Total asymmetric synthesis of (-)-conduramine B-1 and of its enantiomer. N-Benzyl derivatives of conduramine B-1 are β-glucosidase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2005.04.023

The 'naked sugars' (+)- and (-)-7-oxabicyclo[2.2.1]hept-5-en-2-one have been converted into (-)-conduramine B-1 ((-)-3) and its enantiomer (+)-3, respectively. They have been condensed with a variety of aldehydes in the presence of NaBH(OAc)₃.

Full text of DOI:10.1016/j.bmcl.2005.04.023

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3071–3075
Total asymmetric synthesis of (ꢀ)-conduramine B-1 and of
its enantiomer. N-Benzyl derivatives of conduramine B-1 are
b-glucosidase inhibitors
Robert Łysek, Catherine Schutz and Pierre Vogel*
¨
` ´
Laboratoire de Glycochimie et de Synthese Asymetrique, Ecole Polytechnique Federale de Lausanne (EPFL), ISIC, BCH,
CH-1015 Lausanne-Dorigny, Switzerland
´ ´
Received 31 January 2005; revised 1 April 2005; accepted 14 April 2005
Available online 4 May 2005
Abstract—The ꢀnaked sugarsꢁ (+)- and (ꢀ)-7-oxabicyclo[2.2.1]hept-5-en-2-one have been converted into (ꢀ)-conduramine B-1 ((ꢀ)-
3) and its enantiomer (+)-3, respectively. They have been condensed with a variety of aldehydes in the presence of NaBH(OAc)3. The
N-substituted derivatives 4 and ent-4 so-obtained have been tested against two a-glucosidases, two amyloglucosidases, two b-glu-
cosidases and one b-xylosidase for their inhibitory activities. Although (ꢀ)-3 and (+)-3 do not inhibit any of these enzymes at
1 mM concentration, N-benzylated derivatives of (ꢀ)-conduramine B-1 are selective and competitive inhibitors of b-glucosidases
with Ki in low micromolecular range.
Ó 2005 Elsevier Ltd. All rights reserved.
Gaucherꢁs disease is the most prevalent of the lysosomal
storage disorders.1 The deficiency of the enzyme gluco-
sylceramide b-glucosidase leads to accumulation of its
nondegradable substrate glucosylceramide in mono-
cyte-macrophage cells. Patients with Gaucherꢁs disease
exhibit hepatosplenomegaly, anemia, bone lesions and
respiratory failure, with or without progressive neuro-
logical disorders. Current therapeutic strategies include
expensive enzyme replacement and substrate depletion.2
Unfortunately, the efficacy to neurological symptoms
of this therapy is low.3 The addition of competitive
b-glucosidase inhibitor such as N-(n-nonyl)-1-deoxynoj-
irimycin (1) (Fig. 1) to cultured cells stabilizes glucosyl-
ceramide b-glucosidase. The activity of the variant
enzyme is enhanced to such an extent that significant
improvement of therapeutic values could be achieved.4,5
This represents an example of specifically acting chemi-
cal chaperones.6 Recently, N-octyl-b-valienamine (2)7
has also been found to act as a chemical chaperone to
accelerate transport and maturation of F213I mutant
b-glucosidase and it may have a potential as drug in
the treatment of Gaucherꢁs disease. Less polar com-
Figure 1.
pounds than 1 and 2 should pass more readily through
the blood–brain barrier.
We have thus examined whether conduramine B-1 (3),
which can be seen as a de(hydroxymethyl) derivative
of b-valienamine, would not be a b-glucosidase inhibi-
tor.8 We report here its total, asymmetric synthesis
and its inhibitory activity towards two a-glucosidases,
two amyloglucosidases, two b-glucosidases and one b-
xylosidase. Neither (ꢀ)-3, nor (+)-3 did inhibit any of
these enzymes at 1 mM concentration. Interestingly,
Keywords: Asymmetric synthesis; Conduramine B-1; b-Glucosidases;
Inhibition; Naked sugars.
*
Corresponding author. Tel.: +41 21 693 93 71; Fax: +41 21 693 93
75; e-mail: pierre.vogel@epfl.ch
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.04.023

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R. Łysek et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3071–3075
however, N-benzylation of conduramine B-1 generates
derivatives 4 that are b-glucosidase inhibitors in the
low micromolecular range. As expected, enantiomers
ent-4 do not inhibit, or inhibit poorly the same b-gluco-
sidases. A few conduramine B-1 derivatives 4 are weak
inhibitors of b-xylosidase from Aspergillus niger.
was derived from methyl D-glucopyranoside following
a multistep process involving the formation of enone 5
(Scheme 1).15
We report here a new synthesis of (ꢀ)-3 applying our
ꢀnaked sugarꢁ methodology16 and which converts (+)-7-
oxabicyclo[2.2.1]hept-5-en-2-one17 ((+)-7) into enone
(ꢀ)-8 and into (ꢀ)-conduritol F ((ꢀ)-9).18,19 The same
method starting with (ꢀ)-7 allowed one to prepare
(+)-ent-conduramine B-1 ((+)-3) for the first time.
Racemic conduramine B-19 (( )-3) tetraacetate has been
prepared first in 1962 by Nakajima et al.10 A protected
form of (ꢀ)-3 has been obtained through dynamic ki-
netic asymmetric transformation of ( )-conduritol B11
tetrakis(3,3,3-trichloropropionates) by Trost et al.12
Unprotected conduramine B-1 (ꢀ)-3 was prepared first
by Stick and co-workers13 through Overman rearrange-
ment14 of trichloroacetamidate 6. The latter compound
Reduction of cyclohexenone (ꢀ)-8 with NaBH4/CeCl3Æ
7H2O in methanol (0 °C, 3 h) gave a 2.5:1 mixture of
alcohols (ꢀ)-9 and (ꢀ)-10 in 98% yield.18 Treatment of
this mixture with phthalimide, diethyl azodicarboxylate
and triphenylphosphine (all in 1.25 equiv)20 in dry tolu-
ene (0 °C, 12 h) provided a 4:1 mixture of N-substituted
phthalimides (ꢀ)-11 and (ꢀ)-12 (87%) that were sepa-
rated by flash column chromatography on silica gel
(Scheme 2).
In order to study the reactions of these phthalimides we
reacted racemic ( )-11 (51% yield based on ( )-8) with
an excess of hydrazine (5 equiv of NH2NH2ÆH2O,
MeOH, 5 h, 65 °C). This furnished amine ( )-13 in
77% yield. Unfortunately, desilylation (Bu4NFÆ3H2O,
THF) of ( )-13 gave ( )-3 which could not be purified.
Thus, we turned back to enantiomerically pure (ꢀ)-11
and undertook its desilylation under acidic conditions
(1% p-toluenesulfonic acid in MeOH, 30 min under
Scheme 1.
Scheme 2. Reagents and conditions: (a) NaBH4/CeCl3Æ7H2O/MeOH, 0 °C, 3 h; (b) phthalimide, EtOOCN@NCOOEt, Ph3P/toluene, 0 °C, 12 h/
separation by flash chromatography; (c) NH2NH2ÆH2O, MeOH, 5 h, 65 °C; (d) Bu4NFÆ3H2O/THF, 20 °C, 15 min; (e) 1% TsOH in MeOH, 65 °C,
reflux, 30 min; (f) 40% MeNH2 in H2O, 20 °C, 45 min, solvent evaporation in vacuo, filtration on Dowex-50W-X2 (H+ form)/2 N NH4OH; (g)
RCHO (1 equiv), NaBH(OAc)3 (1.4 equiv)/MeOH, 20 °C/2–5 h/yield: 81–99%; (h) RCHO (2.4 equiv), NaBH(OAc)3 (3.4 equiv)/MeOH, 20 °C/2–5 h/
yield: 49–68%.

R. Łysek et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3071–3075
3073
reflux). This provided (ꢀ)-14, the treatment of which
with 40% aqueous solution of methylamine21 (20 °C,
45 min), followed by filtration on acidic Dowex-50W-
X2, (H+) gave (ꢀ)-3 (elution with 2 N NH4OH) in
95% yield (Scheme 2).
not inhibit b-glucosidases from yeast and rice whereas
N-substituted derivatives 4 do, is not a surprise. They
also found that 17 and its N-alkyl derivatives inhibit
a-glucosidase from yeast. This is not the case with the
N-alkyl derivatives of conduramine B-1 (( )-4a–d).28
The latter, however, are moderate inhibitors of b-gluco-
sidase from almonds (IC50 = 32 lM for R = n-hexyl and
CH2CH2Ph). N,N-Disubstitution with n-propyl, n-octyl
or b-phenylethyl groups leads to very bad b-glucosidase
inhibitors (( )-15a–c). However, N-monosubstitution
with benzyl moieties as in 4e–j generates the best and
the most selective b-glucosidase inhibitors. The same
compounds 4e–j neither recognize a-glucosidases nor
amyloglucosidases. The best inhibitors are 4e,i and j
with inhibition constant Ki = 10, 8 and 13 lM, respec-
tively (Table 1). Lineweaver–Burk plots establish that
they are competitive inhibitors. The most potent inhibi-
tor 4i of b-glucosidase from almonds is also the best
The N-substituted derivatives ( )-4a–d, enantiomeri-
cally pure 4e–l and N,N-disubstituted derivatives ( )-
15a–c were prepared by standard reductive amination
of corresponding aldehydes.22 Starting with ꢀnaked
sugarꢁ (ꢀ)-7, (+)-ent-conduramine B-1 ((+)-3) and its
N-substituted derivatives were obtained in the same
way.23–25
We have tested compounds (ꢀ)-3 and (+)-3, ( )-4e–l
some of their enantiomers ent-4e–l, (ꢀ)-14, (+)-ent-14
and ( )-15a–c for their inhibitory activities towards se-
ven commercially available glycosidases. The data are
summarized in Table 1.
inhibitor
of
b-glucosidase
from
Caldocellum
saccharolyticum.
Ogawa et al.27 have found that b-valienamine (17) (Fig.
1) does not inhibit b-glucocerebrosidase whereas N-alkyl
derivatives can be potent inhibitors of this enzyme.
Thus, our finding is that conduramine B-1 ((ꢀ)-3) does
In summary, a new, total asymmetric synthesis of (ꢀ)-
conduramine B-1 ((ꢀ)-3) has been developed. The same
method has been used to prepare its enantiomer (+)-3.
Table 1. Inhibitory activity of (ꢀ)-conduramine B-1 ((ꢀ)-3) and N-substituted derivatives, and of some of their enantiomersa,b,c
Inhibitor
Enzyme
Compounds
R=
a-Glucosidase
Amyloglucosidase
Aspergillus Rhizopus
b-Glucosidase
Caldocellum
b-Xylosidase
Yeast
Rice
Almonds
Aspergillus
niger
niger
mold
saccharolyticum
(ꢀ)-3
(+)-3
( )-4a
( )-4b
( )-4c
( )-4d
4e
H
H
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
n-C3H7
30%
ni
80%, IC50 = 66
92%, IC50 = 32
85%, IC50 = 69
86%, IC50 = 32
96%, IC50 = 32
Ki = 10 (C)
51%
nm
nm
nm
nm
43%
ni
n-C6H13
n-C8H17
CH2CH2Ph
Bn
ni
ni
ni
ni
ni
74%
ni
ent-4e
4f
ni
ni
ni
ni
ni
ni
ni
ni
63%
31%
94%
ni
72%
57%
85%
ni
ni
ni
CH2C6H4OH-p
CH2C6H4OMe-p
93%, IC50 = 72
26%
56%
ni
67%
ni
ent-4f
4g
95%, IC50 = 52
Ki = 25 (C)
51%
68%
74%
ent-4g
4h
ni
ni
ni
ni
ni
ni
ni
ni
63%
ni
72%
ni
ni
ni
ni
ni
ni
CH2C6H4Cl-p
CH2C6H4Ph-p
96%, IC50 = 35
82%
84%, IC50 = 185
ni
94%, IC50 = 35
ent-4h
4i
45%
ni
72%
ni
97%, IC50 = 32
Ki = 8 (C)
56%
ent-4i
4j
ni
ni
ni
ni
ni
ni
ni
ni
ni
71%, IC50 = 52
ni
ni
CH2C6H4OPh-p
97%, IC50 = 43
Ki = 13 (C)
ni
ent-4j
4k
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
ni
41%
ni
ni
29%
41%
ni
ni
ni
ent-4k
4l
42%
ni
ni
ni
ni
ni
43%
ni
ent-4l
( )-15a
( )-15b
( )-15c
ni
ni
ni
ni
36%
n-C3H7
n-C8H17
CH2CH2Ph
ni
ni
ni
ni
ni
ni
ni
ni
36%
83%
ni
ni
ni
ni
Percentage of inhibition at 1 mM concentration of the inhibitor, IC50 and Ki in lM, when measured. Optimal pH, 35 °C.
a For conditions of measurement, see Ref. 26.
b (C): competitive (Lineweaver–Burk plots), ni: no inhibition at 1 mM concentration; nm: not measured.
cBoth phthalimides (ꢀ)-14 and (+)-ent-14 were devoid of inhibitory activity towards the enzymes tested here.

3074
R. Łysek et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3071–3075
K.; Iwasaki, H.; Watanabe, H.; Brady, R. O.; Suzuki, Y.
PNAS 2003, 100, 15912–15917.
Although conduramine B-1 does not inhibit b-glucosi-
dases (from almonds and from C. saccharolyticum)
and b-xylosidase from A. niger, its N-benzyl derivatives
are good competitive inhibitors of these enzymes. The
most potent b-glucosidase inhibitor, N-(p-phenylbenzyl)-
conduramine B-1 (4i) is also the most selective inhibitor.
Because of their relative important hydrophobicity,
N-benzyl derivatives of conduramine B-1 should be
tested for their ability to act as chemical chaperones
and for their therapeutic potential for the Gaucherꢁs
disease.
7. Lin, H.; Sugimoto, Y.; Ohsaki, Y.; Ninomiya, H.; Oka,
A.; Taniguchi, M.; Ida, H.; Eto, Y.; Ogawa, S.; Matsu-
zaki, Y.; Sawa, M.; Inoue, T.; Higaki, K.; Nanba, E.;
Ohno, K.; Suzuki, Y. Biochim. Biophys. Acta 2004, 1689,
219–228.
8. A correlation between glucosylceramide b-glucosidase
activity and lipid storage in the cell culture model system
for Gaucherꢁs disease has been established: Schueler, U.
H.; Kolter, T.; Kaneski, C. R.; Zirzow, G. C.; Sandhoff,
K.; Brady, R. O. J. Inherit. Metab. Dis. 2004, 27, 649–658.
9. For a nomenclature of conduramines, see: Fletcher, H. G.,
Jr.; Anderson, L.; Lardy, H. A. J. Org. Chem. 1951, 16,
1238–1246; Angyal, S. J.; Anderson, L. Adv. Carbohydr.
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Acknowledgements
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1981, 114, 3242–3252; (b) Guo, Z.-X.; Haines, A. H.;
Pyke, S. M.; Pyke, S. G.; Taylor, R. J. K. Carbohydr. Res.
1994, 264, 147–153.
´ ´
We are grateful to the Office Federal de la Recherche et
de la Science (OFES, No. 030738, European FP6 pro-
ject, TRIoH) for financial support. We thank also Mr.
Martial Rey, F. Sepu´lveda and S. Reddy Dubbaka for
their technical help and Professor Inmaculada Robina,
University of Seville, for useful discussions.
12. Trost, B. M.; Patterson, D. E.; Hembre, E. J. J. Am.
Chem. Soc. 1999, 121, 10834–10835.
13. McDonough, M. J.; Stick, R. V.; Tilbrook, D. M. G. Aust.
J. Chem. 1999, 52, 143–147.
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5. For earlier proposals of b-glucosidase inhibitors as
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Hrebicek, M.; Platt, F. M.; Butters, T. D.; Dwek, R. A.;
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19. For a route to both enantiomeric forms of azido-condur-
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20. Mitsunobu, O. Synthesis 1981, 1–28; see also: Renaut, P.;
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21. Sanfilippo, C.; Patti, A.; Piattelli, M.; Nicolosi, G.
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1948.
23. All compounds were obtained in analytically pure form
25
and fully characterized. Data of (+)-3: ½aꢁ589 +173
(c = 0.29, MeOH); IR (film): 3340, 2860, 1650, 1615,
1575, 1400 cmꢀ1; UV (MeOH): dmax 207 (e = 965); 1H
NMR (400 MHz, CD3OD): d 5.62, 5.54 (2H, 2ddd,
J1,6 ffi J1,5 ffi J6,4 ffi J5,4 = 2.4, J5,6 = 10.2, H-5, H-6), 4.09
(1H, m, H-1), 3.42 (1H, dd, J2,3 = 9.8, J3,4 = 7.8, H-3), 3.47–
4.26 (2H, m, H-2, H-4); 13C NMR (100.6 MHz, CD3OD):
d 131.3, 129.7 (2d, 162, C-5, C-6), 77.8, 77.7 (2d, 143, C-2,
C-3), 73.8 (d, 144, C-1), 55.7 (d, 139, C-4). Anal. Calcd for
C6H11NO3 (145.074): C, 49.65, H, 7.64. Found: C, 50.01;
H, 7.51.

R. Łysek et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3071–3075
3075
25
24. Data of (+)-ent-4e: ½aꢁ589 +87 (c = 0.075, MeOH); IR
J1,2 = 7.9, H-2); 13C NMR (100.6 MHz, CD3OD): d
142.6, 141.6, 135.1 (3s), 134.7 (d, 163, C-5), 131.0, 129.9,
128.6, 128.4, 127.9 (5d, 160), 123.9 (d, 158, C-6), 77.7 (d,
139, C-2), 73.1, 73.0 (2d, 144, C-1, C-3), 61.4 (d, 141, C-4),
49.9 (t, 142); HRMS (MALDI-TOF): calcd for
C19H21NO3Na: 334.1419 [M+Na+]. Found: 334.1414.
26. Appropriate p-nitrophenyl glucoside substrates buffered to
optimum pH of the enzymes were used: for details, see:
Brandi, A.; Cicchi, S.; Cordero, F. M.; Frignoli, R.; Goti,
A.; Picasso, S.; Vogel, P. J. Org. Chem. 1995, 60, 6806–
6812; Picasso, S.; Chen, Y.; Vogel, P. Carbohydr. Lett.
1994, 1, 1–8.
27. Ogawa, S.; Ashiura, M.; Uchida, C.; Watanabe, S.;
Yamazaki, C.; Yamagishi, K.; Inokuchi, J.-i. Bioorg.
Med. Chem. Lett. 1996, 6, 929–932.
28. N-Benzylation of a-valienamine29 and 2-(aminomethyl)-
pyrrolidine-3,4-diols22 also enhances their inhibitory activi-
ties and selectivities towards glycosidases.
(KBr): 3405, 1610, 1545, 1420, 1210, 1125 cmꢀ1; UV
(MeOH): dmax 260 (e = 360), 258 (350), 215 (3290); 1H
NMR (400 MHz, CD3OD): d 7.45–7.30 (5H, m), 5.76–
5.72 (2H, m, H-5, H-6), 4.12 (dd, J1,2 = 7.9, J1,6 = 3.2, H-
1), 4.05, 3.93 (2d, 2J = 12.9, H2C(Bn)), 3.59 (dd,
J2,3 = 10.0, J3,4 = 8.7, H-3), 3.46 (dd, J3,4 = 8.7, J4,5
=
3.2, H-4), 3.43 (dd, J2,3 = 10.0, J1,2 = 7.9, H-2); 13C NMR
(100.6 MHz, CD3OD): d 138.8 (s), 132.9, 126.1 (2d, 162,
C-5, C-6), 130.0, 129.7, 128.8 (3d, 160, CHar), 77.9 (d, 145,
C-2), 73.9 (d, 138, C-3), 73.4 (d, 147, C-1), 61.4 (d, 136, C-
4), 50.8 (t, 137). Anal. Calcd for C13H17NO3 (235.121): C,
66.36; H, 7.28; N, 5.95. Found: C, 65.87; H, 7.01; N, 6.04.
25
25. Data of (+)-ent-4i: ½aꢁ589 +107 (c = 0.15, MeOH); IR
(KBr): 3365, 2855, 1560, 1410, 1340, 1125, 1040 cmꢀ1
;
UV (MeOH): dmax 268 (e = 6370), 249 (7160), 217 (5450);
1H NMR (400 MHz, CD3OD): d 7.68–7.61 (4H, m), 7.54–
7.32 (5H, m), 5.85 (ddd, J5,6 = 10.4, J4,5 = 2.0, J1,5 = 1.9,
H-5), 5.80 (1H, ddd, J5,6 = 10.4, J4,6 = 2.1, J1,6 = 2.0, H-6),
4.15, 4.03 (2d, 2J = 13.0), 4.12 (1H, dd, J1,2 = 7.9,
J1,6 = 2.0, H-1), 3.63 (dd, J2,3 = 9.7, J3,4 = 8.8, H-3), 3.53
(dd, J3,4 = 8.8, J4,5 = 3.1, H-4), 3.45 (dd, J2,3 = 9.7,
29. (a) Kameda, Y.; Asano, N.; Yoshikawa, M.; Matsui, K.;
Horri, S.; Fukase, H. J. Antibiot. 1982, 35, 1624–1626; (b)
Chen, X.; Fan, Y.; Zheng, Y.; Shen, Y. Chem. Rev. 2003,
103, 1955–1977.