A short and concise synthesis of isofagomine, homoisofagomine, and 5′-deoxyisofagomine

Article abstract of DOI:10.1016/j.tetlet.2004.07.127

A short and concise synthesis of isofagomine derivatives via the epoxidation of chiral N-Boc-5-hydroxy-3-piperidene, followed by regioselective epoxide ring opening is described. This constitutes the first reported synthesis of homoisofagomine and the 5′-

Full text of DOI:10.1016/j.tetlet.2004.07.127

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7053–7056
A short and concise synthesis of isofagomine, homoisofagomine,
and 50-deoxyisofagomine
Hidekazu Ouchi, Yukiko Mihara, Hitomi Watanabe and Hiroki Takahata*
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1, Kamatsushima, Aoba-ku, Sendai 981-8558, Japan
Received 25 June 2004; revised 23 July 2004; accepted 28 July 2004
Available online 12 August 2004
Abstract—A short and concise synthesis of isofagomine derivatives via the epoxidation of chiral N-Boc-5-hydroxy-3-piperidene, fol-
lowed by regioselective epoxide ring opening is described. This constitutes the first reported synthesis of homoisofagomine and the
50-deoxyisofagomine.
Ó 2004 Elsevier Ltd. All rights reserved.
Based on their structural analogy to sugars, polyhydrox-
ylated nitrogen heterocycles (azasugars) competitively
and selectively inhibit glycosidases, carbohydrate
processing enzymes.1 Thus glycosidase inhibitors may
be potential agents for the treatment of diseases related
to metabolic disorders of carbohydrates such as diabe-
tes, cancer, AIDS, hepatitis, Gaucherꢀs disease, and
Figure 1.
influenza.2 A particularly effective route to enzyme
ars and 6-deoxyazasugars with a D-glucose-type config-
uration with a nitrogen in place of the anomeric
carbon, namely homoisofagomine (2) and 50-deoxyiso-
fagomine (3), has been prepared to date. Herein, we
describe a new route to the concise synthesis of isofago-
mine derivatives 1–3 through the nucleophilic opening
of the epoxide 7 starting from the chiral N-Boc-5-hyd-
roxy-3-piperidene (Fig. 2).
inhibitors is the design of transition state analogues. In
the case of the enzymatic hydrolysis of glycosides, the
putative transition state has considerable oxocarbe-
nium-ion characteristics in which the anomeric carbon
acquires sp2 hybridization and a partial positive charge
develops at the anomeric carbon and the endocyclic oxy-
gen.3 A new class of sugar mimic inhibitor having a
nitrogen atom at the anomeric position are 1-azasugars.
These compounds are highly potent inhibitors of b-gly-
cosidases, whose substrates they mimic.4 Among them,
isofagomine (1),4a isogalactofagomine,4c and isofucofag-
omine4d,g have been found to be particularly potent and
selective inhibitors of b-glycosidases (Fig. 1).
Racemic N-Boc-5-hydroxy-3-piperidene (4), which is
readily obtained via the reaction of 1,3-butadiene mono-
epoxide with allylamine and subsequent catalytic ring-
closing metathesis,8 served as the starting material. Oga-
sawara and co-workers reported9 on the lipase catalyzed
enantioselective transesterification of a N-Cbz-5-hyd-
roxy-3-piperidene with vinyl acetate. We applied this
Therefore, isofagomine (1) and analogues have been the
target of a number of recent syntheses.5 In recent years,
the synthesis and evaluation of homoazasugars and 6-
deoxyazasugars, such as 1-deoxyhomonojirimycin6 and
1,6-dideoxynojirimycin,7 have received considerable
attention. However, to our knowledge, no homoazasug-
Keywords: Isofagomine; 5-Hydroxy-3-piperidene; Epoxidation; Epox-
ide ring opening; Homoisofagomine; 50-Deoxyisofagomine.
*
Corresponding author. Tel.: +81 22 234 4181; fax: +81 22 275
2013; e-mail: takahata@tohoku-pharm.ac.jp
Figure 2.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.127

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H. Ouchi et al. / Tetrahedron Letters 45 (2004) 7053–7056
due to the somewhat less steric hindrance of the pseudo-
equatorial OTBDPS group. Therefore, it appears that
an attack on the dioxirane preferably occurred at the
less hindered anti-side to the large OTBDPS group.
The nucleophilic opening of the anti epoxide 7 with
ꢁhigher orderꢀ cuprates12 free halide ions in the presence
of boron trifluoride etherate as the activating species
was carried out as follows: treatment of 7 with
(CH2@CH)2CuCNLi2 in the presence of BF3OEt2 at
ꢀ78°C for 2h, gave 9 as the sole product in 74% yield.
Analogously, the reaction of 7 with Me2CuCNLi2
afforded only 10 in 71% yield. An attempt to employ
Grignard reagents in the presence of cuprous bromide13
resulted in no reaction. Although the rationale for this
high selectivity remains unclear, the following mecha-
nism is consistent with the results. The regiochemistry
of the nucleophilic opening of the epoxide on a six-mem-
bered ring is mainly controlled by trans diaxial opening
Scheme 1. Reagents and conditions: (a) vinyl acetate, lipase PS
(immobilized on ceramic particles)/t-BuOMe, 40°C, 18h; (b) lipase PS
(immobilized on ceramic particles)/0.1M phosphate buffer (pH7),
acetone, 40°C, 18h.
method to 4 using lipase and vinyl acetate. The resolu-
tion was best achieved using lipase PS (Pseudomonas
cepacia), immobilized on ceramic particles, in tert-butyl
methyl ether at 40°C to give the acetate (ꢀ)-5 in 49%
yield, along with the unreacted alcohol (+)-4, in 48%
yield. Enzymatic hydrolysis of the acetate (ꢀ)-5 using
the same lipase in 0.1M phosphate buffer afforded the
enantiomeric alcohol (ꢀ)-4 in 98% yield. The enantio-
meric purities of (+)- and (ꢀ)-4 were >99% ee, as deter-
mined by chiral HPLC analysis (Chiralcel OD column,
9:1 hexane/2-propanol, 0.5mLminꢀ1) after replacing
the N-protecting group with Cbz (Scheme 1).
(Furst–Plattner rule).14 Consequently, a high regioselec-
¨
tivity could result, if the opening proceeded through
only one of the two possible half chair conformations
(A and B). Thus, the exclusive attack of the nucleophile
at C-5 through conformer A would occur with trans
diaxial opening. On the other hand, an attack of the
nucleophile at C-4 of 7 through conformer B would be
subject to steric hindrance by the pseudoequatorial
OTBDPS group at the C-3. Therefore, a trans diaxial
opening through one of the half chair conformers,
namely conformer A would take place. A similar regio-
selectivity has been reported in ring-opening reactions of
trans-3-(benzyloxy)-1,2-epoxycyclohexane derivatives15
(Scheme 3).
Alcohol (+)-4 was initially converted into the TBDPS
derivative 6, thus avoiding the possible assistance of
the hydroxyl group in the favored approach of the oxi-
dant. Treatment of (+)-4 with tert-butyldiphenylsilyl
chloride under basic conditions gave the TBDPS deriv-
ative 6 in 99% yield. Oxidation of 6 with m-CPBA gave
the anti epoxide 7 and the syn epoxide 8 in 41% and 23%
yields, respectively. However, the diastereoselectivity
was low. The use of (trifluoromethyl)methyldioxirane
instead of m-CPBA as an oxidizing agent improved both
the yield and the diastereoselectivity. Thus, the dioxi-
rane, generated in situ10 from OxoneÒ with 1,1,1-tri-
fluoroacetone was reacted with 6 to give the anti
epoxide 7 and the syn epoxide 8 in 71% and 15% yields,
respectively (Scheme 2).
With the vinyl product 9 in hand, our interest was direc-
ted to its conversion to isofagomine (1) and homoisofag-
omine (2). Oxidative cleavage of the vinyl group of 9
using OsO4 and NaIO4 afforded the aldehyde, which
without purification, and after reduction with NaBH4
followed by deprotection, afforded 116 in 85% combined
yield. Next, the hydroboration of the vinyl group of 9
using 9-BBN followed by treatment with hydrogen per-
oxide gave the corresponding primary alcohol. Depro-
tection of the alcohol with 10% HCl in 1,4-dioxane
afforded 216,17 in 86% combined yield. Conversion of
10 to 50-deoxyisofagomine (3) was accomplished by
deprotection. The complete deprotection of 10 by treat-
ment with 10% HCl in 1,4-dioxane afforded 316,18 in 92%
The epoxidation is primarily governed by steric influ-
ence of the substituents.11 An attack at the syn-side of
the OTBDPS group is highly hindered by the pseudoax-
ial OTBDPS group. On the other hand, an attack at the
syn-side would lead to syn epoxide 8 as a minor product
Scheme 2. Reagents and conditions: (a) TBDPSCl, imidazole, cat.
DMAP/CH2Cl2, rt, 3h; (b) OxoneÒ, aq Na2EDTA, NaHCO3,
CF3COCH3/CH3CN, 0°C, overnight.
Scheme 3. Regiochemistry of the nucleophilic opening of the epoxide
7.

H. Ouchi et al. / Tetrahedron Letters 45 (2004) 7053–7056
7055
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Scheme 4. Reagents and conditions: (a) (CH2@CH)2CuCNLi2
(5equiv), BF3ÆOEt2 (2equiv)/Et2O, ꢀ78°C, 2h; (b) Me2CuCNLi2
(5equiv), BF3ÆOEt2 (2equiv)/Et2O, ꢀ78°C; (c) (i) cat. OsO4, NaIO4/
50% EtOH, rt, overnight; (ii) NaBH4/50% EtOH, rt, 1h; (iii) 10% HCl/
dioxane, reflux, 1h; (d) (i) 9-BBN/THF, rt, 6h; (ii) H2O2, 3mol/L
NaOH/THF, rt, 1h; (iii) 10% HCl/dioxane, reflux, 1h; (e) 10% HCl/
dioxane, reflux, 1h.
Figure 3.
yield. Thus the first synthesis of 2 and 3 was performed
(Scheme 4).
Søhoel, H. H.; Bulow, A.; Bols, M. J. Am. Chem. Soc.
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2001, 123, 5116–5117.
Enantiomers 11–13 of 1–3 were also prepared starting
from (ꢀ)-4, following the same procedure as above
(Fig. 3).
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In summary, an efficient synthesis of isofagomine (1),
homoisofagomine (2), 50-deoxyisofagomine (3), and
enantiomers 11–13 was achieved in 44–50% overall
yields from readily obtainable chiral N-Boc-5-hydroxy-
3-piperidene (4). The reaction employed epoxidation
into a double bond and a regioselective epoxide ring
opening reaction with ꢁhigher orderꢀ cuprates. To our
knowledge our route to isofagomine (1) is shorter and
more efficient than the other reported syntheses.5 This
synthetic route permits the preparation of substantional
amounts of 1-azasugars having a glucose configuration
and would be suitable for further studies of such com-
pounds as glycosidase inhibitors.
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Acknowledgements
Koman, M.; Prønayova, N.; Liptaj, T. Tetrahedron:
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This work was supported by Grant-in-Aid for Scientific
Research on Priority Areas (A) ꢁExploitation of Multi-
Element Cyclic Moleculesꢀ from the Ministry of Educa-
tion, Culture, Science, Sports and Technology of Japan
and Takeda Science Foundation (to H.O.).
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1
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2H), 1.72–1.85 (m, 1H), 2.10 (dd, J = 12.8, 11.4Hz, 1H),
2.22 (dd, J= 12.0, 10.9Hz, 1H), 2.87 (dd, J= 12.9, 4.2Hz,
1H), 2.92–3.02 (m, 2H), 3.24–3.34 (m, 1H), 3.43–3.58 (m,
2H); 13C NMR (67.8MHz, D2O): d 76.5, 71.3, 58.8, 48.8,
47.6, 39.1, 30.7; MS (EI): m/z 161 (M+); HRMS (EI): calcd
for C7H15NO3161.0152. Found 161.1088; [a]D +17.70 (c
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2.23 (t, J= 11.4Hz, 1H), 2.75 (d, J= 11.9Hz, 1H), 2.83–
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d 78.1, 71.2, 49.7, 49.0, 36.8, 13.1; MS (EI): m/z 131 (M+);
HRMS (EI): calcd for C6H13NO2 131.0946. Found
131.0984; [a]D +3.93 (c 1.12, EtOH).