Asymmetric 1,3-dipolar cycloaddition of a (Z)-alkene dipolarophile. Synthesis of (3S,4R) ethyl 1-azabicyclo[2.2.1]heptane-3-carboxylate

Full text of DOI:10.1021/jo001797f

2526
J . Org. Chem. 2001, 66, 2526-2529
Sch em e 2
Asym m etr ic 1,3-Dip ola r Cycloa d d ition of a
(Z)-Alk en e Dip ola r op h ile. Syn th esis of
(3S,4R) Eth yl
1-Aza bicyclo[2.2.1]h ep ta n e-3-ca r boxyla te
J ohn S. Carey
Synthetic Chemistry, GlaxoSmithKline Pharmaceuticals,
Old Powder Mills, Nr. Leigh, Tonbridge,
Kent, TN11 9AN. UK
ylide with an achiral dipolarophile did not lead to any
observed asymmetric induction,4 there are reports indi-
cating that a chiral auxiliary located within the dipo-
larophile can lead to useful levels of asymmetric induc-
tion.5 Our retrosynthesis based upon this type of approach
is outlined (Scheme 2). The key disconnection was
envisaged as the diastereoselective addition of the achiral
azomethine ylide derived from 5 to the (Z)-alkene B. The
(Z)-alkene geometry is required to set the relative ster-
eochemistry at C-3 and C-4 required in the final product.
Precedent for the use of (Z)-crotonic acid derivatives in
the Lewis acid promoted Diels-Alder reaction suggested
alkene isomerization prior to [4 + 2] cycloaddition could
be a problem.6 However, it was hoped that the milder
conditions required for the [3 + 2] dipolar cycloaddition
the alkene geometry would be retained. With regard to
the choice of chiral auxiliary (Xc), we opted for the
bornane-2,10-sultam derivative because it has been
reported to give good levels of asymmetric induction in
nonchelation-controlled processes.7 It was planned to
protect the hydroxyl group as a tert-butyldimethylsilyl
ether (P ) TBS), this would allow selective hydroxyl
deprotection of intermediate A and hence allow conver-
sion to 4 by standard chemistry.3,4
J ohn•S•Carey@sbphrd.com
Received December 27, 2000
In tr od u ction
Versatile syntheses of the stereoisomers of 3-carboxy-
1-azabicyclo[2.2.1]heptane derivatives represent a sig-
nificant challenge because of the important physiological
properties of this class of compounds.1 Many methods
have been reported for the preparation of completely
racemic material,2 the racemic endo (3S*,4R*) diastere-
oisomers3 or the racemic exo (3R*,4R*) diastereoisomers.3
Our particular interest was in the synthesis of the
enantiomerically pure (3S,4R) stereoisomer 4. The re-
ported4 preparation of 4 involves the 1,3-dipolar addition
of a chiral azomethine ylide derived from 2 with 5,6-
dihydro-2H-pyran-2-one 1 (Scheme 1). This results in a
1:1 mixture of diastereoisomers 3, which are separated
at a later stage by fractional recrystallization and the
appropriate diastereoisomer converted through to 4.
Sch em e 1
Resu lts a n d Discu ssion
Alkyne 6 was prepared from 3-butyn-1-ol (97%) ac-
cording to the published procedure8 (Scheme 3). Treat-
ment of 6 with butyllithium and the quenching with solid
carbon dioxide9 gave a quantitative yield of the unstable
acid 7. Although 7 could be isolated, it was not stable to
column chromatography nor could it be stored for longer
than 2 or 3 days and therefore was used directly in
subsequent reactions. Bornane-2,10-sultam derivative 8
was prepared from acid 7 (63%) by nucleophilic attack
of the lithium salt of the chiral auxiliary on an interme-
diate pivaloyl mixed anhydride.10 Controlled hydrogena-
tion of alkyne 8 over Lindlar’s catalyst in toluene gave
We potenially had the requirement for multi-kilogram
amounts of 4; therefore, the development of new, more
stereoselective methods for the preparation of 3-carboxy-
1-aza-bicyclo[2.2.1]heptane derivatives was warranted.
Although the 1,3-dipolar addition of a chiral azomethine
(1) (a) J enkins, S. M.; Wadsworth, H. J .; Bromidge, S.; Orlek, B. S.;
Wyman, P. A.; Riley, G. J .; Hawkins, J . J . Med. Chem. 1992, 35, 2392.
(b) Street, L. J .; Baker, R.; Book, T.; Reeve, A. J .; Saunders, J .; Willson,
T.; Marwood, R. S.; Patel, S.; Freedman, S. B. J . Med. Chem. 1992,
35, 295. (c) Showell, G. A.; Baker, R.; Davis, J .; Hargreaves, R.;
Freedman, S. B.; Hoogsteen, K.; Patel, S.; Snow, R. J . J . Med. Chem.
1992, 35, 911. (d) Street, L. J .; Baker, R.; Book, T.; Kneen, C. O.;
MacLeod, A. M.; Merchant, K. J .; Showell, G. A.; Saunders, J .; Herbert,
R. H.; Freedman, S. B.; Harley, E. A. J . Med. Chem. 1990, 33, 2690.
(e) Bromidge, S. M.; Brown, F.; Cassidy, F.; Clark, M. S. G.; Dabbs,
S.; Hadley, M. S.; Hawkins, J .; Loudon, J . M.; Naylor, C. B.; Orlek, B.
S.; Riley, G. J . J . Med. Chem. 1997, 40, 4265.
(5) (a) Fevig, J . M.; Abelman, M. M.; Brittelli, D. R.; Kettner, C. A.;
Knabb, R. M.; Weber, P. C. Bioorg. Med. Chem. Lett. 1996, 6, 295. (b)
Ma, Z.; Wang, S.; Cooper, C. S.; Fung, A. K. L.; Lynch, J . K.; Plagge,
F.; Chu, D. T. W. Tetrahedron Asymm. 1997, 8, 883. (c) Karlsson, S.;
Han, F.; Hogberg, H. E.; Caldirola, P. Tetrahedron Asymm. 1999, 10,
2605. (d) Mish, M. R.; Guerra, F. M.; Carreira, E. M. J . Am. Chem.
Soc. 1997, 119, 8379. (e) Whitlock, G. A.; Carreira, E. M. J . Org. Chem.
1997, 62, 7916.
(6) Evans, D. A.; Chapman, K. T.; Bisaha, J . J . Am. Chem. Soc. 1988,
110, 1238.
(7) Kim, B. H.; Curren, D. P. Tetrahedron 1993, 49, 293.
(8) Oehlschlager, A. C.; Wong, J . W.; Verigin, V. G.; Pierce, H. D. J .
Org. Chem. 1983, 48, 5009.
(2) (a) Saunders, J .; MacLeod, A. M.; Merchant, K.; Showell, G. A.;
Snow, R. J .; Street, L. J .; Baker, R. J . Chem. Soc., Chem. Commun.
1988, 1618. (b) Della, E. W.; Kostakis, C.; Smith, P. A. Org. Lett. 1999,
1, 363.
(3) Orlek, B. S.; Wadsworth, H.; Wyman, P.; Hadley, M. S. Tetra-
hedron Lett. 1991, 32, 1241.
(4) Cottrell, I. F.; Hands, D.; Kennedy, D. J .; Paul, K. J .; Wright, S.
H. B.; Hoogsteen, K. J . Chem. Soc., Perkin Trans. 1 1991, 1091.
(9) Adams, M. A.; Duggan, A. J .; Smolanoff, J .; Meinwald, J . J . Am.
Chem. Soc. 1979, 101, 5364.
(10) Fonquerna, S.; Moyano, A.; Pericas, M. A.; Riera, A. J . Am.
Chem. Soc. 1997, 119, 10225.
10.1021/jo001797f CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/13/2001

Notes
J . Org. Chem., Vol. 66, No. 7, 2001 2527
Sch em e 3a
Sch em e 5a
a
Reagents and conditions: (a) n-BuLi, CO2(s), THF, -75 °C; (b)
t-BuCOCl, NEt3, THF, -75 °C and then 2(R)-(-)-bornane-2,10-
sultam, n-BuLi, THF, -75 °C; (c) H2, 5% Pd/CaCO3+Pb, toluene,
rt.
a
Reagents and conditions (a) cat. TFA, toluene, rt; (b) 2 M aq
Sch em e 4a
HCl, THF, rt; (c) NEt3, MsCl, CH2Cl2, -20 °C to room temperature;
(d), H2, Pd/C, EtOH, 80 °C; (e) LiOH, H2O, THF, rt and then HCl(g)
EtOH, 80 °C.
a
Reagents and conditions: (a) TMSCH2Cl, CH3CN, 82 °C; (b)
ref 12.
the (Z)-alkene 9 (100%).11 Extended reaction time or high
catalyst loading led to the partial formation of the
unwanted corresponding (E)-alkene and the fully satu-
rated alkane.
F igu r e 1.
It was felt that the published procedure12 for the
preparation of 5 would not be suitable for scale-up to a
large scale (Scheme 4), the main limitations being the
high temperature (220 °C) required for the formation of
11, the absence of solvent in this reaction which would
lead to handling difficulties upon cooling, and finally the
requirement to purify 11 by distillation.
Initial studies on the reaction of 10 with chlorometh-
yltrimethylsilane in high boiling solvents such as o-xylene
or 1,2-dichlorobenzene were unsuccessful. However it was
found that acetonitrile was a suitable solvent and gave
an 82% yield of 11 after 16 h at reflux (82 °C). The
material obtained was of suitable purity, and no distil-
lation was required. Conversion of 11 to 5 was carried
out by the published procedure.12
The [3 + 2] dipolar cycloaddition of alkene 9 with
azomethine ylide precursor 5 in the presence of a catalytic
quantity of TFA5a-c provided a 4:1 mixture of diastere-
oisomers, as determined by HPLC analysis (Scheme 5).
The major component 12 was readily isolated by column
chromatography in 73% yield. Stereochemical assignment
of 12 was not possible at this stage, vide infra, the
structure of the minor component is assumed to be the
corresponding (3R,4S) stereoisomer. The stereochemistry
observed in 12 is consistent with the cycloaddition
proceeding via the accepted7 transition state structure
for the reactions of acryoyl bornane-2,10-sultam deriva-
tives. Silyl ether 12 was readily deprotected with aq HCl
to give alcohol 13 (84%). Treatment of 13 with NEt3 and
MsCl13 gave rise directly to the quaternary ammonium
salt 14 (85%). Hydrogenolysis of 14 over palladium on
carbon resulted in N-benzyl deprotection, and tertiary
amine 15 was isolated as the hydrochloride salt (77%).
Conversion of 15 to ethyl ester 4 could be achieved by a
two-step procedure. LiOH hydrolysis14 of 15 gave the
carboxylate salt, which was not isolated but converted
into the ethyl ester 4 by treatment with HCl in ethanol.
Ethyl ester 4 was isolated in 92%, and the chiral auxiliary
could be recovered in 95%. A one-step procedure involving
the treatment of 15 with Ti(OiPr)4 in ethanol15 resulted
in the formation of 4, but the product could not be
separated from the titanium salts due to its water
solubility and highly polar nature. The relative and
absolute stereochemistry of 4 was determined by chiral
HPLC. Authentic samples of all four stereoisomers of
ethyl 1-aza-bicyclo[2.2.1]heptane-3-carboxylate were pre-
pared by published literature methods3,4 to enable chiral
HPLC comparison.
During the course of the work, exploratory trials on
two other (Z)-alkene dipolarophiles was undertaken, the
substrates were prepared using similar chemistry, and
a brief study of [3 + 2] dipolar cycloadditions performed.
O-Benzyl ether 16 (Figure 1) generated a 3.5:1 mixture
of diastereoisomers when reacted with the dipole derived
from 5, where as 17, which contained the 4(S)-phenyl-
methyloxazolidinone auxiliary, generated a 2.6:1 mixture
of diastereoisomers. In neither example could the ster-
(13) Maurer, P. J .; Rapoport, H. J . Med. Chem. 1987, 30, 2016.
(14) Oppolzer, W.; Kingma, A. J .; Poli, G. Tetrahedron 1989, 45, 479.
(15) Garner, P.; Ho, W. B.; Grandhee, S. K.; Youngs, W. J .; Kennedy,
V. O. J . Org. Chem. 1991, 56, 5893.
(11) J akubowski, A. A.; Guziec, F. S.; Sugiura, M.; Tam, C. C.;
Tishler, M.; Omura, S. J . Org. Chem. 1982, 47, 1221.
(12) Padwa, A.; Dent, W. Org. Syn. 1989, 67, 133.

2528 J . Org. Chem., Vol. 66, No. 7, 2001
Notes
temperature under a H2 atmosphere for 3 h. The catalyst was
removed by filtration through Celite and the filtercake washed
with toluene (2 × 20 mL). The filtrate was concentrated in vacuo
to give 9 as a white solid (5.30 g, 100%): mp 62-63 °C; 1H NMR
(400 MHz, CDCl3) δ 6.52 (d, 1 H, J ) 11.3 Hz), 6.45 (dt, 1 H, J
) 11.2, 6.7 Hz), 3.92 (dd, 1 H, J ) 7.5, 5.4 Hz), 3.72 (t, 2 H, J )
6.25 Hz), 3.51 (d, 1 H, J ) 13.7 Hz), 3.43 (d, 1 H, J ) 13.7 Hz),
2.89-2.81 (m, 2 H), 2.16-2.06 (m, 2 H), 1.95-1.88 (m, 3 H),
1.45-1.33 (m, 2 H), 1.18 (s, 3 H), 0.97 (s, 3 H), 0.88 (s, 9 H),
0.05 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 164.5, 149.4, 120.7,
65.5, 62.4, 53.6, 48.8, 48.3, 45.2, 39.1, 33.9, 33.4, 27.0, 26.5, 21.3,
eochemistry of the pyrrolidine products be determined
nor were they taken through to final products due to the
nonorthogonal nature of the nitrogen and oxygen protect-
ing groups. From these studies it is apparent that the
nature of the auxiliary can have a significant effect on
the process where as the effect of the O-protecting group
is relatively minor.
In conclusion, an efficient synthesis of (3S,4R) ethyl
1-aza-bicyclo[2.2.1]heptane-3-carboxylate 4 using a ste-
reoselective [3 + 2] dipolar cycloaddition of a chiral (Z)-
alkene dipolarophile has been demonstrated. The abso-
lute stereochemistry was controlled by the use of 2(R)-
(-)-bornane-2,10-sultam chiral auxiliary and the relative
C-3, C-4 stereochemistry by the (Z)-alkene geometry.
Using the same methodology it should be possible to
prepare the corresponding (3R,4S) enantiomer simply by
using the readily available 2(S)-(+)-enantiomer of the
sultam chiral auxiliary.
20.4, 18.8, -4.9; [R]25 -72.7 (c ) 1.07, MeOH); IR (neat, cm-1
)
D
1681, 1331, 834; HRMS calcd for C21H37 NO4SSi; 427.2213, found
427.2220; LRMS (CI +ve) m/z 428 (M+ + H). Anal. Calcd for
C21H37NO4SSi; C, 58.98; H, 8.72; N, 3.28. Found: C, 58.98; H,
8.72; N, 3.02.
Tr im eth ylsilylm eth ylben zyla m in e (11).12 A stirred solu-
tion of benzylamine 10 (17.8 mL, 163 mmol) and chloromethyl-
trimethylsilane (10.0 g, 81.5 mmol) in acetonitrile (200 mL) was
heated at reflux for 16 h. Upon cooling to room temperature the
solution was filtered and the filtrate concentrated in vacuo to
100 mL. Water (100 mL) was added and the solution extracted
with hexane (2 × 100 mL). The combined organic phase was
washed with brine (100 mL), dried over MgSO4, and concen-
trated in vacuo to give 11 as a colorless liquid (12.95 g. 82%);
1H NMR (400 MHz, CDCl3) δ 7.30-7.17 (m, 5 H), 3.79 (s, 2 H),
2.00 (s, 2 H), 0.04 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 140.7,
128.5, 128.3, 126.7, 58.1, 39.5, -2.6; IR (neat, cm-1) 2953, 1453,
1246; HRMS calcd for C11H19NSi: 193.1282. Found: 193.1285;
LRMS (CI +ve ) m/z 194 (M+ + H). Anal. Calcd for C11H19NSi;
C, 68.33; H, 9.90; N, 7.24. Found: C, 68.22; H, 9.86; N, 7.11.
(3S,4R)-1-Ben zyl-3-[(2R)-N-bor n a n e-2,10-su lta m ]ca r bo-
n yl-4-(2-ter t-bu tyld im eth ylsiloxyeth yl)p yr r olid in e (12). To
a stirred solution of 9 (1.93 g, 4.52 mmol) and 5 (1.60 g, 6.75
mmol) in toluene (20 mL) at room temperature was added TFA
(35 µL, 0.45 mmol). After 1 h, EtOAc (50 mL) was added, and
the solution was washed with saturated NaHCO3 solution (40
mL) and brine (40 mL), dried over MgSO4, and concentrated in
vacuo to give the crude products. Purification by flash column
chromatography on SiO2 (petroleum ether 40-60/EtOAc, 4:1 and
then 2:1) gave 12 as a white solid (1.84 g, 73%) and the minor
diastereoisomer as a white solid (370 mg, 15%). 12: mp 89-91
°C; 1H NMR (400 MHz, CDCl3) δ 7.32-7.22 (m, 5 H), 3.90-3.86
(m, 1 H), 3.79-3.57 (m, 3 H), 3.53 (t, 2 H, J ) 6.7 Hz), 3.49 (d,
1 H, J ) 13.8 Hz), 3.41 (d, 1 H, J ) 13.8 Hz), 3.13-3.08 (m, 2
H), 2.68-2.60 (m, 1 H), 2.57 (t, 1 H, J ) 8.5 Hz), 2.24-2.20 (m,
1 H), 2.10-2.05 (m, 2 H), 1.93-1.85 (m, 2 H), 1.70-1.56 (m, 3
H), 1.42-1.34 (m, 2 H), 1.10 (s, 3 H), 0.95 (s, 3 H), 0.85 (s, 9 H),
0.00 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 172.4, 139.0, 128.8,
128.2, 127.0, 68.0, 62.4, 60.6, 60.2, 57.9, 53.2, 48.2, 47.7, 46.4,
44.8, 38.7, 38.6, 33.8, 33.0, 26.4, 26.0, 21.1, 19.9, 18.3, -5.3, -5.4;
Exp er im en ta l Section
5-(ter t-Bu tyld im eth ylsiloxy)p en t-2-yn oic Acid (7). To a
stirred solution of 68 (5.00 g, 27.17 mmol) in THF (50 mL) at
-75 °C was added n-BuLi (2.5 M in hexanes, 11.4 mL, 28.5
mmol) at such a rate to maintain an internal temperature <-60
°C. After 20 min at -75 °C, CO2(s) (5 g, 110 mmol) was added.
The reaction was stirred at -75 °C for 45 min and then allowed
to warm to 10 °C before being added to 5% citric acid solution
(50 mL). The layers were separated, and the aqueous phase was
acidified to pH 5 by the addition of 2 M HCl solution (5 mL)
and then extracted with EtOAc (3 × 50 mL). The combined
organic phase was washed with brine (50 mL), dried over MgSO4,
and concentrated in vacuo to give 7 as a colorless liquid (6.50 g,
100%); 1H NMR (400 MHz, CDCl3) δ 3.80 (t, 2 H, J ) 11.7 Hz),
2.57 (t, 2 H, J ) 11.7 Hz), 0.89 (s, 9 H), 0.08 (s, 6 H); IR (neat,
cm-1) 2240, 1690; LRMS (EI -ve) m/z 227 (M - H)-.
2(R)-[N-5-(ter t-Bu t yld im et h ylsiloxy)p en t -2-yn oyl]b or -
n a n e-2,10-su lta m (8). To a stirred solution of 7 (5.30 g, 23.25
mmol) in THF (175 mL) at -75 °C was added pivaloyl chloride
(3.00 mL, 24.36 mmol) at such a rate to maintain an internal
temperature <-70 °C. Triethylamine (3.41 mL, 24.51 mmol) was
added at such a rate to maintain an internal temperature <-60
°C. After stirring at -75 °C for 15 min, the mixture was stirred
at 0 °C for 30 min and then recooled to -75 °C, to give a solution
of the pivaloyl mixed anhydride. Concomitantly, to a stirred
solution of 2(R)-(-)-bornane-2, 10-sultam (5.00 g, 23.22 mmol)
in THF (40 mL) at -75 °C was added n-BuLi (2.5 M in hexanes,
9.8 mL, 24.50 mmol). After 15 min at -75 °C, the solution was
added to pivaloyl mixed anhydride solution at -75 °C by cannula
at such a rate to maintain the internal temperature <-65 °C.
After 45 min at -75 °C, the reaction was allowed to warm to
room temperature and 5% citric acid solution (150 mL) added.
The solution was extracted with EtOAc (2 × 200 mL), and the
combined organic phase was washed with saturated NaHCO3
solution (200 mL) and brine (200 mL), dried over MgSO4, and
concentrated in vacuo to give the crude product. Purification by
flash column chromatography on SiO2 (petroleum ether 40-60/
EtOAc, 4:1) gave 8 as a white solid (6.22 g, 63%): mp 117-118
°C; 1H NMR (400 MHz, CDCl3) δ 3.88 (dd, 1 H, J ) 7.5, 5.0 Hz),
3.82 (t, 2 H, J ) 7.1 Hz), 3.50 (d, 1 H, J ) 13.8 Hz), 3.43 (d, 1 H,
J ) 13.8 Hz), 2.63 (t, 2 H, J ) 6.9 Hz), 2.27-2.18 (m, 1 H), 2.08
(dd, 1 H, J ) 13.8, 7.9 Hz), 1.98-1.84 (m, 3 H), 1.44-1.31 (m, 2
H), 1.17 (s, 3 H), 0.97 (s, 3 H), 0.89 (s, 9 H), 0.07 (s, 6 H); 13C
NMR (100 MHz, CDCl3) δ 149.8, 93.3, 74.3, 64.9, 60.5, 53.0, 48.5,
[R]25 -51.2 (c ) 0.25, MeOH); IR (neat, cm-1) 1690, 1333;
D
HRMS Calc’d for C30H48N2O4SSi: 560.3104, found 560.3100;
LRMS (CI +ve) m/z 561 (M+ + H). Min or d ia ster eoisom er :
mp 83-85 °C; 1H NMR (400 MHz, CDCl3 δ 7.33-7.21 (m, 5 H),
3.87 (t, 1 H, J ) 6.3 Hz), 3.83-3.76 (m, 1 H), 3.66-3.64 (m, 2
H), 3.56-3.48 (m, 3 H), 3.42 (d, 1 H, J ) 13.8 Hz), 3.20-3.16
(m, 1 H), 3.05-3.01 (m, 1 H), 2.74-2.67 (m, 2 H), 2.26-2.22 (m,
1 H), 2.10-2.08 (m, 2 H), 1.93-1.87 (m, 2 H), 1.79-1.64 (m, 2
H), 1.55-1.47 (m, 1 H), 1.42-1.32 (m, 2 H), 1.17 (s, 3 H), 0.97
(s, 3 H), 0.84 (s, 9H), -0.02 (s, 6 H); 13C NMR (100 MHz, CDCl3)
δ 172.4, 139.1, 128.8, 128.3, 126.9, 65.4, 61.8, 60.3, 59.6, 56.5,
53.2, 47.8, 47.7, 46.4, 44.7, 39.5, 38.8, 33.0, 32.9, 26.5, 26.0, 21.0,
19.9, 18.2, -5.4; [R]25 -60.8 (c ) 1.01, MeOH); IR (neat, cm-1
)
D
1689, 1331; HRMS calcd for C30H48N2O4SSi: 560.3104, found
560.3108; LRMS (CI +ve) m/z 561 (M+ + H). Anal. Calcd for
C30H48N2O4 SSi: C, 64.25; H, 8.63; N, 4.99. Found: C, 64.15; H,
8.97; N, 5.04.
47.8, 44.8, 38.4, 32.9, 26.5, 25.8, 23.5, 20.9, 19.9, 18.2, -5.4; [R]25
D
(3S,4R)-1-Ben zyl-3-[(2R)-N-bor n a n e-2,10-su lta m ]ca r bo-
n yl-4-(2-h yd r oxyeth yl)p yr r olid in e (13). To a stirred solution
of 12 (1.69 g, 3.02 mmol) in acetone (25 mL) at 0 °C was added
2 M HCl solution (3.0 mL, 6.00 mmol). After 10 min, the solution
was allowed to warm to room temperature. After 30 min at room
temperature, saturated NaHCO3 solution (25 mL) was added
and the solution stirred for 30 min. Water (20 mL) was added
and the solution extracted with EtOAc (4 × 20 mL). The
combined organic phase was washed with brine (40 mL), dried
-84.5 (c ) 1.03, MeOH); IR (neat, cm-1) 2230, 1661, 1297; HRMS
calcd for C21H35NO4SSi; 425.2056, found 425.2044; LRMS (CI
+ve) m/z 443 (M+ + NH4). Anal. Calcd for C21H35NO4SSi: C,
59.26; H, 8.29; N, 3.29. Found: C, 59.26; H, 8.74; N, 3.20.
2(R)-[(Z)-N-5-(ter t-Bu tyldim eth ylsiloxy)pen t-2-en oyl]bor -
n a n e-2,10-su lta m (9). A solution of 8 (5.18 g, 12.19 mmol) and
palladium on calcium carbonate, poisoned with lead (Lindlar’s
catalyst, Pd 5%, 78 mg), in toluene (100 mL) was stirred at room

Notes
J . Org. Chem., Vol. 66, No. 7, 2001 2529
over MgSO4, and concentrated in vacuo to give the crude product.
Purification by flash column chromatography on SiO2 (EtOAc)
gave 13 as a white solid (1.13 g, 84%): mp 144-145 °C; 1H NMR
(400 MHz, CDCl3) δ 7.32-7.24 (m, 5 H), 3.89-3.86 (m, 1 H),
3.81-3.75 (m, 1 H), 3.66 (d, 1 H, J ) 12.9 Hz), 3.60 (d, 1 H, J )
12.5 Hz), 3.58 (t, 2 H, J ) 6.5 Hz), 3.51 (d, 1 H, J ) 13.7 Hz),
3.44 (d, 1 H, J ) 13.7 Hz), 3.13-3.06 (m, 2 H), 2.77-2.72 (m, 1
H), 2.65 (dd, 1 H, J ) 9.2, 8.3 Hz), 2.27 (t, 1 H, J ) 9.0 Hz),
2.12-2.04 (m, 2 H), 1.95-1.86 (m, 3 H), 1.81-1.60 (m, 3 H),
1.43-1.34 (m, 2 H), 1.11 (s, 3 H), 0.96 (s, 3 H); 13C NMR (100
MHz, CDCl3) δ 172.2, 138.9, 128.7, 128.3, 127.2, 65.5, 61.6, 60.6,
60.1, 57.8, 53.2, 48.2, 47.7, 46.0, 44.7, 38.7, 38.0, 33.6, 33.0, 26.4,
washed with a 1:1 EtOH/H2O solution (100 mL). Concentration
of the filtrate in vacuo gave 15 as a hydrated white solid (1.23
g, 77%): mp >230 °C; 1H NMR (400 MHz, CD3OD) δ 4.03-3.94
(m, 2 H), 3.75 (d, 1 H, J ) 13.7 Hz), 3.78-3.56 (m, 3 H), 3.55-
3.45 (m, 3 H), 3.39-3.28 (m, 2 H), 2.22-1.94 (m, 1 H), 2.10-
1.83 (m, 6 H), 1.53-1.47 (m, 1 H), 1.44-1.36 (m, 1 H), 1.15 (s,
3 H), 1.03 (s, 3 H); 13C NMR (100 MHz, d6DMSO) δ 170.1, 66.9,
61.6, 56.9, 53.6, 53.5, 50.1, 48.9, 46.6, 45.9, 41.4, 39.4, 33.5, 27.3,
23.8, 20.7, 19.7; [R]25 -59.0 (c ) 0.70, H2O); IR (neat, cm-1
)
D
1698, 1331, 1211; HRMS calcd for C17H27N2O3S; 339.1742, found
339.1733; LRMS (CI +ve) m/z 339 (M+ - Cl). Anal. Calcd for
C17H27ClN2O3S‚0.2 H2O: C, 53.94; H, 7.30; N, 7.40. Found: C,
53.86; H, 7.24; N, 7.31; Karl Fisher Titrimetry (KF) ) 1.01% w/w
H2O.
21.0, 19.9; [R]25 -65.2 (c ) 0.49, MeOH); IR (neat, cm-1) 1689,
D
1329; HRMS, calcd for C24H34N2O4S; 446.2239, found 446.2232;
LRMS (CI +ve) m/z 447 (M+ + H). Anal. Calcd for C24
-
(3S,4R)-Eth yl 1-Aza bicyclo[2.2.1]h ep ta n e-3-ca r boxyla te
(4).4 Lithium hydroxide monohydrate (280 mg, 6.68 mmol) was
added to a suspension of amide 15 (500 mg, 1.34 mmol) in water
(10 mL) and THF (2 mL) and then stirred at room temperature
for 18 h. The solution was then extracted with CH2Cl2 (5 × 20
mL) followed by Et2O (2 × 20 mL). The combined organic
extracts were dried over MgSO4 and concentrated in vacuo to
give 2(R)-(-)-bornane-2,10-sultam (272 mg, 95%). The aqueous
phase was concentrated in vacuo and then azeotroped with
EtOH (2 × 20 mL). The residue was then dissolved in EtOH (20
mL) which had been saturated with dry HCl(g). The mixture was
then heated at reflux for 1h before being allowed to cool to room
temperature. The solvent was removed in vacuo and the residue
azeotroped with CH2Cl2 (2 × 20 mL). CH2Cl2 (20 mL) was added
and the suspension stirred for 15 min and then filtered. The
filtercake was washed with CH2Cl2 (2 × 20 mL), and the filtrate
was concentrated in vacuo to give 4 as a hygroscopic white solid
H
34N2O4S: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.29; H, 7.65;
N, 5.98.
(3S,4R)-1-Ben zyl-3-[(2R)-N-bor n a n e-2,10-su lta m ]ca r bo-
n yl-1-azon ia-bicyclo[2.2.1]h eptan e Ch lor ide (14). To a stirred
solution of 13 (860 mg, 1.93 mmol) in CH2Cl2 (20 mL) at -20 °C
were added triethylamine (670 µL, 4.82 mmol) and methane-
sulfonyl chloride (180 µL, 2.33 mmol). After 20 min, the solution
was allowed to warm to room temperature, diluted with CH2-
Cl2 (12 mL), and washed with saturated NaHCO3 solution (6
mL). The aqueous phase was extracted with CH2Cl2 (3 × 12 mL),
and the combined organic phase was washed with brine (6 mL),
2 M HCl solution (6 mL), and brine (6 mL), dried over MgSO4,
and concentrated in vacuo to give 14 as a hydrated white solid
1
(761 mg, 85%): mp 160 °C (dec); H NMR (400 MHz, CDCl3) δ
7.71-7.65 (m, 2 H), 7.47-7.36 (m, 3 H), 5.31 (d, 1 H, J ) 12.6
Hz), 5.18 (d, 1 H, J ) 12.6 Hz), 4.41-4.35 (m, 1 H), 4.25-4.20
(m, 1 H), 4.10-4.05 (m, 3 H), 3.87-3.84 (m, 1 H), 3.56-3.43 (m,
4 H), 3.30-3.24 (m, 1 H), 2.29-2.23 (m, 1 H), 2.09-1.98 (m, 2
H), 1.94-1.80 (m, 4 H), 1.46-1.31 (m, 2 H), 1.07 (s, 3 H), 0.95
(s, 3 H); 13C NMR (100 MHz, CDCl3) δ 168.7, 132.0, 130.2, 129.2,
128.9, 67.3, 65.5, 61.9, 60.6, 59.6, 52.8, 48.8, 47.9, 44.7, 44.3,
1
(253 mg, 92%); H NMR (400 MHz, CD3OD) δ 4.27-4.22 (m, 2
H), 3.68-3.50 (m, 5 H), 3.44 (d, 1 H, J ) 8.8 Hz), 3.36-3.26 (m,
2 H), 2.17-2.07 (m, 1 H), 1.77-1.71 (m, 1 H), 1.31 (t, 3 H, J )
7.2 Hz); 13C NMR (100 MHz, CD3OD) δ 171.7, 62.6, 61.4, 55.5,
53.5, 45.0, 40.4, 24.4, 14.4; [R]25 +28.9 (c ) 0.96, MeOH); IR
D
39.6, 38.2, 32.7, 26.3, 24.4, 20.7, 19.7; [R]25 -40.7 (c ) 1.00,
(neat, cm-1) 1725, 1196; LRMS (CI +ve) m/z 170 (M+ - Cl).
D
MeOH); IR (neat, cm-1) 1678, 1328, 1133; HRMS calcd for
C
24H33N2O3S; 429.2212, found 429.2208; LRMS (CI +ve) m/z 429
Ack n ow led gm en t. We thank Dr. Mark Hadley,
Analytical Sciences, GlaxoSmithKline Pharmaceuticals,
for his work on the chiral HPLC.
(M+ - Cl). Anal. Calcd for C24H33ClN2O3S‚2.5 H2O: C, 56.51;
H, 7.51; N, 5.49. Found: C, 56.74; H, 7.14; N, 5.40; Karl Fisher
Titrimetry (KF) ) 8.83% w/w H2O.
(3S,4R)-3-[(2R)-N-Bor n a n e-2,10-su lta m ]ca r bon yl-1-a za -
bicyclo[2.2.1]h ep ta n e Hyd r och lor id e (15). EtOH (30 mL)
was added to a flask containing 10% Pd/C (250 mg) and 14 (1.98
g, 4.26 mmol). The mixture was placed under an atmosphere of
H2 and heated to 80 °C. After 5 h, it was allowed to cool to room
temperature and water (30 mL) added. The catalyst was
removed by filtration through Celite, and the filtercake was
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of selected compounds and compounds for which no
elemental analysis was obtained as well as chiral HPLC for
compound 4.
J O001797F