Efficacious preparation of Oppolzer's glycylsultam via the Delepine reaction

Article abstract of DOI:10.1055/s-0028-1088021

A new preparative route to Oppolzer's glycylsultam, the 'NC' component in the asymmetric [C+NC+CC] coupling reaction leading to functionalized pyrrolidines, is described. The synthesis features a novel application of the Delepine reaction, providing a saf

Full text of DOI:10.1055/s-0028-1088021

PAPER
1261
Efficacious Preparation of Oppolzer’s Glycylsultam via the Delépine Reaction
Preparation of
O
pp
l
olzer’s
p
G
lycylsulta
e
m
r Isleyen, Carolyn Gonsky, Robert C. Ronald, Philip Garner*
Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA
Fax +1(509)3358867; E-mail: ppg@wsu.edu
Received 10 September 2008; revised 15 December 2008
Initially, we employed a variation of Oppolzer’s synthesis
Abstract: A new preparative route to Oppolzer’s glycylsultam, the
‘NC’ component in the asymmetric [C+NC+CC] coupling reaction
leading to functionalized pyrrolidines, is described. The synthesis
features a novel application of the Delépine reaction, providing a
of a-amino acids to prepare the glycylsultam.6 This syn-
thesis involved trimethylaluminum-mediated acylation of
the parent sultam using methyl N-[bis(methylsulfa-
safe, efficient, and environmentally benign route to this useful nyl)methylene]glycinate [(MeS)2C=NCH2CO2Me]7 to
chiral reagent for pyrrolidine synthesis.
give (MeS)2C=NCH2COX*, which was hydrolyzed to
provide the amine. Chassaing and co-workers8 synthe-
Key words: asymmetric synthesis, chiral auxiliaries, chiral pool,
sized the 15N-labeled hydrochloride salt of the glycylsul-
Delépine reaction, Oppolzer’s camphorsultam
tam via alkylation of labeled potassium phthalimide with
BrCH2COX* followed by N-deprotection. The sodiosul-
tam could also be acylated with the mixed anhydride of la-
beled N-Boc-protected glycine, followed by N-
deprotection. Dogan and co-workers reported acylation of
the sodiosultam with azidoacetyl chloride to give the
N3CH2COX*, which was then subjected to a Staudinger
reaction.9 Our group subsequently developed an alterna-
tive route to H2NCH2COX* via SN2 displacement of
BrCH2COX* with azide followed by hydrogenolysis.10
Since this last sequence involved potentially explosive
and/or toxic azides,11 as well as flammable hydrogen gas,
a safer and environmentally benign process was clearly
desirable.
We recently described a set of stereocomplementary mul-
ticomponent [C+NC+CC] coupling reactions that provide
direct access to functionalized pyrrolidines (Scheme 1,
‘C’ can be a complex aldehyde).1,2 Since the pyrrolidine
ring is an important structural motif found in many bioac-
tive molecules, the asymmetric [C+NC+CC] coupling re-
action is expected to find widespread application in
synthesis.3 During the course of these studies, we required
a supply of both the L- and D-versions of Oppolzer’s
glycylsultam4,5 (H2NCH2COX*, where X* = camphor-
sultam), which serves as the ‘NC’ component in the
[C+NC+CC] coupling reaction. Prior syntheses of this
glycylsultam were deemed unsuitable for our purposes.
We now report an efficient, scalable, and environmentally
friendly synthesis of Oppolzer’s glycylsultam 6 (see
Scheme 2) based on the Delépine reaction.
It was in this context that we began investigating a new
route to the glycylsultam based on the Delépine reaction.
Though often overlooked, this classical transformation12
can provide an excellent route to primary amines on a pre-
parative scale.13 The mechanism of this two-step process
involves (a) nucleophilic displacement of an activated ha-
lide by the inexpensive and relatively nontoxic hexameth-
ylenetetramine (HMTA), followed by (b) decomposition
of the intermediate quaternary hexamethylenetetramine
salt with ethanolic hydrogen chloride. This reaction se-
quence results in a mixture of ammonium salts and di-
ethoxymethane, from which the desired primary amine
can be obtained after neutralization. The first step of the
process is usually performed in a chlorinated hydrocarbon
solvent, from which the quaternary hexamethylenetetra-
mine salt precipitates. A simplified one-pot Delépine pro-
cedure using ethanol as the solvent for both steps has also
been reported.14
H2N
COXL/D
'NC'
AgI (cat.)
THF, r.t.
CuI (cat.), ligand
DMSO, r.t.
+
EWG
'CC'
RCHO
'C'
(ref. 1)
(ref. 2)
H
H
COXL
R
COXL
N
N
R
EWG
EWG
H
N
H
COXD
R
COXD
N
R
EWG
endo
EWG
We began by developing a more convenient and scalable
exo
synthesis of the known15 chloroacetylsultam
2
Scheme 1 Asymmetric [C+NC+CC] synthesis of pyrrolidines (XL
(Scheme 2). Acid-catalyzed acylation of the parent L-
camphorsultam 116 with chloroacetic anhydride gave 2 in
high yield. This compound had previously been made via
N-metalation of 1 with sodium hydride followed by low-
temperature acylation with chloroacetyl chloride. Al-
though there was a precedent for the Delépine displace-
ment of activated chlorides,13b compound 2 did not react
and XD = antipodes of Oppolzer’s camphorsultam)
SYNTHESIS 2009, No. 8, pp 1261–1264
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x
.
x
x
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0
0
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Advanced online publication: 16.03.2009
DOI: 10.1055/s-0028-1088021; Art ID: M05308SS
© Georg Thieme Verlag Stuttgart · New York

1262
A. Isleyen et al.
PAPER
significantly with hexamethylenetetramine under a vari- In conclusion, the Delépine reaction forms the basis for a
ety of reaction conditions. Conversion of chloride 2 into convenient synthesis of Oppolzer’s glycylsultam 6. This
the more reactive bromoacetylsultam 317 by use of lithium short sequence proceeds in good overall yield (52% over
bromide in tetrahydrofuran (Scheme 2) solved this reac- 3 steps) on a multigram scale and does not require any
tivity dilemma. Bromide 3 could also be formed directly chromatographic separations. The ready availability of 6
from 1 – albeit in lower yield18 – by acylation in the pres- (as well as its antipode ent-6), made possible by this new
ence of a mixture of bromoacetyl bromide and catalytic procedure, will encourage use of the asymmetric
bromoacetic acid (Scheme 2). Both of these routes to 3 [C+NC+CC] coupling technology.
were found to be more practical than the previously re-
ported synthesis.
Oven-dried glassware under Drierite drying tubes were used for
nonaqueous reactions. Anhyd THF was distilled from Na/benzo-
phenone ketyl under argon. Hexamethylenetetramine (HMTA) was
(ClCH2CO)2O
recrystallized from 95% EtOH prior to use. All other commercial
reagents were used as received. The progress of reactions was mon-
itored by analytical TLC. Plates were visualized by charring with
5% anisaldehyde in EtOH–AcOH–H2SO4 (95:5:1). Melting points
are uncorrected. Optical rotations were measured at 589 and 546 nm
with a Jasco DIP-181 digital polarimeter calibrated with a sucrose
O
H2SO4 (cat.), 140 °C
NH
N
93%
Cl
S
S
O2
O2
1
2
BrCH2COBr
BrCH2CO2H (cat.)
LiBr
THF, 90 °C
1
CH2Cl2, r.t.
75%
standard. H NMR spectra of samples in CDCl3 were recorded at
300 MHz and are referenced to TMS. 13C NMR spectra were re-
corded at 75 MHz and are referenced to CDCl3 (d = 77.00). Data
from COSY, NOESY, and HMQC 2D experiments were used for
making the 1H and 13C NMR assignments for compounds 2, 3, and
6. MALDI-HRMS was carried out with an a-cyano-4-hydroxycin-
namic acid matrix.
49%
N
HMTA
CHCl3, r.t.
O
O
N
N
N+
N
N
Br
S
S
O2
O2
(3aS,6R,7aR)-1-(Chloroacetyl)-8,8-dimethylhexahydro-3a,6-
methano-2,1-benzothiazole 2,2-Dioxide (2)
Br–
3
4
Sultam 1 (20.5 g, 95.0 mmol) was added in five portions over 5 min
to a stirred soln of chloroacetic anhydride (technical grade, 19.9 g,
0.105 mol) and concd H2SO4 (0.254 mL, 4.57 mmol) at 80 °C. The
temperature was then increased to 140 °C, and the mixture was
stirred until TLC analysis showed the reaction to be completed (ca.
2.5 h). The mixture was cooled to r.t. and then transferred to an
Erlenmeyer flask containing a mixture of CH2Cl2 (200 mL) and
H2O (100 mL); it was then carefully neutralized with 0.712 M
NaOH (200 mL, 0.142 mol) to pH 7.5. The aqueous layer was ex-
tracted further with CH2Cl2 (200 mL). The combined organic layers
were dried (MgSO4), filtered through a pad of charcoal and Celite,
and concentrated under reduced pressure; this yielded crude 2 as a
tan solid, which was used for the next step without further purifica-
tion.
EtOH
concd HCl, r.t.
NaHCO3
83%
O
O
N
N
+
NH2
NH3
S
S
O2
O2
Cl/Br–
6
5
Scheme 2 Delépine route to Oppolzer’s glycylsultam
Under optimized conditions, bromoacetylsultam 3 reacted
cleanly with 1.1 equivalents of hexamethylenetetramine
in chloroform at room temperature to give a quaternary
hexamethylenetetramine salt (Scheme 2). In contrast to
more typical Delépine salts, this compound was found to
be fairly soluble in the reaction medium. Evaporation of
Yield: 25.8 g (93%); mp 115–120 °C (Lit.15b 120–122 °C); Rf = 0.44
(hexanes–EtOAc, 3:1).
A sample was recrystallized from i-Pr2O–CH2Cl2 for optical rota-
23
tion and combustion analysis; mp 131–134 °C; [a]D –118.2,
[a]54623 –140.7 (c 2.16, CHCl3).
1H NMR (300 MHz, CDCl3): d = 4.50 (s, 2 H), 3.92 (dd, J = 7.5, 5.1
Hz, 1 H), 3.54 (d, J = 13.8 Hz, 1 H), 3.47 (d, J = 13.8 Hz, 1 H),
2.23–2.07 (m, 2 H), 1.99–1.84 (m, 3 H), 1.48–1.33 (m, 2 H), 1.15
(s, 3 H), 0.98 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.6, 65.5, 52.6, 49.1, 47.9, 44.5,
42.3, 38.0, 32.7, 26.4, 20.7, 19.8.
1
the solvent gave a white solid whose H NMR spectrum
was consistent with the classical Delépine hexamethyl-
enetetramine adduct 4.19 Decomposition of 4 was effected
with hydrogen chloride in aqueous ethanol at room tem-
perature (Scheme 2). After removal of precipitated am-
monium halide, the filtrate was concentrated to give the
ammonium salt 5. It was essential to remove all of the di-
ethoxymethane (or other volatile formaldehyde equiva-
lents) at this stage to avoid the formation of a 1,3,5-
triazinane in the next step.20 Neutralization of 5 with sodi-
um bicarbonate followed by extraction gave the desired
free glycylsultam 6 in good yield (Scheme 2). This crude
material invariably contained traces of camphorsultam
1,21 but was suitable for use in the [C+NC+CC] coupling
reaction.
Anal. Calcd for C12H18ClNO3S: C, 49.39; H, 6.22; N, 4.80. Found:
C, 49.60; H, 6.19; N, 4.64.
(3aS,6R,7aR)-1-(Bromoacetyl)-8,8-dimethylhexahydro-3a,6-
methano-2,1-benzothiazole 2,2-Dioxide (3) by Procedure A
(from 2)
A soln of crude (chloroacetyl)sultam 2 (12.9 g, 44.1 mmol) in anhyd
THF (20 mL) was added to a stirred soln of LiBr (38.1 g, 0.441 mol)
in anhyd THF (67 mL) kept in a bath at 90–95 °C. The mixture was
stirred at this temperature for 20 h, after which it was allowed to
cool to r.t. and partitioned between H2O (125 mL) and CH2Cl2 (250
Synthesis 2009, No. 8, 1261–1264 © Thieme Stuttgart · New York

PAPER
Preparation of Oppolzer’s Glycylsultam
1263
mL). The aqueous layer was extracted further with CH2Cl2 (2 × 100
mL). The combined organic layers were dried (MgSO4), filtered
through a pad of charcoal and Celite, and concentrated at reduced
pressure; this yielded crude 3 as a light brown solid. Recrystalliza-
tion from a mixture of i-Pr2O (45 mL) and CH2Cl2 (50 mL) afforded
(bromoacetyl)sultam 3 as colorless needles.
HRMS (MALDI): m/z [M + H]+ calcd for C12H21N2O3S: 273.1267;
found: 273.1365.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Yield: 10.9 g (79%); mp 111–115 °C (Lit.17 113 °C); [a]D23 –101.8,
23
[a]546 –120.7 (c 1.95, CHCl3) [Lit.17 [a]D –118.5 (c 1, CH2Cl2)];
Acknowledgment
Rf = 0.45 (hexanes–EtOAc, 3:1).
This research was supported by a grant from the National Science
Foundation (Grant CHE-0553313). C. G. was the recipient of a
WSU College of Sciences Undergraduate Student Research Mini-
grant.
1H NMR (300 MHz, CDCl3): d = 4.35 (d, J = 12.9 Hz, 1 H), 4.21 (d,
J = 12.9 Hz, 1 H), 3.92 (dd, J = 7.5, 5.1 Hz, 1 H), 3.54 (d, J = 13.8
Hz, 1 H), 3.47 (d, J = 13.8 Hz, 1 H), 2.21–2.04 (m, 2 H), 2.00–1.83
(m, 3 H), 1.49–1.31 (m, 2 H), 1.16 (s, 3 H), 0.99 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.5, 65.4, 52.7, 49.0, 47.8, 44.5,
37.9, 32.7, 27.5, 26.4, 20.7, 19.8.
References
Anal. Calcd for C12H18BrNO3S: C, 42.86; H, 5.40; N, 4.17. Found:
C, 42.57; H, 5.25; N, 4.25.
(1) Garner, P.; Kaniskan, H. Ü.; Hu, J.; Youngs, W. J.; Panzner,
M. Org. Lett. 2006, 6, 3647.
(2) Garner, P.; Hu, J.; Parker, C. G.; Youngs, W. J.; Medvetz, D.
Tetrahedron Lett. 2007, 48, 3867.
(3) The value of our [C+NC+CC] coupling reaction in a
complex synthetic scenario (synthesis of the natural
products cyanocycline A and bioxalomycin b2) has already
been demonstrated. See: Kaniskan, H. Ü.; Garner, P. J. Am.
Chem. Soc. 2007, 129, 15460.
(4) (a) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett.
1989, 30, 6009. (b) Oppolzer, W.; Moretti, R.; Zhou, C.
Helv. Chim. Acta 1994, 77, 2363.
(5) Although Oppolzer did not actually report a synthesis of the
parent glycylsultam, we feel that it is appropriate to refer to
it as ‘Oppolzer’s glycylsultam’ for descriptive reasons.
(6) Garner, P.; Dogan, Ö.; Youngs, W. J.; Kennedy, V. O.;
Protasiewicz, J.; Zaniewski, R. Tetrahedron 2001, 57, 71.
(7) Hoppe, D.; Kloft, M. Liebigs Ann. Chem. 1980, 1512.
(8) Martin, A.; Chassaing, G.; Vanhove, A. Isot. Environ.
Health Stud. 1996, 32, 15.
Compound 3 by Procedure B (from 1)
Bromoacetyl bromide (7.5 mL, 86.0 mmol) was added to a stirred
soln of camphorsultam 1 (15.0 g, 69.7 mmol) and bromoacetic acid
(485 mg, 5 mol%) in CH2Cl2 (7.5 mL). The orange-colored mixture
was stirred at r.t. for 3.5 h, at which point 1H NMR analysis showed
a 2:1 ratio of (bromoacetyl)sultam 3 to HBr addition product 7.18
The reaction mixture was partitioned between ice-cold CH2Cl2 (to-
tal volume 150 mL) and ice-cold, distilled H2O (300 mL). The aque-
ous layer was extracted further with CH2Cl2 (150 mL). The
combined CH2Cl2 layers were washed with H2O (2 × 400 mL),
dried (MgSO4), filtered, and concentrated, to give a slightly yellow-
ish oil, which solidified upon standing overnight (22.1 g). 1H NMR
analysis of this crude mixture showed a 3/1 ratio of 3:1. Recrystal-
lization from CH2Cl2–absolute EtOH gave pure 3 as a colorless sol-
id; yield: 11.52 g (49%); mp 114–115 °C. The filtrate was
concentrated to give a yellow oil, which consisted of a 3/1 mixture
in a 2:3 ratio.
(9) Dogan, Ö.; Öner, I.; Ülku, D.; Arici, C. Tetrahedron:
(3aS,6R,7aR)-1-(Aminoacetyl)-8,8-dimethylhexahydro-3a,6-
methano-2,1-benzothiazole 2,2-Dioxide (6)
Asymmetry 2002, 13, 2099.
(10) Kaniskan, H. Ü. Ph.D. Dissertation; Case Western Reserve
University: Cleveland, OH, 2007.
A mixture of (bromoacetyl)sultam 3 (10.0 g, 29.8 mmol) and
HMTA (4.61 g, 32.8 mmol) in CHCl3 (reagent grade, 50 mL) was
stirred at r.t. for 20 h, and was then concentrated by rotary evapora-
tion to give the crude Delépine adduct 4. EtOH (95%, 25 mL) and
12 N HCl (7.5 mL) were added to this white solid. After stirring at
r.t. for 6 h, the heterogeneous reaction mixture was cooled in an ice
bath and filtered to remove NH4Cl; the filter cake was washed with
EtOH (95%, 200 mL). The filtrate and washings were concentrated
by rotary evaporation to leave a solid, which was kept under vacu-
um (ca. 0.02 Torr) at 75 °C until it reached a constant weight (13.45
g). This crude ammonium salt 5 was partitioned between H2O (200
mL) and CH2Cl2 (200 mL) to remove any neutral materials. The
aqueous phase was then carefully neutralized to pH 7.5 with a soln
of NaHCO3 (3.27 g) in H2O (220 mL), and extracted with CH2Cl2
(2 × 200 mL). The combined organic layers were dried (MgSO4)
and concentrated; this gave glycylsultam 6 as a colorless solid. This
material contained 5 mol% camphorsultam 1.21
(11) Nicolaides, E. D.; Westland, R. D.; Wittle, E. L. J. Am.
Chem. Soc. 1954, 76, 2887.
(12) Delépine, M. C. R. Hebd. Seances Acad. Sci. 1895, 120, 501.
(13) See: (a) Bottini, A. T.; Dev, V.; Klinck, J. Org. Synth. 1963,
43, 6. (b) Meyers, A. I.; Warmus, J. S.; Dilley, G. J. Org.
Synth. 1996, 73, 246.
(14) Galat, A.; Elion, G. J. Am. Chem. Soc. 1939, 61, 3585.
(15) (a) Oppolzer, W.; Dupuis, D.; Poli, G.; Raynham, T. M.;
Bernardinelli, G. Tetrahedron Lett. 1988, 29, 5885.
(b) Cecil, A. R. L.; Hu, Y.; Vicent, M. J.; Duncan, R.;
Brown, R. C. D. J. Org. Chem. 2004, 69, 3368.
(16) For a very convenient synthesis of Oppolzer’s
camphorsultam that uses sodium borohydride rather than
lithium aluminum hydride for reduction of the sulfoximine,
see: Capet, M.; David, F.; Bertin, L.; Hardy, J. C. Synth.
Commun. 1995, 25, 3323.
Yield: 6.09 g (75%); mp 112–117 °C; [a]D23 –115.0, [a]54623 –135.2
(c 2.00, abs EtOH); Rf = 0.51 (CH2Cl2–MeOH, 9:1).
1H NMR (300 MHz, CDCl3): d = 3.90 (d, J = 18.0 Hz, 1 H), 3.88
(dd, J = 7.5, 5.1 Hz, 1 H), 3.76 (d, J = 18.0 Hz, 1 H), 3.50 (d,
J = 13.8 Hz, 1 H), 3.43 (d, J = 13.8 Hz, 1 H), 2.20–2.04 (m, 2 H),
1.95–1.83 (m, 3 H), 1.52 (br s, 2 H), 1.46–1.33 (m, 2 H), 1.15 (s, 3
H), 0.98 (s, 3 H).
(17) Sweeney, J. B.; Cantrill, A. A.; McLaren, A. B.; Thobhani,
S. Tetrahedron 2006, 62, 3681.
(18) The modest yield of this reaction was due to competitive
addition of HBr to 1 that resulted in an unstable compound
tentatively identified as 7 on the basis of diagnostic peaks in
its 1H NMR spectrum: 1H NMR (300 MHz, CDCl3): d = 8.15
+
(br s, NH3 ), 5.28 (d, J = 14.2 Hz, 1 H), 3.94 (d, J = 14.2 Hz,
1 H). Attempts to suppress this side reaction were
unsuccessful. In a separate control experiment, compound 7
was produced quantitatively by the action of HBr gas on 1
13C NMR (75 MHz, CDCl3): d = 172.9, 65.1, 52.7, 49.1, 47.8, 45.4,
44.6, 38.2, 32.8, 26.4, 20.7, 19.8.
Synthesis 2009, No. 8, 1261–1264 © Thieme Stuttgart · New York

1264
A. Isleyen et al.
PAPER
dissolved in CDCl3 (Scheme 3). Byproduct 7 reverts back to
camphorsultam 1 upon exposure to water.
O2S
N
Br–
HBr
O
O
N
NH
+
NH3
SO2Br
N
N
O
H2O
S
O2
N
O2S
N
SO2
1
7
Scheme 3
8
(19) Monoalkylation of HMTA with the chiral bromide 3 breaks
its Td molecular symmetry, resulting in AB quartets for both
sets of diastereotopic HMTA methylene protons in 4. This
Delépine salt was unstable, but these key HMTA signals
could be observed in the 1H NMR spectrum: 1H NMR (300
MHz, CDCl3): d = 5.90 (d, J = 11.1 Hz, 3 H), 5.82 (d,
J = 11.1 Hz, 3 H), 4.76 (d, J = 13.0 Hz, 3 H), 4.54 (d,
J = 13.0 Hz, 3 H).
(20) The proposed structure of 8 (Figure 1) was supported by its
exact mass (HRMS: m/z [M – H]+ calcd for C39H59N6O9S3:
851.3500; found: 851.2368) and the presence of an aminal
carbon signal in its 13C NMR spectrum: 13C NMR (75 MHz,
CDCl3): d = 73.1.
Figure 1
(21) Solutions of the free glycylsultam 6 were found to be
susceptible to nucleophile-induced deacylation to give back
starting camphorsultam 1. The level of contamination
ranged from 3 mol% on a 0.5-g scale to 5 mol% on a 10-g
scale of bromosultam 3. However, a solid sample of 6 that
had been kept at room temperature for more than one month
showed minimal decomposition.
Synthesis 2009, No. 8, 1261–1264 © Thieme Stuttgart · New York