triflate (TMSOTf) and borane-THF complex gave rise to
allylic alcohol (()-17.
Scheme 4
The asymmetric epoxidation or osmylation of 6 was
explored under a variety of conditions. Although these
transformations were highly regioselective for the disubsti-
tuted alkene in 6, only modest (20-25%) enantioselectivities
were achieved. As an alternative, oxidation of racemic 17
using Jones reagent gave the achiral enone 18, which was
immediately subjected to asymmetric LiAlH4 reduction using
(-)-N-methylephedrine as the chiral auxiliary12 to afford
optically active alcohol (+)-17 in 85% yield and 83% ee,
based on Mosher ester analysis. Hydrolysis of (+)-17
afforded unsaturated hydroxyacid (+)-19 in near-quantitative
yield. The hydroboration of (+)-19, following a protocol for
other â-substituted R,â-cyclohexenones,13 was performed
using BH3-THF (5 molar equiv) followed by oxidative
workup, affording trans,trans-triol (+)-20 as the exclusive
product in 65% yield. Hydrolysis of (+)-20 afforded (+)-
isofagomine 1 in 95% yield, thus confirming the assigned
absolute configuration of (+)-17.14 Overall, the synthesis of
isofagomine required eight steps and gave (+)-1 in 41% yield
from methyl nicotinate.
group in (-)-23 (or its methyl ester, not shown) proved
fruitless. Therefore, to improve its poor solubility in organic
solvents, (-)-23 was transformed to the moisture-sensitive
persilylated ester 24, which was smoothly reduced to the
desired aminotetraol (-)-4 in good yield.14
In summary, an efficient and flexible route to 1-azasugars
has been developed from a readily available and inexpensive
starting material.15 As part of that strategy, an improved
procedure has been devised for the 1,2-reduction of substi-
tuted pyridines with high regioselectivity. Taken together,
the methodology reported herein should provide access to
other new 1-N-iminosugars for use as anomer-specific
glycosidase inhibitors.
Intermediate (+)-20 also afforded ready access to glu-
curonidase inhibitor (+)-2 (Scheme 3). Oxidation of (+)-20
Scheme 3
Acknowledgment. We thank the National Institutes of
Health (GM 35712, GM 08500) for generous financial
assistance and for training grant support (to U.C.D.). Support
of the Cornell NMR Facility by the NSF and NIH is
gratefully acknowledged.
with platinum and oxygen furnished carboxylic acid (+)-21
(80%), which was deprotected in base to give (+)-214 in a
total of nine steps and 33% overall yield from methyl
nicotinate.
Supporting Information Available: Detailed experi-
mental procedures for 16, (()-17 18, and (+)-17, along with
1H and 13C NMR data for all new compounds. This material
Allylic alcohol (+)-17 was also useful in synthesizing
tetraol (-)-4, a hydroxylated analogue of isofagomine that
is also a potent and highly selective â-glucosidase inhibitor.6
Osmylation of (+)-17 afforded triol (-)-22 with excellent
anti-selectivity. Alkaline hydrolysis of the urethane and meth-
yl ester groups in (-)-22 afforded triol-amino acid (-)-23,
an hydroxylated analogue of 2 and prospective glucuronidase
inhibitor (Scheme 4). All attempts to reduce the carboxyl
OL006810X
(15) Representative procedure for the Fowler reduction: To a
suspension of methyl nicotinate 5 (10 g, 72.6 mmol) and sodium borohydride
(2.89 g, 72.6 mmol) in methanol (200 mL) at -78 °C was added phenyl
chloroformate (9.11 mL, 72.6 mmol) in a dropwise manner, over an interval
of 40 min. The mixture was stirred for 3 h and then poured onto 800 mL
of distilled water to give a yellow precipitate. The precipitate was filtered,
washed with distilled water (150 mL), and dried under vacuum to give 6
1
(18 g, 97%). H NMR (CDCl3, 300 MHz) δ 7.42-7.35 (m, 2 H), 7.28-
7.21 (m, 1 H), 7.18-7.13 (m, 3 H), 7.02 (d, 1 H, J ) 3.0 Hz), 5.44-5.37
(m, 1 H), 4.77 (s, 1 H), 4.63 (s, 1 H), 3.77 (s, 3 H); 13C NMR (CDCl3, 75
MHz) δ 66.1 and 165.7, 150.9 and 150.8, 132.7, 131,2. 129.8 and 129.7,
126.5-126.4, 121.7 and 121.6, 120.4, 118.5, 105.1 and 105.0, 52.1 and
51.9, 43.4 and 43.0; IR (CH2Cl2) 2950, 1740, 1720, 1230, 1190 cm-1; EIMS
m/z 259 (M+, 87%), 77 (100%).
(12) Kawasaki, M.; Suzuki, Y.; Terashima, S. Chem. Lett. 1984, 239-
242.
(13) Klein, J.; Dunkelblum, E. Tetrahedron 1968, 24, 5701-5710.
(14) Spectroscopic, chiroptical, and physical characterization data for this
compound matched literature values.
Org. Lett., Vol. 3, No. 2, 2001
203