Novel Methods for the Facile Construction of 3,3-Disubstituted and 3,3-Spiro-2H,4H-benzo[e]1,2-thiazine-1,1-diones: Synthesis of (11S,12R,14R)-2-Fluoro-14-methyl-11-(methylethyl)spiro[4H-benzo[e]-1,2-thiazine- 3,2′-cyclohexane]-1,1-dione, an Agent for the Electrophilic Asymmetric Fluorination of Aryl Ketone Enolates

Article abstract of DOI:10.1021/jo0055584

Novel methods for the facile construction of 3,3-disubstituted and 3,3-spiro 2H,4H-benzo[e][1,2]-thiazine-1,1-diones 8a-h are described. o-Methyl lithiation of N-Boc-o-toluenesulfonamide 6 followed by reaction with a variety of ketones gave the corresponding carbinol sulfonamides 7a-g, which underwent cyclization under acidic (methanesulfonic acid) or neutral (NaI/TMSCl/MeCN) conditions to afford the sultams 8a-h in high yields. The chiral spiro sultams 8g,h were subjected to FClO₃ fluorination to give the N-fluorosultams 11a,b, respectively, which were tested for electrophilic asymmetric fluorination of aryl ketone enolates. As a result, the N-fluorosultam 11a exhibited modest asymmetric inducing abilities with the highest ee, reaching 70% for enantioselective fluorination of the lithium enolate of 2-methyl-1-tetralone.

Full text of DOI:10.1021/jo0055584

J . Org. Chem. 2000, 65, 7583-7587
7583
Novel Meth od s for th e F a cile Con str u ction of 3,3-Disu bstitu ted
a n d 3,3-Sp ir o-2H,4H-ben zo[e]1,2-th ia zin e-1,1-d ion es: Syn th esis of
(11S,12R,14R)-2-F lu or o-14-m eth yl-11-(m eth yleth yl)sp ir o[4H-ben zo[e]-
1,2-th ia zin e-3,2′-cycloh exa n e]-1,1-d ion e, a n Agen t for th e
Electr op h ilic Asym m etr ic F lu or in a tion of Ar yl Keton e En ola tes
Zhaopeng Liu, Norio Shibata, and Yoshio Takeuchi*
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630,
Toyama 930-0194, J apan
takeuchi@ms.toyama-mpu.ac.jp
Received J une 26, 2000
Novel methods for the facile construction of 3,3-disubstituted and 3,3-spiro 2H,4H-benzo[e][1,2]-
thiazine-1,1-diones 8a -h are described. o-Methyl lithiation of N-Boc-o-toluenesulfonamide 6 followed
by reaction with a variety of ketones gave the corresponding carbinol sulfonamides 7a -g, which
underwent cyclization under acidic (methanesulfonic acid) or neutral (NaI/TMSCl/MeCN) conditions
to afford the sultams 8a -h in high yields. The chiral spiro sultams 8g,h were subjected to FClO3
fluorination to give the N-fluorosultams 11a ,b, respectively, which were tested for electrophilic
asymmetric fluorination of aryl ketone enolates. As a result, the N-fluorosultam 11a exhibited
modest asymmetric inducing abilities with the highest ee, reaching 70% for enantioselective
fluorination of the lithium enolate of 2-methyl-1-tetralone.
In tr od u ction
The sulfonamide antibiotics hold the prestigious posi-
tion of being the first synthetic compounds to have had
general utility in human therapy.1 These exciting devel-
opments spawned considerable interest in their use in
veterinary practice and in the preparation of many
hundreds of cyclic variants (i.e., sultams).2 In recent
years, sultam templates have also become one of the
synthetic strategies for the development of novel elec-
F igu r e 1.
structure at the 3 position. In this paper, we report novel
methods for the construction of these kinds of sultams
that led to the synthesis of (11S,12R,14R)-2-fluoro-14-
methyl-11-(methylethyl)-spiro[4H-benzo[e]-1,2-thiazine-
3,2′-cyclohexane]-1,1-dione, an agent for the electrophilic
asymmetric fluorination of aryl ketone.
trophilic fluorinating agents. Representative examples
include nonracemic N-fluoro-2,10-camphorsultams 13 and
24 and saccharin-based electrophilic fluorinating agents
35 and 46 (Figure 1). Recently, we reported a novel
method for the synthesis of 3-monosubstituted 2H,3H,4H-
benzo[e]1,2-thiazine-1,1-diones using orthomethyl lithia-
tion-cyclization of N-acyl-o-toluenesulfonamides and proved
that the N-fluorosultam 5 had some ability for the
electrophilic fluorination of aryl ketone enolates.7 As a
part of our continuing research on the development of
highly efficient enantioselective fluorinating agents,8 we
were interested in the 3,3-disubstituted 2H,4H-benzo-
[e]1,2-thiazine-1,1-diones, especially those with a spiro
Resu lts a n d Discu ssion
It is well documented that N-substituted o-toluene-
sulfonamides undergo metalation at the methyl group as
well as the nitrogen atom.7,9 Therefore, it is reasonable
to expect that a properly N-protected o-toluenesulfona-
mide will react with ketones after o-methyl lithiation to
generate tertiary alcohols, which might undergo cycliza-
tion to form our target compounds. However, there is only
one reported example of N-methyl- or N-phenyl-substi-
tuted o-toluenesulfonamides which, when treated with
excess butyllithium and reacted with benzophenone, gave
carbinol sulfonamides. These were not very stable and
* To whom correspondence should be addressed. Phone: +81 76 434
7555. Fax: +81 76 434 5053.
(1) Bowman, W. C.; Rand, M. J . Textbook of Pharmacology, 2nd ed.;
Blackwell: London, 1979; Chapter 34.
(2) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Comprehensive
Heterocyclic Chemistry II; Elsevier: Oxford, 1996; Vols. 3 and 4.
(3) Differding, E.; Lang, R. W. Tetrahedron Lett. 1988, 29, 6087-
6090.
(4) (a) Davis, F. A.; Han, W. Tetrahedron Lett. 1991, 32, 1631-1634.
(b) Davis, F. A.; Zhou, P.; Murphy, C. K.; Sundarababu, G.; Qi, H.;
Han, W.; Przeslawski, R. M.; Chen, B.-C.; Carroll, P. J . J . Org. Chem.
1998, 63, 2273-2280.
(8) (a) Davis, F. A.; Qi, H.; Sundarababu G. In Enantiocontrolled
Synthesis of Fluoro-organic Compounds; Soloshonok, V. A., Ed.; J ohn
Wiley & Sons, Ltd: Chichester, 1999; pp 1-32. (b) Bravo, P.; Resnati,
G. Tetrahedron: Asymmetry 1990, 1, 661-692.
(9) (a) Watanabe, H.; Hauser, C. R. J . Org. Chem. 1968, 33, 4278-
4279. (b) Watanabe, H.; Mao, C.-L.; Barnish, I. T.; Hauser, C. R. J .
Org. Chem. 1969, 33, 919-924. (c) Takahashi, M.; Ohtsuki, K.; Taga,
T.; Chohnan, Y. Hetereocycles 1998, 48, 1643-1648. (d) Snieckus, V.
Chem. Rev. 1990, 90, 879-933. (e) Narashimhan, N. S.; Mali, R. S.
Synthesis 1983, 957-986.
(5) (a) Differding, E.; Lang, R. W. Helv. Chim. Acta 1989, 72, 1248-
1252. (b) Differding, E.; Ru¨egg, G. W.; Lang, R. W. Tetrahedron Lett.
1991, 32, 1779-1782.
(6) Takeuchi, Y.; Suzuki, T.; Satoh, A.; Shiragami, T.; Shibata, N.
J . Org. Chem. 1999, 64, 5708-5711.
(7) Takeuchi, Y.; Liu, Z.; Satoh, A.; Shiragami, T.; Shibata, N. Chem.
Pharm. Bull. 1999, 47, 1730-1733.
10.1021/jo0055584 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/06/2000

7584 J . Org. Chem., Vol. 65, No. 22, 2000
Liu et al.
Ta ble 1. F or m a tion of th e Ca r bin ol Su lfon a m id es 7a -g
via o-Meth yl Lith ia tion of 6 F ollow ed by Rea ction w ith
Keton es
Ta ble 2. F or m a tion of th e Su lta m s 8a -g by Cycliza tion
of th e Su lfon a m id es 7
underwent thermal dehydration to afford unsaturated
sulfonamides.9a Considering that the N-protective group
should be easily removable, and inspired by the reports
that N-Boc-p-toluenesulfonamide had shown significant
utility as a Mitsunobu N-nucleophile,10 we chose the
readily available N-Boc-o-toluenesulfonamide 6 as our
starting material. In fact, when 6 was treated with 2
equiv of BuLi at -78 °C, o-methyl lithiation occurred
rapidly. The resulting anion reacted with a variety of
ketones to give the corresponding carbinol sulfonamides
7a -g in good yields (Table 1). In the case of l-menthone,
only one isomer 7g was isolated. The diastereoselectivity
is probably due to the predominant preference for the
equatorial attack of the hindered carbanion toward the
menthone carbonyl. Thus, the S configuration is assumed
for the newly created stereogenic center of 7g.
To obtain the sultam structure, we first examined the
intramolecular cyclization of the carbinol sulfonamides
7 under Mitsunobu reaction conditions.10a,11 However,
this approach did not work at all, possibly owing to the
bulkiness of the various tertiary alcohol groups. We then
investigated the cyclization of 7a -f under acidic condi-
tions and found that methanesulfonic acid was effective
and the corresponding sultams 8a -f were obtained in
high yields (Table 2, method A).
a
b
Method A: MeSO3H, CH2Cl2, rt, 24 h. Method B: TMSCl,
NaI,MeCN,reflux,1h. c 8g:(11S,12R,14R)-isomer.8h :(11S,12S,14R)-
isomer. 8g:8h ) 1:2.5. e 8g:8h ) 5.5:1.
d
Sch em e 1
A sequence of the consecutive N-deprotective cycliza-
tion process under acidic conditions is shown in Scheme
1, with the substrate 7b as an example. When a solution
of 7b in CH2Cl2 was treated with 3 equiv of methane-
sulfonic acid at room temperature, dehydration occurred
rapidly to form the unsaturated sulfonamide 9, which
slowly deprotected to give 10. The intermediate 10
appears to undergo an acid-catalyzed addition process to
produce the sultam 8b. Both intermediates, 9 and 10,
could be isolated, and their structures were confirmed
by spectral studies.
However, when this procedure was applied to 7g, a
mixture of two separable diastereomers, 8g and 8h , was
obtained in only 35% yield, with a ratio of 1:2.5 (Table 2,
entry 7, method A). The stereochemistry of the newly
created spiro carbon was confirmed by X-ray crystal-
(10) (a) Henry, J . R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.;
Harris, G. D.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709-5712.
(b) Degerbeck, F.; Fransson, B.; Grehn, L.; Ragnarsson, U. J . Chem.
Soc., Perkin Trans 1 1992, 245-253. (c) Campbell, J . A.; David, J . H.
J . Org. Chem. 1993, 58, 2900-2903. (d) O’Brien, P.; Towers, T. D.;
Voith, M. Tetrahedron Lett. 1998, 39, 8175-8178.
(11) For a review, see: Mitsunobu, O. Synthesis 1981, 1-28.

Construction 3,3-Spiro-2H,4H-benzo[e]1,2-thiazine-1,1-diones
J . Org. Chem., Vol. 65, No. 22, 2000 7585
Ta ble 3. Asym m etr ic F lu or in a tion of Ar yl Keton e
Sch em e 2
En ola tes Usin g N-F lu or osu lta m s 11
lographic analysis of a crystalline descendant 11a . The
low yield in the case of 7g may be due to steric hindrance
by the neighboring isopropyl group in the cyclohexane
ring and/or the rearrangement of the putative carbocation
thus formed. Since the enantiopure sultams 8g,h might
be good templates for developing new electrophilic asym-
metric fluorinating agents, we examined the reaction
conditions for this cyclization.
When the TMSCl/NaI/MeCN/reflux system was em-
ployed, the cyclization went smoothly to produce the
sultams 8g,h in 91% yield, with a ratio of 5.5:1 (Table 2,
entry 7, method B). The reversed ratio of 8g and 8h can
be explained from the mechanistic considerations. As
shown in Scheme 1, partial racemization might occur in
this acid-mediated cyclization process (Scheme 1), and
the major product 8h retains the S configuration of 7g
at the newly formed spiro carbon. In contrast, the TMSCl/
NaI/MeCN mediated cyclization (method B) might pro-
ceed mainly via an SN2 process, therefore the major
products 8g should have the reversed configuration of
7g. The confirmed R configuration of the spiro carbon of
8g also supports the assumed S configuration of 7g.
The TMSCl/NaI/MeCN system is well-known as a vers-
atile reagent for reaction with many functional groups.12
As far as we know, this is the first report of its use to
effect a cyclization. In the same way, sultams 8a -f were
also obtained in almost quantitative yields (Table 2,
method B). Finally, both 8g and 8h were separately
a
b
Chiral OB column (10% i-PrOH/hexane). Chiral OJ column
(10% i-PrOH/hexane). c Chiral OJ column (EtOH). References 4
d
and 6. e ND: not determined.
12R,14R)-2-fluoro-14-methyl-11-(methylethyl)-spiro[4H-
benzo[e]-1,2-thiazine-3,2′-cyclohexane]-1,1-dione (11a ) for
the electrophilic asymmetric fluorination of aryl ketone
enolates. This agent exhibited modest asymmetric induc-
ing abilities with the highest ee obtained being 70%. This
is comparable to Differding’s (1) and Davis’s (2) agents.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined on a
micro-melting point apparatus and are uncorrected. IR spectra
(cm-1) were recorded on a 1600 FT-IR spectrometer. 1H NMR-
(270 MHz) and 13C NMR spectra (75.5 MHz) were recorded at
room temperature for CDCl3 solutions, unless otherwise stated.
All chemical shifts are reported as δ values (ppm) relative to
Me4Si (0.00 ppm) and CDCl3 (77.0 ppm) as internal standards
for 1H and 13C NMR spectra, respectively. 19F NMR spectra
were measured with CFCl3 as an internal standard and were
taken with a 254 MHz spectrometer. Upfield shifts are quoted
as negative δ values. Mass spectra were obtained by EI
method. Column chromatography and preparative TLC were
performed on BW-200 (Fuji Silysia) and Kieselgel 60 F-254
plates, respectively. All reactions involving oxygen- or moisture-
sensitive compounds were carried out under a dry N2 atmo-
sphere. Unless otherwise noted, reagents were added by
syringe. THF was distilled from sodium/benzophenone im-
mediately prior to use.
13
treated with FClO3 in the presence of NaH in THF
to give the corresponding diastereomerically pure N-
fluoro sultams 11a [(11S,12R,14R)-isomer] and 11b
[(11S,12S,14R)-isomer] in 81% and 44% yields, respec-
tively (Scheme 2).
Asymmetric enolate fluorinations were typically car-
ried out at -50 °C by adding 1.2 equiv of 11a or 11b to
the preformed enolates generated by treatment of 1.5
equiv of LHMDS with the corresponding ketones. The
results are summarized in Table 3. For comparing the
asymmetric inducing abilities of 11a or 11b, 2-methylin-
danone and 2-benzylindanone were tested as substrates.
In both cases, 11a gave much better ee’s than 11b (Table
3, entries 1-4). The highest asymmetric induction was
observed for the fluorination of 2-methyl-1-tetralone with
11a , affording the 2-fluoro-2-methyl-1-tetralone (12e) in
65% yield with an ee of 70%.
In summary, we have developed two novel methods for
the preparation of 3,3-disubstituted and 3,3-spiro- 2H,4H-
benzo[e]1,2-thiazine-1,1-diones. The TMSCl/NaI/MeCN
reagent system (method B) was used for the first time to
cause a cyclization. This system gave better results than
the method using methanesulfonic acid (method A). The
success of this new method led us to synthesize (11S,-
P r ep a r a tion of N-Boc-o-tolu en esu lfon a m id e 6.14 o-Tol-
uenesulfonamide (8.55 g, 50 mmol) was suspended in CH2Cl2
(60 mL) containing Et3N (7.65 mL, 55 mmol) and DMAP (610
mg, 5 mmol). A solution of di-tert-butyl dicarbonate (12.5 g,
57.5 mmol) in CH2Cl2 (100 mL) was added dropwise with
stirring over 10 min. After 4 h, the solution was concentrated
in vacuo and the residue treated with EtOAc (300 mL) and 1
N HCl (200 mL). The EtOAc layer was washed successively
with water and brine, dried (MgSO4), and concentrated.
Crystallization from hexane provided 6 as a white solid (12.57
g, 93%): mp 109-110 °C; IR (KBr) 3240, 1741, 1710, 1346,
1154, 758 cm-1; 1H NMR δ 1.34 (s, 9H), 2.67 (s, 3H), 7.35 (m,
2H), 7.44 (br s, 1H), 7.53 (td, J ) 7.6, 1.5 Hz, 1H), 8.12 (dd, J
) 7.6, 1.5 Hz, 1H); 13C NMR δ 20.4, 28.0, 84.5, 126.1, 131.2,
132.5, 133.8, 136.9, 137.5, 149.7; MS m/z 271 (M+), 256 (M+
-
Me); HRMS calcd for C12H17NO4S 271.0878, found 271.0902.
Anal. Calcd for C12H17NO4S: C, 53.12; H, 6.32; N, 5.16.
Found: C, 53.23; H, 6.39; N, 5.13.
(12) For a review, see: Olah, G. A.; Narang, S. C. Tetrahedron 1982,
38, 2225-2277.
(13) (a) Takeuchi, Y.; Nagata, K.; Koizume, T. J . Org. Chem. 1987,
52, 5061-5063. (b) Takeuchi, Y.; Nagata, K.; Koizume, T. J . Org. Chem.
1989, 54, 5453-5459. See also J . Org. Chem. 1988, 53, 4160.
(14) Neustadt, B. R. Tetrahedron Lett. 1994, 35, 379-380.

7586 J . Org. Chem., Vol. 65, No. 22, 2000
Liu et al.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ca r bin ol
Su lfon a m id es 7a -g. To a stirred solution of N-Boc o-toluene-
sulfonamide (1.09 g, 4 mmol) in THF (20 mL) was added a
1.53 M solution of BuLi in hexane (5.22 mL, 4 mmol) under
nitrogen at -78 °C. The reaction mixture was stirred for 10
min and a solution of ketone (4 mmol) in 4 mL THF was added.
After 1 h, saturated aqueous NH4Cl was added. The mixture
was extracted with EtOAc, the combined organic layers were
washed with brine, dried (MgSO4) and concentrated in vacuo.
The residue was chromatographed (30% EtOAc in hexane) to
give the carbinol sulfonamide 7 (Table 1).
Meth od B. To a stirred solution of 7 (2 mmol) in MeCN
(10 mL) was added under nitrogen sodium iodide (0.93 g, 6.2
mmol) and chlorotrimethylsilane (0.76 mL, 6 mmol). The
reaction mixture was refluxed for 1 h. It was cooled to room
temperature, and 10% sodium thiosulfate aqueous solution
was added. The mixture was extracted with EtOAc, and the
combined organic layers were washed with water, brine, dried
(MgSO4), and concentrated in vacuo. The residue was chro-
matographed (30% EtOAc in hexane) to give sultam 8 (Table
2).
3,3-Dim eth yl-2H,4H-ben zo[e][1,2]th iazin e 1,1-dion e (8a):
colorless oil; IR (neat) 3262, 1318, 1216, 758 cm-1; 1H NMR δ
1.36 (s, 6H), 3.02 (s, 2H), 4.23 (s, 1H), 7.27 (d, J ) 7.3 Hz,
1H), 7.41 (td, J ) 7.6, 1.5 Hz, 1H), 7.49 (td, J ) 7.6, 1.5 Hz,
1H), 7.80 (dd, J ) 7.6, 1.5 Hz, 1H); 13C NMR δ 30.3, 40.5, 56.4,
123.1, 127.6, 129.6, 132.3, 135.3, 138.3; MS m/z 211 (M+), 196
(M+ - Me); HRMS calcd for C10H13NO2S 211.0667, found
211.0657. Anal. Calcd for C10H13NO2S: C, 56.85; H, 6.20; N,
6.63. Found: C, 56.76; H, 6.34; N, 6.59.
7a : colorless oil; IR (neat) 3502, 3227, 1740, 1342, 1148, 758
1
cm-1; H NMR δ 1.31 (s, 6H), 1.35 (s, 9H), 3.30 (s, 2H), 7.42
(d, J ) 7.3 Hz, 2H), 7.57 (td, J ) 7.3, 1.5 Hz, 1H), 8.17 (m,
2H); 13C NMR δ 28.1, 30.5, 45.2, 71.8, 84.2, 126.8, 131.5, 133.2,
133.9, 137.8, 138.2, 149.9; MS m/z 273 (M+ + H - t-Bu); HRMS
calcd for C11H15NO5S (M+ + H - t-Bu) 273.0671, found
273.0663. Anal. Calcd for C15H23NO5S: C, 54.69; H, 7.04; N,
4.25. Found: C, 54.54; H, 7.16; N, 4.19.
7b: colorless glass; IR (CHCl3) 3420, 1732, 1339, 1161, 758
3-ter t-Bu tyl-3-m eth yl-2H,4H-ben zo[e][1,2]th ia zin e 1,1-
d ion e (8b): colorless prisms; mp 204-206 °C; IR (KBr) 3257,
1
cm-1; H NMR δ 0.95 (s, 3H), 1.01 (s, 9H), 1.29 (s, 9H), 2.11
(s, 1H), 2.93, 3.68 (ABq, J ) 14.2 Hz, 2H), 7.34 (m, 2H), 7.47
(m, 1H), 8.09 (s, 1H), 8.13 (d, J ) 7.8 Hz, 1H); 13C NMR δ
21.5, 25.7, 28.1, 38.6, 39.2, 78.0, 84.1, 126.6, 131.4, 132.9, 134.7,
138.6, 138.7, 149.3; MS m/z 371 (M+), 315 (M+ + H - t-Bu);
HRMS calcd for C18H29NO5S 371.1766, found 371.1763. Anal.
Calcd for C18H29NO5S: C, 58.20; H, 7.87; N, 3.77. Found: C,
58.17; H, 7.89; N, 3.59.
1312, 1216, 756 cm-1 1H NMR δ 1.04 (s, 3H), 1.07 (s, 9H),
;
2.70, 3.46 (ABq, J ) 14.9 Hz, 2H), 3.88 (s, 1H), 7.31 (d, J )
7.3 Hz, 1H), 7.41 (td, J ) 7.3, 1.5 Hz, 1H), 7.48 (td, J ) 7.3,
1.5 Hz, 1H), 7.80 (dd, J ) 7.3, 1.5 Hz, 1H); 13C NMR δ 23.0,
25.7, 33.6, 38.0, 65.1, 122.3, 127.3, 130.0, 132.1, 136.5, 138.4;
MS m/z 254 (M+ + 1), 253 (M+), 238 (M+ - Me), 196 (M+
-
t-Bu); HRMS calcd for C13H19NO2S 253.1137, found 253.1129.
Anal. Calcd for C13H19NO2S: C, 61.63; H, 7.56; N, 5.53.
Found: C, 61.77; H, 7.60; N, 5.48.
7c: colorless glasses; IR (CHCl3) 3679, 3381, 1741, 1343,
1
1216, 757 cm-1; H NMR δ 1.34 (s, 9H), 1.64 (s, 3H), 3.12 (br
s, 1H), 3.38, 3.69 (ABq, J ) 14.1 Hz, 2H), 6.85 (m, 1H), 7.21-
3-Meth yl-3-p h en yl-2H,4H-ben zo[e][1,2]th ia zin e 1,1-d i-
on e (8c): colorless glass; IR (CHCl3) 3267, 1318, 1169, 757
7.42 (m, 7H), 7.84 (br s, 1H), 8.13 (m, 1H). Anal. Calcd for
1
C
20H25NO5S: C, 61.36; H, 6.44; N, 3.58. Found: C, 61.37; H,
6.51; N, 3.49.
cm-1; H NMR δ 1.58 (s, 3H), 3.22, 3.49 (ABq, J ) 15.1 Hz,
2H), 4.50 (s, 1H), 7.29-7.58 (m, 8H), 7.85 (d, J ) 7.1 Hz, 1H);
13C NMR δ 29.4, 41.1, 61.5, 122.6, 125.2, 127.5, 127.7, 128.7,
129.6, 132.4, 135.1, 138.6, 145.9; MS m/z 274 (M+ + 1), 273
(M+), 258 (M+ - Me); HRMS calcd for C15H15NO2S 273.0823,
found 273.0815. Anal. Calcd for C15H15NO2S: C, 65.91; H, 5.53;
N, 5.12. Found: C, 65.89; H, 5.56; N, 5.09.
7d : colorless glasses; IR (CHCl3) 3361, 1725, 1309, 1216, 758
1
cm-1; H NMR δ 1.34 (s, 9H), 3.50, 4.15 (ABq, J ) 14.1 Hz,
2H), 4.83 (s, 1H), 6.40 (d, J ) 7.8 Hz, 1H), 7.19 (td, J ) 7.6,
1.5 Hz, 1H), 7.31-7.39 (m, 4H), 7.53 (m, 2H), 7.64 (br s, 1H),
8.12 (dd, J ) 7.6, 1.5 Hz, 1H); 19F NMR δ -74.9 (s). Anal. Calcd
for C20H22F3NO5S: C, 53.93; H, 4.98; N, 3.14. Found: C, 53.85;
H, 4.78; N, 3.06.
3-P h en yl-3-t r iflu or om et h yl-2H ,4H -b en zo[e][1,2]t h ia -
zin e 1,1-d ion e (8d ): colorless prisms; mp 194-195 °C; IR
1
7e: colorless oil; IR (neat) 3506, 3219, 1739, 1341, 1149, 758
(KBr) 3377, 3255, 1316, 1216, 758 cm-1; H NMR (CD3OD) δ
1
cm-1; H NMR δ 1.35 (s, 9H), 1.48-1.68 (m, 10H), 2.44 (br s,
3.80, 4.20 (ABq, J ) 14.9 Hz, 2H), 6.74 (d, J ) 7.6 Hz, 1H),
7.10 (t, J ) 7.6 Hz, 1H), 7.25 (d, J ) 7.8 Hz, 1H), 7.31-7.36
(m, 3H), 7.55 (m, 2H), 7.96 (d, J ) 7.8 Hz, 1H); 19F NMR δ
-78.98 (s); 13C NMR (CD3OD) δ 37.7, 102.0, 127.8, 128.0, 128.3,
128.8, 129.1, 132.1, 133.4, 134.0, 138.0, 144.0; MS m/z 345 (M+
+ H2O), 327 (M+), 258 (M+ - CF3); HRMS calcd for C15H12F3-
NO2S 327.0541, found 327.0552. Anal. Calcd for C15H12F3-
NO2S‚H2O: C, 52.16; H, 4.09; N, 4.06. Found: C, 51.94; H,
4.26; N, 4.01.
1H), 3.27 (s, 2H), 7.40 (t, J ) 7.6 Hz, 1H), 7.52 (t, J ) 7.6 Hz,
1H), 8.16 (d, J ) 7.8 Hz, 1H), 8.44 (s, 1H); 13C NMR δ 22.3,
25.9, 28.1, 31.2, 38.4, 72.3, 84.1, 126.7, 131.5, 133.0, 133.9,
137.4, 138.2, 149.3. Anal. Calcd for C18H27NO5S: C, 58.51; H,
7.37; N, 3.79. Found: C, 58.65; H, 7.46; N, 3.62.
7f: colorless oil; IR (neat) 3487, 3222,1739, 1345, 1150, 759
cm-1 1H NMR δ 1.36 (s, 9H), 2.06 (m, 1H), 2.44 (ddd, J )
;
11.2, 7.6, 3.9 Hz, 1H), 2.81-3.20 (m, 2H), 2.93 (br s, 1H), 3.52,
3.69 (ABq, J ) 14.2 Hz, 2H), 7.03-7.18 (m, 3H), 7.25-7.27
Spir o(2H,4H-ben zo[e][1,2]th iazin e-3,1′-cycloh exan e) 1,1-
d ion e (8e): colorless prisms; mp 154-155 °C; IR (KBr) 3258,
1323, 1216, 759 cm-1; 1H NMR δ 1.32 (m, 1H), 1.42-1.82 (m,
9H), 3.01 (s, 2H), 4.13 (s, 1H), 7.36 (d, J ) 7.6 Hz, 1H), 7.39
(td, J ) 7.6, 1.5 Hz, 1H), 7.48 (td, J ) 7.6, 1.5 Hz, 1H), 7.80
(dd, J ) 7.3, 1.5 Hz, 1H); 13C NMR δ 21.6, 25.4, 38.1, 40.0,
58.4, 123.1, 127.4, 129.7, 132.2, 135.0, 138.4; MS m/z 251 (M+);
HRMS calcd for C13H17NO2S 251.0980, found 253.0977. Anal.
Calcd for C13H17NO2S: C, 62.12; H, 6.82; N, 5.57. Found: C,
61.96; H, 6.91; N, 5.47.
(m, 3H), 7.38-7.48 (m, 2H), 8.20 (dd, J ) 7.6, 1.8 Hz, 1H); 13
C
NMR δ 28.1, 29.6, 41.3, 41.8, 84.1, 84.4, 123.5, 125.1, 126.6,
126.9, 128.6, 131.4, 133.0, 134.0, 137.2, 138.3, 142.6, 147.0,
149.3. Anal. Calcd for C21H25NO5S: C, 62.51; H, 6.25; N, 3.47.
Found: C, 62.61; H, 6.28; N, 3.43.
7g: colorless glass; [R]25D + 26.7 (c 0.99, CHCl3); IR (CHCl3)
1
3528, 3214, 1742, 1344, 1150, 758 cm-1; H NMR δ 0.78 (d, J
) 6.3 Hz, 3H), 0.99 (d, J ) 7.1 Hz, 6H), 1.36 (s, 9H), 1.16-
1.80 (m, 8H), 2.24 (br s, 1H), 2.37 (m, 1H), 2.76, 4.15 (ABq, J
) 14.2 Hz, 2H), 7.40 (t, J ) 7.3 Hz, 2H), 7.53 (t, J ) 7.6 Hz,
1H), 8.19 (d, J ) 7.6 Hz, 1H), 8.68 (s, 1H); 13C NMR δ 18.5,
21.3, 22.7, 24.2, 25.9, 28.1, 35.1, 43.8, 46.5, 52.4, 76.3, 83.7,
126.7, 131.4, 132.8, 134.8, 137.8, 138.3, 149.4. Anal. Calcd for
Sp ir o(2H,4H-ben zo[e][1,2]th ia zin e-3,1′-in d a n e) 1,1-d i-
on e (8f): colorless needles; mp 124-126 °C; IR (KBr) 3247,
1
1315, 1169, 757 cm-1; H NMR δ 2.31 (m, 2H), 2.99 (m, 2H),
3.31 (s, 2H), 4.49 (s, 1H), 7.05 (d, J ) 7.6 Hz, 1H), 7.15-7.32
(m, 4H), 7.48 (m, 2H), 7.88 (d, J ) 7.3 Hz, 1H); 13C NMR δ
29.5, 37.9, 41.1, 68.8, 122.8, 122.9, 125.2, 127.5, 127.6, 128.9,
129.4, 132.4, 135.4, 139.5, 142.2, 145.9; MS m/z 285 (M+);
HRMS calcd for C16H15NO2S 285.0823, found 285.0805. Anal.
Calcd for C16H15NO2S: C, 67.34; H, 5.30; N, 4.91. Found: C,
67.25; H, 5.38; N, 4.81.
C
22H35NO5S: C, 62.09; H, 8.29; N, 3.29. Found: C, 61.96; H,
8.50; N, 3.18.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Su lt a m s
8a -g. Meth od A. Methanesulfonic acid (0.39 mL, 6 mmol)
was added to a stirred solution of 7 (2 mmol) in CH2Cl2 (10
mL) at room temperature. The reaction mixture was stirred
for 24 h. CH2Cl2 (20 mL) was added, and the organic layer
was washed with water, brine, dried (MgSO4), and concen-
trated in vacuo. The residue was chromatographed (30%
EtOAc in hexane) to give sultam 8 (Table 2).
(11S,12R,14R)-14-Meth yl-11-(m eth yleth yl)-spir o(2H,4H-
ben zo[e][1,2]th ia zin e-3,2′-cycloh exa n e) 1,1-d ion e (8g):
colorless needles; mp 96 °C; [R]28 -44.7 (c 1.22, CHCl3); IR
D
(KBr) 3288, 1316, 1169, 757 cm-1; 1H NMR δ 0.82 (d, J ) 6.6

Construction 3,3-Spiro-2H,4H-benzo[e]1,2-thiazine-1,1-diones
J . Org. Chem., Vol. 65, No. 22, 2000 7587
Hz, 6H), 0.92 (d, J ) 7.1 Hz, 3H), 0.81-1.00 (m, 2H), 1.14-
1.35 (m, 2H), 1.59-1.82 (m, 4H), 2.62 (m, 1H), 2.65, 3.56 (ABq,
J ) 15.3 Hz, 2H), 4.12 (s, 1H), 7.29 (d, J ) 7.3 Hz, 1H), 7.39
(t, J ) 7.3 Hz, 1H), 7.49 (t, J ) 7.3 Hz, 1H), 7.79 (d, J ) 7.3
Hz, 1H); 13C NMR δ 18.0, 22.1, 22.3, 24.7, 26.1, 28.0, 34.9, 38.6,
48.8, 51.7, 62.2, 122.5, 127.1, 129.5, 132.2, 136.4, 138.5; MS
m/z 307 (M+), 292 (M+ - Me); HRMS calcd for C17H25NO2S
307.1606, found 307.1618. Anal. Calcd for C17H25NO2S: C,
66.41; H, 8.20; N, 4.56. Found: C, 66.54; H, 8.40; N, 4.54.
(11S,12S,14R)-14-Meth yl-11-(m eth yleth yl)sp ir o(2H,4H-
ben zo[e][1,2]th ia zin e-3,2′-cycloh exa n e) 1,1-d ion e (8h ):
colorless needles; mp 145-147 °C; [R]28D -3.1 (c 0.30, CHCl3);
δ 0.79 (d, J ) 6.1 Hz, 3H), 0.87 (d, J ) 6.8 Hz, 3H), 0.99 (d, J
) 6.8 Hz, 3H), 1.01-1.16 (m, 1H), 1.32-1.54 (m, 4H), 1.70-
1.85 (m, 3H), 2.46 (m, 1H), 3.14, 3.43 (ABq, J ) 14.9 Hz, 2H),
7.32 (d, J ) 7.6 Hz, 1H), 7.50 (t, J ) 7.6 Hz, 1H), 7.56 (t, J )
7.6 Hz, 1H), 7.93 (d, J ) 7.6 Hz, 1H); 19F NMR δ -75.5 (s); 13
C
NMR δ 19.0, 22.6, 23.1, 24.8, 25.5, 29.2 (29.3), 30.9, 34.6, 38.8
(39.1), 49.5, 76.9, 125.7, 128.0, 129.4, 133.8, 134.7, 135.8; MS
m/z 325 (M+), 306 (M+ - HF); HRMS calcd for C17H24FNO2S
325.1512, found 325.1521. Anal. Calcd for C17H24FNO2S: C,
62.74; H, 7.43; N, 4.30. Found: C, 62.79; H, 7.47; N, 4.24.
Gen er a l P r oced u r e for Asym m etr ic F lu or in a tion of
Keton e En ola tes w ith 11a a n d 11b. To a stirred solution
of ketone (0.15 mmol) in THF (2.0 mL) was added a 1.0 M
solution of LiHMDS in THF (0.225 mL, 0.225 mmol) under
nitrogen atmosphere at -78 °C. The mixture was stirred for
10 min at -78 °C, warmed to 0 °C, stirred for an additional 1
h, and cooled to -40 °C. A solution of 11 (58.5 mg, 0.18 mmol)
in THF (2 mL) was added to the reaction mixture. After the
reaction was complete, as indicated by TLC, the reaction
mixture was quenched by addition of saturated aqueous NH4-
Cl. EtOAc (10 mL) was added. The aqueous layer was
extracted with EtOAc, the combined organic phases were
washed with water and brine, dried (MgSO4), and concentrated
to give an oil that was purified by preparative TLC (Table 3).
(S)-2-Meth yl-2-flu or o-1-in d a n on e (12a ): (76%) oil; 40%
1
IR (KBr) 3353, 3271, 1308, 1168, 758 cm-1; H NMR δ 0.73-
0.98 (m, 2H), 0.79 (d, J ) 6.3 Hz, 3H), 0.86 (d, J ) 6.8 Hz,
3H), 0.97 (d, J ) 7.0 Hz, 3H), 1.25-1.45 (m, 2H), 1.50-1.84
(m, 4H), 2.45 (m, 1H), 2.97, 3.39 (ABq, J ) 14.9 Hz, 2H), 3.85
(s, 1H), 7.28 (d, J ) 7.3 Hz, 1H), 7.41 (t, J ) 7.3 Hz, 1H), 7.48
(t, J ) 7.3 Hz, 1H), 7.80 (d, J ) 7.3 Hz, 1H); 13C NMR δ 19.1,
22.4, 23.0, 24.7, 25.4, 29.6, 29.9, 35.0, 48.6, 52.6, 64.5, 122.4,
127.4, 129.4, 132.2, 135.6, 138.9; MS m/z 307 (M+), 292 (M+
-
Me); HRMS calcd for C17H25NO2S 307.1606, found 307.1616.
Anal. Calcd for C17H25NO2S: C, 66.41; H, 8.20; N, 4.56.
Found: C, 66.51; H, 8.27; N, 4.63.
In ter m ed ia tes 9,10. Methanesulfonic acid (0.08 mL, 1.2
mmol) was added to a stirred solution of 7b (148 mg, 0.4 mmol)
in CH2Cl2 (4 mL) at room temperature. After stirring for 1 h,
the reaction mixture was diluted with CH2Cl2 (10 mL). The
organic layer was separated, washed with water, brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified
by preparative TLC (30% EtOAc in hexane) to give compounds
9 (109 mg, 77.2%) and 10 (16 mg, 15.8%) as a colorless oil,
together with 8b (6.1 mg, 6%) as colorless prisms.
ee; [R]28 -21.6 (c 0.47, CHCl3). Its spectral properties were
D
in agreement with literature values.4-6
(R)-2-Meth yl-2-flu or o-1-in d a n on e (12b): (69%) oil; 13%
ee; [R]28D +6.3 (c 0.51, CHCl3). 12b exhibited the same spectral
1
properties (IR, MS, H NMR, and 19F NMR) as 12a .
(S)-2-Ben zyl-2-flu or o-1-in d a n on e (12c): (59%) oil; 54%
ee; [R]28 -57.5 (c 0.42, CHCl3). Its spectral properties were
D
in agreement with literature values.4-6
9: IR (CHCl3) 3404, 1744, 1151, 909, 826, 735 cm-1; 1H NMR
δ 1.14 (s, 9H), 1.21 (s, 9H), 1.74 (d, J ) 1.2 Hz, 3H), 4.37 (s,
1H), 6.81 (s, 1H), 7.23 (d, J ) 7.6 Hz, 1H), 7.33 (td, J ) 7.6,
1.5 Hz, 1H), 7.47 (td, J ) 7.6, 1.5 Hz, 1H), 8.03 (dd, J ) 7.6,
1.5 Hz, 1H); MS m/z 353 (M+), 296 (M+ - t-Bu); HRMS calcd
for C18H27NO4S 353.1661, found 353.1682.
(R)-2-Ben zyl-2-flu or o-1-in d a n on e (12d ): (42%) oil; 24%
ee; [R]28 +27.2 (c 0.62, CHCl3). 12d exhibited the same
D
spectral properties (IR, MS, H NMR, and 19F NMR) as 12c.
1
(-)-2-p-Meth oxyben zyl-2-flu or o-1-in dan on e (12e): (52%)
oil; 51% ee; [R]28 -44.3 (c 0.41, CHCl3); IR (neat) 3018, 1726,
D
1610, 1513, 1250, 917, 836, 757 cm-1
;
19F NMR δ -154.8 (m);
1
10: IR (CHCl3) 3418, 1215, 909, 759 cm-1; H NMR δ 1.21
1H NMR δ 2.92 (dd, J ) 29.7, 14.3 Hz, 1H), 3.15 (dd, J ) 22.8,
17.3 Hz, 1H), 3.35 (m, 2H), 3.78 (s, 3H), 6.82 (d, J ) 8.6 Hz,
2H), 7.18 (d, J ) 8.6 Hz, 2H), 7.39 (dd, J ) 13.2, 7.6 Hz, 2H),
7.61 (t, J ) 7.6 Hz, 1H), 7.80 (d, J ) 7.6 Hz, 1H); MS m/z 271
(s, 9H), 1.67 (d, J ) 1.0 Hz, 3H), 4.65 (s, 2H), 6.80 (s, 1H),
7.27 (d, J ) 7.6 Hz, 1H), 7.36 (td, J ) 7.6, 1.5 Hz, 1H), 7.53
(td, J ) 7.6, 1.5 Hz, 1H), 8.03 (dd, J ) 7.6, 1.5 Hz, 1H); MS
m/z 253 (M+), 238 (M+ - Me); HRMS calcd for C13H19NO2S
253.1136, found 253.1121.
(M+ + 1), 270 (M+), 250 (M+ - HF); HRMS calcd for C17H15
-
FO2 270.1056, found 270.1051.
(11S,12R,14R)-2-F lu or o-14-m et h yl-11-(m et h ylet h yl)-
sp ir o(2H,4H-ben zo[e][1,2]th ia zin e-3,2′-cycloh exa n e) 1,1-
d ion e (11a ). A solution of 8g (1.8 g, 5.86 mmol) in THF (60
mL) was treated with NaH (60% dispersion in mineral oil, 470
mg, 11.72 mmol) under N2 at 0 °C, and the mixture was stirred
at room temperature for 1 h. To the solution was introduced
diluted perchloryl fluoride [FClO3, generated from KClO4 (8.12
g, 58.60 mmol) and FSO3H (17 mL, 586 mmol)] for 3 h. The
reaction was quenched by saturated aqueous NH4Cl, and the
mixture was extracted with EtOAc. The combined organic
layers were washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed (20%
EtOAc in hexane) to give 11a (1.54 g, 81%) as colorless
prisms: mp 114-116 °C; [R]28D -48.7 (c 0.47, CHCl3); IR (KBr)
(-)-5,6-Dim eth oxy-2-ben zyl-2-flu or o-1-in d a n on e (12f):
(61%) oil; 33% ee; [R]28D -33.8 (c 0.65, CHCl3); IR (neat) 3021,
1
1710, 1593, 1501, 1283, 919, 866, 756 cm-1; H NMR δ 2.89
(dd, J ) 29.8, 14.1 Hz, 1H), 2.98 (dd, J ) 22.9, 17.5 Hz,
1H), 3.23 (dd, J ) 17.5, 12.0 Hz, 1H), 3.33 (t, J ) 13.5 Hz,
1H), 3.84 (s, 3H), 3.87 (s, 3H), 6.68 (s, 1H), 7.13 (s,1H), 7.20
(m, 5H); 19F NMR δ -153.5 (m); MS m/z 301 (M+ + 1), 300
(M+), 280 (M+ - HF); HRMS calcd for C18H17FO3 300.1162,
found 300.1174.
(S)-2-F lu or o-2-m eth yl-1-tetr a lon e (12g): (65%) oil; 70%
ee; [R]28 -15.1 (c 0.62, CHCl3). Its spectral properties were
D
in agreement with literature values.4-6
(S)-2-Ben zyl-2-flu or o-1-tetr a lon e (12h ): (61%) oil; 56%
ee; [R]28 -28.2 (c 0.49, CHCl3). Its spectral properties were
1
3027, 1363, 1184, 758 cm-1; H NMR δ 0.77 (d, J ) 6.4 Hz,
D
in agreement with literature values.4-6
3H), 0.90 (d, J ) 6.6 Hz, 3H), 0.98 (d, J ) 7.1 Hz, 3H), 0.76-
1.15 (m, 2H), 1.32-1.41 (m, 1H), 1.61-1.78 (m, 2H), 1.82-
1.96 (m, 2H), 2.12-2.25 (m, 2H), 2.45 (dd, J ) 14.9, 1.2 Hz,
1H), 3.74 (d, J ) 14.9 Hz, 1H), 7.32 (d, J ) 7.6 Hz, 1H), 7.49
(t, J ) 7.6 Hz, 1H), 7.58 (t, J ) 7.6 Hz, 1H), 7.93 (d, J ) 7.6
Hz, 1H); 19F NMR δ -52.9 (s); 13C NMR δ 18.2 (18.3), 22.4,
22.8, 25.8, 26.3, 28.5, 35.6, 35.9 (36.0), 47.0 (47.2), 54.5, 73.5
(73.6), 126.6, 128.1, 129.9, 132.7, 133.6, 136.3; MS m/z 325
(M+), 306 (M+ - HF); HRMS calcd for C17H24FNO2S 325.1512,
found 325.1536. Anal. Calcd for C17H24FNO2S: C, 62.74; H,
7.43; N, 4.30. Found: C, 62.48; H, 7.71; N, 4.25.
Ack n ow led gm en t. This work was supported by a
Grant-in Aid for Scientific Research from the Ministry
of Education, Science, Sports and Culture, J apan. We
are also grateful to Dr. Bando Masahiko, Institute of
Organic Chemistry, Otsuka Pharmaceutical Co., for his
X-ray analysis of the absolute structure of compound
11a .
Su p p or tin g In for m a tion Ava ila ble: ORTEP diagram of
11a , its details of crystallographic information, and 1H NMR
spectra for compounds 9, 10, and 12a ,c,e-h . This material is
available free of charge via the Internet at http://pubs.acs.org.
(11S,12S,14R)-2-F lu or o-14-m et h yl-11-(m et h ylet h yl)-
sp ir o(2H,4H-ben zo[e][1,2]th ia zin e-3,2′-cycloh exa n e)1,1-
Dion e (11b). In the same way, 11b was obtained from 8h as
colorless prisms (44%): mp 114-116 °C; [R]28 -4.6 (c 1.00,
D
CHCl3); IR (KBr) 3027, 1455, 1361, 1180, 757 cm-1; H NMR
J O0055584
1