Glycal-mediated syntheses of enantiomerically pure polyhydroxylated γ- and δ-lactams

Article abstract of DOI:10.1016/S0040-4039(02)00852-3

Syntheses of new enantiomerically pure γ-lactams 4a,b and δ-lactams 5a,b from D-glucal (3a) and D-galactal (3b) as starting materials are described.

Full text of DOI:10.1016/S0040-4039(02)00852-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4653–4655
Glycal-mediated syntheses of enantiomerically pure
polyhydroxylated g- and d-lactams
Antonella Squarcia, Fabrizio Vivolo, Hans-Georg Weinig, Pietro Passacantilli* and
Giovanni Piancatelli*
Dipartimento di Chimica, Universita` ‘La Sapienza’ and Centro CNR di Studio per la Chimica delle Sostanze Organiche Naturali,
Piazzale Aldo Moro 5, I-00185 Roma, Italy
Received 22 March 2002; revised 2 May 2002; accepted 3 May 2002
Abstract—Syntheses of new enantiomerically pure g-lactams 4a,b and d-lactams 5a,b from
starting materials are described. © 2002 Elsevier Science Ltd. All rights reserved.
D-glucal (3a) and D-galactal (3b) as
Azasugars, structurally related to cyclic carbohydrates in
which the ring oxygen is replaced by a nitrogen atom, and
analogues compounds are potent and selective glycosi-
dase inhibitors, and thus they have potential chemother-
apeutic applications in the prevention and treatment of
diseases such as cancer, diabetes and AIDS.1
Glycals (1,5-anhydro-hex-1-enitols) are important build-
ing blocks in the oligosaccharide chemistry,8 and only
very recently have they been employed via imino-glycals
in the synthesis of polyhydroxylated piperidines and
dihydropyridones.9
Herein we report a new synthetic strategy to the
These considerations have stimulated over the last
decades a vigorous activity for the syntheses of such
compounds, and excellent studies on the relationship
between their structures and inhibitory properties have
been reported.2,3 Since the hemiaminal moiety in azasug-
ars is reported to undergo easy dehydration, and the lack
of hydroxyl at C-2 to lower inhibition,3,4 recent work
showed that more stable d-lactams can act as nonbasic
glycosidase inhibitors.5 The syntheses of all eight
unknown enantiomerically pure g-lactams 4 and d-lac-
tams 5 from
1).
D
-glucal (3a) and
D
-galactal (3b) (Scheme
Starting material for the synthesis of g-lactams 4 were,
respectively, -glucal (3a) and -galactal (3b), which
D
D
were converted in an optimized one-pot procedure via
selective 3,6-di-O-benzoylation10 into the mesylates 6
(Scheme 2). Subsequent treatment with sodium azide/tet-
rabutylammonium chloride in toluene gave the corre-
sponding azides 7. A two-step hydration oxidation
sequence with pyridinium chlorochromate (PCC) in
dichloromethane was required to yield lactones 8. The
direct oxidation of 7, although an efficient procedure for
analogues substrates,11 gave unsatisfactory results.
Hydrogenation in the presence of palladium on carbon
yielded the protected g-lactams 9, which were quantita-
tively debenzoylated with sodium methanolate in
methanol to give the target compounds 4.12
stereoisomers of
D
-glyconic-d-lactams 16 and g-lactams
2 (Fig. 1) have been accomplished mainly from carbohy-
drates or other naturally occurring compounds,7 and
their glycosidase inhibitory properties have been evalu-
ated.
H
N
HO
OH
O
HO
HO
X
O
N
H
OH
H
HO
OH
1
2a: X = CH2OH
2b: X = H
The syntheses of the epimeric d-lactams 5a and 5b
obtained from
D
-glucal (3a) and -galactal (3b), respec-
D
Figure 1.
tively, are summarized in Scheme 3. Tri-O-benzyl-
D-
glucal (10a) and tri-O-benzyl- -galactal (10b), easily
D
prepared by total protection of the starting glycals,
were converted into lactones 11 by direct oxidation
with PCC in 1,2-dichloroethane at reflux. Transesterifi-
Keywords: lactams; azasugars; glycals; carbohydrates.
* Corresponding authors. Fax: +39-06/490631;
pietro.passacantilli@uniroma1.it; giovanni.piancatelli@uniroma1.it
e-mail:
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00852-3

4654
A. Squarcia et al. / Tetrahedron Letters 43 (2002) 4653–4655
H
N
HO
O
O
O
HO
HO
HO
HO
O
HO
HO
N
H
H
OH
3a
HO
OH
5a
4a
H
N
HO
O
HO
HO
HO
HO
O
N
H
H
OH
HO
OH
4b
3b
5b
Scheme 1.
Scheme 2. Reagents and conditions: (a) 2.3 equiv. BzCl, pyridine, 0°C, 1.5 h, then 2 equiv. MsCl, 0°C“rt, 0.5 h; (b) 3.5 equiv.
NaN3, 3 equiv. Bu4NCl, toluene, reflux, 24 h; (c) 30 equiv. HCl (12 M), dioxane, rt, 12 h; (d) PCC, CH2Cl2, rt, 48 h; (e) H2, Pd/C,
AcOEt, rt, 2 h; (f) p-TsOH cat., benzene, reflux, 1 h; (g) NaOMe, MeOH, rt, 0.5 h.
Scheme 3. Reagents and conditions: (a) 2.2 equiv. PCC, 1,2-dichloroethane, reflux, 6 h; (b) MeOH, H2SO4 cat., reflux, 6 h; (c) 2
equiv. MsCl, pyridine, 0°C“rt, 6 h; (d) 10 equiv. NaN3, DMF, reflux, 24 h; (e) H2, Pd/C, EtOH/MeOH (3:1), rt, 24 h.
cation with MeOH/H2SO4 cat. led to the open chain
hydroxy methyl esters 12 which, after mesylation to 13,
underwent SN2 substitution with sodium azide in DMF
at reflux to give the azides 14. Finally, hydrogenation
with palladium on carbon as catalyst in EtOH/MeOH
provided the target molecules 5a and 5b in one step.13
Reductive hydrogenation on 14b in AcOEt as solvent
afforded the totally protected d-lactam 15, which, after
treatment with lithium aluminiumhydride and subse-
quent debenzylation, yielded fagomine14 isomer 1615
(Scheme 4). The yields for this reaction sequence were
not optimized.
To demonstrate the utility of our synthetic strategy, we
report an example of further synthetic application
toward highly functionalized piperidines.
In summary, we have shown the synthetic potential and
versatility of glycals leading to novel polyhydroxylated
lactams and piperidines. The target compounds 4, 5,

A. Squarcia et al. / Tetrahedron Letters 43 (2002) 4653–4655
4655
H
N
H
9. (a) De´sire´, J.; Dransfield, P. J.; Gore, P. M.; Shipman, M.
Synlett 2001, 1329–1331; (b) Koulocheri, S. D.;
Haroutounian, S. A. Synthesis 1999, 1889–1892.
10. Graziani, A.; Passacantilli, P.; Piancatelli, G.; Tani, S.
Tetrahedron Lett. 2001, 42, 3857–3860.
O
N
BnO
BnO
b,c
HO
HO
a
14b
BnO
HO
15
16
11. Piancatelli, G.; Scettri, A.; D’Auria, M. Synthesis 1982,
245–258.
Scheme 4. Reagents and conditions: (a) H2, Pd/C, AcOEt, rt,
6 h, 50%; (b) LiAlH4, THF, reflux, 4 h, 50%; (c) H2, Pd/C,
EtOH, rt, 24 h, 50%.
12. Compound 4a: [h]2D5 −19 (c 1.1, MeOH). H NMR (200
1
MHz, D2O): l=2.26 (dd, J=18.0/2.2 Hz, 1H, H-2); 2.85
(dd, J=18.0/6.6 Hz, 1H, H-2%); 3.53 (dd, J=11.7/6.6 Hz,
1H, H-6); 3.59 (dd, J=11.7/4.4 Hz, 1H, H-6%); 3.65 (dd,
J=7.2/2.2 Hz, 1H, H-4); 3.81 (ddd, J=7.2/6.6/4.4 Hz,
1H, H-5); 4.45 (dt, J=6.6/2.2 Hz, 1H, H-3). 13C NMR
(50.3 MHz, D2O): l=41.2 (C-2); 64.5 (C-6); 66.8 (C-4);
71.1, 73.4 (C-3,5); 170.5 (CO).
and 16 extend the general class of known azasugars and
analogues. The protocol described herein provides an
easy access to the synthesis of other related azasugar
analogues, and further work is in progress in our
laboratory.
Compound 4b: [h]D25 +6 (c 1.2, MeOH). 1H NMR (200
MHz, D2O): l=2.33 (dd, J=17.6/1.7 Hz, 1H, H-2); 2.80
(dd, J=17.6/6.0 Hz, 1H, H-2%); 3.68 (dd, J=12.0/5.7 Hz,
1H, H-6); 3.77 (dd, J=8.5/4.6 Hz, 1H, H-4); 3.80 (dd,
J=12.0/3.5 Hz, 1H, H-6%); 3.93 (ddd, J=8.5/5.7/3.5 Hz,
1H, H-5); 4.64 (ddd, J=6.0/4.6/1.7 Hz, 1H, H-3). 13C
NMR (50.3 MHz, D2O): l=41.4 (C-2), 62.2 (C-4); 65.3
(C-6), 69.2, 71.3 (C-3,5); 174.4 (CO).
Acknowledgements
We gratefully acknowledge financial support from
CNR and from the Deutsche Forschungsgemeinschaft
(postdoctoral fellowship to H.-G.W.).
1
13. Compound 5a: [h]2D5 −10 (c 1.1, MeOH). H NMR (200
References
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