ) 9.3, 8.7 Hz), 3.80-3.66 (m, 2H, CH2), 3.56-3.50 (m, 1H);
13C NMR (75 MHz, acetone-d6) δ 140.2, 137.7, 132.5, 128.5,
128.2, 123.1, 64.4, 61.0, 60.9; MS (EI) m/z (rel intensity) 229
(M+, 4), 198 [M+ - 31(CH2OH), 27].
27.3 mmol) in DMF (20 mL) through a cannula, followed by
p-methoxybenzyl chloride (4.0 mL, 30.0 mmol) dropwise. The
resulting mixture was warmed to 25 °C, and the reaction flask
was equipped with a reflux condenser and was heated to reflux
(bath temperature 110 °C) for 5 h. After being cooled to 25 °C,
the reaction was quenched with water, and the resulting mixture
was extracted with ethyl acetate. The extracts were washed with
water three times and finally with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure to give 20.
Recrystallization of the crude product from CH2Cl2-hexanes
afforded 20 as a colorless crystalline solid (7.37 g, 89% yield):
Rf ) 0.42 (ethyl acetate/hexanes ) 3/7); mp 153.1-154.0 °C; IR
(NaCl, cm-1) 1730, 1612, 1514, 1461, 1333, 1249, 1180, 1034;
1H NMR (300 MHz, CDCl3) δ 8.03-7.80 (m, 4H), 7.49-7.46 (m,
2H), 6.91-6.88 (m, 2H), 4.87 (s, 2H), 3.80 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 159.9, 159.3, 138.1, 135.2, 134.7, 130.8, 127.7,
127.0, 125.6, 121.4, 114.4, 55.7, 42.7; MS (EI) m/z (rel intensity)
303 (M+, 44).
(()-3-Hydr oxy-2-(4-m eth oxyph en yl)m eth yl-1,2-ben zisoth i-
a zolin e 1,1-d ioxid e (21). To a solution of sultam 20 (7.0 g, 23.0
mmol) in CH2Cl2 (77 mL) at -78 °C under an argon atmosphere
was added dropwise DIBALH (25.4 mL, 25.4 mmol, 1.0 M
solution in hexanes), and the mixture was stirred for 1 h. The
reaction was carefully quenched with 30% aqueous solution of
Rochelle’s salt, and the resulting mixture was vigorously stirred
at 25 °C for 3 h. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2. The combined organic
layer was washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
recrystallized from ethyl acetate-hexanes to give 3-hydroxysul-
tam 21 (6.24 g, 88% yield): Rf ) 0.56 (ethyl acetate/hexanes )
3/2); mp 108.2-108.8 °C; IR (KBr pellet, cm-1) 3377, 1614, 1519,
1437, 1347, 1285, 1249, 1170, 1045; 1H NMR (300 MHz, CDCl3)
δ 7.77-7.52 (m, 4H), 7.40 (d, 2H, J ) 8.4 Hz). 6.89 (d, 2H, J )
8.4 Hz), 5.53 (d, 1H, J ) 11.1 Hz), 4.60 (d, 1H, J ) 14.7 Hz),
4.32 (d, 1H, J ) 14.7 Hz), 3.80 (s, 3H), 3.29 (d, OH, J ) 11.1
Hz); 13C NMR (75 MHz, CDCl3) δ 159.8, 136.7, 135.3, 133.8,
131.3, 130.9, 127.0, 125.8, 121.4, 114.5, 80.3, 55.7, 43.2; MS (EI)
m/z (rel intensity) 305 (M+, 72).
3(R)-Hyd r oxym eth yl-1,2-ben zisoth ia zolin e 1,1-Dioxid e
(15). To a solution of NaIO4 (1.67 g, 7.8 mmol) in water (12 mL)
at 0 °C was added diol 12 (1.49 g, 6.5 mmol) in MeOH (22 mL),
and the mixture was stirred for 10 min. To this mixture was
added NaBH4 (295 mg, 7.7 mmol), and the resulting solution
was stirred for 10 min at 0 °C. The reaction mixture was
neutralized with 1 N aqueous HCl and evaporated under reduced
pressure, and the residue was subjected to column chromatog-
raphy (50% ethyl acetate in hexanes) to afford 3-hydroxy-sultam
15 (1.24 g, 96% yield). This product was found to be essentially
enantiopure by 19F NMR analysis of the corresponding Mosher
ester prepared with (+)-Mosher’s acid chloride. 15: mp 116.5-
117.8 °C; [R]24D +34.5 (c 1.1, MeOH); IR (KBr pellet, cm-1) 3506,
3218, 1470, 1390, 1269, 1159, 1130; 1H NMR (300 MHz, acetone-
d6) δ 7.77-7.57 (m, 4H), 6.62 (br s, 1H), 4.78 (dd, 1H, J ) 11.2,
5.6 Hz), 4.24 (t, 1H, J ) 5.6 Hz), 3.88 (m, 2H); 13C NMR (75
MHz, acetone-d6) δ 138.3, 137.0, 132.3, 129.0, 125.1, 120.3, 64.1,
58.8; MS (FAB) m/z (rel intensity) 222 (MNa+, 87), 200 (M + 1,
90).
3(R)-{1(R),2-O-Isop r op ylid en e-1,2-d ih yd r oxyeth a n -1-yl}-
1,2-ben zisoth ia zolin e 1,1-Dioxid e (16). To a solution of diol
12 (2.02 g, 8.8 mmol) in acetonitrile (44 mL) at 25 °C was added
2,2-dimethoxypropane (2.6 mL, 21 mmol) followed by pyridinium
p-toluenesulfonate (88 mg, 0.35 mmol). After being stirred at
the same temperature for 2 h, the reaction mixture was
concentrated under reduced pressure. The residue was purified
by column chromatography (50% ethyl acetate in hexanes) to
give acetonide 16 (2.37 g, 100%): Rf ) 0.42 (ethyl acetate/
hexanes ) 2/3); mp 167.2-168.0 °C; [R]20D -2.9 (c 1.05, CHCl3);
IR (NaCl, cm-1) 3278, 2988, 1453, 1378, 1292, 1170, 1088; 1H
NMR (300 MHz, CDCl3) δ 7.78 (d, 1H, J ) 7.5 Hz), 7.65-7.53
(m, 3H), 5.20 (br s, 1H), 4.73 (dd, 1H, J ) 5.6, 6.8 Hz), 4.32 (dd,
1H, J ) 6.8, 12.5 Hz), 4.02 (dd, 1H, J ) 6.2, 8.9 Hz), 3.91 (dd,
1H, J ) 5.0, 9.4 Hz), 1.55 (s, 3H), 1.37 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 137.6, 136.4, 133.8, 130.5, 126.5, 122.1, 111.1,
78.3, 67.1, 59.3, 27.5, 25.7; MS (EI) m/z (rel intensity) 269 (M+,
60); Anal. Calcd for C12H15NO4S: C, 53.52; H, 5.61; N, 5.20.
Found: C, 53.66; H, 5.74; N, 5.23.
(()-3-Cya n o-2-(4-m eth oxyp h en yl)m eth yl-1,2-ben zisoth i-
a zolin e 1,1-Dioxid e (22). To a solution of 3-hydroxysultam 21
(22.3 g, 73 mmol) in CH2Cl2 (360 mL) at -78 °C (dry ice-acetone
bath) under an argon atmosphere was added boron trifluoride
etherate (9.0 mL, 73.0 mmol) followed by trimethylsilyl cyanide
(18.3 mL, 146.0 mmol) dropwise, and the resulting mixture was
stirred for 1 h. The dry ice-acetone bath was replaced with an
ice-water bath, and the reaction was quenched with a saturated
aqueous NaHCO3 solution. The separated organic layer was
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude product was recrystallized
from CH2Cl2-hexanes to give nitrile compound 22 (21.1 g, 92%
yield): Rf ) 0.53 (ethyl acetate/hexanes ) 1/1); mp 153.4-154.0
°C; IR (NaCl, cm-1) 2932, 2352, 1611, 1513, 1456, 1311, 1249,
3(R )-{1(R ),2-Dih yd r oxye t h a n -1-yl}-2-(4-m e t h oxyp h e -
n yl) Meth yl-1,2-ben zisoth ia zolin e 1,1-Dioxid e (18). To a
solution of sultam 16 (2.3 g, 8.5 mmol) in DMF (43 mL) at 0 °C
was added NaH (372 mg, 9.3 mmol, 60% dispersion in mineral
oil) followed by p-methoxybenzyl chloride (1.3 mL, 9.3 mmol),
and the mixture was stirred for 4 h. The reaction was quenched
with a small amount of water, and the mixture was extracted
with ethyl acetate. The extracts were washed with water, dried
over MgSO4, filtered, and concentrated under reduced pressure.
This crude N-protected sultam (17) was subjected to next step
without further purification.
1
To a solution of 17 in THF (14 mL) was added 2 N HCl (14
mL), and the resulting solution was stirred at 25 °C for 12 h.
Most of THF was evaporated under reduced pressure, and the
residue was extracted with ethyl acetate. The extracts were
washed with brine, dried over MgSO4, and filtered. The residue
was purified by column chromatography (50% ethyl acetate in
hexanes) to give diol 18 (2.73 g, overall 92%). Rf ) 0.5 (ethyl
1175, 1130, 1036; H NMR (300 MHz, CDCl3) δ 7.92-7.56 (m,
4H), 7.78-7,52 (m, 4H), 7.44 (d, 2H, J ) 8.1 Hz), 6.95 (d, 2H, J
) 8.5 Hz), 5.06 (s, 1H), 4.84 (d, 1H, J ) 14.3 Hz), 4.32 (d, 1H, J
) 14.3 Hz), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.5,
135.0, 134.2, 131.8, 131.2, 129.1, 125.2, 124.9, 122.4, 115.0, 114.0,
55.9, 49.0, 45.8; MS (EI) m/z (rel intensity) 314 (M+, 70); Anal.
Calcd for C15H13N2O3S: C, 61.13; H, 4.49; N, 8.91. Found: C,
61.01; H, 4.58; N, 8.88.
acetate/hexanes ) 4/1); [R]24 +82.7 (c 1.0, CHCl3); IR (Nalco,
D
cm-1) 3453, 2926, 1611, 1586, 1512, 1457, 1272, 1171, 1044; 1H
NMR (300 MHz, CDCl3) δ 7.78-7.75 (m, 1H), 7.57-7.47 (m, 2H),
7.36-7.26 (m, 3H), 6.86-6.81 (m, 2H), 4,64-4.47 (m, 3H), 3.99
(br s, -OH), 3.75 (s, 3H), 3.60 (dd, 1H, J ) 6.2, 11.2 Hz), 3.47 (d
(overlapped dd), 1H, J ) 11.2 Hz), 3.20 (d, 1H, J ) 4.4 Hz), 2.54
(br s, -OH); 13C NMR (75 MHz, CDCl3) δ 160.1, 136.1, 135.8,
133.3, 130.2, 127.8, 125.9, 121.9, 114.7, 74.4, 62.9, 62.8, 55.9,
49.1; MS (EI) m/z (rel intensity) 349 (M+, 48).
(()-3-Meth oxyca r bon yl-2-(4-m eth oxyp h en yl)m eth yl-1,2-
ben zisoth ia zolin e 1,1-Dioxid e (23). To a solution of nitrile
22 (21.0 g, 67.0 mmol) in dry dioxane (100 mL) at 0 °C was added
dry MeOH (220 mL) followed by acetyl chloride (40.0 mL, 558.0
mmol) dropwise, and the resulting mixture was warmed to 25
°C and was stirred for 3 days. The mixture was treated with
water and extracted with ethyl acetate. The combined organic
phase was washed sequentially with an aqueous saturated
NaHCO3 solution, water, and brine, and then it was dried over
MgSO4, filtered, and concentrated under reduced pressure to
give ester 23 as a colorless oil (23.37 g, 100%): Rf ) 0.40 (ethyl
acetate/hexanes ) 2/3); IR (NaCl, cm-1) 2846, 1750, 1612, 1513,
1453, 1300, 1249, 1175, 1132, 1061; 1H NMR (300 MHz, CDCl3)
δ 7.87-7.84 (m, 1H), 7.62-7.51 (m, 3H), 7.31 (d, 2H, J ) 8.6
Hz), 6.89 (d, 3H, J ) 8.6 Hz), 4.86 (s, 1H), 4.76 (d, 1H, J ) 14.5
Hz), 4.40 (d, 1H, J ) 14.5 Hz), 3.81 (s, 3H), 3.73 (s, 3H); 13C
3(R)-Car boxy-2-(4-m eth oxyph en yl)m eth yl-1,2-ben zisoth i-
a zolin e 1,1-Dioxid e (19). See the experimental of (()-19 in
Scheme 6 for the physical and spectroscopic data: [R]24 -24.0
D
(c 1.0, CHCl3).
2-(4-Me t h oxyp h e n yl)m e t h yl-3-oxo-1,2-b e n zisot h ia zo-
lin e 1,1-Dioxid e (20). To a solution of NaH (1.2 g, 30 mmol,
60% dispersion in mineral oil) in DMF (50 mL) at 0 °C under
an argon atmosphere was added a solution of saccharin (5.0 g,

Notes
J . Org. Chem., Vol. 65, No. 22, 2000 7695
NMR (75 MHz, CDCl3) δ 168.5, 160.1, 134.8, 133.5, 131.4, 131.0,
130.7, 126.3, 125.1, 122.0, 114.6, 60.8, 55.7, 53.6, 45.5; MS (EI)
m/z (rel intensity) 347 (M+, 63); HRMS Calcd for C17H17NO5S:
347.082745. Found: 347.082886.
(()-3-Ben zyl-3-ca r boxy-1,2-ben zisoth ia zolin e 1,1-Diox-
id e (6). Hydrolysis of ester 26 (2.89 g, 9.1 mmol) with LiOH in
THF-water afforded 6 in a yield of 96% (2.64 g): Rf ) 0.47
(methanol/ethyl acetate ) 1/4); mp 164.2-165.1 °C; IR (KBr
pellet, cm-1) 3337, 1714, 1456, 1427, 1367, 1281, 1236, 1160,
(()-3-Meth oxyca r bon yl-1,2-ben zisoth ia zolin e 1,1-Diox-
id e (24). To an acetonitrile solution (99 mL) of sultam 23 (2.87
g, 8.26 mmol) at 25 °C was ceric ammonium nitrate (18.11 g,
33.04 mmol) dissolved in water (33 mL). After being stirred for
1 h at the same temperature, the reaction mixture was diluted
with water and extracted with ethyl acetate. The organic phase
was washed with brine, dried over MgSO4, filtered, and concen-
trated under reduced pressure. Column chromatography of the
crude product (30% ethyl acetate in hexanes) gave deprotected
sultam 24 (1.78 g, 95%): Rf ) 0.38 (ethyl acetate/hexanes ) 1/1);
mp 98.5-99.4 °C; IR (NaCl, cm-1) 3273, 2958, 1749, 1455, 1297,
1108, 1067; 1H NMR (300 MHz, CDCl3) δ 7.82-7.62 (m, 4H),
5.56 (br s, NH), 5.32 (d, 1H, J ) 4.02 Hz), 3.94 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 168.8, 135.5, 133.9, 131.0, 126.3, 125.6, 122.0,
58.7, 54.4; MS (EI) m/z (rel intensity) 227 (M+, 63); Anal. Calcd
for C9H9NO4S: C, 47.57; H, 3.99; N, 6.16. Found: C, 47.59; H,
4.10; N, 6.09.
1
1120, 1066; H NMR (300 MHz, acetone-d6) δ 8.08 (d, 1H, J )
7.8 Hz), 7.87-7.73 (m, 3H), 7.40-7.24 (m, 5H), 6.49 (s, -NH),
3.70 (d, 1H, J ) 13.6 Hz), 3.22 (d, 1H, J ) 13.6 Hz); 13C NMR
(75 MHz, acetone-d6) δ 170.6, 138.5, 136.4, 135.6, 133.7, 131.0,
128.4, 127.6, 126.3, 126.0, 121.3, 69.8, 45.6; MS (EI) m/z (rel
intensity) 303 (M+, 60).
Resolution of (()-6. Ethanol was added dropwise to a hetero-
geneous mixture of (()-carboxylic acid 6 (938 mg, 3.0 mmol) and
brucine hydrate (1.2 g, 3.0 mmol) in a small amount of ethanol
at reflux temperature until the mixture became a homogeneous
solution. The resulting solution was allowed to cool to room
temperature whereupon a solid precipitated. The precipitate was
filtered and dried in vacuo, which exhibited [R]25D ) +7.8 (c 1.2,
AcOH). The solid, which was obtained from the filtrate, after
evaporating the solvent and drying in vacuo, exhibited [R]25
)
D
-21.7 (c 1.2, MeOH). Each salt was treated with concentrated
HCl and was subjected to extractive workup with diethyl ether
to afford the corresponding resolved carboxylic acid 6. From the
(()-3-Ca r boxy-1,2-ben zisoth ia zolin e 1,1-Dioxid e (5). To
a solution of ester 24 (1.56 g, 6.86 mmol) in THF (17 mL) at 25
°C was added LiOH‚H2O (630 mg, 15.0 mmol) followed by water
(17 mL), and the mixture was stirred for 10 min. The reaction
mixture was concentrated under reduced pressure to remove
most of THF, and the residue was washed with diethyl ether to
remove organic side products. The mixture was acidified to pH
) 2 with 2 N HCl, and it was extracted with ether. The organic
layer was dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was recrystallized from
ethyl acetate-hexanes to produce 3-carboxysultam 5 as a white
solid (1.17 g, 80% yield): Rf ) 0.34 (methanol/ethyl acetate )
1/4); mp 164.1-165.0 °C; IR (KBr pellet, cm-1) 3264, 2945, 1723,
1597, 1433, 1288, 1162, 1091; 1H NMR (300 MHz, methanol-d4)
δ 7.74-7.53 (m, 4H), 5.30 (s, 1H), 4.92 (br s, 2H, NH and COOH);
13C NMR (75 MHz, methanol-d4) δ 171.4, 136.4, 135.8, 134.6,
131.5, 126.9, 122.0, 59.6; MS (EI) m/z (rel intensity) 213 (M+,
48). Anal. Calcd for C8H7NO4S: C, 45.07; H, 3.31; N, 6.57.
Found: C, 44.85; H, 3.54; N, 6.32.
(+)-salt, (+)-6 was obtained, which exhibited [R]22 ) +50.4 (c
D
1.0, EtOH); and from the (-)-salt, (-)-6 was obtained, which
exhibited [R]22 ) -51.2 (c 1.0, EtOH).
D
(()-3-Car boxy-2-(4-m eth oxyph en yl)m eth yl-1,2-ben zisoth i-
a zolin e 1,1-Dioxid e (19). Hydrolysis of ester 23 (5.2 g, 14.9
mmol) with LiOH in THF-water afforded 19 in a yield of 77%
(3.82 g): Rf ) 0.50 (methanol/ethyl acetate ) 1/4); mp 129.7-
130.5 °C; IR (NaCl, cm-1) 3157, 1742, 1611, 1514, 1459, 1293,
1248, 1174, 1128, 1061, 1032; 1H NMR (300 MHz, CDCl3) δ 9.59
(br s, -COOH), 7.87 (m, 1H), 7.67-7.60 (m, 3H), 7.31 (d, 2H, J
) 8.4 Hz), 6.88 (d, 2H, J ) 8.4 Hz), 4.87 (s, 1H), 4.84 (d, 1H, J
) 14.5 Hz), 4.37 (d, 1H, J ) 14.5 Hz), 3.80 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 172.7, 160.1, 134.7, 133.7, 131.1, 130.8, 126.3,
126.0, 125.5, 122.1, 114.8, 60.2, 55.7, 45.5; MS (EI) m/z (rel
intensity) 333 (M+, 48). Anal. Calcd for C16H15NO5S: C, 57.65;
H, 4.53; N, 4.20, Found: C, 57.44; H, 4.64; N, 4.11.
2-(4-Me t h o x y p h e n y l)m e t h y l-3(R /S )-{(S )-(1-p h e n y l)-
eth ylam in o}car bon yl-1,2-ben zisoth iazolin e 1,1-Dioxide (27).
To a solution of acid 19 (2.25 g, 6.75 mmol) in CH2Cl2 (34 mL)
at -10 °C under an argon atmosphere was added isobutyl
chloroformate (0.92 mL, 6.75 mmol) followed by 4-methylmor-
pholine (0.68 mL, 6.75 mmol), and the mixture was stirred for
10 min. To the mixture was added (S)-(-)-R-methylbenzylamine
(0.82 mL, 6.75 mmol), and the reaction temperature was slowly
raised to 25 °C and was further stirred for 5 h. The reaction
mixture was filtered through a short pad of Celite to remove
precipitates, and the filtrate was washed sequentially with 1 N
HCl, a saturated aqueous NaHCO3 solution, and water. The
organic layer was dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (40% ethyl acetate in hexanes) to give a
diastereomeric mixture of 27 in a yield of 90% (2.65 g). The two
diastereomers were hardly separable on SiO2, but they exhibited
separate 13C NMR peaks: Rf ) 0.62 (ethyl acetate/hexanes )
3/2); IR (NaCl, cm-1) 3316, 2994, 1675, 1611, 1522, 1453, 1296,
(()-3-Ben zyl-3-m et h oxyca r b on yl-2-(4-m et h oxyp h en yl)
Meth yl-1,2-ben zisoth ia zolin e 1,1-Dioxid e (25). To a solution
of NaH (632 mg, 15.8 mmol, 60% dispersion in mineral oil) in
DMF (40 mL) at 0 °C under argon atmosphere was added a
solution of ester 23 (4.6 g, 13.2 mmol) in DMF (26 mL) through
a cannula followed by benzyl bromide (1.7 mL, 14.5 mmol)
dropwise, and the mixture was stirred for 2 h. The reaction was
carefully quenched with water, and the resulting mixture was
extracted with ethyl acetate. The extracts were washed three
times with water and then with brine. The organic layer was
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(20% ethyl acetate in hexanes) to give benzylated sultam 25 (5.48
g, 95%): Rf ) 0.55 (ethyl acetate/hexanes ) 2/3); mp 147.9-
148.7 °C; IR (NaCl, cm-1) 3023, 1738, 1514, 1452, 1297, 1247,
1
1176, 1138, 1044; H NMR (300 MHz, CDCl3) δ 7.76-7.74 (m,
1H), 7.54-7.44 (m, 4H), 7.14-7.07 (m, 4H), 6.91-6.83 (m, 4H),
4.64 and 4.56 (AB q, 2H, J AB) 15.7 Hz), 3.81 (s, 3H), 3.80 (d,
1H, J ) 14.6 Hz), 3.48 (d, 1H, J ) 14.6 Hz), 3.37 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 170.5, 159.8, 135.7, 134.4, 134.1, 132.8,
131.4, 130.8, 130.4, 128.5, 127.6, 127.2, 124.9, 121.9, 114.2, 71.5,
55.7, 53.4, 44.4, 39.5; MS (EI) m/z (rel intensity) 437 (M+, 50),
113 (75), 99 (80), 85 (90), 71 (90).
1
1248, 1175, 1130; H NMR (300 MHz, CDCl3) δ 7.83-6.73 (m,
14H, 13 aromatic and one NH protons), 4.93-4.34 (m, 4H), 3.83
and 3.78 (s, 3H; s, 3H, from each diastereomer), 1.30 (d, 3H, J
) 6.9 Hz) and 1.25 (d, 3H, J ) 7.0 Hz) from each diastereomer;
13C NMR (75 MHz, CDCl3) δ (167.2, 167.1), (160.5, 160.3), (143.1,
142.9), (134.2, 134.0), (133.9,133.7), (131.2, 131.0), (130.7, 130.6),
(129.3, 129.0), (128.1, 127.7), (126.9, 126.7), (126.4, 126.0), (125.7,
125.5), (121.8, 121.7), (115.1, 115.0), (65.6, 65.0), (55.9, 55.7),
(50.0, 49.6), (49.3, 49.2), (22.8, 22.1); MS (FAB) m/z (rel intensity)
459 (MNa+, 45), 437 (M + 1, 16).
(()-3-Ben zyl-3-m eth oxyca r bon yl-1,2-ben zisoth ia zolin e
1,1-Dioxid e (26). Deprotection of the MPM group of 25 (3.91 g,
8.9 mmol) with ceric ammonium nitrate in CH3CN-water (3:1)
afforded 26 in a yield of 95% (2.68 g) after purification by column
chromatography (20% ethyl acetate in hexanes): Rf ) 0.55 (ethyl
3(R /S )-{(S )-1-(P h e n yl)e t h yla m in o}ca r b on yl-1,2-b e n -
zisoth ia zolin e 1,1-Dioxid e (28). Deprotection of the MPM
group of 27 (350 mg, 0.8 mmol) afforded a diastereomeric
mixture of 28. Each diastereomer can be separated by SiO2
column chromatography: (-)-28 (107 mg, 43% yield); Rf ) 0.47
acetate/hexanes ) 2/3); mp 122.9-123.7 °C; IR (NaCl, cm-1
)
3286, 3030, 1740, 1495, 1450, 1376, 1304, 1254, 1204, 1167,
1134, 1035; 1H NMR (300 MHz, CDCl3) δ 7.94-7.61 (m, 4H),
7.32 (s, 5H), 5.58 (br s, -NH), 3.83 (s, 3H), 3.61(d, 1H, J ) 13.5
Hz), 3.20 (d, 1H, J ) 13.5 Hz); 13C NMR (75 MHz, CDCl3) δ
170.0, 138.2, 135.9, 134.0, 131.0, 130.7, 128.9, 128.1, 126.3, 125.6,
121.9, 70.2, 54.2, 46.7; MS (EI) m/z (rel intensity) 318 (M + 1,
57).
(ethyl acetate/hexanes ) 2/3); mp 165.7-166.5 °C; [R]24 -63.7
D
(c 1.0, CHCl3); IR (NaCl, cm-1) 3174, 1668, 1528, 1454, 1305,
1
1168, 1130, 1063; H NMR (300 MHz, CDCl3) δ 7.86-7.57 (m,
4H), 7.33-7.24 (m, 6H), 5.71 (d, J ) 7.0 Hz, SO2NH), 5.04 (d, J

7696 J . Org. Chem., Vol. 65, No. 22, 2000
Notes
) 7.0 Hz, 1H), 5.00-4.90 (m, 1H), 1.73 (br s, 1H), 1.38 (d, 3H, J
) 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 167.6, 143.0, 135.6, 134.5,
134.2, 130.7, 129.2, 127.8, 126.8, 126.2, 121.6, 60.0, 49.9, 23.1;
MS (EI) m/z (rel intensity) 316 (M+, 50). (+)-28 (95 mg, 37%);
Rf ) 0.37 (ethyl acetate/hexanes ) 2/3); mp 167.8-168.7 °C;
[R]24D +10.1 (c 1.875, CHCl3); IR (NaCl, cm-1) 3227, 1668, 1526,
1452, 1382, 1304, 1167. 1130. 1064; 1H NMR (300 MHz, CDCl3)
δ 7.76-7.72 (m, 2H), 7.60-7.55 (m, 2H), 7.19-7.07 (m, 6H), 5.86
(d, -SO2NH-, J ) 6.8 Hz), 5.15 (d, 1H, J ) 6.8 Hz), 5.05-4.95
(m, 1H), 1.70 (br s, 1H), 1.48 (d, 3H, J ) 6.9 Hz); 13C NMR (75
MHz, CDCl3) δ 167.6, 142.9, 135.6, 134.5, 134.2, 130.7, 129.2,
127.8, 126.8, 126.2, 121.6, 60.0, 49.9, 23.1; MS (EI) m/z (rel
intensity) 317 (M + 1, 76).
Ack n ow led gm en t. This work was financially sup-
ported by the Ministry of Education, Korea (BSRI-97-
3437), and the KOSEF (CBM center).
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for compounds 5, 6, 9-13, 15-28 and ORTEP plots of
(R,R)-16 and (S)-29. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O000952N