Enantioselective synthesis of AL-4414A, a topically active carbonic anhydrase inhibitor

Full text of DOI:10.1021/jo971550r

9372
J . Org. Chem. 1997, 62, 9372-9375
Sch em e 1
En a n tioselective Syn th esis of AL-4414A, a
Top ica lly Active Ca r bon ic An h yd r a se
In h ibitor
Mark T. DuPriest,* Paul W. Zinke, Raymond E. Conrow,
Daniel Kuzmich,† Anura P. Dantanarayana, and
Steven J . Sproull‡
Alcon Laboratories, Inc., 6201 South Freeway, Fort Worth,
Texas 76134
Received August 19, 1997X
Systemically administered carbonic anhydrase inhibi-
tors (CAIs) have long been used to control the elevated
intraocular pressure associated with glaucoma.1 How-
ever, the wide range of side effects associated with their
use limits compliance, particularly among the elderly.
Recently, the synthesis2 and clinical evaluation3 of sev-
eral water-soluble topically active CAIs, having the
potential to avoid these problems by local delivery of a
lower dose, have been reported. AL-4414A, (R)-4-(ethyl-
amino)-3,4-dihydro-2-methyl-2H-thieno[3,2-e]-1,2-thi-
azine-6-sulfonamide 1,1-dioxide hydrochloride, is a rep-
resentative of a new class of topically active water-soluble
CAIs4 and was identified as a clinical candidate. Initial
samples of AL-4414A were obtained by resolution of
racemic material via the diastereomeric di-p-toluoyl-D-
tartaric acid salts.4 The lack of an efficient way to recycle
the S enantiomer, as well as difficulties encountered in
scale-up of the racemic synthesis, led us to develop the
present synthesis in which R-bromo ketone 7 is reduced
with (+)-B-chlorodiisopinocampheylborane ((+)-Ipc2BCl),5
and the resulting (S)-bromohydrin 8 is cyclized to form
the thieno[3,2-e]thiazine ring system.
Sch em e 2
bromide perbromide (PBP) and catalytic HCl in THF
provided 7 (70-80%).
Consonant with results documented for reductions of
phenacyl halides,5 (+)-Ipc2BCl reduced bromo ketone 7
with excellent enantioselectivity (Scheme 2). Treatment
of a solution of 7 in THF with (+)-Ipc2BCl (2 equiv)8 at
-25 °C effected complete reduction in 18-24 h. Crude
bromohydrin 8, obtained after addition of diethanolamine
to precipitate boron species,5 cyclized to 9 on exposure
to aqueous NaOH. When K2CO3 or DBU was used
instead, 8 cyclized more slowly, allowing isolation of the
presumed intermediate epoxide. Thieno[3,2-e]thiazine
alcohol 9 was obtained in 75-85% yield after chroma-
tography to remove R-pinene and a small amount of
isopinocampheol. The ee of 9, typically 92-94%, was
increased to >98% by recrystallization from toluene.
Upon esterification of 9 with (R)-(-)-R-methoxyphenyl-
acetic acid, the thienyl proton resonances shifted upfield9
(H-5, 0.6; H-6, 0.2 ppm) in accord with the expected5
absolute configuration.
Ketal 2,4 obtained from 3-acetylthiophene (1) in 60-
70% yield, was treated with BuLi6 followed by SO2 to give
lithium sulfinate 3 (Scheme 1). Slow addition of 3 to
excess aqueous Cl2 produced sulfonyl chloride 4.
A
simpler procedure, in which NCS was added to a suspen-
sion of 3 in THF, gave a side product suspected to be the
symmetrical bis-sulfone7 resulting from reaction of 3 with
4. Without delay, 4 was added to a cold solution of
MeNH2 in THF to afford sulfonamide ketal 5, which was
hydrolyzed to give sulfonamide 6 in 70-80% overall yield
after recrystallization. Bromination of 6 with pyridinium
Hoping to avoid chromatographic purification of 9 on
a multihundred gram scale, we studied the route shown
in Scheme 3, wherein crude 9 is converted to amine 10
that is freed of pinene and other byproducts by extraction
into aqueous acid. We planned to install the C-6 sul-
fonamide via electrophilic sulfonation of 10, as reported2a
for compound 12. Both of these reactions proved inef-
ficient. Although amine 10 could be obtained in accept-
able yield from purified 9 via the mesylate or tosylate,
the yield fell to 20-30% when crude 9 was used.
Sequential treatment of 10 with SO3-H2SO4, SOCl2, and
NH4OH2a provided bis-sulfonamide 11 in only 25-35%
yield; furthermore, the quench into aqueous ammonia
was difficult to perform even on a small scale. An
alternative approach to the sulfonyl chloride, direct
chlorosulfonation with ClSO3H, was unsuccessful.
* To whom correspondence should be addressed. Phone: (817) 551-
8143. Fax: (817) 551-4584. E-mail: Mark.DuPriest@AlconLabs.Com.
† Present address: Boehringer Ingelheim Pharmaceuticals, Ridge-
field, CT.
‡ Present address: Sigma-Aldrich Fine Chemicals, St. Louis, MO.
X Abstract published in Advance ACS Abstracts, December 1, 1997.
(1) Sugrue, M. F.; Smith, R. L. Annu. Rep. Med. Chem. 1985, 20,
83.
(2) (a) J ones, T. K.; Mohan, J . J .; Xavier, L. C.; Blacklock, T. J .;
Mathre, D. J .; Sohar, P.; Turner J ones, E. T.; Reamer, R. A.; Roberts,
F. E.; Grabowski, E. J . J . J . Org. Chem. 1991, 56, 763. (b) Blacklock,
T. J .; Sohar, P.; Butcher, J . W.; Lamanec, T.; Grabowski, E. J . J . J .
Org. Chem. 1993, 58, 1672.
(3) Wilkerson, M.; Cyrlin, M.; Lippa, E. A.; Esposito, D.; Deasy, D.;
Panebianco, D.; Fazio, R.; Yablonski, M.; Shields, B. Arch. Ophthalmol.
1993, 111, 1343 and cited references.
(4) Dean, T. R.; Chen, H.-H.; May, J . A. Alcon Laboratories, Inc.
U.S. Patents 5,378,703 (3 J an 1995); 5,240,923 (31 Aug 1993);
5,153,192 (6 Oct 1992).
(5) Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res 1992, 25,
16.
(6) March, J . Advanced Organic Chemistry, 4th ed.; J ohn Wiley &
Sons: New York, 1992; p 607.
(7) This side product was distinct from 4 by TLC but had a similar
1H NMR spectrum and reacted with MeNH2 to form 5: Backer, H. J .
Rec. Trav. Chim. Pays-Bas 1951, 70, 254.
(8) At least 2 equiv of (+)-Ipc2BCl were required for an acceptable
reaction rate.
(9) Trost, B. M.; Belletire, J . L.; Godleski, S.; McDougal, P. G.;
Balkovec, J . M.; Baldwin, J . J .; Christy, M. E.; Ponticello, G. S.; Varga,
S. L.; Springer, J . P. J . Org. Chem. 1986, 51, 2370.
S0022-3263(97)01550-8 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 26, 1997 9373
Temperatures recorded are those of the reaction mixture.
Concentration refers to removal of volatile components by rotary
evaporation at reduced pressure. Coupling constants (J ) are
reported in Hz. Elemental analyses were performed by Atlantic
Microlabs, Norcross, GA. Melting points are uncorrected.
Enantiomeric excess (ee) was determined by HPLC using a
Daicel OF analytical column with a mobile phase consisting of
1:1 hexane/i-PrOH, containing ca. 0.05% Et3N. The R enanti-
omer of both 9 and 11 eluted first.
Sch em e 3
3-(2,5,5-Tr im eth yl-1,3-d ioxa n -2-yl)th iop h en e (2).4 A mix-
ture of 3-acetylthiophene (1) (400 g, 3.17 mol), 2,2-dimethyl-1,3-
propanediol (4.76 mol, 492 g), and H2SO4 (0.5 mL) in toluene
(2.6 L) was refluxed for 2 days with water removal (Dean-Stark
trap) and then concentrated by distillation at 1 atm, removing
1.5 L of toluene. After the mixtured was cooled to rt under a
drying tube, K2CO3 (50 g) was added, followed by saturated
NaHCO3 (1 L) and hexane (1 L). The organic phase was
separated, and the aqueous phase was extracted with EtOAc (3
× 250 mL). The combined organic extracts were washed with
brine (6 × 1 L), dried (MgSO4), treated with decolorizing carbon,
filtered through Celite 521, and concentrated. The residue was
distilled through a 12 in. Vigreux column to provide 442 g (65%)
of 2: bp0.1 88 °C; mp 35-37 °C; IR (KBr) 3095, 2952, 2866, 1473,
Sch em e 4
1
1366, 1248, 1178, 1080, 1013, 841, 686 cm-1; H NMR (CDCl3)
δ 7.31 (dd, 1H, J ) 3, 5), 7.23 (dd, 1H, J ) 1, 3), 7.02 (dd, 1H,
J ) 1, 5), 3.54 (d, 2H, J ) 11), 3.39 (d, 2H, J ) 11), 1.57 (s, 3H),
1.23 (s, 3H), 0.62 (s, 3H). Repeated attempts to secure a
satisfactory microanalytical sample of 2 were not successful.
N-Meth yl-3-acetyl-2-th ioph en esu lfon am ide (6). BuLi (1.32
mol, 574 mL of a 2.3 M hexane solution) was added to a stirred
solution of 2 (255 g, 1.20 mol) in hexane (2 L) under N2 over 10
min at -30 to -20 °C. The solution was allowed to warm to rt,
kept at rt for 2 h, and then cooled to -40 °C and treated with
SO2 until an aliquot quenched into water was acidic (pH 4-5).
The mixture was stirred overnight while being warmed to rt
and then concentrated. The solid residue was dissolved in water
(2 L) and added dropwise over 2 h to a vigorously stirred, 0 °C
saturated solution of Cl2 in water (4 L of Cl2 was bubbled into
the mixture during this operation). The mixture was stirred
for a further 15 min, and then 4 was collected by filtration and
washed with cold water. The moist sulfonyl chloride 4 was
slurried in THF (1 L) and added over 15 min to a -10 °C
saturated solution of MeNH2 in THF (1.5 L). The mixture was
allowed to warm to rt overnight and then concentrated to provide
sulfonamide ketal 5. The crude ketal was dissolved in a solution
of acetone (1.8 L) and 2 M HCl (0.6 L) and stirred at rt for 3 d.
Upon concentration, a white solid precipitated, which was
collected by filtration, washed with water, and dried to provide
223 g (86%) of crude 6. Another 10 g of crude 6 separated from
the filtrate. Recrystallization from MeOH with carbon treat-
ment provided 201 g (76%) of 6: mp 102-103 °C; IR (KBr) 3322,
3093, 3076, 1677, 1506, 1391, 1355, 1337, 1244, 1166, 1120,
The C-6 sulfonic acid could be obtained in 55-60%
yield, as zwitterion 13, by treating 10 with fuming H2-
SO4 at rt. However, attempted conversion of 13 to the
sulfonamide via the sulfonyl chloride, by treatment with
SOCl2 or POCl3 followed by NH4OH, gave only traces of
11.
As an alternative to electrophilic sulfonation, we
turned to a lithiation/sulfonamidation procedure similar
to that used for converting 2 to 7. Sequential treatment
of 10 with BuLi (2 equiv), SO2, and hydroxylamine-O-
sulfonic acid (HOSA)10 provided 11 in low yield. This
procedure suffered from poor solubility of the dianion of
10 in THF below -20 °C. When the lithiation was
conducted at 0 °C, reversion to ketone 6 was observed.
In contrast to our experience with 10, conversion of 9
to sulfonamide alcohol 14 worked well (Scheme 4). A
solution of 9 in THF at ca. -70 °C was treated with 2.2
equiv of BuLi followed by excess SO2 to produce the C-6
lithium sulfinate, which in turn reacted with HOSA to
give 14 (65-75%). Conversion of 14 to 11 was ac-
complished in about 40% yield via the tosylate, which
was treated directly with EtNH2. The yield of 11 was
limited by elimination and by formation of sulfonimide
15, isolated in 24% yield from one run. Treatment of 11
with HCl, followed by recrystallization of the salt from
aqueous EtOH, provided AL-4414A in 84% yield and
>98% ee. Despite the need for chromatographic purifica-
tion of the key intermediate 9, this route readily afforded
multihundred gram quantities of AL-4414A for toxico-
logical and clinical evaluation.
1066, 767, 689 cm-1 1H NMR (CDCl3) δ 7.59 (d, 1H, J ) 5),
;
7.55 (d, 1H, J ) 5), 6.16 (br, 1H), 2.70 (d, 3H, J ) 5), 2.63 (s,
3H). Anal. Calcd for C7H9NO3S2: C, 38.34; H, 4.14; N, 6.39.
Found: C, 38.41; H, 4.13; N, 6.42.
Data for 4: 1H NMR (CDCl3) δ 7.73 (d, 1H, J ) 5), 7.24 (d,
1H, J ) 5), 3.58 (d, 2H, J ) 10), 3.48 (d, 2H, J ) 10), 1.81 (s,
3H), 1.27 (s, 3H), 0.71 (s, 3 H); MS (CI, Me3CH) 311 (M + 1).
Data for 5: 1H NMR (CDCl3) δ 7.50 (d, 1H, J ) 5), 7.16 (d,
1H, J ) 5), 5.30 (m, 1H), 3.52 (s, 4H), 2.80 (d, 3H, J ) 5), 1.71
(s, 3H), 1.20 (s, 3H), 0.75 (s, 3H); MS (CI, Me3CH) 306 (M + 1).
N-Meth yl-3-(br om oa cetyl)-2-th iop h en esu lfon a m id e (7).
Pyridinium bromide perbromide (524 g, ∼1.64 mol, 0.9 equiv)
was added in portions over 10 min to a stirred, 10 °C solution of
6 (398 g, 1.82 mol) in anhydrous THF (2 L) containing 1 mL of
12 M HCl. After 30 min, the mixture was allowed to warm to
13 °C, whereupon a precipitate formed. The mixture was cooled
to 0 °C, kept at 0 °C for 1 h, and poured into ice-water (8 L).
After the mixture was stirred for 30 min, the solid was collected
by filtration and washed with water (4 L). The moist solid was
added to EtOH (2 L), and the suspension was stirred for 30 min.
The solid was collected by filtration and dried at rt under
vacuum for 2 d to provide 403 g (74%) of 7, which was used
without further purification. The analytical sample was secured
by recrystallization from toluene-MeOH: mp 118-119 °C; IR
(KBr) 3310, 3106, 1675, 1503, 1394, 1323, 1250, 1171, 1160,
Exp er im en ta l Section
Gen er a l Meth od s. Anhydrous THF, (+)-Ipc2BCl, and pyri-
dinium bromide perbromide (pyridinium tribromide, “tech, 90%”,
mfr. assay 98%) were used as received from Aldrich Chemical
Co. 3-Acetylthiophene was obtained from Lancaster Synthesis.
1
(10) Graham, S. L.; Scholz, T. H. Synthesis 1986, 1031.
1125, 1063, 732, 697 cm-1; H NMR (acetone-d6) δ 7.95 (d, 1H,

9374 J . Org. Chem., Vol. 62, No. 26, 1997
Notes
J ) 5), 7.81 (d, 1H, J ) 5), 6.45 (br m, 1H), 4.78 (s, 2H), 2.68 (s,
3H). Anal. Calcd for C7H8BrNO3S2: C, 28.20; H, 2.69; N, 4.70.
Found: C, 28.26; H, 2.67; N, 4.76.
SO4 (4 mL) was added to a stirred solution of 10 (3.0 g, 0.12
mol) in CH2Cl2 (5 mL). After 22 h at rt, the CH2Cl2 was decanted
and the viscous residue poured onto ice, using water to rinse.
The solution was adjusted to pH 7 with 0.5 M Ba(OH)2, filtered
through Celite 521, and concentrated. The residue was dissolved
in EtOH, and the solution was concentrated to give 3.1 g (78%)
of crude 13.
(S)-(+)-4-H yd r oxy-3,4-d ih yd r o-2-m et h yl-2H -t h ien o[3,2-
e]-1,2-th ia zin e 1,1-Dioxid e (9). A solution of (+)-Ipc2BCl (900
g, 2.8 mol, 1.56 equiv) in anhyd THF (1 L) was added to a stirred
solution of 7 (536 g, 1.80 mol) in anhyd THF (14 L) under N2 at
-35 to -25 °C. After 6 h at -25 °C, TLC indicated incomplete
reduction, so 200 g of (+)-Ipc2BCl was added. After an additional
2.5 h, 100 g of (+)-Ipc2BCl was added, and the mixture was
allowed to warm to rt overnight. Acetone (150 mL) was added
and the mixture stirred for 30 min and then cooled to 10 °C.
Diethanolamine (320 g) was added in portions, and the mixture
was stirred for 6 h and then filtered through Celite 521. The
filtrate was concentrated, removing 11 L of solvent. To the
residue was added acetone (2 L), water (1 L), and 50% NaOH
(120 mL). The temperature rose to 40 °C and then cooled to rt.
The mixture was stirred overnight and then concentrated, and
the remaining aqueous solution was extracted with EtOAc (4
L). After drying (MgSO4), the extract was concentrated, leaving
1.5 kg of crude product. This material was purified by chroma-
tography on silica gel (230-400 mesh), eluting with 30% EtOAc/
hexane to remove R-pinene, and then with 50% EtOAc/hexane,
followed by EtOAc, to secure 9 (319 g, 81%, 94% ee). Recrys-
tallization from toluene afforded analytically pure material of
>98% ee: mp 98-99 °C; IR (KBr) 1330, 1168, 1138, 1065, 962,
708 cm-1; 1H NMR (CDCl3) δ 7.57 (d, 1H, J ) 5), 7.15 (d, 1H, J
) 5), 4.87 (m, 1H), 4.04 (dd, 1H, J ) 4, 15), 3.76 (dd, 1H, J ) 5,
15), 3.00 (s, 3H), 2.97 (d, 1H, J ) 7); 13C NMR (CDCl3) δ 143.5,
132.5, 130.0, 126.8, 61.7, 56.0, 37.7; MS (CI, Me3CH) m/z 220
(M + 1), 202 ((M + 1) - H2O); [R]25D +21.6°(c ) 1, MeOH). Anal.
Calcd for C7H9NO3S2: C, 38.34; H, 4.14; N, 6.39. Found: C,
38.34; H, 4.13; N, 6.44.
(R)-r-Meth oxyp h en yla ceta te of 9. To a stirred solution
of 9 (0.3 g, 1.4 mmol) in 5 mL of CH2Cl2 were added DMAP (0.02
g, 0.16 mmol), (R)-(-)-R-methoxyphenylacetic acid (0.27 g, 1.6
mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hy-
drochloride (0.3 g, 1.6 mmol). After 1.5 h, the solution was
washed with saturated KH2PO4 and brine, dried (Na2SO4),
filtered, and concentrated. The residue was purified by flash
chromatography (25% EtOAc-hexanes) to give 0.3 g of ester: 1H
NMR (CDCl3) δ 7.40 (d, 1H, J ) 5), 7.34 (br s, 5H), 6.58 (d, 1H,
J ) 5), 5.89 (dd, 1H, J ) 3, 4), 4.80 (s, 1H), 4.29 (dd, 1H, J )
4.5, 16), 3.71 (dd, 1H, J ) 3, 16), 3.40 (s, 3H), 2.88 (s, 3H).
(R)-4-(Eth yla m in o)-3,4-d ih yd r o-2-m eth yl-2H-th ien o[3,2-
e]-1,2-th ia zin e 1,1-Dioxid e (10). A solution of p-toluene-
sulfonic anhydride (7.40 g, 22.7 mmol) in CH2Cl2 (40 mL) was
added over 10 min to a stirred, 5 °C solution of 9 (4.37 g, 20.0
mmol) and DMAP (3.16 g, 25.9 mmol) in CH2Cl2 (40 mL) under
Ar. The mixture was stirred in ice for 15 min and then allowed
to warm to rt over 2 h. Water was added, and after being stirred
for 30 min, the mixture was partitioned between EtOAc and 0.2
M H2SO4. The organic phase was washed with water and brine,
dried (MgSO4), and concentrated to provide 6.32 g (85%) of crude
tosylate: 1H NMR (CDCl3) δ 7.85 (d, 1H, J ) 8), 7.52 (d, 1H, J
) 5), 7.42 (d, 1H, J ) 8), 6.78 (d, 1H, J ) 5), 5.48 (m, 1H), 4.30
(dd, 1H, J ) 4, 16), 3.82 (dd, 1H, J ) 2, 16), 2.87 (s, 3H), 2.50 (s,
3H).
A 1.5 g sample of this solid was dissolved in 50% aqueous
MeOH (30 mL), and the pH of the solution was adjusted to 3
using 0.2 M H2SO4. The solution was filtered and concentrated
to provide 1.05 g of a solid that was dissolved in hot MeOH (80
mL), treated with decolorizing carbon, filtered, and cooled to 0
°C. The solid that separated was collected by filtration, provid-
ing 0.1 g of 13. Dilution of the filtrate with an equal volume of
Et2O, filtration, and concentration left a residue that, after
trituration with MeOH (5 mL), provided another 0.4 g of 13:
mp 283-285 °C; IR (KBr) 3446, 3022, 2853, 1459, 1319, 1244,
1196, 1165, 1070 cm-1 1H NMR (DMSO-d6) δ 9.00 (br d, 2H,
;
exchanges), 7.60 (s, 1H), 4.90 (br s, 1H), 4.04 (d, 2H, J ) 7),
3.10 (br s, 2H), 2.86 (s, 3H), 1.22 (t, 3H, J ) 7). Anal. Calcd for
C9H14N2O5S3: C, 33.11; H, 4.32; N, 8.58; S, 29.47. Found: C,
33.18; H, 4.34; N, 8.61; S, 29.38.
(S)-(-)-4-H yd r oxy-3,4-d ih yd r o-2-m et h yl-2H -t h ien o[3,2-
e]-1,2-th ia zin e- 6-su lfon a m id e 1,1-Dioxid e (14). BuLi (1.3
mol, 520 mL of a 2.5 M hexane solution) was added to a
mechanically stirred solution of 9 (129.5 g, 0.591 mol) in anhyd
THF (1.7 L) under N2 over 40 min at -72 to -60 °C. The
solution was allowed to warm to -23 °C over 4 h, and then SO2
was introduced via a gas inlet tube for 30 min. The mixture
was allowed to warm to 10 °C and then concentrated. The white
solid obtained was dissolved in water (5 L) containing
NaOAc‚3H2O (746 g, 5.49 mol). HOSA (300 g, 2.65 mol) was
added, and the solution was stirred at rt for 24 h. NaHCO3 was
added to adjust the pH to 7, and the solution was extracted with
EtOAc (2 × 1.5 L). The combined extracts were dried (MgSO4)
and concentrated to give a white solid, which was washed with
CH2Cl2 (3 × 200 mL) and Et2O (2 × 800 mL) and dried in air to
a constant weight of 135 g (77%) of 14, which was used without
further purification. The analytical sample was secured by
recrystallization from toluene-MeOH: mp 173-174 °C; IR
(KBr) 3497, 3388, 3244, 1354, 1332, 1164, 1066, 1009, 965, 680,
614 cm-1; 1H NMR (DMSO-d6) δ 8.05 (s, 2H), 7.60 (s, 1H), 6.16
(d, 1H, J ) 6), 4.90-4.83 (m, 1H), 3.92 (dd, 1H, J ) 5, 15), 3.69
(dd, 1H, J ) 6, 15), 2.92 (s, 3H); [R]25 -1.4° (c ) 1, MeOH).
D
Anal. Calcd for C7H10N2O5S3: C, 28.18; H, 3.38; N, 9.39.
Found: C, 28.24; H, 3.44; N, 9.30.
(R)-4-(Eth yla m in o)-3,4-d ih yd r o-2-m eth yl-2H-th ien o[3,2-
e]-1,2-th ia zin e-6-su lfon a m id e 1,1-Dioxid e (11). Et3N (155
mL, 1.11 mol) and p-TsCl (211 g, 1.11 mol) were added to a
stirred, -10 °C solution of 14 (330 g, 1.11 mol) in anhyd THF
(6.6 L), and the mixture was allowed to warm to rt over 18 h.
TLC analysis indicated incomplete tosylation, so another 0.5
equiv each of Et3N and p-TsCl were added. This was repeated
8 h later, and the mixture was then stirred at rt for another 24
h. The mixture was cooled to 10 °C, and anhyd EtNH2 (1.19 L,
16.5 equiv) was added slowly, keeping the temperature below
15 °C. After 36 h at rt, the solution was concentrated. Residual
THF was removed by adding EtOAc (2 L) and concentration.
Upon attempted partition of the residue between 1 M HCl (6 L)
and Et2O (2 L), a precipitate, believed to be AL-4414A, separated.
The material was collected by filtration, washed with Et2O (1.5
L), and dried to provide 114 g of “solid A.” The aqueous phase
was removed from the filtrate and extracted with Et2O, and the
combined organic phases were back-extracted with 1 M HCl. The
aqueous solutions were combined, and the pH was adjusted to
9-10 using concd NH4OH. After NaCl (300 g) was added, the
solution was extracted with EtOAc, and the combined extracts
were washed with water and brine. Solid A was partitioned
between EtOAc (1.6 L) and concd NH4OH. The aqueous phase
was removed, and the EtOAc solution was washed with water.
The combined EtOAc solutions were dried (MgSO4) and concen-
trated to leave a solid residue, which was dissolved in a boiling
solution of EtOAc (2 L) and CH2Cl2 (3 L). Crystallization
occurred as the solution was cooled to rt overnight. The solid
was collected by filtration, washed with CH2Cl2, and dried under
vacuum to provide 96.9 g of 11. A second crop, 52.6 g, was
obtained for a total yield of 149.5 g (42%) of 11: >98% ee; mp
A solution of the crude tosylate (6.65 g, 17.8 mmol) in THF
(35 mL) was added to ice-cold 70% aqueous EtNH2 (200 mL),
and the mixture was allowed to warm to rt over 5 h. EtOAc
(500 mL) was added, and the solution was washed twice with
water. The water washes were combined and back-extracted
with EtOAc. The combined organic solutions were then ex-
tracted with 0.2 M H2SO4 (to pH 1), water, and brine, and the
combined aqueous extracts were washed with EtOAc, basified
with 50% NaOH, and extracted with CH2Cl2. After a water
wash, the CH2Cl2 extract was dried (MgSO4) and concentrated
to give 2.52 g (57%) of 10. The analytical sample was secured
by recrystallization from toluene-MeOH: mp 99-100 °C; IR
(KBr) 1344, 1326, 1316, 1189, 1162, 1136, 1103, 750, 624, cm-1
;
1H NMR (CDCl3) δ 7.53 (d, 1H, J ) 5), 7.12 (d, 1H, J ) 5), 4.11-
4.04 (m, 1H), 3.93-3.70 (m, 2H), 2.98 (s, 3H), 2.75 (q, 2H, J )
7), 1.35 (br, 1H), 1.13 (t, 3H, J ) 7); [R]25D -14.8° (c ) 1, MeOH).
Anal. Calcd for C9H14N2O2S2: C, 43.88; H, 5.73; N, 11.37.
Found: C, 43.93; H, 5.76; N, 11.42.
(R)-4-(E t h yla m in o)-3,4-d ih yd r o-2-m et h yl-1,1-d ioxo-2H-
th ien o[3,2-e]-1,2-th ia zin e-6-su lfon ic Acid (13). Fuming H2-
130-132 °C; IR (KBr) 3354, 3326, 2965, 1327, 1165, 651 cm-1
;

Notes
J . Org. Chem., Vol. 62, No. 26, 1997 9375
1H NMR (DMSO-d6) δ 8.01 (s, 2H, exchanges), 7.67 (s, 1H), 4.14
(m, 1H), 3.77 (m, 1H), 2.89 (s, 3H), 2.58 (m, 3H, 1H exchanges),
1.02 (t, 3H, J ) 7); 13C NMR (DMSO-d6) δ 148.5, 146.5, 134.4,
129.8, 52.7, 48.7, 39.9, 36.2, 15.6; MS (CI, Me3CH) 326 (M + 1).
Anal. Calcd for C9H15N3O4S3: C, 33.22; H, 4.65; N, 12.91.
Found: C, 33.36; H, 4.59; N, 13.00.
collected by filtration, washed with EtOAc and Et2O, and dried
under vacuum to provide 247 g (96%) of AL-4414A. Recrystal-
lization from aqueous EtOH provided two crops totalling 217 g
(88% recovery): mp 261-263 °C dec; IR (KBr) 3385, 3071, 2683,
1353, 1157, 652 cm-1 1H NMR (DMSO-d6) δ 10.0 (br, 2H,
;
exchanges), 8.24 (s, 1H), 8.20 (s, 2H, exchanges), 4.93 (br, 1H),
Data for sulfonimide 15: 1H NMR (DMSO-d6) δ 9.3-9.0 (br,
2H, exchanges), 7.80 (s, 1H), 7.59 (d, 2H, J ) 8), 7.22 (d, 2H, J
) 8), 4.87 (br, 1H), 4.1-4.0 (m, 2H), 3.15-3.0 (br, 2H), 2.89 (s,
3H), 2.32 (s, 3H), 1.23 (t, 3H, J ) 7).
4.15 (m, 2H), 3.02 (br, 2H), 2.92 (s, 3H), 1.27 (t, 3H, J ) 7); 13
C
NMR (DMSO-d6) δ 149.6, 137.6, 136.6, 129.7, 49.1, 47.2, 11.5;
[R]25 +14.5° (c ) 1, H2O). Anal. Calcd for C9H16ClN3O4S3: C,
D
29.87; H, 4.46; N, 11.61. Found: C, 29.81; H, 4.53; N, 11.55.
(R)-4-(Eth yla m in o)-3,4-d ih yd r o-2-m eth yl-2H-th ien o[3,2-
e]-1,2-th ia zin e-6-su lfon a m id e 1,1-Dioxid e Hyd r och lor id e
(AL-4414A). A mixture of 11 (232 g) and decolorizing carbon
(76 g) in EtOAc (5 L) was stirred for 1 h and filtered through
Celite 521. A 1.5 M solution of HCl in EtOAc was added to the
stirred, pale yellow filtrate resulting in precipitation of the
hydrochloride. After being stirred for 1 h, the material was
Ack n ow led gm en t . We thank Karen Haggard for
performing HPLC analyses, and Dr. V. M. B. Baghdanov
of TCI America, Portland, OR, for carrying out the
conversion of 14 to AL-4414A on the scale described.
J O971550R