Preparation of novel bridged bicyclic thiomorpholines as potentially useful building blocks in medicinal chemistry

Article abstract of DOI:10.1055/s-0033-1338528

Thiomorpholine and thiomorpholine 1,1-dioxide are important building blocks in medicinal chemistry research, and some analogues containing these moieties have entered human clinical trials. Analogues containing bridged bicyclic thiomorpholines have also s

Full text of DOI:10.1055/s-0033-1338528

2966▌
PAPER
paper
Preparation of Novel Bridged Bicyclic Thiomorpholines as Potentially Useful
Building Blocks in Medicinal Chemistry
Preparation of Bicyclic Thiomorpholine Building Blocks
Daniel P. Walker,* D. Joseph Rogier
Kalexsyn, Inc., 4502 Campus Drive, Kalamazoo, MI 49008, USA
Fax +1(269)4888490; E-mail: daniel.p.walker@monsanto.com
Received: 24.06.2013; Accepted after revision: 19.08.2013
F
Abstract: Thiomorpholine and thiomorpholine 1,1-dioxide are im-
portant building blocks in medicinal chemistry research, and some
analogues containing these moieties have entered human clinical
O
F
CO2H
Me
N
trials. Analogues containing bridged bicyclic thiomorpholines have
also shown interesting biological profiles. 3-Thia-6-azabicyc-
lo[3.1.1]heptane, 3-thia-8-azabicyclo[3.2.1]octane, and their corre-
sponding 1,1-dioxide counterparts were prepared as novel bicyclic
thiomorpholine building blocks. Each heterocycle was synthesized
from an inexpensive starting material by straightforward chemistry.
CF3
X
N
N
N
O
N
N
CF3
O
S
1 X = S
2 X = SO2
Key words: stereoselective synthesis, heterocycles, bicyclic com-
pounds, pyrroles, hydrogenation
3
O
Figure 2 Biologically active compounds containing bridged bicyclic
thiomorpholine rings
Thiomorpholine (TM) and thiomorpholine 1,1-dioxide
(TMD) are important building blocks in drug discovery
research. Numerous biologically active analogues con-
taining a TM or TMD ring have been described in the me-
dicinal chemistry literature.1 Of these, artemisone2 and
sutezolid3 are currently undergoing human clinical trials
for the treatment of malaria and tuberculosis, respectively
(Figure 1).
Of the parent bridged bicyclic TM and TMD ring systems
shown in Figure 3, syntheses of 5,6 64a and 7,7 and an an-
alogue incorporating 84b have previously been reported.
As part of our continued interest in preparing new bicyclic
heterocycles as useful building blocks in medicinal chem-
istry,8 we became interested in preparing 3-thia-6-azabi-
cyclo[3.1.1]heptane (9), 3-thia-8-azabicyclo[3.2.1]octane
(11), and their corresponding S,S-dioxides (10 and 12, re-
spectively). Compared with building blocks 5 and 6, an at-
tractive feature of compounds 9–12 is that they all have
meso stereochemistry, so there is no need to separate and
test individual enantiomers. Below, we describe practical
syntheses of heterocycles 9–12 as their tosylate salts,
which, to the best of our knowledge, are the first syntheses
of these potentially useful medicinal chemistry building
blocks.
H
O
S
F
H
O
O
N
O
O
N
O
N
S
NH
O
O
O
artemisone
sutezolid
NH
NH
NH
NH
X
X
Figure 1 Drugs containing a thiomorpholine ring that are undergo-
ing clinical trials in humans
X
X
5 X = S
6 X = SO2
7 X = S
8 X = SO2
9 X = S
10 X = SO2
11 X = S
12 X = SO2
Biologically active analogues incorporating a bridged bi-
cyclic TM or TMD ring have also been described in the
medicinal chemistry literature and patent literature; some
recent examples are shown in Figure 2.4 In general, rigid
bicycles are important ring systems in medicinal chemis-
try because, in many instances, analogues containing a
rigid bicyclic system show superior biological activity
and/or metabolic stability in comparison with the corre-
sponding monocyclic analogues.5
Figure 3 Synthetic targets 9–12, together with various bridged bicy-
clic thiomorpholines and thiomorpholine S,S-dioxides used in medic-
inal chemistry
We began our synthesis of 3-thia-6-azabicyclo[3.1.1]hep-
tane hydrotosylate (9·TsOH) from the known bistosylate
138c (Scheme 1). Compound 13 can be obtained in three
steps (63% overall yield) from the azetidine diester 14.8b,c
Compound 14 can, in turn, be prepared in two steps and
37% yield from inexpensive glutaryl chloride.9,10 Treat-
ment of bistosylate 13 with sodium sulfide effected ring
closure to give the bicyclic thiomorpholine 15. The struc-
SYNTHESIS 2013, 45, 2966–2970
Advanced online publication: 12.09.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338528; Art ID: SS-2013-M0435-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Preparation of Bicyclic Thiomorpholine Building Blocks
2967
1
ture of 15 was confirmed by H NMR spectroscopy and catalyst was crucial to the success of this transformation.
LC/MS. Cleavage of the tert-butoxycarbonyl group in 15 Other catalysts, such as platinum15 or palladium on car-
with 4-toluenesulfonic acid gave the bridged thiomorpho- bon, gave no reaction, whereas rhodium/carbon led only
line 9·TsOH directly.
to partial reduction. Diol 17 was obtained in 86% yield by
treatment of the diester 19 with calcium borohydride. Un-
der these conditions, no reduction of the tert-butoxycar-
bonyl group occurred. Lithium aluminum hydride has also
been shown to convert 19 into 17 (84%),16 but in our
hands, significant cleavage of the tert-butoxycarbonyl
group also occurred.
O
O
a, b
EtO2C
CO2Et
N
ref. 9, 10
37%
Cl
Cl
Bn
14
b
c–e
a
f
TsO
OTs
MeO2C
CO2Me
ref. 13
67%
N
N
ref. 8b,c
63%
99%
93%
N
Boc
Boc
Boc
18
13
c, d
61%
Boc
R
R
g
N
MeO2C
CO2Me
N
9 ·TsOH
N
S
86%
Boc
Boc
17 R = OH
20 R = OTs
19
15
Scheme 1 Reagents and conditions: (a) Br2, hν, 80 °C, 6 h; EtOH,
0 °C to r.t., 24 h; (b) BnNH2 (3.0 equiv), DMF, 80 °C, 10 h; (c) H2 (60
psi), 20% Pd(OH)2/C, (Boc)2O (1.2 equiv), EtOH, 24 h; (d) CaCl2 (3.0
equiv), NaBH4 (5.0 equiv), EtOH–MeOH (9:1), r.t., 5 h; (e) Ts2O, py,
0 °C, 4 h; (f) Na2S·9H2O (3.0 equiv), EtOH–H2O (1:1), 90 °C, 2 h; (g)
TsOH·H2O (1.2 equiv), EtOH, 85 °C, 1 h.
Boc
e
62%
f
N
11·TsOH
12·TsOH
X
70–84%
21 X = S
g
22 X = SO2
Oxidation of sulfide 15 with tetrapropylammonium
perruthenate11 gave an 87% yield of sulfone 16 (Scheme
2), which on treatment with 4-toluenesulfonic acid in eth-
anol gave 10·TsOH. The spectral properties of 10·TsOH
were in complete agreement with the proposed structure.
Scheme 3 Reagents and conditions: (a) LTMP (2.5 equiv), THF,
–78 °C, 3 h; ClCO2Me (3.0 equiv), –78 °C, 30 min.; (b) H2 (60 psi),
5% Rh/Al2O3, AcOH, r.t., 8 h; (c) CaCl2 (3.0 equiv), NaBH4 (5.0
equiv), EtOH–MeOH (9:1), r.t., 5 h; (d) Ts2O, py, 0 °C, 4 h; (e)
Na2S·9H2O (3.0 equiv), EtOH–H2O (1:1), 90 °C, 2 h; (f) TsOH·H2O
(1.2 equiv), EtOH, 85 °C, 1 h; (g) Pr4N+RuO4 (0.06 equiv), NMO
–
(3.0 equiv), powdered 4 Å MS, MeCN, 40 °C, 3 h (93%).
Boc
a
b
N
O
15
10 ·TsOH
S
87%
95%
Having prepared 17, we focused our efforts on the forma-
tion of the thiomorpholine ring. Toward this end, diol 17
was transformed in 71% yield into the corresponding bis-
tosylate 20. Treatment of 20 with sodium sulfide gave a
62% yield of the bicyclic thiomorpholine 21. Cleavage of
the tert-butoxycarbonyl group with 4-toluenesulfonic acid
gave 11·TsOH, the spectral properties of which were in
complete agreement with proposed structure. Oxidation
of sulfide 21 with tetrapropylammonium perruthenate,11
followed by treatment with 4-toluenesulfonic acid, gave
the corresponding sulfone 12·TsOH.
O
16
Scheme 2 Reagents and conditions: (a) Pr4N+RuO4 (0.06 equiv),
NMO (3.0 equiv), powdered 4 Å MS, MeCN, 40 °C, 3 h; (b)
TsOH·H2O (1.2 equiv), EtOH, 85 °C, 1 h.
–
Our next synthetic targets were 3-thia-8-azabicyc-
lo[3.2.1]octane hydrotosylate (11·TsOH) and its corre-
sponding S,S-dioxide (12·TsOH). We conceived a route in
which the thiomorpholine ring of 11 would be constructed
from the known bis(hydroxymethyl)pyrrolidine 1712 by a
strategy similar to that used for the construction of thio-
morpholine 9 (Scheme 3). Before addressing this key re-
action, we focused on the synthesis of diol 17. Under the
conditions developed by Donohoe and co-workers,13 bis-
carbomethoxylation of commercial N-(tert-butoxycar-
bonyl)pyrrole smoothly gave diester 18.14 Catalytic
hydrogenation (5% Rh/Al2O3, AcOH, 60 psi, 8 h) of pyr-
role 18 gave pyrrolidine 19 as a single stereoisomer in
99% yield. The use of a conventional low-pressure Parr
hydrogenation apparatus with rhodium/alumina as the
In summary, we have developed concise syntheses of 3-
thia-6-azabicyclo[3.1.1]heptane hydrotosylate (9·TsOH),
3-thia-8-azabicyclo[3.1.1]octane hydrotosylate (11·TsOH),
and the corresponding sulfones 10·TsOH and 12·TsOH.
Building block 9·TsOH was prepared in seven steps and
18% overall yield, 10·TsOH was prepared in eight steps
and 17% overall yield, 11·TsOH was prepared in six steps
and 21% overall yield, and 12·TsOH was prepared in sev-
en steps and 16% overall yield. Each synthesis began with
inexpensive starting materials and involved straightfor-
ward chemistry. The achiral nature of the bicyclic thio-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2966–2970

2968
D. P. Walker, D. J. Rogier
PAPER
2 H), 2.81 (dt, J = 10.86, 7.07 Hz, 1 H), 2.29 (s, 3 H), 2.13 (dd,
J = 10.62, 5.06 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 145.6, 137.7, 128.1, 125.5,
58.65, 29.42, 26.54, 20.80.
MS (ESI+): m/z = 115.9 [M + H]+.
morpholines 9–12 and their structural similarity to
thiomorpholine and thiomorpholine 1,1-dioxide suggest
that these new isosteres might be useful building blocks in
medicinal chemistry research.
1H and 13C NMR spectra were recorded at r.t. on a Bruker Avance
400 spectrometer with a 5-mm DUL probe. Chemical shifts are re-
ported in ppm (δ) relative to TMS (δ = 0.0 ppm), and are referenced
to residual solvent resonances (CDCl3, δ = 7.27 or 77.00 ppm;
CD3OD, δ = 3.31 or 49.15 ppm; DMSO-d6, δ = 2.50 or 39.51 ppm).
Low-resolution ESI mass spectra were recorded on a Micromass-
Waters LC-ZMD single quadrupole liquid chromatograph–mass
spectrometer. IR spectra were recorded on a Bio-Rad Excalibur
FTS 3000MX with a diamond anvil cell. Combustion analyses were
performed by Robertson Microlit, Ledgewood, NJ. Melting points
were recorded on a Stanford Research Systems OptiMelt apparatus
and are uncorrected. Reactions were monitored by TLC on An-
altech silica gel GF 250 micron plates visualized by staining with
ninhydrin or KMnO4 dip stains, or by reversed-phase HPLC on an
Agilent 1100 chromatograph equipped with a an Agilent XDB-C18
(1.8 µm, 4.6 × 50 mm) column and diode array detector tuned to
210–254 nm. Flash chromatography was performed in a glass col-
umn on SiliCycle silica gel (230–400 mesh). All reagents were pur-
chased from the Aldrich Chemical Co. and used without further
purification. All solvents were of HPLC grade unless otherwise
stated; anhydrous solvents were purchased from Aldrich Chemical
Co. and were used as supplied.
Anal. Calcd for C12H17NO3S2 (287.3): C, 50.16; H, 5.96; N, 4.88.
Found: C, 50.13; H, 6.08; N, 4.82.
tert-Butyl 3-Thia-6-azabicyclo[3.1.1]heptane-6-carboxylate 3,3-
Dioxide (16)
Pr4N+RuO4– (33 mg, 0.09 mmol) was added to a stirred mixture of
ester 15 (400 mg, 1.9 mmol), NMO (650 mg, 5.6 mmol), and pow-
dered 4 Å MS (200 mg) in MeCN (10 mL), and the resulting mix-
ture was warmed to 40 °C for 3 h. The solvent was removed in
vacuo and the residue was passed through a short plug of silica gel
with elution by hexanes–EtOAc (75:25) to give a white solid; yield:
400 mg (87%); mp 120–122 °C; Rf = 0.18 (hexanes–EtOAc, 75:25).
IR (neat): 2986, 2939, 1707, 1370, 1350, 1310, 1280, 1260, 1147,
1116 cm–1.
1H NMR (400 MHz, CD3OD): δ = 4.41 (br d, J = 6.82 Hz, 2 H),
4.12–3.85 (m, 2 H), 3.55 (br d, J = 13.13 Hz, 2 H), 2.84–2.76 (m, 1
H), 2.08 (d, J = 10.61 Hz, 1 H), 1.48 (s, 9 H).
13C NMR (100 MHz, CD3OD): δ (two rotamers; 1:1) = 156.2,
82.93, 61.38, 60.45, 58.12, 57.30, 28.71, 27.08.
MS (ESI+): m/z = 270.0 [M + Na]+.
Anal. Calcd for C10H17NO4S (247.3): C, 48.57; H, 6.93; N, 5.67.
Found: C, 48.56; H, 6.87; N, 5.68.
tert-Butyl 3-Thia-6-azabicyclo[3.1.1]heptane-6-carboxylate (15)
Na2S·9 H2O (5.76 g, 24.0 mmol) was added to a stirred suspension
of azetidine 138b,c (4.2 g, 8.0 mmol) in 1:1 EtOH–H2O (64 mL), and
the mixture was heated to 90 °C. After 20 min at 90 °C, all the solids
dissolved. After 2 h, the mixture was cooled to r.t., the solvent was
removed in vacuo, and the residue was treated with H2O (30 mL)
and Et2O (50 mL). The aqueous layer was extracted with Et2O (20
mL) and the organic layers were combined, washed with brine (10
mL), dried (MgSO4), filtered, and concentrated in vacuo to give a
yellow oil. This crude product was purified by flash chromatogra-
phy [silica gel, hexanes–EtOAc (90:10)] to give a white solid; yield:
1.6 g (93%); mp 54–56 °C; Rf = 0.60 (hexanes–EtOAc, 75:25).
3-Thia-6-azabicyclo[3.1.1]heptane 3,3-Dioxide Hydrotosylate
(10·TsOH)
TsOH·H2O (230 mg, 1.2 mmol) was added to a stirred solution of
ester dioxide 16 (250 mg, 1.0 mmol) in absolute EtOH (15 mL), and
the mixture was heated at 85 °C for 1 h. The mixture was then
cooled to r.t., and the solvent was removed in vacuo. The remaining
solid was triturated with THF (3 mL) for 3 h to give a fine precipi-
tate. The precipitate was collected by filtration and washed with
THF (2 mL) and Et2O (5 mL). The solid was dried in vacuo to give
a white solid; yield: 307 mg (95%); mp 177–178 °C.
IR (neat): 2986, 2939, 1627, 1400, 1352, 1306, 1280, 1256, 1217,
1147, 1116 cm–1.
IR (neat): 3000, 2960, 1681, 1433, 1374, 1175, 1147 cm–1.
1H NMR (400 MHz, CD3OD): δ = 4.27 (br d, J = 4.85 Hz, 2 H),
3.51–3.39 (br m, 2 H), 2.84 (br t, J = 9.60 Hz, 2 H), 2.63 (ddd,
J = 9.35, 7.07, 7.07 Hz, 1 H), 1.70 (d, J = 9.35 Hz, 1 H), 1.49 (s, 9
H).
13C NMR (100 MHz, CD3OD): δ (two rotamers; 1:1) = 158.5,
81.50, 61.20, 60.21, 29.64, 29.30, 28.84, 28.59.
1H NMR (400 MHz, DMSO-d6): δ = 9.75–8.75 (br s, 2 H), 7.48 (d,
J = 8.08 Hz, 2 H), 7.12 (d, J = 7.83 Hz, 2 H), 4.49 (br d, J = 6.31 Hz,
2 H), 3.99–3.87 (m, 4 H), 2.96 (dt, J = 11.87, 6.82 Hz, 1 H), 2.41 (d,
J = 11.62 Hz, 1 H), 2.28 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 145.6, 137.7, 128.1, 125.5,
57.45, 56.58, 25.67, 20.80.
MS (ESI+): m/z = 115.9 [M – Boc + 2H]+
MS (ESI+): m/z = 148.0 [M + H]+.
Anal. Calcd for C10H17NO2S (215.27): C, 55.79; H, 7.90; N, 6.51.
Found: C, 56.04; H, 8.13; N, 6.52.
Anal. Calcd for C12H17NO5S2 (319.3): C, 45.13; H, 5.37; N, 4.39.
Found: C, 45.15; H, 5.38; N, 4.34.
3-Thia-6-azabicyclo[3.1.1]heptane Hydrotosylate (9·TsOH)
TsOH·H2O (530 mg, 2.8 mmol) was added to a stirred solution of
15 (500 mg, 2.3 mmol) in absolute EtOH (18 mL), and the mixture
was heated at 85 °C for 1 h. The mixture was then cooled to r.t., and
the solvent was removed in vacuo. The remaining oil was triturated
with THF (5 mL) for 3 h, which caused a white precipitate to form.
The precipitate was collected by filtration, washed with THF (2 mL)
and Et2O (10 mL), and dried in vacuo to give a white solid; yield:
575 mg (86%); mp 155–157 °C.
1-tert-Butyl 2,5-Dimethyl 1H-pyrrole-1,2,5-tricarboxylate (18)
This compound was prepared by a slight modification of an estab-
lished procedure.13
A 2.5 M solution of BuLi in hexanes (58.0 mL) was added dropwise
from a syringe to a stirred solution of 2,2,6,6-tetramethylpiperidine
(24.4 mL, 145 mmol) in anhydrous THF (180 mL) at –78 °C, and
the mixture was stirred at –78 °C for 15 min. In a separate flask, N-
(tert-butoxycarbonyl)pyrrole (9.63 g, 58 mmol) was dissolved in
anhydrous THF (40 mL). The solution was cooled to –78 °C then
slowly added through a cannula to the first solution. The resulting
mixture was stirred at –78 °C for 3 h then transferred through a can-
nula to a solution of ClCO2Me (13.4 mL, 174 mmol) in THF (20
mL) at –78 °C, and the resulting mixture was stirred at –78 °C for
15 min. Sat. aq NH4Cl (50 mL) was added, and the mixture was al-
lowed to warm to r.t. Et2O (200 mL) and H2O (100 mL) were added,
IR (neat): 2960, 1608, 1222, 1165, 1123 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 9.30 (br s, 1 H), 7.98 (br s, 1
H), 7.50 (d, J = 8.08 Hz, 2 H), 7.13 (d, J = 7.58 Hz, 2 H), 4.49–4.41
(m, 2 H), 3.45 (d, J = 12.13 Hz, 2 H), 3.16 (dd, J = 13.14, 3.03 Hz,
Synthesis 2013, 45, 2966–2970
© Georg Thieme Verlag Stuttgart · New York

PAPER
Preparation of Bicyclic Thiomorpholine Building Blocks
2969
and the layers were separated. The aqueous layer was extracted with
Et2O (2 × 50 mL). The ethereal layers were combined, washed se-
quentially with 1.0 M aq HCl (2 × 50 mL) and brine (50 mL) then
dried (MgSO4), filtered, and concentrated in vacuo to give an or-
ange semi-solid. This crude product was triturated with Et2O–hex-
anes (80:20; 30 mL) to give a white precipitate. The precipitate was
collected by filtration, washed with cold (0 °C) Et2O–hexanes
(80:20; 30 mL), and dried in vacuo to give a white solid; yield: 11.0
g (67%).
gel, hexanes–EtOAc (70:30)] to give a white solid; yield: 3.0 g
(71%); mp 82–84 °C; Rf = 0.19 hexanes–EtOAc (75:25).
IR (neat): 2985, 1695, 1396, 1173 cm–1.
1H NMR (400 MHz, CDCl3): δ (two rotamers; 1:1) = 7.85–7.62 (m,
4 H), 7.42–7.31 (m, 4 H), 4.16–4.08 (m, 1 H), 4.08–3.95 (m, 4 H),
3.95–3.84 (m, 1 H), 2.47 (s, 6 H), 1.95–1.88 (m, 2 H), 1.88–1.80 (m,
2 H), 1.36 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ (two rotamers; 1:1) = 153.9, 144.9,
132.7, 129.9, 127.9, 80.70, 69.55, 69.33, 56.69, 28.17, 26.65, 25.45,
21.63.
The spectral properties of 18 were identical in all respects to those
reported in the literature.13b
MS (ESI+): m/z = 440.2 [M – Boc + 2 H]+.
1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 2 H), 3.87 (s, 6 H), 1.67
(s, 9 H).
Anal. Calcd for C25H33NO8S2 (539.6): C, 55.64; H, 6.16; N, 2.60.
Found: C, 55.54; H, 6.00; N, 2.57.
1-tert-Butyl 2,5-Dimethyl (2R*,5S*)-Pyrrolidine-1,2,5-tricar-
boxylate (19)
tert-Butyl 3-Thia-8-azabicyclo[3.2.1]octane-8-carboxylate (21)
A solution of Na2S·9H2O (1.67 g, 6.95 mml) in H2O (10 mL) was
added to a stirred solution of ester 20 (1.25 g, 2.32 mmol) in EtOH
(10 mL). The cloudy mixture was heated under argon in an oil bath
at 90 °C for 2 h. (After 45 min at 90 °C, the cloudy mixture became
clear.) The mixture was then cooled to r.t., and the solvent was re-
moved in vacuo. The remaining solid was partitioned between H2O
(15 mL) and Et2O (25 mL). The aqueous layer was extracted with
Et2O (20 mL), and the ethereal layers were combined, washed with
brine (10 mL), dried (MgSO4), filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography [silica gel,
hexanes–EtOAc (90:10)] to give a white solid; yield: 330 mg
(62%); mp 76–78 °C; Rf = 0.61 (hexanes–EtOAc, 75:25).
A 500-mL Parr bottle was charged with 5% Rh/Al2O3 (0.500 g, 0.24
mmol). The bottle was flushed with argon, and a solution of tricar-
boxylate 18 (5.3 g, 19 mmol) in glacial AcOH (250 mL) was added.
The mixture was hydrogenated at 60 psi for 8 h then filtered through
Celite. The catalyst was washed with AcOH (100 mL) and the col-
lected filtrate was concentrated in vacuo to give a white solid; yield:
5.35 g (99%); mp 69–71 °C; Rf = 0.38 (hexanes–EtOAc, 1:1).
The spectral properties of 19 were identical in all respects to those
reported in the literature.16,17
1H NMR (400 MHz, CDCl3): δ (two rotamers; 1:1) = 4.45–4.35 (m,
1 H), 4.35–4.20 (m, 1 H), 3.76 (s, 6 H), 2.30–2.05 (m, 4 H), 1.43 (s,
9 H).
13C NMR (100 MHz, CDCl3): δ (two rotamers; 1:1) = 172.5, 172.2,
153.5, 80.79, 60.00, 59.48, 52.20, 52.04, 29.50, 28.73, 28.16.
IR (neat): 2979, 1689, 1423, 1254 cm–1.
1H NMR (400 MHz, CD3OD): δ = 4.40–4.34 (m, 2 H), 3.15–3.05
(m, 2 H), 2.15 (br d, J = 12.8 Hz, 2 H), 2.11–2.03 (m, 4 H), 1.52 (s,
9 H).
tert-Butyl (2R*,5S*)-2,5-Bis(hydroxymethyl)pyrrolidine-1-car-
boxylate (17)
13C NMR (100 MHz, CD3OD): δ (two rotamers; 1:1) = 154.8,
CaCl2 (3.0 g, 27 mmol) and NaBH4 (2.0 g, 53 mmol) were added to
a stirred solution of tricarboxylate 19 (2.6 g, 9.0 mmol) in EtOH–
MeOH (9:1; 100 mL) at r.t. The NaBH4 was added in 5 × 400 mg
portions at 30 min intervals, and MeOH (10 mL) was added every
2 h. When the mixture had been stirred for a total of 5 h, H2O (15
mL) was added, and the mixture was stirred for a further 15 min.
The mixture was then concentrated in vacuo until ~5 mL of liquid
remained. H2O (100 mL) and EtOAc (100 mL) were added to the
remaining solid mass, and the layers were separated. The aqueous
layer was extracted with EtOAc (2 × 50 mL), and the organic layers
were combined, washed with brine (10 mL), dried (MgSO4), fil-
tered, and concentrated in vacuo to give an oil. The crude product
was purified by flash chromatography [silica gel, hexanes–EtOAc
(4:1 to 1:1)] to give a colorless oil; yield: 1.8 g (86%); Rf = 0.11
(hexanes–EtOAc, 1:1).
81.39, 55.97, 55.14, 33.41, 32.73, 29.82, 29.18, 28.90.
MS (ESI+): m/z = 174.2 [M – t-Bu + 2H]+.
Anal. Calcd for C11H19NO2S (229.3): C, 57.61; H, 8.35; N, 6.11.
Found: C, 57.74; H, 8.07; N, 6.15.
3-Thia-8-azabicyclo[3.2.1]octane Hydrotosylate (11·TsOH)
A mixture of ester 21 (150 mg, 0.65 mmol) and TsOH·H2O (150
mg, 0.79 mmol) in EtOH (10 mL) was heated to 85 °C for 1 h. The
mixture was then cooled to r.t. and the solvent was removed in vac-
uo to give a solid that was triturated with THF (1.5 mL) for 30 min.
The resulting precipitate was collected by filtration, washed sequen-
tially with THF (1 mL) and Et2O (5 mL), and dried in vacuo to give
a white solid; yield: 165 mg (84%); mp 185–187 °C.
IR (neat): 2952, 1221, 1167, 1124 cm–1.
The spectral properties of 17 were identical in all respects to those
1H NMR (400 MHz, DMSO-d6): δ = 9.00–8.55 (br s, 2 H), 7.50 (d,
J = 7.80 Hz, 2 H), 7.13 (d, J = 7.80 Hz, 2 H), 4.20–4.10 (m, 2 H),
3.19 (dd, J = 13.8, 1.6 Hz, 2 H), 2.45 (dd, J = 13.8, 3.2 Hz, 2 H),
2.30 (s, 3 H), 2.01 (m, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 145.3, 137.9, 128.2, 125.5,
54.29, 30.16, 26.50, 20.80.
reported in the literature.12,16
1H NMR (400 MHz, CD3OD): δ = 3.92–3.82 (m, 2 H), 3.70–3.50
(m, 4 H), 2.05–1.85 (m, 4 H), 1.47 (s, 9 H).
13C NMR (100 MHz, CD3OD): δ (two rotamers; 1:1) = 154.3,
82.58, 60.26, 59.74, 54.64, 54.26, 28.69, 28.26, 27.58.
MS (ESI+): m/z = 130.1 [M + H]+.
tert-Butyl (2R*,5S*)-2,5-Bis[(tosyloxy)methyl]pyrrolidine-1-
carboxylate (20)
Anal. Calcd for C13H19NO3S2 (301.3): C, 51.82; H, 6.36; N, 4.65.
Found: C, 51.58; H, 6.21; N, 4.56.
Ts2O (5.3 g, 16 mmol) was added to a stirred solution of diol 17 (1.8
g, 7.8 mmol) in pyridine (25 mL) at 0 °C, and the mixture was
stirred at 0 °C for 3 h. H2O (5.0 mL) was added, and the mixture was
allowed to warm to r.t. The volatiles were removed in vacuo, and
the remaining oil was partitioned between H2O (20 mL) and EtOAc
(50 mL). The aqueous layer was extracted with EtOAc (2 × 25 mL)
and the organic layers were combined, washed sequentially with 1.0
M aq HCl (2 × 10 mL), sat. aq NaHCO3 (20 mL), and brine (15 mL),
then dried (MgSO4), filtered, and concentrated in vacuo to give an
oil. The crude product was purified by flash chromatography [silica
tert-Butyl 3-Thia-8-azabicyclo[3.2.1]octane-8-carboxylate 3,3-
Dioxide (22)
Pr4N+ RuO4– (26 mg, 0.07 mmol) was added to a stirred mixture of
ester 21 (260 mg, 1.13 mmol), NMO (389 mg, 3.32 mmol), and
powdered 4 Å MS (160 mg) in MeCN (6.0 mL), and the resulting
mixture was warmed to 40 °C for 3 h. The solvent was removed in
vacuo and the residue was passed through a short plug of silica gel
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2966–2970

2970
D. P. Walker, D. J. Rogier
PAPER
with elution by hexanes–EtOAc (75:25) to give a white solid; yield:
Kotecka, B. M.; Rieckmann, K. H.; Edstein, M. D.
275 mg (93%); mp 139–141 °C; Rf = 0.67 (hexanes–EtOAc, 1:1).
Antimicrob. Agents Chemother. 2008, 52, 3085.
(3) (a) Barbachyn, M. R.; Hutchinson, D. K.; Brickner, S. J.;
Cynamon, M. H.; Kilburn, J. O.; Klemens, S. P.; Glickman,
S. E.; Grega, K. C.; Hendges, S. K.; Toops, D. S.; Ford, C.
W.; Zurenko, G. E. J. Med. Chem. 1996, 39, 680.
IR (neat): 2979, 1706, 1406, 1303, 1177, 1123 cm–1.
1H NMR (400 MHz, CD3OD): δ = 4.64–4.54 (m, 2 H), 3.43–3.32
(m, 2 H), 3.24 (br d, J = 14.2 Hz, 2 H), 2.35 (d, J = 8.33 Hz, 2 H),
2.20–2.05 (m, 2 H), 1.50 (s, 9 H).
(b) Villemagne, B.; Crauste, C.; Flipo, M.; Baulard, A. R.;
Déprez, B.; Willand, N. Eur. J. Med. Chem. 2012, 51, 1.
(4) (a) Huang, X.; Chen, D.; Wu, N.; Zhang, A.; Jia, Z.; Li, X.
Bioorg. Med. Chem. Lett. 2009, 19, 4130. (b) Hoffmann, T.;
Koblet, A.; Peters, J.-U.; Schnider, P.; Sleight, A.; Stadler,
H. WO 2005/002577, 2005; Chem. Abstr. 2005, 142, 134463
(5) (a) Roecker, A. J.; Coleman, P. J.; Mercer, S. P.; Schreier, S.
D.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.;
Tao, W.; Diehl, R. E.; South, V. J.; Davide, J. P.; Kohl, N.
E.; Yan, Y.; Kuo, L. C.; Li, C.; Fernandez-Metzler, C.;
Mahan, E. A.; Prueksaritanont, T.; Hartman, G. D. Bioorg.
Med. Chem. Lett. 2007, 17, 5677. (b) Zask, A.; Kaplan, J.;
Verheijen, J. C.; Richard, D. J.; Curran, K.; Brooijmans, N.;
Bennett, E. M.; Toral-Barza, L.; Hollander, I.; Ayral-
Kaloustian, S.; Yu, K. J. Med. Chem. 2009, 52, 7942.
(c) Kiely, J. S.; Hutt, M. P.; Culbertson, T. P.; Bucsh, R. A.;
Worth, D. F.; Lesheski, L. E.; Gogliotti, R. D.; Sesnie, J. C.;
Solomon, M.; Mich, T. F. J. Med. Chem. 1991, 34, 656.
(d) Zhang, Y.; Rothman, R. B.; Dersch, C. M.; de Costa, B.
R.; Jacobson, A. E.; Rice, K. C. J. Med. Chem. 2000, 43,
4840. (e) Wang, X.; Berger, D. M.; Salaski, E. J.; Torres, N.;
Hu, Y.; Levin, J. I.; Powell, D.; Wojciechowicz, D.; Collins,
K.; Frommer, E. Bioorg. Med. Chem. Lett. 2009, 19, 6571.
(f) Trujillo, J. I.; Huang, W.; Hughes, R. O.; Rogier, D. J.;
Turner, S. R.; Devraj, R.; Morton, P. A.; Xue, C.-B.; Chao,
G.; Covington, M. B.; Newton, R. C.; Metcalf, B. Bioorg.
Med. Chem. Lett. 2011, 21, 1827.
13C NMR (100 MHz, CD3OD): δ (two rotamers; 1:1) = 157.2,
81.38, 64.75, 64.40, 61.58, 28.88, 27.79, 27.43.
MS (ESI+): m/z = 206.2 [M – t-Bu + 2H]+.
Anal. Calcd for C11H19NO4S (261.3): C, 50.56; H, 7.33; N, 5.36.
Found: C, 50.34; H, 7.10; N, 5.30.
3-Thia-8-azabicyclo[3.2.1]octane 3,3-Dioxide Hydrotosylate
(12·TsOH)
A mixture of 22 (185 mg, 0.71 mmol) and TsOH·H2O (161 mg, 0.84
mmol) in EtOH (8.0 mL) was heated to 85 °C for 1 h. The mixture
was then cooled to r.t., and the solvent was removed in vacuo to af-
ford a solid that was triturated with THF (1.0 mL) for 60 min. The
resulting precipitate was collected by filtration, washed sequentially
with THF (0.5 mL) and Et2O (7 mL), and dried in vacuo to give a
white solid; yield: 164 mg (70%); mp 241–242 °C.
IR (neat): 2958, 1602, 1321, 1250, 1153, 1113 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 9.49–9.30 (br s, 2 H), 7.50 (d,
J = 8.08 Hz, 2 H), 7.13 (d, J = 7.8, 2 H), 4.49–4.39 (m, 2 H), 3.70–
3.58 (m, 4 H), 2.40–2.30 (m, 2 H), 2.29 (s, 3 H), 2.15–2.00 (m, 2 H).
13C NMR (400 MHz, DMSO-d6): δ = 145.2, 138.0, 128.2, 125.5,
56.19, 54.52, 24.80, 20.82.
MS (ESI+): m/z = 162.2 [M + H]+.
Anal. Calcd for C13H19NO5S2 (333.3): C, 46.84; H, 5.75; N, 4.20.
Found: C, 46.86; H, 5.64; N, 4.15.
(6) Jordis, U.; Sauter, F.; Siddiqi, S. M. Indian J. Chem., Sect.
B: Org. Chem. Incl. Med. Chem. 1989, 28, 294.
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10, 279.
(8) (a) Wishka, D. G.; Beagley, P.; Lyon, J.; Farley, K. A.;
Walker, D. P. Synthesis 2011, 2619. (b) Walker, D. P.;
Eklov, B. M.; Bedore, M. W. Synthesis 2012, 44, 2859.
(c) Walker, D. P.; Bedore, M. W. Tetrahedron Lett. 2012,
53, 6332.
Acknowledgment
We thank Dr. Gary Chinigo of Kalexsyn for his valuable sugges-
tions regarding the preparation of this manuscript.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
(9) Guanti, G.; Riva, R. Tetrahedron: Asymmetry 2001, 12, 605.
(10) Kozikowski, A. P.; Tückmantel, W.; Reynolds, I. J.;
Wroblewski, J. T. J. Med. Chem. 1990, 33, 1561.
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Synthesis 2013, 45, 2966–2970
© Georg Thieme Verlag Stuttgart · New York