Concise and highly stereocontrolled synthesis of 1-deoxygalactonojirimycin and its congeners using dioxanylpiperidene, a promising chiral building block

Article abstract of DOI:10.1021/ol034886y

(Matrix presented) A concise and stereoselective synthesis of the chiral building block, dioxanylpiperidene 4 as a precursor for deoxyazasugars, starting from the Garner aldehyde 5 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring is described. The asymmetric synthesis of 1-deoxygalactonojirimycin and its congeners 1-3 was carried out via the use of 4 in a highly stereocontrolled mode.

Full text of DOI:10.1021/ol034886y

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2527-2529
Concise and Highly Stereocontrolled
Synthesis of 1-Deoxygalactonojirimycin
and Its Congeners Using
Dioxanylpiperidene, a Promising Chiral
Building Block
,†
Hiroki Takahata,* Yasunori Banba,‡ Hidekazu Ouchi,† and Hideo Nemoto‡
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical UniVersity,
Sendai 981-8558, Japan, and Faculty of Pharmaceutical Sciences,
Toyama Medical & Pharmaceutical UniVersity, Toyama 930-0194, Japan
takahata@tohoku-pharm.ac.jp
Received May 20, 2003
ABSTRACT
A concise and stereoselective synthesis of the chiral building block, dioxanylpiperidene 4 as a precursor for deoxyazasugars, starting from
the Garner aldehyde 5 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring is described. The asymmetric
synthesis of 1-deoxygalactonojirimycin and its congeners 1−3 was carried out via the use of 4 in a highly stereocontrolled mode.
Interest continues to mount in new applications of natural
and synthetic glycosidase inhibitors in basic research and
medicine.1 Polyhydroxylated piperidines and their synthetic
analogues have attracted a great deal of attention in recent
years due to their ability to mimic sugars and competitively
and selectively inhibit glycosidases and glycotransferases2
of carbohydrate processing enzymes. Inhibition of digestive
glycosidases by inhibitors leads to the regulation of carbo-
hydrate absorption from the wall of the small intestine, and
hence such inhibitors can be used for the treatment of type
II diabetes. In addition, since inhibition of glycoprotein
processing glycosidases can alter cell-cell or cell-virus
recognition processes, such inhibitors are applicable for
cancer cell invasion and migration and viral infection.3
Included among the polyhydroxylated piperidines of recent
interest are 1-deoxygalactonojirimycin (1) and its derivatives.
These compounds are strong inhibitors of R-galactosidase
A and are currently in preclinical trials as a potential therapy
for Farby’s disease, a severe lysosomal storage disorder.4
Because of the therapeutic importance of these compounds
many synthetic efforts have been directed toward their
preparation.5 However, most of the reported methodologies
are lengthy and/or lead to low selectivity. In a project devoted
to the asymmetric synthesis of glycosidase inhibitors,6 our
† Tohoku Pharmaceutical University.
‡ Toyama Medical & Pharmaceutical University.
(1) (a) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed. 1999,
38, 750-770. (b) Zechel, D. L.; Withers, S. G. Acc. Chem. Res. 2000, 33,
11-18. (c) Stu¨tz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin
and Beond; Wiley-VCH: Weinheim, 1999. (d) Meyers, A. I.; Andres, C.
J.; Resek, J. E.; Woodall, C. C.; McLaughlin, M. A.; Lee, P. H.; Price, D.
A. Tetrahedron 1999, 55, 8931-8952.
(3) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahe-
dron: Asymmetry 2000, 11, 1645-1680.
(4) Asano, N.; Ishii, S.; Kizu, H.; Ikeda, K.; Yasuda, K.; Kato, A.; Martin,
O. R.; Fan, J.-Q. Eur. J. Biochem. 2000, 267, 4179-4186.
(2) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. ReV. 2000, 100,
4683-4696.
10.1021/ol034886y CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/19/2003

The D-serine-derived Garner aldehyde 5 provided an
attractive starting point for the synthesis because it reacts
with organometallic reagents with a high degree of diaste-
reoselectivity and little racemization.9 The diastereoselective
addition of vinyl metals to 5 may furnish the syn vinyl
alcohol, depending on the reaction conditions.10 The reagent
formed from in situ prepared vinyllithium and anhydrous
zinc dibromide in diethyl ether was found to provide the
syn alcohol as a solid with a 5:1 diastereoselectivity (syn:
anti) in 91% yield.11 The diastereoselectivity can be rational-
ized by considering the preferred transition state in each
reaction. The vinyl zinc bromide complex coordinated with
the carbamate carbonyl in the transition state is delivered to
the re face of the aldehyde carbonyl to afford the vinyl
alcohol syn-6. The chromatographic separation of a diaster-
eomeric mixture of alcohols 6 was incomplete. However,
the 67% de of the syn-preferred 6 was improved to 92% de
(72%) by one recrystallization. When the recrystallized 6
was treated with HCl gas in chloroform, it was converted to
the 1,3-acetonide 8 (69%) together with the recovery of syn-6
(24%) (Scheme 2).
Figure 1. Structure of 1-deoxygalactonojirimycin (1) and its
congeners (2 and 3).
goal involved the preparation of a new common chiral
building block, dioxanylpiperidene 4, which represents an
ideal precursor for the synthesis of 1-deoxygalactonojirimy-
cin (1) and its congeners (Figure 1). Herein we describe a
straightforward and stereoselective synthesis of 1-deoxyga-
lactonojirimycin and its congeners 1-3 via 4 starting from
the Garner aldehyde 57 using catalytic ring-closing metathesis
(RCM) for the construction of the piperidine ring.8
Our retrosynthetic analysis of 1-deoxyazasugars 1-3 is
outlined in Scheme 1. The common intermediate 4 can be
Scheme 2 a
Scheme 1
a Reagents and conditions: (a) vinyl zinc bromide, ether, -78
°C to rt; (b) (i) recrystallization from n-hexanes-ethyl acetate (5:
1), (ii) HCl gas, CHCl3, rt; (c) allyl iodide, NaH, THF, 0 °C; (d)
Grubbs’ catalyst, CH2Cl2, rt; (e) (i) H2, cat. 10% Pd-C, MeOH,
rt, (ii) 5 N HCl, MeOH, 60 °C; (iii) 30% NaOH, 0 °C.
prepared by the RCM of diolefin 7, produced by the
stereoselective coupling of 5 with vinyl metals.
N-Allylation of 8 with allyl iodide using NaH as a base
gave the diolefin product 7 in 76%. Finally, 7 was subjected
to RCM in the presence of Grubbs’ catalyst, (benzylidine)-
bis(tricyclohexylphosphine)ruthenium(IV) dichloride, in dichlo-
romethane to provide the desired piperidene 4 in excellent
yield. In addition, the stereochemistry of 4 was unambigu-
ously confirmed by its transformation to the known cis-3-
hydroxy-2-hydroxymethyl piperidine 95p (Scheme 2).
(5) 1-Deoxygalactonojirimycin: (a) Liguchi, T.; Tajiri, K.; Ninomiya,
I.; Naito, T. Tetrahedron 2000, 56, 5819-5833. (b) Mehta, G.; Mohal, N.
Tetrahedron Lett. 2000, 41, 5741-5745. (c) Asano, K.; Hakogi, T.; Iwama,
S.; Katsumura, S. Chem. Commun. 1999, 41-42. (d) Johnson, C. R.;
Golebiowsky, A.; Sundram, H.; Miller, M. W.; Dwaihy, R. L. Tetraherdon
Lett. 1995, 36, 653-654. (e) Uriel, C.; Santoyo-Gonzalez, F. Synlett 1999,
593-595. (f) Ruiz, M.; Ruanova, T. M.; Ojea, V.; Quintela, J. M.
Tetrahedron Lett. 1999, 40, 2021-2024. (g) Shilvock, J. P.; Fleet, G. W.
J. Synlett 1998, 554-556. (h) Chida, N.; Tanikawa, T.; Tobe, T.; Ogawa,
S. J. Chem. Soc., Chem. Commun. 1994, 1247-1248. (i) Aoyagi, S.;
Fujimaki, S.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1991, 56, 815-
819. (j) Kajimoto, T.; Chen, L.; Liu, K. K. C.; Wong, C. H. J. Am. Chem.
Soc. 1991, 113, 6678-6680. (k) Bernotas, R. C.; Pezzone, M. A.; Ganem,
B. Carbohydr. Res. 1987, 167, 305-311. 1-Deoxyidonojirimycin: (l) Singh,
O. V.; Han, H. Tetrahedron Lett. 2003, 44, 2387-2391. (m) Schaller, C.;
Vogel, P.; Jager, V. Carbohydr. Res. 1998, 314, 25-35. (n) Fowler, P. A.;
Haines, A. H.; Taylor, R. J. K.; Chrystal, E. J. T.; Gravestock, M. B.
Carbohydr. Res. 1993, 246 377-381. (o) Liu, K. K. C.; Kajimoto, T.; Chen,
L.; Zhong, Z.; Ichikawa, Y.; Wong, C. H. J. Org. Chem. 1991, 56, 6280-
6289. 1-Deoxygulonojirimycin: ref 5l. (p) Haukaas, M. H.; O’Doherty, G.
A. Org. Lett. 2001, 3, 401-404. (q) Ruiz, M.; Ojea, V.; Ruanova, T. M.;
Quintela, J. M. Tetrahedron: Asymmetry 2002, 13, 795-799. (r) Liao, L.-
X.; Wang, Z.-M.; Zhang, H.-X.; Zhou, W.-S. Tetrahedron: Asymmetry
1999, 10, 3649-3657.
(6) (a) Banba, Y.; Abe, C.; Nemoto, H.; Kato, A.; Adachi, I.; Takahata,
H. Tetrahedron: Asymmetry 2001, 12, 817-819. (b) Takahata, H.; Banba,
Y.; Ouchi, H.; Nemoto, H.; Kato, A.; Adachi, I. J. Org. Chem. 2003, 68,
3603-3607.
(7) Dondoni, A.; Perrome, D. Org. Synth. 1999, 77, 64-77.
(8) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(9) (a) Garner, P.; Park, J. M.; Malecki, E. J. Org. Chem. 1988, 53,
4395-4398. (b) Herold, P. HelV. Chim. Acta. 1988, 71, 354-363.
(10) (a) Williams, L.; Zhang, Z.: Shao, F.; Carroll, P. J.; Joullie´, M. M.
Tetrahedron 1996, 52, 11673-11694. (b) Coleman, R. S.; Carpenter, A. J.
Tetrahedron Lett. 1992, 33, 1697-1700.
(11) On the other hand, the use of HMPA as an additive in place of
ZnBr2 showed an anti-diastereoselectivity (68% de) in 91% yield.
2528
Org. Lett., Vol. 5, No. 14, 2003

With the promising educt 4 in hand, our interest was
directed to the stereoselective synthesis of compounds 1-3.
We first introduced an epoxy functionality into the double
bond to obtain both 1 and 2 containing a trans diol in the 3
and 4 positions. The dioxirane, generated in situ from Oxone
with 1,1,1-trifuluoroacetone, was reacted with 4 to give the
anti epoxide 10 as a single diastereomer in 99% yield. The
Chem 3D MOPAC calculation12 indicated that the most
stable conformer of 4 was 11 (Scheme 3). This indicates
Scheme 4 a
a Reagents and conditions: (a) (i) H2SO4, 1,4-dioxane, H2O,
reflux, (ii) Amberlite IRA-410 (OH- form), (iii) DOWEX 1x2 (OH-
form); (b) (i) H2SO4, 1,4-dioxane, H2O, reflux, (ii) Amberlite IRA-
410 (OH- form); (c) (i) 0.3 M KOH,1,4-dioxane, H2O, reflux, (ii)
6 N HCl, MeOH, rt, (iii) Amberlite IRA-410 (OH- form).
Scheme 3 a
treatment of 4 with a catalytic amount of K2OsO4‚2H2O (5
mol %) and 4-methylmorphorine N-oxide as a cooxidant gave
the diol 15 as a single diastereomer in 85% yield. This
remarkably high diastereoselectivity of the dihydroxylation
would arise from the same steric blocking of the concave
face as explained for the epoxidation of 4. Deprotection of
15 with HCl in methanol followed by treatment with an ion-
exchange (DOWEX 50Wx8 H+ form) afforded 1-deoxy-
gulonojirimycin (3)13 in 90% combined yield.
a Reagents and conditions: (a) Oxone, CF3COCH3, NaHCO3,
aqueous Na2‚EDTA, CH3CN, 0 °C; (b) p-TsOH‚H2O, MeOH, rt;
(c) (i) m-CPBA, NaH2PO4, CH2Cl2, 0 °C to room temperature, (ii)
2,2-dimethoxypropane, cat. PPTS, acetone, rt.
Scheme 5 a
that the epoxidation occurred exclusively from the less
hindered convex face, because the concave face is shielded
by a methyl substituent. On the other hand, the syn epoxide
was obtained by the hydroxy-directed epoxidation of the diol
12, prepared by hydrolysis of the acetonide of 4 with p-TsOH
in methanol. The epoxidation of the diol with m-CPBA
followed by acetonization afforded the syn epoxide 13 in
53% overall yield (Scheme 3).
a Reagents and conditions: (a) K2OsO4‚2H2O, NMO, acetone,
H2O, rt; (b) (i) 6 N HCl, MeOH, rt, (ii) DOWEX 50Wx8 (H+ form).
Acid hydrolysis of the epoxy ring of the syn epoxide 13
was accomplished by using a mixture of H2SO4/1.4-dioxane/
H2O in a ratio of 0.2/3/2, and further treatment with an ion-
exchange resin (DOWEX 1x2, OH- form) gave only 113 in
83% yield.14 Surprisingly, a similar treatment of anti epoxide
10 provided the abnormal bicyclic product 14 in 83% yield.
The structure of 14 was confirmed by X-ray crystallographic
analysis (Scheme 4). Presumably, the hydroxymethyl group
generated by acid hydrolysis of the acetonide would in-
tramolecularly attack the epoxide ring to form a bicyclo-
[3.2.1]ring. Fortunately, basic cleavage of the epoxide with
a mixture of KOH/1,4-dioxane/H2O followed by a sequence
of deprotection and desalting gave 1-deoxyidonojirimycin
(2)13 exclusively in 87% combined yield.
In summary, the newly promising chiral building block 4
in the synthesis of 1-deoxyazasugars was prepared in only
four steps from the Garner aldehyde 5. In practice, a
straightforward synthesis of 1-3 using 4 has been demon-
strated in a highly stereocontrolled fashion. This developed
method provides stereoisomeric diversity for the synthesis
of deoxyazasugars11 suitable for further studies of their
abilities as glycosidase inhibitors.
Acknowledgment. This research was supported by
Uehara Memorial Foundation and a Grant-in-Aid for Sci-
entific Research on Priority Areas (A) “Exploitation of Multi-
Element Cyclic Molecules” from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
The stereoselective dihydroxylation of the double bond
was also examined. Under modified Upjohn condition,15
(12) The optimal configuration for 11 was simulated using the semiem-
pirical method PM3 (software package Chemdraw ultra 6.0/Chem 3D Pro
5.0).
(13) The specific rotations and spectral data of these compounds were
consistent with the reported values; see Supporting Information.
(14) Severino, E. A.; Correia, C. R. D. Org. Lett. 2000, 2, 3039-3042.
(15) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973-1976.
Supporting Information Available: Experimental details
and characterization data for all new compounds, including
crystallographic details for 14. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL034886Y
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