A novel synthetic route to 2-alkylpropane-1,3-sultones and its application to the synthesis of 2-alkyl derivatives of tramiprosate

Article abstract of DOI:10.1016/j.tetlet.2007.10.042

A practical synthetic route to various 2-alkylpropane-1,3-sultones, the key intermediates for the preparation of 2-substituted homotaurines as analogs of tramiprosate, was developed.

Full text of DOI:10.1016/j.tetlet.2007.10.042

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8587–8589
A novel synthetic route to 2-alkylpropane-1,3-sultones and its
application to the synthesis of 2-alkyl derivatives of tramiprosate
*
´
Benoit Bachand, Mohamed Atfani, Bita Samim, Sophie Levesque,
Daniel Simard and Xianqi Kong
Department of Chemistry, Neurochem Inc., 275, boul. Armand-Frappier, Laval, QC, Canada H7V 4A7
Received 4 June 2007; accepted 8 October 2007
Available online 11 October 2007
Abstract—A practical synthetic route to various 2-alkylpropane-1,3-sultones, the key intermediates for the preparation of 2-substi-
tuted homotaurines as analogs of tramiprosate, was developed.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Tramiprosate (3-amino-1-propanesulfonic acid or
3APS, homotaurine, ALZHEMEDTM) is a candidate
drug that has recently completed a phase III clinical trial
for treating Alzheimer’s disease (AD) in North America
(United States, Canada). This small ionic compound
binds preferably to soluble amyloid b-peptide (Ab)
and decreases Ab42-induced cell death in neuronal cell
culture. Treatment of TgCRND8 mice with tramipro-
sate resulted in significant reduction in the brain amy-
loid plaque load and a significant decrease in the
cerebral levels of soluble and insoluble Ab40 and
Ab42.1 This compound is one of the first drug candidates
that are potentially disease-modifying agents in treating
AD. To understand further the impact of different sub-
stitution groups on the activity of tramiprosate, a series
of analogs were necessary for biological evaluation.
Compounds bearing different substituting groups at
C-2 position of 3-amino-1-propanesulfonic acid skeleton
are one of the sub-classes of homotaurine analogs tar-
geted in the current project (Fig. 1).
H2N
SO3H
SO3H
H2N
R
tramiprosate
(ALZHEMEDTM, 3APS)
2-alkyl-3-amino-1-
propanesulfonic acid
Figure 1.
propane-1,3-sultones were reported in the literature.2
Cyclization of 3-hydroxyl-1-propanesulfonic acid and
its derivatives3 and sulfonation of alkenes with sulfur
trioxide4 were the first methods for making simple sul-
tones. For the syntheses of more complex sultones, reac-
tions such as alkylation of sultones,5 cyclization of
alkanedisulfonate,6 and cyclization of allylated sulfo-
nate7 have been reported. The synthesis specifically
related to the 2-alkylpropane-1,3-sultone is the one
involving sulfur dioxide or thionyl chloride insertion
into functional vinylic Grignard reagents, which affor-
ded, after oxidation, a,b-unsaturated sultones.8–10
Another synthetic route was the cyclization of 2,3-epox-
yalkanesulfonylchlorides to the unsaturated sultones.11
Although those two last methods could be applied to
some of the target compounds, a more direct, versatile,
and simpler method of preparation was indeed necessary
for making different analogs for the project. Here a
practical synthetic route to 2-alkylpropane-1,3-sultones
starting from a-bromomethyl ketones either commer-
cially available or easily prepared from the correspond-
ing ketones is presented (Scheme 1).
A quick access to the C-2 substituted analogs of 3-ami-
no-1-propanesulfonic acid is the ring-opening reaction
of the corresponding 2-substituted propane-1,3-sultones
with different nucleophiles; this further requires easy
preparation of the corresponding 2-alkylpropane-1,3-
sultones. A number of synthetic methods for preparing
Keywords: Sultones; Tramiprosate (3-amino-1-propanesulfonic acid);
Alzheimer’s disease; Amyloid b (Ab).
*
The reaction was initiated by generating the lithium salt
of ethyl methanesulfonate with LiHMDS in THF at
Corresponding author. Tel.: +1 450 680 4500; fax: +1 450 680
4676; e-mail: bbachand@neurochem.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.042

8588
B. Bachand et al. / Tetrahedron Letters 48 (2007) 8587–8589
O
O
is presumably the nucleophilic attack of the methane-
sulfonate anion to the carbonyl in I, followed by an
intramolecular SN2 displacement of the bromine by
the in situ formed oxygen anion at the adjacent carbon
to give epoxide II. Base-catalyzed ring-opening of the
epoxide led to allylic alcoholate III, which is trans-
formed to 1,2-unsaturated sultone IV upon cyclization.
Similar base-catalyzed reactions in which epoxy esters
provided cyclic a,b-unsaturated lactones have been
reported in the literature.13,14 An example closely
related to the current work, in which 2,3-epox-
yalkanesulfonylchlorides were cyclized to unsaturated
sultones upon the treatment with base, has been
published.11
O
O
S
S
O
O
Pd/C 10 %,
O
LiCH2SO3Et,
THF, -78 °C
H2, 40-45 psi
Br
methanol
R
R
3a-e
R
2a-e
1a-e
R: a, 1-adamantyl; b, t-butyl; c, α,α-dimethylbenzyl; d, phenyl; e, ethyl.
Scheme 1. A two-step transformation of a-bromomethyl ketones to
2-substituted propane-1,3-sultones.
À78 ꢁC,12 and the resulting anion was reacted with
a-bromomethyl ketones (1a–e) to afford, after warming
to À50 ꢁC, the corresponding 1,2-unsaturated sultones
(2a–e). Hydrogenation of the 1-propene-1,3-sultones
led to the corresponding 2-alkylpropane-1,3-sultones
(3a–e) in good yields (Table 1). This two-step transfor-
mation proceeded smoothly with a variety of a-bromo-
methyl ketones, including sterically hindered ones. For
example, this two-step transformation starting from
1-adamantyl bromomethyl ketone (1a) gave 2-(1-ada-
mantyl)-propane-1,3-sultone (3a) in almost quantitative
yield. Good yields (40–67%) were also achieved with
other sterically hindered a-bromomethyl ketones such
as bromomethyl t-butyl ketone (1b) and bromomethyl
a,a-dimethylbenzyl ketone (1c). Aryl bromomethyl
ketone 1d and bromomethyl ethyl ketone 1e also pro-
vided the corresponding 1,2-unsaturated sultones in
good yields. In the case of phenyl derivative 2d, the
hydrogenation step resulted in sultone ring-opening,
providing 2-phenyl-1-propanesulfonic acid as the final
product.
With 2-substituted propane-1,3-sultones in hand, we
turned our attention to the sultone ring-opening with
various nucleophiles (Scheme 2). Opening of different
sultones (R = t-butyl, 1-adamantyl, a,a-dimethylbenzyl)
was performed using various nucleophiles such as
sodium azide, water, as well as hindered and unhindered
amines. The solvent of choice for performing these reac-
tions has been found to be DMF with prolonged reac-
tion times (between 24 and 72 h) and at elevated
temperature (up to 130 ꢁC). Under these conditions,
good yields (59–77%) of 3-amino-1-propropanesulfonic
acid derivatives (5a, 6a–c, 7a, and 8a,b) were obtained
with the exception of 5b (5% yield), which seems to have
encountered severe double steric effect from both the
sultone (1-adamantyl) and the nucleophile (t-butyl).
Sodium hydroxide opening of the sultones also gave in
modest to good yields the sulfonates (4a,b). Sultones
(3a–c) ring-opening by sodium azide15 gave the corres-
ponding azido compounds (6a–c) in good yields (60–
72%).
Figure 2 describes a plausible mechanism explaining
how the unsaturated sultone is formed. The initial step
Table 1. Reaction of a-bromomethyl ketones with lithioethylmethane-
sulfonate and the preparation of propane-1,3-sultones
Finally, the three azido derivatives 6a–c were converted,
upon hydrogenolysis, to the corresponding 2-substituted
1a–e
R
2a–e (%)
3a–e (%)
a
b
c
d
e
1-Adamantyl
t-Butyl
a,a-Dimethylbenzyl
Phenyl
97
75
ND
70
55
98
89
40a
96b
59
HO
SO3Na
R
4a : R = t-butyl (84 %)
4b : R = 1-adamantyl (40 %)
Ethyl
a Yield for two steps.
b 2-Phenylpropane-1-sulfonic acid isolated.
a
O
O
O
e
S
b
HN
SO3H
H3C
N
H
SO3H
R
R
R
O
O
8a : R = t-butyl (62 %)
8b : R = 1-adamantyl (59 %)
3a : R = t-butyl
5a : R = t-butyl (62 %)
5b : R = 1-adamantyl (5 %)
Br
3b : R = 1-adamantyl
3c : R = 1,1-dimethybenzyl
R
R
O
II
S
I
H
OEt
d
c
O
-CH2SO3Et
B-
N3
SO3Na
R
BnHN
R
SO3H
R
R
7a : R = t-butyl (77 %)
6a : R =
t
-butyl (72 %)
OLi
6b : R = 1-adamantyl (76 %)
O
S
O
O
6c : R = 1,1-dimethybenzyl (60 %)
O
III
IV
S
OEt
Scheme 2. Ring opening of sultones with various nucleophiles.
Reagents and conditions: (a) NaOH, DMF/water, reflux, 24 h; (b)
t-butylamine, DMF, 130 ꢁC, 48 h; (c) NaN3, DMF, 130 ꢁC, 36 h; (d)
BnNH2, DMF, 130 ꢁC; (e) MeNH2, THF, 130 ꢁC, sealed tube, 72 h.
O
Figure 2. Proposed mechanism for the formation of 1-propene-1,3-
sultones IV.

B. Bachand et al. / Tetrahedron Letters 48 (2007) 8587–8589
8589
Pd/C 10 %
5. Durst, T.; Du Manoir, J. Can. J. Chem. 1969, 47, 1230–
1233.
6. Durst, T.; Tin, K. C. Can. J. Chem. 1970, 48, 845–
851.
7. Enders, D.; Harnying, W.; Vignola, N. Eur. J. Org. Chem.
2003, 3939–3947.
H2N
SO3H
X
SO3H
H2, 40-45 psi,
methanol
R
R
6a : X = N3, R = 1-adamantyl
6b : X = N3, R = t-butyl
9a : R = 1-adamantyl (57 %)
9b : R = t-butyl (98 %)
6c : X = N3, R = dimethylbenzyl
9c : R = dimethylbenzyl (60 %)a
8. Thoumazeau, E.; Jousseaume, B.; Tiffon, F.; Duboudin,
J.-G. Heterocycles 1982, 19, 2247–2250.
9. Franks, M. A.; Schrader, E. A.; Pietsch, E. C.; Pennella,
D. R.; Torti, S. V.; Welker, M. E. Bioorg. Med. Chem.
2005, 13, 2221–2233.
Scheme 3. Formation of 2-alkyl-3-amino-1-propanesulfonic acids
9a–c. a Yield from sultone 3c.
derivatives of 3-amino-1-propanesulfonic acid (9a–c) in
good yields (Scheme 3).
10. Smil, D. V.; Souza, F. E. S.; Fallis, A. G. Bioorg. Med.
Chem. Lett. 2005, 15, 2057–2060.
11. Bonini, B. F.; Kemperman, G.; Willems, S. T. H.; Fochi,
M.; Mazzanti, G.; Zwanenburg, B. Synlett 1998, 1411–
1413.
In conclusion, a novel methodology has been developed
that allows rapid construction of several 2-alkyl-
propane-1,3-sultones in good to excellent yields. The
two-step transformation is easy, practical, and utilizes
only simple reagents such as ethyl methanesulfonate
and a-bromomethyl ketones, the latter often commer-
cially available or conveniently synthesized. The sultone
products, as the key intermediates for the preparation of
2-alkyl-3-amino-1-propanesulfonic acids, were success-
fully converted to the desired tramiprosate derivatives
in good yields.
12. To a stirred solution of lithium bis(trimethylsilyl)amide
(1.0 M solution in THF, 42 mL, 42 mmol, 1.5 equiv) at
À78 ꢁC was added dropwise a solution of ethyl methane-
sulfonate (4.3 mL, 10 mmol, 1.5 equiv) in dry THF
(5 mL). The mixture was stirred at À78 ꢁC for 30 min
followed by the addition of a solution of 1-bromopinaco-
lone (5.0 g, 28 mmol) in dry THF (10 mL). The mixture
was then stirred at À78 ꢁC for 2 h and later stirred at
À50 ꢁC for an additional 2 h. The reaction mixture was
quenched with a saturated aqueous solution of ammonium
chloride (100 mL), extracted with EtOAc (3 · 100 mL).
The combined organic layers were washed subsequently
with water (2 · 50 mL) and brine (100 mL), dried over
MgSO4, and concentrated under vacuum. The residue was
purified by flash chromatography using hexane/EtOAc
(90:10) to provide 3.8 g of 2b (75% yield): 1H NMR
(500 MHz, CDCl3) d 1.21 (s, 9H), 5.12 (d, J = 2.0 Hz, 2H),
6.45 (t, J = 2.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) d
28.7, 33.8, 71.7, 116.4, 161.7. HRMS for C7H13O3S; m/z
177.0585 (expected), 177.0593 (found).
References and notes
1. Gervais, F.; Paquette, J.; Morrissette, C.; Krzywkowski,
P.; Yu, M.; Azzi, M.; Lacombe, D.; Kong, X.; Aman, A.;
Laurin, J.; Szarek, W. A.; Tremblay, P. Neurobiol. Aging
2007, 28, 537–547.
2. For a review on sultone chemistry, see Roberts, D. W.;
Williams, D. L. Tetrahedron 1987, 43, 1027–1062.
3. Breslow, D. S.; Skolnik, H. Multi-sulfur and oxygen five-
and six-membered heterocycles. In The Chemistry of
Heterocyclic Compounds; Part II; Interscience: New York,
1966; Vol. 21, pp 774–780.
13. Concellon, J. S.; Riego, E.; Bernad, P. Org. Lett. 2002, 4,
1303–1305.
14. Klein, L. L.; Yeung, C. M.; Kurath, P.; Mao, J. C.;
Fernandes, P. B.; Lartey, P. A.; Pernet, A. G. J. Med.
Chem. 1989, 32, 151–160.
4. Bordwell, F. G.; Osborne, C. E.; Chapman, R. D. J. Am.
Chem. Soc. 1959, 81, 2698–2705.
15. Enders, D.; Harnying, W. Synthesis 2004, 2910–2918.