Synthetic access to the first spirocyclopropyl iminosugar

Article abstract of DOI:10.1055/s-2005-923582

The synthesis of the first spirocyclopropyl iminosugar has been achieved in six steps and 13% overall yield from commercially available 2,3,5-tri-O-benzyl-D-arabinose. The synthesis is based on an efficient two-step reaction involving the titanium-mediate

Full text of DOI:10.1055/s-2005-923582

LETTER
223
Synthetic Access to the First Spirocyclopropyl Iminosugar
Cyclopropyl
I
min
h
osugar ristophe Laroche, Richard Plantier-Royon, Jan Szymoniak, Philippe Bertus,* Jean-Bernard Behr*
Laboratoire ‘Réactions Sélectives et Applications’, UMR URCA/CNRS 6519, UFR Sciences, Université de Reims Champagne-Ardenne,
BP 1039, 51687 Reims Cedex 2, France
Fax +33(3)26913166; E-mail: jb.behr@univ-reims.fr; E-mail: philippe.bertus@univ-reims.fr
Received 13 October 2005
that induces essential binding interactions with the bio-
Abstract: The synthesis of the first spirocyclopropyl iminosugar
logical receptor. However, the introduction of a spiro-
has been achieved in six steps and 13% overall yield from commer-
cyclopropyl group in the structure of iminosugars has not
been achieved yet. To our minds, such compounds should
cially available 2,3,5-tri-O-benzyl-D-arabinose. The synthesis is
based on an efficient two-step reaction involving the titanium-me-
diated aminocyclopropanation of 2,3,5-tri-O-benzyl-4-O-methane- have great potential due to conformational and electronic
sulfonyl-D-arabinononitrile and the subsequent cyclization
modifications in the structure of iminosugars, which
resulting from in situ nucleophilic attack of the so-formed amine.
might induce new and potent interactions in the binding
Addition of a Lewis acid during the cyclopropanation–cyclization
site of glycosidases. We present here the synthesis of
sequence greatly improved the yields.
spirocyclopropyl polyhydroxypyrrolidine (4, Figure 1)
based on a straightforward titanium-mediated transforma-
tion of a sugar-derived nitrile into the corresponding
Key words: azasugars, glycosidases, metallacycle, nitriles, spiro
compounds, titanium
cyclopropylamine with concomitant cyclization.
The conversion of aromatic or aliphatic nitriles into pri-
Polyhydroxypyrrolidines, also termed iminosugars or
mary cyclopropylamines can readily be achieved by using
azasugars, have been found to act as potent reversible
Grignard reagents, in the presence of titanium tetraiso-
glycosidase inhibitors.1 As such, they represent important
propoxide.7 The reactive intermediate involved in this
tools for the isolation and characterization of glycosidases
transformation is assumed to be a titanacyclopropane. Re-
as well as for the study of their mechanism of action.2
cently, we described an application of this method to poly-
Interestingly, iminosugars were also shown to induce
functionalized substrates such as sugar-derived nitriles.8
notable biological effects and have been envisaged as
A range of protecting groups like acetals, esters or ethers
anti-diabete, anti-retroviral or antitumour agents.3 DMDP
were shown to be well tolerated under the reaction
(1, 2,5-dideoxy-2,5-imino-D-mannitol) and its epimer 2
are representatives of this class of sugar mimics
conditions. Particularly, 2,3,5-tri-O-benzyl-4-O-pivaloyl-
D-arabinononitrile (7), prepared in two steps from com-
mercially available 2,3,5-tri-O-benzyl-D-arabinose (5),
was smoothly transformed into the corresponding cyclo-
propylamine 9 by reaction with EtMgBr and Ti(Oi-Pr)4
(Scheme 1).
(Figure 1). Both compounds strongly inhibit a- and b-
glucosidases and have been applied to the affinity purifi-
cation of invertase.4 DMDP also displayed some anti-HIV
activity.5 However, its high cytotoxicity has precluded its
use as an effective antiviral drug. The development of new
series of iminosugars might permit the identification of
more potent and selective glycosidase inhibitors with
improved biological profiles.
BnO
BnO
NH2OH, HCl
NaHCO3
OH
O
OH
NOH
PivCl, py
99%
91%
BnO
OBn
BnO
OBn
R
HO
OH HO
OH
HO
6
5
H
N
H
N
H
N
N
Ti(Oi-Pr)4 + 2 EtMgBr
BnO
OPiv
BnO PivO
BnO
HO
OH
HO
OH
HO
OH
H2N
CN
(i-PrO)2Ti
NH2
OBn
1
2
3
4
8
BnO
OBn
Figure 1
62%
7
9
Scheme 1 Synthesis of sugar-derived cyclopropylamine 9.8
The spirocyclopropyl moiety is part of the structure of a
number of bioactive molecules like sitafloxacin (DU-
6859, 3), a potent antibacterial agent.6 The three-mem-
bered ring was identified as a prominent pharmacophore
In an initial approach we envisioned the synthesis of 4 by
simple functional group transformations starting from the
cyclopropylamine 9 (Scheme 2). To this purpose, the
deprotection of the pivaloyl protecting group (MeONa/
MeOH) was followed by mesylation of the free hydroxyl
group (MsCl, pyridine). The corresponding mesylate was
SYNLETT 2006, No. 2, pp 0223–0226
0
1.
0
2.
2
0
0
6
Advanced online publication: 23.12.2005
DOI: 10.1055/s-2005-923582; Art ID: G33405ST
© Georg Thieme Verlag Stuttgart · New York

224
C. Laroche et al.
LETTER
not isolated and underwent spontaneous intramolecular the targeted pyrrolidine 11 (18%) in addition with the
nucleophilic displacement with the primary amine to yield unexpected imine 15 which appeared as the major con-
pyrrolidine 11 (42%) with inversion of the configuration stituent (47%).
at the C-5 stereocenter.9
A cyclic titanium iminate has been postulated as inter-
We then focused on the deprotection conditions to afford mediate in the aminocyclopropanation reaction, which is
4. Hydrogenolysis of benzyl-protected iminosugars is thought to undergo a ring contraction into the correspond-
generally a difficult task, due to the presence of the nitro- ing three-membered carbacycle.7b,8 Accordingly, the
gen base which is known to inhibit the process.10 Never- competing formation of pyrrolidine 11 and imine 15 can
theless, harsh conditions should be used to succeed, which be rationalized by an in situ nucleophilic displacement
are not compatible with the presence of a cyclopropyl occurring either with the carbacycle B or the titanium
moiety. Therefore, we performed debenzylation on the N- iminate A (Scheme 3).
Boc protected derivative 12. The reaction conditions used
(2.8% Pd, 1 atm H2, r.t., 16 h) led the cyclopropyl group
unchanged and provided polyhydroxypyrrolidine 13 in
76% yield. Targeted iminosugar 4 was finally obtained in
Though the key ring contraction occurs spontaneously at
room temperature when a-alkoxy nitriles like 7 are used
as substrates,7b the addition of a Lewis acid is required in
other cases to afford acceptable yields of the correspond-
ing cyclopropylamines. Accordingly, we investigated the
66% yield after acidic removal of the remaining Boc pro-
tection (1 M HCl, 16 h) and purification on a Dowex 50
influence of additional BF3·OEt2 on the reaction outcome.
W-X8 resin (elution with 0.8 M NH4OH). Compound 4
was isolated as a yellow foam and proved to be quite
BnO
OR
stable towards air and moisture. The structure of 4 was
CN
iii
i or ii
ascertained by spectral and analytical data.11
6
BnO
OBn
14a (R = Ms)
14b (R = Ts)
BnO
H
N
OH
BnO
ii
i
NH2
OBn
9
M
OR
TiL3
TiL2
N
N
BnO
BnO
OR
iv
BnO
BnO
OBn
10
11
ring
contraction
BnO
OBn
BnO
OBn
iii
B
A
Boc
N
Boc
N
v
v
HO
HO
BnO
iv
H
N
5
2
BnO
BnO
v
H
H
H
8.9%
N
N
Et
and/or
4
3
HO
OH
HO
OH
BnO
OBn
4
13
12
BnO
OBn
BnO
OBn
11
11
15
Scheme 2 Reagents and conditions: i) MeONa/MeOH, r.t., 48 h,
100%; ii) MsCl, pyridine, 0 °C, 1.5 h, 42%; iii) Boc2O (2 equiv),
Et3N, THF, r.t., 88%; iv) H2, 10% Pd/C (2.8% amount of Pd), MeOH,
r.t., 16 h, 76%; v) 1 M HCl, r.t., 16 h, then Dowex 50 W-X8, 66%.
L = Oi-Pr and/or OR
M = MgBr or BF3− (see text)
15
Yield (%)
Yield (%)
R = Ms (without BF3·OEt2)
47%
45%
20%
–
18%
17%
42%
20%
R = Ms (addition of BF3·OEt2 after 60 min)
R = Ms (addition of BF3·OEt2 after 10 min)
R = Ts (addition of BF3·OEt2 after 60 min)
A second set of experiments was devoted to an improve-
ment of the synthetic pathway. We reasoned that the intro-
duction of a leaving group (mesyl or tosyl) instead of the
pivaloyl protecting group in the starting nitrile would
shorten the reaction sequence. Indeed, cyclization might
occur in situ during the cyclopropanation step, affording
the key intermediate 11 in a more straightforward manner.
To this purpose, the initial dehydration of oxime 6 was
performed according to previously described procedures12
either with methanesulfonyl chloride or toluenesulfonyl
chloride in pyridine and produced nitrile 14a12 and 14b in
76% and 35% yield, respectively (Scheme 3). Cyclo-
propanation of 14a with EtMgBr (2 equiv) and Ti(Oi-Pr)4
(1 equiv) was carried out according to the previously op-
timized conditions (Et2O, –78 °C to r.t. then 1 h at r.t.).8
Mainly two compounds were isolated from the reaction
mixture after hydrolytic work up, which were identified as
Scheme 3 Reagents and conditions: i) MsCl (6 equiv) in pyridine,
0 °C to r.t., 3 h, 76%; ii) TsCl (6 equiv) in pyridine, 70 °C, 8 h, 35%;
iii) EtMgBr (2.2 equiv), Ti(Oi-Pr)4, –78 °C to r.t.; iv) BF3·OEt2 (2
equiv); v) H2O.
The addition of BF3·OEt2 to the reaction mixture after 60
minutes at room temperature did modify neither the yields
nor the ratio of the products. In contrast, a rapid addition
of the Lewis acid after 10 minutes at room temperature
greatly improved the yield of the targeted pyrrolidine 11
(42%) at the expense of imine 15 (20%).13 Coordination
of BF3·OEt2 to the nitrogen atom of the five-membered
titanacycle A would induce a more efficient ring contrac-
tion into B, limiting the formation of the imine 15.
Synlett 2006, No. 2, 223–226 © Thieme Stuttgart · New York

LETTER
Cyclopropyl Iminosugar
225
87, 3167. (l) Singh, S.; Han, H. Tetrahedron Lett. 2004, 45,
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Takebayashi, K.; Adachi, I.; Kato, I.; Ouchi, H.; Takahata,
H.; Fleet, G. W. J. Tetrahedron: Asymmetry 2005, 16, 223.
(n) Kim, J. H.; Curtis-Long, M. J.; Seo, W. D.; Lee, J. H.;
Lee, B. W.; Yoon, Y. J.; Kang, K. Y.; Park, K. H. Bioorg.
Med. Chem. 2005, 15, 4282. (o) Badorrey, R.; Cativiela, C.;
Diaz-de-Villegas, M. D.; Diez, R.; Galvez, J. A. Synlett
2005, 1734.
Cyclopropanation of tosylate 14b in the presence of
BF3·OEt2 gave 11 as the only reaction product. No trace of
by-product 15 was observed in the crude reaction mixture
1
by H NMR. It was assumed that the nucleophilic dis-
placement of the secondary tosyl leaving group in A was
slow enough to permit the initial ring contraction into
intermediate B. Unfortunately, the synthesis of substrate
14b as well as its cyclopropanation were low yielding,
which precluded the use of this compound on a prepara-
tive scale.
(2) Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond; Stütz, A. E., Ed.; Wiley-VCH: Weinheim, 1999.
(3) (a) Mehta, A.; Zitzmann, N.; Rudd, P.; Block, T.; Dwek, R.
FEBS Lett. 1998, 430, 17. (b) Iminosugars: Recent Insights
into their Bioactivity and Potential as Therapeutic Agents,
Martin, O. R., Compain, P., Eds. Curr. Top. Med. Chem.
2003, 3. (c) Fiaux, H.; Popowycz, F.; Favre, S.; Schütz, C.;
Vogel, P.; Gerber-Lemaire, S.; Juillerat-Jeanneret, L. J.
Med. Chem. 2005, 48, 4237. (d) Kim, J. H.; Curtis-Long, M.
J.; Seo, W. D.; Ryu, Y. B.; Yang, M. S.; Park, K. H. J. Org.
Chem. 2005, 70, 4082.
(4) Legler, G.; Korth, A.; Berger, A.; Ekhart, C.; Gradnig, G.;
Stütz, A. E. Carbohydr. Res. 1993, 250, 67.
(5) Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson, S.;
Namgoong, S. K.; Ramsden, N. G.; Jacob, G. S.;
Rademacher, T. W. Proc. Natl. Acad. Sci. U.S.A. 1988, 85,
9229.
(6) (a) Bogdanovitch, T.; Esel, D.; Kelly, L. M.; Bozdogan, B.;
Credito, K.; Lin, G.; Smith, K.; Ednie, L. M.; Hoellman, D.
B.; Appelbaum, P. C. Antimicrob. Agents Chemother. 2005,
49, 3325. (b) Dhople, A. M.; Namba, K. J. Chemother.
2003, 15, 47.
(7) (a) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 1792.
(b) Bertus, P.; Szymoniak, J. J. Org. Chem. 2002, 67, 3965.
(c) Bertus, P.; Szymoniak, J. Synlett 2003, 265.
In short, two alternative routes were explored for the syn-
thesis of protected azasugar 11 from the protected arabi-
nose 5. According to Scheme 1 and Scheme 2, 11 was
obtained in 5 steps and 24% overall yield whereas only 3
steps (36% overall yield) were required via the mesylate
14a (Scheme 3). This latter procedure was greatly im-
proved by the time-controlled addition of BF3·OEt2 during
the aminocyclopropanation–cyclization step. Deprotec-
tion of azasugar 11 to target compound 4 was achieved in
44% overall yield via the N-Boc derivative 12.
In summary, the first synthesis of a spiro cyclopropyl
iminosugar was achieved in a few steps from a carbo-
hydrate-derived nitrile. This synthetic approach seems to
be general and constitutes a useful methodology for the
synthesis of this new class of compounds. Work is in
progress to extend this methodology to the synthesis of a
series of azasugars in order to evaluate their biological
properties.
(d) Laroche, C.; Bertus, P.; Szymoniak, J. Tetrahedron Lett.
2003, 44, 2485. (e) Bertus, P.; Szymoniak, J. J. Org. Chem.
2003, 68, 7133. (f) Laroche, C.; Harakat, D.; Bertus, P.;
Szymoniak, J. Org. Biomol. Chem. 2005, 3, 3482.
(g) Gensini, M.; Kozhushkov, S. I.; Yufit, D. S.; Howard, J.
A. K.; Es-Sayed, M.; de Meijere, A. Eur. J. Org. Chem.
2002, 2499.
Acknowledgment
The authors thank the ‘Ministère de l’Enseignement Supérieur et de
la Recherche’ for a doctoral fellowship (C.L.) and the Université de
Reims-Champagne-Ardenne (BQR program 2004) for a financial
support.
(8) Laroche, C.; Behr, J.-B.; Szymoniak, J.; Bertus, P.; Plantier-
Royon, R. Eur. J. Org. Chem. 2005, 5084.
(9) The cis-relationship between the H-4 and H-5 hydrogen
atoms was confirmed by NOE experiments on the final
product 4. The irradiation of H-4 resulted in a NOE (8.9%)
on H-5 (Scheme 2).
(10) (a) Nishimura, S. Handbook of Heterogeneous Catalytic
Hydrogenation for Organic Synthesis; John Wiley and Sons:
New York, 2001. (b) Bronislaw, P.; Bartsch, C. J. Org.
Chem. 1984, 49, 4076. (c) Sajiki, H.; Hirota, K.
Tetrahedron 1998, 54, 13981.
References and Notes
(1) (a) Asano, N.; Kato, A.; Miyauchi, M.; Kizy, H.; Kameda,
Y.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J. J. Nat. Prod.
1998, 61, 625. (b) Takebayashi, M.; Hiranuma, S.; Kanie,
Y.; Kajimoto, T.; Kanie, O.; Wong, C.-H. J. Org. Chem.
1999, 64, 5280. (c) Wrodnigg, T. M.; Withers, S. G.; Stütz,
A. E. Bioorg. Med. Chem. Lett. 2001, 11, 1063.
(d) Yamashita, T.; Yasuda, K.; Kizu, H.; Kameda, Y.;
Watson, A. A.; Nash, R. J.; Fleet, G. W. J.; Asano, N. J. Nat.
Prod. 2002, 65, 1875. (e) Behr, J.-B.; Guillerm, G.
(11) Selected data for compound 4: [a]D20 +45 (c 0.16, H2O). 1H
NMR (250 MHz, D2O): d = 0.55 (m, 1 H, CH2CH2), 0.68 (m,
3 H, CH2CH2), 3.37 (ddd, 1 H, J = 4.7 Hz, J = 6.6 Hz, J = 6.6
Hz, H-5), 3.53 (dd, 1 H, J = 6.6 Hz, J = 11.2 Hz, CH2OH),
3.60 (d, 1 H, J = 1.6 Hz, H-3), 3.66 (dd, 1 H, J = 6.6 Hz,
J = 11.2 Hz, CH2OH), 4.10 (dd, 1 H, J = 1.6 Hz, J = 4.7 Hz,
H-4). 13C NMR (62.5 MHz, D2O): d = 6.1, 12.2, 45.1, 60.5,
61.3, 78.2, 81.9. HRMS-ESI: m/z calcd for C7H13NO3 + H+:
160.0974; found: 160.0975.
Tetrahedron: Asymmetry 2003, 111. (f) Tschamber, T.;
Gessier, F.; Dubost, E.; Newsome, J.; Tarnus, C.; Kohler, J.;
Neuburger, M.; Streith, J. Bioorg. Med. Chem. 2003, 11,
3559. (g) Carmona, A. T.; Popowycz, F.; Gerber-Lemaire,
S.; Rodriguez-Garcia, E.; Schütz, C.; Vogel, P.; Robina, I.
Bioorg. Med. Chem. 2003, 11, 4897. (h) Behr, J.-B.;
Chevrier, C.; Defoin, A.; Tarnus, C.; Streith, J. Tetrahedron
2003, 59, 543. (i) Chevrier, C.; LeNouen, D.; Neuburger,
M.; Defoin, A.; Tarnus, C. Tetrahedron Lett. 2004, 45,
5363. (j) Wrodnigg, T. M.; Diness, F.; Gruber, C.; Häusler,
H.; Lundt, I.; Rupitz, K.; Steiner, A. J.; Stütz, A. E.; Tarling,
C. A.; Withers, S. G.; Wölfler, H. Bioorg. Med. Chem. 2004,
12, 3485. (k) Lysek, R.; Vogel, P. Helv. Chim. Acta 2004,
(12) Buchanan, J. G.; Lumbard, K. W.; Sturgeon, R. J.;
Thompson, D. K.; Wightman, R. H. J. Chem. Soc., Perkin
Trans. 1 1990, 699.
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C. Laroche et al.
LETTER
(13) Typical Procedure for the Cyclopropanation of Nitrile
14a.
Imine 15: Rf = 0.58 (Et2O–Et3N, 98:2). 1H NMR (250 MHz,
CDCl3): d = 1.10 (t, 3 H, J = 7.0 Hz, CH2CH3), 2.30–2.50
(m, 2 H, CH2CH3), 3.73 (d, 2 H, J = 4.0 Hz, CH2OBn). 4.21
A solution of ethylmagnesium bromide (2.2 mmol, 1 to 2 M
in Et2O) was added at –78 °C under argon to a solution of
nitrile 14a (0.49 g, 1 mmol) and Ti(Oi-Pr)4 (0.33 mL, 1.1
mmol) in Et2O (25 mL). The yellow solution was stirred for
10 min, and warmed for ca. 1 h to 0 °C. The orange reaction
mixture was warmed directly to r.t. (water bath) and after 10
min, BF3·OEt2 (0.25 mL, 2 mmol) was added. After stirring
for 1 h, 1 N HCl (3 mL) and Et2O (15 mL) were added. The
resulting two clear phases were neutralized with 10% aq
NaOH (10 mL) and the mixture was extracted with Et2O
(2 × 30 mL). The combined organic layers were dried
(Na2SO4), filtered and concentrated under reduced pressure.
The residue was purified by silica gel flash chromatography
(Et2O–Et3N, 98:2) giving 15 (86 mg, 20%) and 11 (182 mg,
42%).
(m, 2 H), 4.47–4.62 (m, 7 H), 7.20–7.40 (m, 15 H, Ar-H). 13
C
NMR (62.5 MHz, CDCl3): d = 10.5, 25.2, 68.7, 70.6, 73.0,
73.1, 73.8, 84.5, 88.4, 127.8–128.9, 138.4, 138.5, 139.0,
179.7.
Cyclopropylamine 11: Rf = 0.10 (Et2O–Et3N, 98:2). 1H NMR
(250 MHz, CDCl3): d = 0.55–0.72 (m, 3 H, cyclopropyl-H),
0.92 (m, 1 H, cyclopropyl-H), 3.60–3.72 (m, 4 H, H-3, H-5,
H-6a,b), 4.11 (dd, 1 H, J = 1.6 Hz, J = 4.3 Hz, H-4), 4.40 (d,
1 H, JAB = 12.0 Hz, CH2Ph), 4.50–4.60 (m, 5 H, -CH2Ph),
7.20–7.40 (m, 15 H, Ar-H). 13C NMR (62.5 MHz, CDCl3):
d = 8.3, 12.6, 44.6, 60.2, 69.2, 71.7, 72.1, 73.5, 84.7, 86.8,
127.58–128.54, 138.4, 138.4, 138.5. HRMS-ESI: m/z calcd
for C28H31NO3 + H+: 430.2382; found: 430.2375.
Synlett 2006, No. 2, 223–226 © Thieme Stuttgart · New York