Chemistry of epoxysulfones: A new route to polyhydroxylated pyrrolidines

Article abstract of DOI:10.1055/s-2005-861792

A new methodology for the synthesis of polyhydroxylated pyrrolidines using epoxysulfones is described. The synthesis of two natural glycosidase inhibitors, 1,4-dideoxy-1,4-imino-D-lyxitol and 1,4-dideoxy-1,4-imino-D-mannitol (DIM), is reported.

Full text of DOI:10.1055/s-2005-861792

PAPER
565
Chemistry of Epoxysulfones: A New Route to Polyhydroxylated Pyrrolidines
A
New Route to
P
a
olyhydroxy
v
lated Pyrrolid
i
ines d Díez,* M. Templo Benéitez, M. J. Gil, R. F. Moro, Isidro S. Marcos, N. M. Garrido, P. Basabe,
Julio G. Urones
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5,
37008 Salamanca, Spain
Fax +34(92)3294574; E-mail: ddm@usal.es
Received 14 October 2004
O
HO
O
SO2Ph
Abstract: A new methodology for the synthesis of polyhydroxylat-
ed pyrrolidines using epoxysulfones is described. The synthesis of
two natural glycosidase inhibitors, 1,4-dideoxy-1,4-imino-D-lyxitol
and 1,4-dideoxy-1,4-imino-D-mannitol (DIM), is reported.
1
Ref. 10
HO OH
N
Ref. 11
O
O
O
O
O
Ref. 9
Key words: epoxysulfones, iminosugars, 1,4-dideoxy-1,4-imino-
D-lyxitol, 1,4-dideoxy-1,4-imino-D-mannitol
TsO
TsO
O
OH
5
2
3
4
H
SO2Ph
Ref. 12
SO2Ph
HO
O
O
O
The synthesis of iminosugars has been the subject of
much continued effort in recent years.1 These compounds
are known as glycosidase inhibitors,2 and more recently
have been shown to be inhibitors of other enzymes such
as glycosyltransferases3 and nucleoside phosporylases.4
Many natural and unnatural polyhydroxylated pyrro-
lidines or piperidines (commonly referred to as azasugars
or iminocyclitols) are potent glycosidase inhibitors5 and
hence could be applied in the treatment of numerous pa-
thologies such as diabetes,6 viral infections7 or even can-
cer.8
Ref. 12
TsO
Ref. 12
O
Br
SO2Ph
O
Br
7
6
O
8
O
SO2Ph
Scheme 1
epoxysulfone such as 6, would give polyhydroxylated
pyrrolidines in one step, with a hydroxymethyl group at
C-2.
Treatment of compound 6 with benzylamine in MeOH at
reflux gave pyrrolidine 9 (Scheme 2). The reaction oc-
curred as expected, with further reaction of the aldehyde
due to the excess of benzylamine. Pyrrolidine 9 was hy-
drolyzed on silica gel to give aldehyde 10 [an unstable
compound, which has been transformed by Ikota et al.
into (–)-swansonine14], which was reduced straightfor-
wardly with sodium borohydride under the usual condi-
tions to give the known alcohol 11.15 The enantiomer of
this compound has been transformed by Kim et al. via ring
expansion, into piperidines.16 Finally, hydrogenolysis and
acetonide deprotection gives 1,4-dideoxy-1,4-imino-D-
lyxitol (12), which has previously been synthesized by
several authors17 and has been shown to be a reversible in-
hibitor of a-galactosidase from green coffee beans.18
In our previous work, we reported the synthesis of the
enantiomerically pure vinyl sulfones 2 and 3, with com-
plete stereoselection, from the same epoxide, 1.9 Com-
pound 3 was further elaborated to the pyrrolidine 4,9,10
inhibitor of glycosidases. The key step is the synthesis of
the pyrrolidines by SN2 displacement of the tosylate and
intramolecular Michael addition to the vinyl sulfone. Al-
though the method described for the synthesis of 2 is very
versatile, multigram quantities of 2 are better obtained
from 2,3-O-isopropylidene-D-erythronolactol (5) in only
two steps11 (Scheme 1).
Very recently we have described a stereoselective epoxi-
dation of 2 and its use for the synthesis of the versatile
chiral building blocks 7 and 8, among others12
(Scheme 1).
Having opened a new route to polyhydroxylated pyrro-
lidines, we decided to apply the method to a more chal-
lenging target, such as 1,4-dideoxy-1,4-imino-D-mannitol
(DIM), a potent a-mannosidase inhibitor19 that has been
synthesized by Fleet et al.,20 Jäger et al.,21 and Díaz-de-
Villegas and Gálvez et al.22
Due to the ease with which compound 6 and its enantio-
mer could be obtained on a multigram scale, we decided
to extend this methodology to the asymmetric synthesis of
more functionalized pyrrolidines. It is known that the at-
tack of a nucleophile on an epoxysulfone leads to the
elimination of the sulfone group, producing a carbonyl
moiety.13 We therefore anticipated that a cyclization anal-
ogous to that used to prepare pyrrolidine 4, but using an
Treatment of 10 with potassium hexamethyldisilazide
(KHMDS) and methylenetriphenylphosphorane gave the
olefin 13 in good yield. Dihydroxylation of 13 under the
usual conditions led to diol 14, only one diastereoisomer
being observed. In order to establish the stereochemistry
obtained at C-1¢, compound 14 was protected as its ace-
tonide, giving pyrrolidine 15 in good yield; the structure
of this compound was confirmed by synthesis via a differ-
SYNTHESIS 2005, No. 4, pp 0565–0568
x
x
.
x
x
.2
0
0
5
Advanced online publication: 18.01.2005
DOI: 10.1055/s-2005-861792; Art ID: P12204SS
© Georg Thieme Verlag Stuttgart · New York

566
D. Díez et al.
PAPER
eter. Optical Rotations were determined using a Perkin-Elmer 241
polarimeter in 1 dm cells. EI mass spectra were run on a VG-TS 250
spectrometer at 70 eV. HRMS were recorded in a VG Platform
(Fisons) spectrometer using Chemical Ionization (ammonia as gas)
or Fast Atom Bombardment (FAB) techniques. Column chromatog-
raphy was performed with Merck silica gel 60 (70–230 mesh). Sol-
vents and reagents were generally distilled immediately prior to use:
THF from sodium benzophenone ketyl; CH2Cl2 and diisopropyl-
amine from CaH2; pyridine from KOH. 1,4-Dideoxy-1,4-imino-D-
mannitol hydrochloride was purchased from Aldrich.
O
O
O
O
O
O
a
b
H
N
H
O
CHO
N
TsO
HO
N
SO2Ph
Ph
6
9
10
Ph
Ph
c
Ref. 14
OH
OH
O
O
OH
H
H
d
H
OH
CH2OH
N
N
CH2OH
H
N
(2S,3S,4R)-N-Benzyl-2-formyl-3,4-(isopropylidenedioxy)pyrro-
lidine (10)
HCl
Ph
(–)-Swansonine
12
11
To a solution of epoxysulfone 6 (370 mg, 0.86 mmol) in MeOH (7
mL) was added benzylamine (297 mL, 2.72 mmol). The mixture
was refluxed for 12 h, then allowed to cool to r.t., and the solvent
was concentrated. The residue was diluted with H2O (11 mL) and
extracted with EtOAc. The combined organic layers were washed
with H2O and brine, then dried (Na2SO4). Removal of solvent gave
the imine 9. The unstable imine 9 hydrolyzed on silica gel (n-hex-
ane–EtOAc, 8:2) to give aldehyde 10 (224 mg, 79%).
Scheme 2 Reaction conditions: a) BnNH2, MeOH, reflux; b) silica
gel, 79% (from compound 6); c) NaBH4, MeOH, 90%; d) 1. H2, Pd/
C, MeOH; 2. HCl (6 M), 68%
ent route. Thus, starting with (R)-2,3-O-isopropylidene-
glyceraldehyde and following the procedure of Díaz-de-
Villegas and Galvez,22 compound 16 was obtained, in
which the C-1¢ stereochemistry was derived from the
starting material. Protection of 16 as its acetonide gives a
compound identical to 15, confirming the stereochemistry
assigned to 14 at C-1¢. Final removal of all the protecting
groups from 14 led to 17 in excellent yield, whose physi-
cal properties were identical to those described by Fleet et
al. for DIM20 and to an authentic sample purchased from
Aldrich (Scheme 3).
IR (film): 2936, 2810, 1728, 1373, 1209, 1096, 858 cm–1.
1H NMR (CDCl3, 200 MHz): d = 9.42 (1 H, d, J = 3.4 Hz, CHO),
7.34–7.25 (5 H, m, Ar), 4.92 (1 H, dd, J = 5.6, 6.2 Hz, H-3), 4.69 (1
H, dd, J = 4.4, 6.2 Hz, H-4), 3.76 (1 H, d, J = 13.2 Hz, HA of
CH2Ph), 3.52 (1 H, d, J = 13.2 Hz, HB of CH2Ph), 3.25 (1 H, d,
J = 11.0 Hz, HA-5), 2.81 (1 H, m, H-2), 2.25 (1 H, dd, J = 4.4, 11.0
Hz, HB-5), 1.54 (3 H, s, CH3-acetonide ), 1.28 (3 H, CH3-acetonide).
(2R,3S,4R)-N-Benzyl-2-hydroxymethyl-3,4-(isopropylidene-
dioxy)pyrrolidine (11)
To a solution of aldehyde 10 (200 mg, 0.75 mmol) in MeOH (25
mL) was added NaBH4 (30 mg, 0.75 mmol) and the mixture was
stirred for 15 min. The reaction was quenched by the addition of
H2O and the mixture was extracted with EOtAc. The combined or-
ganic layers were washed with H2O and brine, then dried (Na2SO4).
Concentration of the organic layers after filtration gave an oil,
which was purified by column chromatography on silica gel (eluent:
n-hexane–EtOAc, 8:2) to furnish the alcohol 11 (175 mg, 90%). The
physical data are in agreement with those given in the literature.15
Extra data is given for completion of the information.
13C NMR (CDCl3, 50 MHz): d = 139.1 (C-ipso), 128.9 (2 CH-meta),
128.5 (2 CH-ortho), 127.2 (CH-para), 111.2 (C-acetonide), 82.1
(CH-3), 78.1 (CH-4), 67.3 (CH-2), 59.9 (CH2-1¢), 58.9 (CH2-5),
56.9 (CH2-1¢¢), 26.4 (CH3-acetonide), 25.2 (CH3-acetonide).
O
O
O
O
O
O
a
b
H
H
H
OH
CHO
N
1´
N
N
CH2OH
Ph
Ph
Ph
10
13
14
c
e
HO
OH
HO
OH
O
O
d
H
H
H
O
O
OH
OH
N
O
O
N
1´
N
H
1´
Ph
HCl
Ph
16
15
17
HRMS (EI): m/z calcd for C15H21NO3 (M+): 263.1521; found:
263.1524.
Scheme 3 Reaction conditions: a) CH3Ph3P+Br–, KHMDS, THF,
–78 °C, 89%; b) OsO4, dioxane–H2O (6:4), 76%; c) 2,2-DMP, p-
TsOH, acetone, 94%; d) 2,2-DMP, p-TsOH, acetone, 97%; e) 12 M
HCl, H2, 3 atm., Pd(OH)2/C, MeOH, 96%.
(2R,3S,4R)-N-Benzyl-3,4-dihydroxy-2-hydroxymethyl-pyrroli-
dine Hydrochloride (12)
A solution of alcohol 11 (150 mg, 0.55 mmol) in MeOH (5 mL)
containing a catalytic amount of Pd/C was flushed with H2 and
stirred under an atmosphere of H2 at 1 bar for 24 h. The mixture was
filtered over Celite and solvent was concentrated to 1.5 mL. Aq 6 M
HCl (three drops) were added and the mixture was stirred for 12 h.
Concentration gave a residue, which was washed with cold Et2O
and MeOH to give a white solid 12 (55 mg, 68%) whose physical
data are in agreement with those given in the literature.17
In conclusion, in this paper a new route to polyhydroxy-
lated pyrrolidines is described, exploiting the reactivity of
epoxysulfones. Due to the accessibility of 6 and its enan-
tiomer on a multigram scale, this provides a new and very
versatile strategy for the synthesis of pyrrolidine glycosi-
dase inhibitors.
(2R,3S,4R)-N-Benzyl-3,4-(isopropylidenedioxy)-2-vinyl-pyrro-
lidine (13)
1H NMR spectra were recorded in CDCl3 (ref. d = 7.26) at 200 MHz
on a Varian 200 VX spectrometer. 13C NMR spectra were recorded
in CDCl3 (ref. d = 77.0) at 50 MHz on a Varian 200 VX spectro-
meter, and multiplicities were determined by DEPT experiments.
IR spectra were recorded on a BOMEM 100 FT IR spectrophotom-
To a solution of CH3Ph3P+Br– (1.46 g, 4.09 mmol) in anhyd THF
(20 mL) was added a solution 0.5 M KHMDS in toluene (8.8 mL)
at –78 °C under argon. The mixture was stirred for 30 min at this
temperature and then compound 10 (224 mg, 0.86 mmol) dissolved
in anhyd THF (2 mL) was added via cannula. The reaction mixture
Synthesis 2005, No. 4, 565–568 © Thieme Stuttgart · New York

PAPER
A New Route to Polyhydroxylated Pyrrolidines
567
was stirred for 12 h, quenched with aq sat. NH4Cl and extracted with
Et2O. The combined organic layers were washed with H2O and
brine, and dried (Na2SO4). Concentration followed by flash chro-
matography on silica gel gave 13 (198 mg, 89%); [a]D20 –17.6
(c = 0.61, CHCl3).
Hz, HB-5), 1.46 (3 H, s, CH3-acetonide), 1.43 (3 H, s, CH3-ace-
tonide), 1.36 (3 H, s, CH3-acetonide), 1.26 (3 H, s, CH3-acetonide).
13C NMR (CDCl3, 50 MHz): d = 133.0 (C-ipso), 128.9 (2 CH-meta),
128.4 (2 CH-ortho), 127.0 (CH-para), 113.3 (C-acetonide), 107.5
(C-acetonide), 81.2 (CH-3), 77.3 (CH-4), 75.6 (CH-1¢), 68.2 (CH2-
2¢), 67.3 (CH-2), 59.2 (CH2-5), 58.4 (CH2-1¢¢), 29.0 (CH3), 26.4
(CH3), 26.0 (CH3), 24.9 (CH3).
EIMS: m/z (%) = 333 (M+, 1), 318 (10), 232 (100), 91 (100).
HRMS (EI): m/z calcd for C19H27NO4 (M+): 333.1940; found:
IR (film): 2930, 1456, 1379, 1209, 1101, 995 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.24–7.30 (5 H, m, Ar), 5.87 (1 H,
ddd, J = 8.6, 10.2, 16.9 Hz, H-1¢), 5.39–5.29 (2 H, m, H-2¢), 4.69–
4.54 (2 H, m, H-3, H-4), 3.99 (1 H, d, J = 13.6, HA-1¢¢), 3.08 (1 H,
d, J = 11.6 Hz, HA-5), 3.07 (1 H, d, J = 13.6, HB-1¢¢), 2.64 (1 H, m,
H-2), 1.98 (1 H, dd, J = 4.8, 11.6 Hz, HB-5), 1.57 (3 H, s, CH3-ace-
tonide), 1.31 (3H, s, CH3-acetonide).
13C NMR (CDCl3, 50 MHz): d = 140.0 (C-ipso), 135.8 (CH-1¢),
128.8 (2 CH-meta), 128.4 (2 CH-ortho), 126.9 (CH-para), 119.5
(CH2-2¢), 111.6 (C-acetonide), 82.9 (CH-3), 78.7 (CH-4), 72.1 (CH-
2), 58.9 (CH2-5), 56.7 (CH2-1¢¢), 26.5 (CH3-acetonide), 25.7 (CH3-
acetonide).
333.1954.
Compound 15
To a solution of compound 16 (200 mg, 0.68 mmol) (synthesized
following the procedure of Díaz-de-Villegas and Gálvez22) in ace-
tone (6 mL) was added 2,2-DMP (250 mL, 2.04 mmol) and a cata-
lytic amount of p-TsOH and the mixture was stirred at r.t. for 48 h.
The mixture was then neutralized with aq 5% NaHCO3 and extract-
ed with EtOAc. The combined organic layers were washed with
H2O and brine, then dried (Na2SO4) before concentration to give 15
(221 mg, 97%). The physical properties were identical to the com-
pound prepared according to the route described above.
EIMS: m/z (%) = 259 (M+, 52), 159 (52), 91 (100), 68 (60).
HRMS (EI): m/z calcd for C16H21NO2 (M+): 259.1572; found:
259.1591.
(2R,3S,4R)-N-Benzyl-2-[(1¢S)-1,2-dihydroxyethyl]-3,4-(isopro-
pylidenedioxy)pyrrolidine (14)
1,4-Dideoxy-1,4-imino-D-mannitol Hydrochloride (17)
Aminodiol 14 (86 mg, 0.29 mmol) was dissolved in MeOH (9 mL).
A catalytic amount of Pd(OH)2 (20%) and 12 M HCl (0.04 mL) was
added. After flushing with H2 and stirring under 3 atm of H2 for 24
h, the mixture was filtered over Celite and concentrated to give 17
(55 mg, 96%). The physical properties were identical to an authen-
tic sample of 17 purchased from Aldrich .
To a solution of compound 13 (198 mg, 0.77 mmol) in a dioxane–
H2O mixture (6:4, 8 mL) was added NMO (72 mg, 0.77 mmol) and
10 drops of a solution of 2.5% OsO4 in t-BuOH. The mixture was
heated at 60 °C for one day. The resulting mixture was cooled and
a sat. aq solution of Na2SO3 was added (3 mL). After stirring for 30
min, the mixture was extracted with EtOAc, the organic extract was
washed with brine and dried (Na2SO4). Concentration followed by
chromatography (n-hexane–EtOAc, 7:3) gave 14 (172 mg, 76%);
[a]D20 –27.9 (c = 0.73, CHCl3).
Acknowledgment
The authors thank the Spanish DGI for financial support (BQU
2001-1034) and Ministerio de Educación y Ciencia for doctoral fel-
lowship to M. T. B. and Junta de Castilla y León for a doctoral fel-
lowship to M. J. G.
IR (film): 3500, 1717, 1559, 1456, 1373, 1262, 1098 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.30–7.26 (5 H, m, Ar), 4.77–4.47
(3 H, m, H-3, H-4, H-1¢), 4.25 (1 H, d, J = 13.2 Hz, HA-1¢¢), 3.89 (1
H, dd, J = 8.0, 11.0 Hz, HA-2¢), 3.79 (1 H, dd, J = 4.4, 11.0 Hz, HB-
2¢), 3.20 (1 H, d, J = 13.2 Hz, HB-1¢¢), 3.08 (1 H, d, J = 11.4 Hz, HA-
5), 2.34 (1 H, m, H-2), 2.05 (1 H, m, HB-5), 1.54 (3 H, s, CH3-ace-
tonide), 1.29 (3 H, s, CH3-acetonide).
13C NMR (CDCl3, 50 MHz): d = 132.2 (C-ipso), 129.1 (2 CH-meta),
128.6 (2 CH-ortho), 127.4 (CH-para), 111.7 (C-acetonide), 81.5
(CH-3), 77.8 (CH-4), 69.9 (CH-2), 67.1 (CH-1¢), 65.5 (CH2-2¢),
58.4 (CH2-5), 56.2 (CH2-1¢¢), 26.3 (CH3-acetonide), 24.8 (CH3-ace-
tonide).
References
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To a solution of compound 14 (86 mg, 0.29 mmol) in acetone (3
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(4 H, m, H-4, H-1¢, H-2¢, HA-1¢¢), 4.07 (1 H, dd, J = 7.4, 7.8 Hz, H-
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Synthesis 2005, No. 4, 565–568 © Thieme Stuttgart · New York