A practical and improved synthesis of (3S,5S)-3-[(tert-butyloxycarbonyl)methyl]-5- [(methanesulfonyloxy)methyl]-2-pyrrolidinone

Article abstract of DOI:10.1021/jo020433f

A practical and improved synthesis of (3S,5S)-3-[(tert-butyloxycarbonyl)methyl]-5- [(methanesulfonyloxy)-methyl]-2-pyrrolidinone (1) is described. The key transformations involve a highly efficient reaction sequence consisting of ethoxycarbonylation, alkylation, hydrolysis, and decarboxylation to produce compound 10. The process described herein is practical, robust, and cost-effective, and it has been successfully implemented in a pilot plant to produce a multikilogram quantity of mesylate 1.

Full text of DOI:10.1021/jo020433f

SCHEME 1
A P r a ctica l a n d Im p r oved Syn th esis of
(3S,5S)-3-[(ter t-Bu tyloxyca r bon yl)m eth yl]-
5-[(m eth a n esu lfon yloxy)m eth yl]-2-
p yr r olid in on e
Nathan K. Yee,* Yong Dong, Suresh R. Kapadia, and
J inhua J . Song
Department of Chemical Development, Boehringer Ingelheim
Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368,
Ridgefield, Connecticut 06877-0368
nyee@rdg.boehringer-ingelheim.com
Received J une 26, 2002
of 4 over activated Pd/C followed by methanesulfonyla-
tion afforded the mesylate 1.
Some obstacles hindered its use for scale-up production
aiming at potential drug commercialization. The low-
temperature conditions are not favored in the production
environment, and the costs associated with protecting
groups (Cbz and Trityl groups) are high. Therefore, a
more practical and cost-effective synthesis of 1 was
required for further scale-up. In this Note, we will
describe a more efficient synthesis of 1 in terms of
operational simplicity and cost-effectiveness.
The trans stereochemistry in the disubstituted 2-pyr-
rolidinone 1 is the key structural feature. Several meth-
odologies involving the trans or cis stereoselective alky-
lation of pyroglutamic acid derivatives are reported in
the literature.4 Most of them employ bulky substituents
at C-5 (such as CO2tBu, CH2OSiMe2tBu, or trityl groups)
and low-temperature conditions to achieve acceptable
trans selectivity (trans:cis ratio >85:15). On the other
hand, the stereoselective decarboxylation approach de-
veloped by Moloney et al.5 is most attractive to us due to
its high trans:cis selectivity and simplicity. Further
modification of this method seemed to well satisfy our
need for the synthesis of 1.
Abstr a ct: A practical and improved synthesis of (3S,5S)-
3-[(tert-butyloxycarbonyl)methyl]-5-[(methanesulfonyloxy)-
methyl]-2-pyrrolidinone (1) is described. The key transfor-
mations involve a highly efficient reaction sequence consisting
of ethoxycarbonylation, alkylation, hydrolysis, and decar-
boxylation to produce compound 10. The process described
herein is practical, robust, and cost-effective, and it has been
successfully implemented in a pilot plant to produce a
multikilogram quantity of mesylate 1.
Our drug discovery program identified a series of 3,5-
disubstituted-2-pyrrolidinones as potent inhibitors for the
collagen-induced thrombocyte aggregation, and thus they
became potential drug candidates for the treatment of a
variety of inflammation diseases.1 To support related pre-
clinical and clinical studies, we needed to synthesize a
key intermediate, (3S,5S)-3-[(tert-butyloxycarbonyl)-
methyl]-5-[(methanesulfonyloxy)methyl]-2-pyrrolidinone
(1),2 in large quantity, which called for a scalable route
in a production environment.
The impact of the different R groups on the trans
selectivity in decarboxylation of substrates 5a -e was first
investigated (eq 1). Excellent stereoselectivity with trans:
The original preparation of 1 started with commercially
available (5S)-5-hydroxymethyl-2-pyrrolidinone 2 (Scheme
1).1 The carboxybenzyl (Cbz) and trityl (Tr) groups were
employed to protect the NH and OH functionalities to
give 3. Treatment of 3 with LiN(TMS)2 at -65 °C followed
by tert-butyl bromoacetate gave predominantly trans3
alkylated product 4. The bulky trityl group in 3 and low
temperature (-65 °C) for alkylation were required to
achieve the desired trans stereochemistry. Hydrogenation
cis ∼ 95:5 was obtained when R ) Ph, 4-MeOPh, i-Pr,
and t-Bu, while acetonide 5e resulted in a moderate
selectivity with trans:cis ∼ 85:15. Considering the needed
reactivity, the crystallinity of the intermediates, and the
protection/deprotection efficiency,6 we chose 5a to carry
out the synthesis of 1.
(1) (a) Austel, V.; Eisert, W.; Himmelsbach, F.; Linz, G.; Mueller,
T.; Pieper, H.; Weisenberger, J . U.S. Patent 5,455,348, Oct 2, 1995.
(b) Himmelsbach, F.; Austel, V.; Pieper, H.; Eisert, W.; Mueller, T.;
Weisenberger, J .; Linz, G.; Krueger, G. U.S. Patent 5,591,769, J an 7,
1997.
(2) tert-Butyl ester functionality was specifically chosen for the
crystallinity of the intermediates in the synthesis.
(3) The trans/cis stereochemical notation refers to the C3 and C5
positions.
The synthesis of 1 started with (5S)-5-hydroxymethyl-
2-pyrrolidinone (2) (Scheme 2). Formation of N,O-acetal
10.1021/jo020433f CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/31/2002
8688
J . Org. Chem. 2002, 67, 8688-8691

SCHEME 2
7 (PhCHO, pTsOH, toluene, 80% yield)4a was straight-
forward, and excess benzaldehyde was removed by
bisulfite washings. Ethoxycarbonylation of 7 was first
attempted according to Moloney’s procedure (NaH,
EtOCO2Et, toluene, reflux).5 Under these conditions, a
complex mixture was obtained and the desired ethoxy-
carbonylated product was isolated by column chroma-
tography in moderate yields (50-60%). Attempts to
optimize this reaction by using lower temperature or a
different solvent such as THF were not successful. It is
believed the higher temperature is first required to
generate the enolate by NaH and the resulting transient
enolate 8, produced from the ethoxycarbonylated inter-
mediate, is not stable under these forcing conditions. At
this point, a more direct ethoxycarbonylation/alkylation
method was investigated. The use of strong base such
as NaN(TMS)2 can efficiently produce the enolate under
milder conditions (-78 to 0 °C). Furthermore, an ethoxy-
carbonylating reagent such as chloroformate7 is more
reactive and its byproduct (NaCl) will not affect the
following alkylating step. Therefore, a direct one-pot
procedure for ethoxycarbonylation and alkylation is
envisioned for this preparation. Under the optimized
conditions, the N,O-acetal 7 was treated with 2 equiv of
NaN(TMS)2 at -10 to 0 °C to generate the corresponding
enolate (Scheme 2). This enolate reacted with ethyl
chloroformate at the same temperature to afford the
expected enolate intermediate 8. Under these conditions,
the reaction was rapid and clean. Therefore, direct
addition of tert-butyl bromoacetate to this resulting
enolate (0 °C to room temperature) gave the desired
alkylated diastereomeric product 9 smoothly. A simple
aqueous/organic extractive workup procedure afforded
clean product 9 in essentially quantitative yield. The
crude product so obtained was used directly for the next
step.
Basic hydrolysis of 9 (aq NaOH, MeCN, rt) proceeded
smoothly and cleanly. The sodium salt of the carboxylic
acid 5a was suspended in water and the aqueous layer
was washed with toluene to remove all possible organic
soluble side-products and impurities. The pure carboxylic
acid 5a was obtained after acidification by aq HCl.
Decarboxylation of 5a was first achieved according to
the literature procedure described by Moloney,5 in which
the neat substrate 5a was heated to 130 °C under
vacuum. These conditions were not practical for large-
scale production, and an alternative was sought to effect
the same transformation. Attempts to perform direct
decarboxylation of ethyl ester 9 (NaCl, DMSO, 130-175
°C)8 only led to recovery of starting material along with
some decomposition. Later, it was found that refluxing
a suspension of carboxylic acid 5a in toluene achieved
decarboxylation in 2 to 3 h to give 10 cleanly with trans:
cis ) 95:5.9 The overall yield, for the entire 4-step
sequence consisting of ethoxycarbonylation, alkylation,
hydrolysis, and decarboxylation, ranged from 82% to 90%.
This high efficiency was successfully demonstrated on a
multikilogram scale in the pilot plant.
(4) (a) Thottathil, J . K.; Moniot, J . L.; Mueller, R. H.; Wong, M. K.
Y.; Kissick, T. P. J . Org. Chem. 1986, 51, 3140. (b) Thottathil, J . K.;
Przybyla, C.; Malley, M.; Gougoutas, J . Z. Tetrahedron Lett. 1986, 27,
1533. (c) Brena-Valle, L. J .; Sanchez, R. C.; Cruz-Almanza, R.
Tetrahedron: Asymmetry 1996, 7, 1019. (d) Woo, K.-C.; J ones, K.
Tetrahedron Lett. 1991, 32, 6949. (e) Baldwin, J . E.; Miranda, T.;
Moloney, M. Tetrahedron 1989, 45, 7459. (f) Gu, Z.-Q.; Lin, X.-F.;
Hesson, D. P. Bioorg. Med. Chem. Lett. 1995, 5, 1973. (g) Langlois, N.;
Rojas, A. Tetrahedron Lett. 1993, 34, 2477. (h) Hon, Y.-S.; Chang, Y.-
C.; Gong, M.-L. Heterocycles 1990, 31, 191. (i) Ezquerra, J .; Pedregal,
C.; Rubio, A.; Yruretagoyena, B.; Escribano, A.; Sanchez-Ferrando, F.
Tetrahedron 1993, 49, 8665. (j) Dikshit, D. K.; Bajpai, S. N. Tetrahe-
dron Lett. 1995, 36, 3231. (k) Ezquerra, J .; Pedregal, C. Tetrahedron:
Asymmetry 1994, 5, 921. (l) Baldwin, J . E.; Moloney, M. G.; Shim, S.
B. Tetrahedron Lett. 1991, 32, 1379. (m) Armstrong, R. W.; DeMattei,
J . A. Tetrahedron Lett. 1991, 32, 5749.
Deprotection of the N,O-acetal 10 is not trivial. Reduc-
tive cleavage of the N,O-acetal group (hydrazine, Pd/C,
(5) (a) Beard, M. J .; Bailey, J . H.; Cherry, D. T.; Moloney, M. G.;
Shim, S. B.; Statham, K. A. Tetrahedron 1996, 52, 3719. (b) Bamford,
M. J .; Beard, M.; Cherry, D. T.; Moloney, M. G. Tetrahedron: Asym-
metry 1995, 6, 337.
(6) Acetal 5b is too labile under decarboxylation conditions. For 5c
and 5d , isobutyraldehyde (bp 63 °C) and pivalaldehyde (bp 74 °C) can
be conveniently removed by evaporation either in protection or
deprotection steps, but they are more difficult to deprotect under mild
conditions.
(7) (a) Ackermann, J .; Matthes, M.; Tamm, C. Helv. Chim. Acta
1990, 73, 122. (b) Attwood, M. R.; Carr, M. G.; J ordan, S. Tetrahedron
Lett. 1990, 31, 283. (c) Tanaka, K.; Yoshifuji, S.; Nitta, Y. Chem. Pharm.
Bull. 1986, 34, 3879.
(8) (a) Krapcho, A. P.; Lovey, A. J . Tetrahedron Lett. 1973, 12, 957.
(b) Bernard, A. M.; Cerioni, G.; Piras, P. P.; Seu, G. Synthesis 1990,
871. (c) Bringmann, G.; Geuder, T. Synthesis 1991, 829.
(9) The corresponding cis isomer of 10 was independently prepared
(7, LiN(TMS)2, BrCH2CO2tBu, -78 °C). 1H NMR (CDCl3, 400 MHz) δ
7.44 (m, 2H), 7.35 (m, 3H), 6.32 (s, 1H), 4.24 (t, J ) 7.36 Hz, 1H), 4.12
(m, 1H), 3.59 (t, J ) 7.12 Hz, 1H), 3.26 (m, 1H), 2.82 (dd, J ) 3.84,
17.3 Hz, 1H), 2.68 (m, 1H), 2.28 (dd, J ) 8.92, 16.4 Hz, 1H), 1.66 (m,
1H), 1.46 (s, 9H). The trans/cis stereochemistry of 10 was unambigu-
ously assigned based on COSY and NOESY experiments which were
similar to those reported in ref 4m. The trans/cis ratio was determined
by 1H NMR integration in which the C-4 protons are characteristic
for the trans isomer (δ 3.41 ppm) and the cis isomer (δ 3.59 ppm).
J . Org. Chem, Vol. 67, No. 24, 2002 8689

MeOH,10 or H2, Pd(OH)2, MeOH11) was attempted and
failed. Selective acidic hydrolysis of the N,O-acetal group
in the presence of the tert-butyl ester group was inves-
tigated. It was found that the hydrolysis catalyzed by
Lewis acids such as pTsOH or PPTS in MeOH-H2O led
to some success. The HOAc-THF-H2O system developed
by Nagasaka12 seemed to give the best results. The
optimized ratio of HOAc-THF-H2O was 2:3:1, under
which the N,O-acetal group was hydrolyzed at reflux (80
about -10 °C. A solution of N,O-acetal 7 (157.5 g, 0.775 mol) in
90 mL of anhydrous THF was added dropwise over 30 min at
-10 to 0 °C. The reaction mixture was stirred at the same
temperature for 1 h. Ethyl chloroformate (78.0 mL, 0.815 mol)
was added at -10 to 0 °C over 1.5 h and the reaction mixture
was stirred at -5 to 0 °C for 1.5 h. TLC analysis (50% EtOAc in
hexane) indicated the reaction was complete. tert-Butyl bro-
moacetate (150 mL, 1.015 mol) was added over 30 min at -5 to
5 °C. The cooling bath was removed and the reaction mixture
was stirred at room temperature for 1.5 h. TLC analysis showed
the reaction was complete. The reaction mixture was cooled to
0 °C and quenched with saturated NH4Cl (100 mL). The mixture
was concentrated to dryness and the residue was dissolved with
800 mL of EtOAc. The organic layer was extracted with water
(800 mL). The aqueous layer was extracted with EtOAc (2 ×
300 mL). The combined organic layers were washed with water
(300 mL) and saturated NaCl (300 mL). The organic layer was
concentrated to half and then hexane (700 mL) was added. The
resulting solution was filtered through silica gel (50 g) followed
by rinsing the filter cake with EtOAc (200 mL). Concentration
of the organic layer afforded 323.2 g of crude product 9. The
analytically pure sample of 9 was obtained by column chroma-
tography. 1H NMR (CDCl3, 400 MHz) δ 7.45-7.30 (m, 5H), 6.29
(s, 0.28H), 6.27 (s, 0.72H), 4.31 (m, 3H), 4.12-4.09 (m, 1H), 3.75
(t, J ) 8.62 Hz, 0.78H), 3.62 (t, J ) 7.94 Hz, 0.28H), 3.22 (dd, J
) 7.54, 17.4 Hz, 1H), 3.10 (dd, J ) 7.02, 13.1 Hz, 0.28H), 2.81
(dd, J ) 4.34, 14.2 Hz, 0.74H), 2.68 (dd, J ) 6.14, 17.0 Hz, 1H),
2.47 (dd, J ) 8.07, 14.2 Hz, 0.74H), 1.92 (dd, J ) 7.10, 13.2 Hz,
0.27H), 1.44 (s, 2.64H), 1.40 (s, 6.72H), 1.30 (m, 3H).
1
°C) to give crude alcohol 11 (∼80% assay yield13 by H
NMR). The crude product 11 was used for the next step
without purification.
Formation of mesylate 1 (MsCl, CH2Cl2, 0 °C) pro-
ceeded smoothly: treatment of the crude 1 with MTBE
gave crystalline mesylate 1 in 66% overall yield over two
steps from N,O-acetal 10. High chemical and optical
purities of mesylate 1 (>99% by HPLC, trans:cis ) 99.7:
0.3) were achieved,14 and thus satisfied purity specifica-
tions required for the manufacture of related drug
substances.
In summary, we have developed a practical and
improved synthesis of mesylate 1 in terms of operational
simplicity and cost-effectiveness. The key transforma-
tions involve a highly efficient reaction sequence consist-
ing of ethoxycarbonylation, alkylation, hydrolysis, and
decarboxylation, to produce compound 10. The one-pot
procedure, developed for carboxylation [NaN(TMS)2,
ClCO2Et, 0 °C] followed by direct alkylation (RBr, 0 °C
to room temperature), made significant improvements to
the original protocol by Moloney.5 In comparison with the
early synthesis of 1 (Scheme 1), this process removes the
low-temperature conditions, which is undesired in the
production environment. Also, the higher cost associated
with the Cbz and Tr protecting groups was eliminated
while inexpensive benzaldehyde was used to protect both
the NH and OH functionalities. Therefore, the process
described herein is practical, robust, and cost-effective,
and it has been successfully implemented in the pilot
plant to produce a multikilogram quantity of mesylate
1.
The crude 9 (323.2 g, max 0.775 mol) was dissolved in MeCN
(800 mL). The solution was cooled at 0 °C as aqueous 3 N NaOH
(390 mL, 1.17 mol) was added. The mixture was then stirred at
room temperature overnight (18 h). TLC analysis (25% EtOAc
in hexane) indicated the reaction was complete. The reaction
mixture was concentrated and the residue was dissolved in water
(200 mL). After the aqueous layer was washed with toluene (3
× 150 mL) to remove any organic byproducts, the aqueous layer
was mixed with EtOAc (900 mL) and then cooled to 0 °C.
Concentrated HCl (∼97 mL) was added at the rate to keep the
internal temperature below 5 °C to acidify until pH 2-3. The
layers were separated and the aqueous layer was extracted with
EtOAc (2 × 300 mL). The combined organic layers were washed
with water (2 × 200 mL), dried over MgSO4, and concentrated.
The residue was stripped with toluene (2 × 500 mL) to give
carboxylic acid 5a . 1H NMR (CDCl3, 400 MHz) δ 7.43 (m, 2H),
7.36 (m, 3H), 6.29 (s, 1H), 4.30 (m, 1.37H), 4.15 (m, 0.85H), 3.69
(m, 1H), 3.19 (d, J ) 17.4 Hz, 0.32H), 3.10 (d, J ) 16.4 Hz,
1.36H), 2.74 (m, 1.6H), 2.54 (dd, J ) 7.92, 14.2 Hz, 0.67H), 1.95
Exp er im en ta l Section 15
(m, 0.36H), 1.45 (s, 3.5H), 1.38 (s, 5.48H). Anal. Calcd for C19H23
-
NO6: C, 63.15; H, 6.41; N, 3.88. Found: C, 62.66; H, 6.64; N,
3.98.
(2R,5S)-2-P h en yl-3-oxa -1-a za -bicyclo[3,3,0]octa n e (7) was
prepared according to literature procedure by Thoittiol et al.4a
except the crude product 7 was used directly without any
purification: 146 g (83%). Its 1H NMR spectrum was identical
with those reported.
The above crude 5a was suspended in toluene (800 mL) and
the mixture was heated at reflux for 2 h, which became a clear
solution during this period. After cooling to room temperature,
the reaction mixture was washed with a 1:1 mixture (400 mL)
of saturated NaHCO3 and saturated NaCl and then saturated
NaCl (200 mL). The organic layer was dried over MgSO4 and
concentrated to dryness to afford 234.8 g of crude product 10,
which contained 15.6 wt % of toluene in this product based on
the 1H NMR spectrum. The corrected overall yield was 198.2 g
(87%) from compound 7. This crude product was used directly
(2R,5S,7S)-1-Aza -7-[(ter t-Bu toxyca r bon yl)m eth yl]-3-oxa -
2-p h en ylb icyclo[3,3,0]oct a n -8-on e (10). In
a 5-L round-
bottomed flask equipped with a mechanical stirrer, a solution
of NaN(TMS)2 (1.0 M in THF, 1.705 L, 1.705 mol) was cooled to
(10) Hamada, Y.; Hara, O.; Kawai, A.; Kohno, Y.; Shioiri, T.
Tetrahedron 1991, 47, 8635.
(11) The C-O bond was cleaved and the corresponding N-benzyl
product was obtained.
25
for the next step without any purification. Mp 72-73 °C. [R]D
+156.4° (c )1, MeOH). 1H NMR (CDCl3, 400 MHz) δ 7.43 (m,
2H), 7.32 (m, 3H), 6.30 (s, 1H), 4.22 (dd, J ) 6.44, 7.96 Hz, 1H),
4.04 (m, 1H), 3.41 (t, J ) 9.16 Hz, 1H), 3.00 (m, 1H), 2.80 (dd,
J ) 3.88, 16.24 Hz, 1H), 2.48 (dd, J ) 10.0, 16.2 Hz, 1H), 2.26
(m, 1H), 2.10 (m, 1H), 1.42 (s, 9H). 13C NMR (CDCl3, 100 MHz)
δ 179.8, 170.6, 138.8, 128.5, 125.8, 87.6, 70.6, 57.0, 40.8, 37.6,
28.0, 27.1. Anal. Calcd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41.
Found: C, 67.95; H, 7.24; N, 4.31.
(12) (a) Nagasaka, T.; Imai, T. Heterocycles 1995, 41, 1927. (b)
Nagasaka, T.; Imai, T. Chem. Pharm. Bull. 1995, 43, 1081.
(13) 1H NMR spectrum of crude 11 revealed that ∼5% starting
material 10 remained intact as well as some unidentified side-products.
(14) The chemical purity of 1 was determined by HPLC. Column:
Inertsil ODS-2, 5 µm (150 × 4.6 mm). Temperature: 40 °C. Mobile
phase: aq 0.1% H3PO4/MeCN (85:15). Flow rate: 1.2 mL/min. Detec-
tion: 201 nm. Retention time: 24.39 min (trans-1), 27.55 min (cis-1).
The optical purity of 1 was determined by the 1H NMR of the
corresponding Mosher ester of 11 derived from both (5S)- and (5R)-2.
(15) For general procedures, see: Yee, N. K.; Nummy, L. J .; Byrne,
D. P.; Smith, L. L.; Roth, G. P. J . Org. Chem. 1998, 63, 326
(3S,5S)-3-[(ter t-Bu tyloxyca r bon yl)m eth yl]-5-[(m eth a n e-
su lfon yloxy)m eth yl]-2-p yr r olid in on e (1). A solution of the
above crude 10 (50 g, ∼85% purity, 134 mmol) in HOAc (100
mL), THF (150 mL), and water (50 mL) was heated at reflux
8690 J . Org. Chem., Vol. 67, No. 24, 2002

(internal temperature: 81 °C) overnight (18 h). The reaction
mixture was then concentrated to dryness. After the residue was
stripped from toluene (2 × 150 mL), it was dissolved in water
(150 mL). The aqueous layer was washed with hexane (3 × 100
mL) and solid NaCl was added to saturate the aqueous layer.
The aqueous layer was extracted with EtOAc (2 × 100 mL) and
the combined organic layers were concentrated to dryness. The
residue was stripped with toluene (2 × 100 mL) to give 31.6 g
of crude alcohol 11. Analytically pure sample was obtained by
chloride (11.0 g, 96 mmol) was added at the same temperature.
After the reaction mixture was stirred at 0 °C for 1 h, water
(200 mL) was added. The aqueous layer was extracted with CH2-
Cl2 (2 × 100 mL). The combined organic layers were dried over
MgSO4 and concentrated. The residue was treated with CH2Cl2
(20 mL) and MTBE (80 mL). Crystalline mesylate 1 was
smoothly formed and collected by filtration to afford 17.2 g (66%
yield from 10) of the analytically pure product 1 as the first crop.
The filtrate contained ∼10% of mesylate 1 and no attempt was
to 82.1° (c 5.03, MeOH). 1H NMR (CDCl3, 400 MHz) δ 7.00 (s,
1H), 4.21 (dd, J ) 4.10, 10.24 Hz, 1H), 4.08 (dd, J ) 6.71, 10.18
Hz, 1H), 3.93 (br s, 1H), 3.05 (s, 3H), 2.82 (m, 1H), 2.73 (dd, J )
3.86, 16.60 Hz, 1H), 2.35 (dd, J ) 9.10, 16.60 Hz, 1H), 2.20 (m,
1H), 2.06 (m, 1H), 1.43 (s, 9H). 13C NMR (CDCl3, 100 MHz) δ
178.7, 170.8, 81.0, 71.0, 50.8, 37.4, 36.6, 36.5, 29.1, 28. Anal.
Calcd for C12H21NO6S: C, 46.89; H, 6.89; N, 4.56. Found: C,
46.92; H, 6.94; N, 4.43.
25
25
column chromatography. Mp 67-68 °C. [R]D +10.34° (c 1,
made to obtain the second crop. Mp 114-117 °C. [R]D +76.2
1
MeOH). H NMR (CDCl3, 400 MHz) δ 7.30 (s, 1H), 4.16 (t, J )
5.83 Hz, 1H), 3.69 (m, 1H), 3.62 (m, 1H), 3.43 (m, 1H), 2.80 (m,
1H), 2.67 (dd, J ) 3.99, 16.4 Hz, 1H), 2.30 (dd, J ) 9.28, 16.3
Hz, 1H), 2.11 (m, 1H), 1.93 (m, 1H). 13C NMR (CDCl3, 100 MHz)
δ 179.6, 171.2, 80.9, 65.6, 54.3, 37.6, 36.9, 29.3, 28.1. Anal. Calcd
for C11H19NO4: C, 57.63; H, 8.35; N, 6.11. Found: C, 57.42; H,
8.36; N, 6.11.
The crude alcohol 11 (20 g, max. 84.8 mmol) was dissolved in
CH2Cl2 (300 mL) and the reaction mixture was cooled to 0 °C.
Triethylamine (15 mL, 107 mmol) followed by methanesulfonyl
J O020433F
J . Org. Chem, Vol. 67, No. 24, 2002 8691