S. Ogawa et al. / Bioorg. Med. Chem. Lett. 12 (2002) 749–752
751
pyranosylamine 4 was earlier demonstrated to be a
strong inhibitor (Ki=2.0 Â 10À7 M), with decrease to
only one seventeeth of the value of the a-anomer2
(Ki=1.2 Â 10À8 M). Furthermore, contrary to the
expectations, the transition state mimics racemic 5 and 6
were found to be rather weak a-l-fucosidase inhibitors,
possessing Ki=45 and 1.2 Â 10À5 M, respectively.
Scheme 3. For convenience, the formulas depict only one enantiomer
of the respective racemates. Reagents and conditions: (a) Br2, CCl4, rt;
(b) NaBH4 (2 mol equiv), 80% aq HMPA, rt; (c) NaN3 (2 mol equiv),
DMF, rt; (d) 90% aq pyridine, PPh3, 60 ꢀC, 2 days.
The ground state mimics 1 and 4 have, thus, actually
been shown to possess very higher potency, being pro-
mising lead compounds for design of new l-fucosidase
inhibitors of this type. The present results might indir-
ectly suggest that the hydrolytic reaction of the a-l-
fucosidase (bovine kidney) feature an SN2-type
mechanism with nucleophilic displacement rather than
an SN1-type one through an oxocarbenium ion inter-
mediate. On the other hand, the l-enantiomer of 6
would be expected to act as a moderate l-fucosidase
inhibitor on chemical modification of the amino
function.
ment of 21 with bromine in CCl4 at room temperature
gave, after silica gel chromatography, 6-bromo-6-deoxy-
2,3,4-tri-O-methoxymethyl-5a-carba-altro-hex-5(5a)-
enopyranosyl bromides (22 and 23) in 21and 48%
1
yields, respectively. The H NMR spectra of 22 and 23
featured 1-H signals at d=4.85 (dd, J1,2=4.3, J1,5a=4.6
Hz) and 4.56 (dd, J1,2=6.6, J1,5a=3.4 Hz), respectively.
Selective debromination of the major 23 was conducted
by treatment with sodium borohydride in HMPA at
room temperature to give a 1:2 anomeric mixture of 6-
deoxy-5a-carba-altro-hex-5(5a)-enopyranosyl bromides
(24 and 25) in 57% yield, together with a mixture of 22
and 23 (ꢁ45% recovered). Direct nucleophilic sub-
stitution with a bromide ion generated in situ is likely to
occur at allylic C-1, resulting in epimerization to form
an equilibrium mixture of the anomers. Therefore, the
mixture of 24 and 25 should be furnished directly from a
crude mixture of the dibromides. The mixture was trea-
ted with an azide ion (2 mol equiv) in DMF at 0 ꢀC to
give a 1:2 mixture of the azides10 26 and 27 in 88%
yields. Reduction of the azides with triphenylphosphine
in aqueous THF gave a mixture of the amines 28 and
29, which was separated by a silica gel column to give
yields of 17 and 33%, respectively. Their 1H NMR
spectra showed 1-H signals at d=3.66 (dd, J1,2=4.3,
J1,5a=1.8 Hz) and 3.22 (dd, J1,2=6.7, J1,5a=2.7 Hz),
respectively, supporting the assigned structures. Depro-
tection of 28 and 29 was effected by heating with 4 M
hydrochloric acid to afford, after similar purification by
a resin column, the respective free bases 5 and 6 in
quantitative yields, the 1H NMR spectra11 of which
confirmed the assigned structures (Scheme 3).
References and Notes
1. Ogawa, S.; Sekura, R.; Maruyama, A.; Yuasa, H.; Hashi-
moto, H. Eur. J. Org. Chem. 2000, 2089.
2. Ogawa, S.; Maruyama, A.; Odagiri, T.; Yuasa, H.; Hashi-
moto, H. Eur. J. Org. Chem. 2001, 967.
3. Kameda, Y.; Takai, N.; Asanao, N.; Matsui, K. Chem.
Pharm. Bull. 1990, 38, 1970.
4. Takeuchi, M.; Kamata, K.; Yoshida, M.; Kameda, Y.;
Matsui, K. J. Biochem. 1990, 108, 42.
5. Ogawa, S.; Uematsu, Y.; Yoshida, S.; Sasaki, N.; Suami, T.
J. Carbohydr. Chem. 1987, 6, 471.
6. a-Selectivity in oxidation of 13 is highly enhanced by pro-
tecting the hydroxyls with cyclohexylidene group, which pro-
duce, under similar epoxidation conditions, the corresponding
a-epoxide in 62% yield.
1
7. The H NMR spectrum (300 MHz, CDCl3) of the 2-O-ace-
tyl derivative of 16 indicated a 2-H signal at d=4.79 (dd,
J1,2=10.0, J2,3=2.9 Hz), supporting the assigned structure,
the conformer of which adopts the C1form, having the methyl
group in an axial position.
1
8. The H NMR spectrum (300 MHz, CDCl3) of the 2-O-ace-
tyl derivative of 17 obtained in the usual manner revealed 1-H,
2-H, and 3-H signals at d=3.35 [ddd, J1,2=J1,5a(ax)=10.0,
J1,5a(eq)=4.1Hz], d=5.45 (dd, J2,3=10.0 Hz), and d=3.37
(dd, J3,4=2.4 Hz), respectively, confirming the assigned struc-
ture.
9. 1H NMR (300 MHz, D2O) data: d=0.92 (d, J=6.8 Hz, 3H,
Me), 1.30 [ddd, J1,5a(ax)=J5,5a(ax)=J5agem=12.7 Hz, 1H,
5a(ax)-H], 1.62 [ddd, J1,5a(eq)=J5,5a(eq)=4.0 Hz, 1H, 5a(eq)-
H], 1.71 (m, 1H, 5-H), 2.78 (m, 1H, 1-H), 3.40 (m, 2H, 2-H, 3-
H), 3.77 (br s, 1H, 4-H).
An alternative route was later shown to improve the
preparative processing and overall yields of 5 and 6.
Thus, the acetate 20 could similarly be converted into a
mixture (90%) of 30ꢀ,ꢁ dibromides, which were
directly debrominated to give a mixture (90%) of the
31ꢀ,ꢁ monobromides. Conventional azidolysis afforded
a mixture (86%) of the azides 32ꢀ,ꢁ, quantitatively,
then hydrogenolyzed to provide, after separation on a
silica gel column, the amines12 33ꢀ (21%) and 33ꢁ
(71%).
10. Ogawa, S.; Hattori, H.; Toyokuni, T.; Suami, T. Bull.
Chem. Soc. Jpn. 1983, 56, 2077.
11. 1H NMR (300 MHz, D2O) data: 5: d=1.63 (s, 3H, Me),
3.49 (br dd, J1,2=4.8, J1,5a=1.3 Hz, 1H, 1-H), 3.73 (dd,
J2,3=9.6, J3,4=4.1 Hz, 1H, 3-H), 3.81 (dd, 1H, 2-H), 3.97 (d,
1H, 4-H), 5.36 (br d, 1H, 5a-H); 6: d=1.63 (s, 3H, Me), 3.04
(br dd, J1,2=8.5, J1,5a=1.2 Hz, 1H, 1-H), 3.27 (dd, J2,3=10.9
Hz, 1H, 2-H), 3.41 (dd, J3,4=4.0 Hz, 1H, 3-H), 3.90 (d, 1H,
4-H), 5.23 (br d, 1H, 5a-H).
Biological assay
Preliminary biological assays13 of the inhibitory activ-
ities of compounds 4, 5, and 6 towards a-l-fucosidase
(bovine kidney) were performed. 5a-Carba-b-l-fuco-
12. 1H NMR (300 MHz, CDCl3) data: 33ꢀ: d=1.72 (br s, 3H,