5-Trihydroxypropyl-dihydrouracil derivatives as precursors of 1-azasugars: application to the stereoselective synthesis of d-galacto-isofagomine

Article abstract of DOI:10.1016/j.tetlet.2010.02.093

A new route for the synthesis of isofagomine analogues has been carried out by using as precursors enantiopure 5-trihydroxypropyl-dihydrouracil derivatives obtained from aldol-type addition of 1,3-dibenzyl-dihydrouracil to isopropylidene-protected glyceraldehyde. The synthesis of d-galacto-isofagomine is reported.

Full text of DOI:10.1016/j.tetlet.2010.02.093

Tetrahedron Letters 51 (2010) 2400–2402
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5-Trihydroxypropyl-dihydrouracil derivatives as precursors of 1-azasugars:
application to the stereoselective synthesis of D-galacto-isofagomine
*
Pietro Spanu , Cristina de Candia, Fausta Ulgheri
Istituto di Chimica Biomolecolare del CNR, Traversa La Crucca 3, I-07100 Li Punti, Sassari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A new route for the synthesis of isofagomine analogues has been carried out by using as precursors enan-
tiopure 5-trihydroxypropyl-dihydrouracil derivatives obtained from aldol-type addition of 1,3-dibenzyl-
Received 7 October 2009
Revised 15 February 2010
Accepted 16 February 2010
Available online 23 February 2010
dihydrouracil to isopropylidene-protected glyceraldehyde. The synthesis of
reported.
D-galacto-isofagomine is
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1-Azasugars
galacto-Isofagomine
Azasugars, a class of sugar-shaped molecules, have found a
growing interest in the last years because of their ability to inhibit
glycoprocessing enzymes.1 These polyhydroxylated piperidine
alkaloids are used as tools for studying the biological functions of
oligosaccharides2 and since many glycoprocessing enzymes have
been identified as important therapeutic targets, azasugars are
emerging as key molecules to find new drug candidates for antivi-
ral,3 anticancer4 and metabolic disorder therapies.4d,5 Two azasug-
ar-based drugs such as miglustat1a (N-butyl-deoxynojirimicin) for
the treatment of type-1 Gaucher’s disease and recently for type-C
Niemann–Pick disease6 and miglitol1a (N-hydroxyethyl-deoxy-
nojirimicin) for the treatment of type-2 diabetes mellitus have
been already approved.
In the past few years, isofagomine-type monosaccharide mim-
ics (1-azasugars) where the anomeric carbon is replaced by a nitro-
gen atom have shown an high and anomer-selective b-glycosidase
inhibition activity (Fig. 1).7 In their N-protonated form they mimic
the carbenium ion in the enzymatic glycosyl cleavage and form a
strong electrostatic interaction between the protonated endocyclic
nitrogen and the catalytic nucleophile of the enzyme.
synthesis of isofagomine-type azasugars constitutes an area of con-
siderable interest.11
In the past we have performed a new diastereoselective and ste-
reodivergent synthesis of 5-trihydroxypropyl-dihydrouracil deriv-
atives based on the aldol-type addition of 1,3-dibenzyl-
dihydrouracil (DBDHU) to isopropylidene-protected glyceralde-
hyde.12 Here we wish to report a stereoselective and versatile
new route to the synthesis of 1-azasugars by using these enantio-
pure polyfunctionalized compounds as precursors.
Our strategy for the synthesis of isofagomine-type azasugars is
outlined in Figure 2, which shows that a disconnection of C2–N1
bond of the 1-azasugar molecule A would lead to amino polyol B
obtainable from the ureido polyol C via reductive ring opening of
the 5-trihydroxypropyl-dihydrouracil derivative D. This key inter-
mediate is endowed with the appropriate three stereocentres met
in the final 1-azasugars and can be stereoselectively synthesized
from glyceraldehyde homologation using DBDHU.
The extremely potent and selective b-galactosidase inhibitor D-
galacto-isofagomine 10 (IC50 = 12 nM; Ki = 4 nM) was first chosen
to test our approach to 1-azasugars (Scheme 1).13,14 The synthesis
Recently, isofagomine derivatives have received a great atten-
tion because they are new therapeutic candidates for the treatment
of Gaucher’s disease in Phase II of clinical development,8 and be-
cause they are potent inhibitors of liver glycogen phosphorylase
with pharmaceutical application in the treatment of type-2 diabe-
tes9 and cardiovascular diseases.10 As a consequence, the develop-
ment of new stereoselective and versatile procedures for the
OH
OH
HO
OH
R
R
OH
*
*
*
*
*
*
*
N
N
H
H
R=CH2OH, CH3, COOH
Deoxynojirimycin-type azasugars Isofagomine-type 1-azasugars
* Corresponding author. Tel.: +39 079 2841221; fax: +39 079 2841298.
E-mail address: p.spanu@icb.cnr.it (P. Spanu).
Figure 1. Structures of azasugars and 1-azasugars.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.093

P. Spanu et al. / Tetrahedron Letters 51 (2010) 2400–2402
2401
ple, the syntheses of
L
-galacto- and
D
-allo-isofagomine enantiomers
OH
OH
OPG
*
OPG
OPG
OPG
are also possible simply by using readily available 2,3-O-isopropi-
lidene- -glyceraldehyde.
OH
OH
OH
OPG
OPG
*
1
*
*
NH2
*
*
4
L
5
*
3*
2
*
6
In summary we have shown a new stereoselective and versatile
route for the synthesis of isofagomine analogues starting from 5-
trihydroxypropyl-dihydrouracil derivatives obtained from the sim-
ple diastereoselective homologation of isopropylidene-protected
O
N
H2N
N
H
H
C
A
B
OPG
O
O
O
Bn
O
Bn
glyceraldehyde with DBDHU. The stereoselective synthesis of
lacto-isofagomine derivatives 10 was reported and the extension of
this procedure for the synthesis of -allo-isofagomine starting from
compound 3 as well as the synthesis of -allo and -galacto enanti-
-glyceraldehyde is un-
D-ga-
OPG
*
*
N
N
*
OPG
*
+
H
L
OPG
N
Bn
O
N
OPG
D
L
Bn
DBDHU
omers by using isopropylidene-protected
der investigation.
L
D
E
Figure 2. Retrosynthetic analysis.
References and notes
1. (a) Compain, P.; Martin, O. R. Iminosugars: from Synthesis to Therapeutic
Applications; Wiley: Chichester, 2007; (b) Stütz, A. E. Iminosugars as Glycosidase
Inhibitors: Nojirimicin and Beyond; Wiley-VCH: Weinheim, 1999.
2. Dwek, R. A. Chem. Rev. 1996, 96, 683–720.
3. (a) Robina, I.; Moreno-Vargas, A. J.; Carmona, A. T.; Vogel, P. Curr. Drug Metab.
2004, 4, 329–361; (b) Greimel, P.; Spreitz, J.; Stütz, A. E.; Wrodnigg, T. M. Curr.
Top. Med. Chem. 2003, 3, 513–523; (c) Ratner, L.; Heyden, N. V.; Dedera, D.
Virology 1991, 180–192. and references therein; (d) Fenouillet, E.; Papandreou,
M. J.; Jones, I. M. Virology 1997, 231, 89–95.
4. (a) Wrodnogg, T. M.; Steiner, A. J.; Ueberbacher, B. J. Anti-Cancer Agents Med.
Chem. 2008, 8, 77–85; (b) Gerber-Lemaire, S.; Juillerat-Jeanneret, L. Mini-Rev.
Med. Chem. 2006, 6, 1043–1052; (c) Nishimura, Y. Curr. Top. Med. Chem. 2003, 3,
575–591; (d) Balfour, J. A.; McTavish, D. Drugs 1993, 46, 1025–1054.
5. (a) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev. 2000, 100, 4683–4696; (b)
Fan, J.-Q. Trends Pharmacol. Sci. 2003, 24, 355–360.
starts from the required (5S,10S,20R)-5-trihydroxypropyl-dihydro-
uracil 4 synthesized via aldol-type addition of lithium enolate of
DBDHU 1 to 2,3-O-isopropylidene-D-glyceraldehyde 2 (4/3 isomer
ratio = 81/16) as previously reported.12,15 After the protection of
the C-10 hydroxyl group of 4 as TBS-ether, the addition of a large
excess of NaBH4 in 3/1 EtOH/H2O solution effected the reductive
cleavage of DHU ring. The C-1 hydroxyl group of the ureido polyol
5 was protected as TBS-ether and then both benzyl groups of the
urea functionality were removed by using lithium in liquid ammo-
nia in good yield.16 The next step of our synthetic plan was the
transformation of the ureido group of 6 into amino N-Boc-pro-
tected functionality of compound 7. It was obtained in good yield
and in a single step by using copper(II) chloride/lithium t-butox-
ide.17,18 Now, in aminopolyol 7 we have the complete skeleton
with appropriate chirality of the three stereocentres needed to ob-
tain the 1-azasugar target 10. The silyl-protecting groups of com-
6. Patterson, M. C.; Vecchio, D.; Prady, H.; Abel, L.; Wraith, J. E. Lancet Neurol.
2007, 6, 765–772.
7. Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515–554.
and references therein.
8. (a) Dulsat, C.; Mealy, N. Drugs Future 2009, 34, 23–25; (b) Tropak, M. B.;
Kornhaber, G. J.; Rigat, B. A.; Maegawa, G. H.; Buttner, J. D.; Blanchard, J. E.;
Murphy, C.; Tuske, S. J.; Coales, S. J.; Hamuro, Y.; Brown, E. D.; Mahuran, D. J.
ChemBioChem 2008, 9, 2650–2662; (c) Lockhart, D. PCT Int. Appl., WO
2008128106, 2008.; (d) Zhu, X.; Sheth, K. A.; Li, S.; Chang, H. H.; Fan, J.-Q.
Angew. Chem., Int. Ed. 2005, 44, 7450–7453.
9. (a) Oikonomakos, N. G.; Tiraidis, C.; Leonidas, D. D.; Zographos, S. E.;
Kristiansen, M.; Jessen, C. U.; Norskov-Lauritsen, L.; Agius, L. J. Med. Chem.
2006, 49, 5687–5701; (b) Somsak, L.; Nagy, V.; Hadady, Z.; Docsa, T.; Gergely, P.
Curr. Pharm. Des. 2003, 9, 1177–1189; (c) Jakobsen, P.; Lundbeck, J. M.;
Kristiansen, M.; Breiholt, J.; Demuth, H.; Pawlas, J.; Torres Candela, M. P.;
Andersen, B.; Westergaard, N.; Lundgren, K.; Asano, N. Bioorg. Med. Chem. 2001,
9, 733–744.
10. Rytved, K. A.; Dragsted, N.; Nyborg, N. Chresten B.; Iversen, L.; Kristiansen, M.
U.S. Patent Appl. Publ., US 2004082641, 2004.
11. For recent syntheses of isofagomine derivatives, see: (a) Imahori, T.; Ojima, H.;
Yoshimura, Y.; Takahata, H. Chem. Eur. J. 2008, 14, 10762–10771; (b) Mugrace,
B.; Tretyakov, A.; Fuerst, D.; Sheth, K. A.; Rybczynski, P. J.; Zhu, X. PCT Int.
Appl.,WO 2008144773, 2008.; (c) da Cruz, F. P.; Horne, G.; Fleet, G. W. J.
pound
7 were easily substituted with Bn groups to give
derivative 8 and then HCl was added to remove the ketal and the
Boc groups.19 The protection of the nitrogen as N-Cbz gave com-
pound 9 in good yield.20 To complete the synthesis, the free pri-
mary hydroxyl group of aminopolyol 9 was selectively oxidized
to aldehyde21, then catalytic reduction of the crude mixture gave
in one pot the deprotection of Bn and Cbz groups and reductive
amination furnished, after chromatographic purification, D-galac-
to-isofagomine 10 in 88% yield, 10% overall yield in 12 steps.22
Starting from the (5R,10S,20R)-5-trihydroxypropyl-dihydrouracil
3,23 the stereoselective synthesis of the b-galactosidase inhibitor
L-
allo-isofagomine could be performed using the same reaction pro-
tocol described for
D-galacto-isofagomine derivatives 10. In princi-
OH
OH OTBS
NH
OH
O
O
O
O
Bn
Bn
Bn
N
Bn
N
N
b
c
O
O
a
O
+
+
H
O
O
O
O
O
O
O
N
O
N
N
Bn
N
Bn
O
Bn
Bn
1
2
4
3
5
OTBS
BnO
OBn
OH
TBSO
HN
TBSO
NH2
OTBS
BnO
HN
OBn
OH
OH
OH
g
e
f
d
O
O
O
O
O
O
O
N
NH
Cbz
9
OH
N
H
H
Boc
Boc
D-galacto
7
6
8
isofagomine
10
Scheme 1. Reagents and conditions: (a) LDA, THF, 4 h, ꢀ78 °C, 88%; (b) (i) TBSOTf, 2,6-lutidine, CH2Cl2; (ii) NaBH4, EtOH/H2O 3/1 rt, 61% two steps; (c) (i) TBSCl, imidazole,
DMF; (ii) Li/NH3 liq., 52% two steps; (d) CuCl2–LiOtBu, THF, 81%; (e) Bu4NF, THF then BnBr, NaOH in CH2Cl2, 76%; (f) HCl, THF then CbzCl, NaHCO3, CHCl3/H2O, 85% two steps;
(g) TCC, TEMPO, CH2Cl2 then H2, Pd/C, 88% two steps.

2402
P. Spanu et al. / Tetrahedron Letters 51 (2010) 2400–2402
Tetrahedron Lett. 2008, 49, 6812–6815; (d) Chen, C.; You, B. Tetrahedron Lett.
17. Yamaguchi, J.-i.; Shusa, Y.; Suyama, T. Tetrahedron Lett. 1999, 40, 8251–8254.
18. Compound 7: 1H NMR (400 MHz, CDCl3) d 5.41 (br s, 1H), 4.11–4.02 (m, 2H),
3.92 (dd, J = 6.4, 1.8, 1H), 3.79–3.73 (m, 1H), 3.72–3.64 (m, 2H), 3.70 (ddd,
J = 13.6, 6.8, 4.8, 1H), 3.17 (ddd, J = 13.6, 6.0, 3.6, 1H), 2.30–1.96 (m, 1H), 1.42 (s,
9H), 1.39 (s, 3H), 1.32 (s, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H),
0.06 (s, 3H), 0.05 (s, 3H). 13C NMR (100 MHz, CDCl3) d 155.9, 108.9, 78.5, 76.8,
72.9, 67.6, 62.5, 43.6, 39.4, 28.4, 26.5, 25.8, 25.7, 25.2, 18.1, 18.0, ꢀ4.3, ꢀ4.6,
2008, 49, 672–674; (e) Mihara, Y.; Ojima, H.; Imahori, T.; Yoshimura, Y.; Ouchi,
H.; Takahata, H. Heterocycles 2007, 72, 633–645; (f) Goddard-Borger, E. D.;
Stick, R. V. Aust. J. Chem. 2007, 60, 211–213; (g) Ouchi, H.; Mihara, Y.; Takahata,
H. J. Org. Chem. 2005, 70, 5207–5214. and references therein; (h) Ouchi, H.;
Mihara, Y.; Watanabe, H.; Takahata, H. Tetrahedron Lett. 2004, 45, 7053–7056;
(i) Guanti, G.; Riva, R. Tetrahedron Lett. 2003, 44, 357–360; (j) Pandey, G.;
Kapur, M. Org. Lett. 2002, 4, 3883–3886; (k) Pandey, G.; Kapur, M. Synthesis
2001, 1263–1267; (l) Andersch, J.; Bols, M. Chem. Eur. J. 2001, 7, 3744–3747;
(m) Kim, Y. J.; Ichikawa, M.; Ichikawa, Y. J. Org. Chem. 2000, 65, 2599–2602; (n)
Pandey, G.; Kapur, M. Tetrahedron Lett. 2000, 41, 8821–8824; (o) Mehta, G.;
Mohal, N. Tetrahedron Lett. 2000, 41, 5747–5751; (p) Hansen, S. U.; Bols, M. J.
Chem. Soc., Perkin Trans. 1 2000, 911–915; (q) Schneider, C.; Kazmaier, U. Eur. J.
Org. Chem. 1998, 1155–1159; (r) Amat, M.; Llor, N.; Huguet, M.; Molins, E.;
Espinosa, E.; Bosch, J. Org. Lett. 2001, 3, 3257–3260; (s) Liang, X.; Lohse, A.; Bols,
M. J. Org. Chem. 2000, 65, 7432–7437; (t) Ichikawa, Y.; Igarashi, Y.; Ichikawa,
M.; Suhara, Y. J. Am. Chem. Soc. 1998, 120, 3007–3018.
ꢀ5.5. ½a 2D2
ꢁ
+5.2 (c 1.4, CHCl3). Anal. Calcd for C26H55NO6Si2: C, 58.49; H, 10.38;
N, 2.62. Found: C, 58.41; H, 10.43; N, 2.69.
19. Compound 8: 1H NMR (400 MHz, CDCl3) d 7.38–7.22 (m, 10H), 5.19 (br s, 1H),
4.72–4.40 (m, 4H), 4.16 (q, J = 6.4, 1H), 4.04 (dd, J = 8.4, 6.8, 1H), 3.83 (dd,
J = 8.4, 6.8, 1H), 3.79 (dd, J = 5.6, 4.0, 1H), 3.58–3.51 (m, 2H), 3.41–3.33 (m, 1H),
3.31–3.23 (m, 1H), 2.20–2.12 (m, 1H), 1.42 (s, 9H), 1.41 (s, 3H), 1.33 (s, 3H). 13C
NMR (100 MHz, CDCl3) d 156.0, 138.1, 128,4, 127.8, 127.7, 126.9, 108.9, 79.1,
78.8, 74.3, 73.2, 69.8, 66.7, 40.7, 39.7, 28.4, 26.6, 25.2. ½a D22
ꢀ3.0 (c 3.7, CHCl3).
ꢁ
Anal. Calcd for C28H39NO6: C, 69.25; H, 8.09; N, 2.88. Found: C, 69.31; H, 8.08;
N, 2.81.
12. Ulgheri, F.; Bacsa, J.; Nassimbeni, L.; Spanu, P. Tetrahedron Lett. 2003, 44, 671–
675.
13. Ichikawa, Y.; Igarashi, Y. Tetrahedron Lett. 1995, 36, 4585–4586.
14. The stereoselective syntheses of galacto-isofagomine were reported by using a
chemoenzymatic approach (10% overall yield, 10 steps),11s via Wittig
20. Compound 9: 1H NMR (400 MHz, CDCl3) d 7.30–7.13 (m, 15H), 5.45–5.35 (br s,
1H), 5.0 (s, 1H), 4.55–4.41 (m, 4H), 3.83–3.72 (m, 2H), 3.68–3.50 (m, 5H), 3.16
(dd, J = 13.6, 6.0, 1H), 2.76 (br s, 2H), 2.30 (br s, 1H). 13C NMR (100 MHz, CDCl3)
d 156.9, 137.9, 137.6, 136.5, 128.5, 128.0, 127.8, 78.4, 73.7, 73.3, 71.9, 69.8,
66.7, 63.9, 40.6, 40.1. ½a D22
ꢀ8.8 (c 0.9, CHCl3). Anal. Calcd for C28H33NO6: C,
ꢁ
rearrangement of
resolution,11e via chiral auxiliary approach in very low yield11r or starting
from
-lyxose in 12 steps.11t
a
chiral 3-hydroxypiperidene obtained via enzymatic
70.13; H, 6.94; N, 2.92. Found: C, 70.10; H, 7.12; N, 2.96.
21. De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 3041–3043.
22. Spectral data for compound 10 were found in good agreement with the
reported values from the literature (Ref. 11t): 1H NMR (400 MHz, D2O + DCl) d
3.94 (br s, 1H), 3.83 (ddd, J = 11.2, 4.4, 2.4, 1H), 3.55 (dd, J = 11.0, 6.8, 1H), 3.45
(dd, J = 11.6, 6.6, 1H), 3.22 (dd, J = 12.8, 4.4, 1H), 3.17 (dd, J = 12.6, 5.2, 1H), 2.92
(d, J = 11.6, 1H), 2.79 (t, J = 12.2, 1H), 1.95–2.02 (m, 1H). 13C NMR (100 MHz,
D
15. Three percent of a third diastereomer was detected by NMR analysis.
16. Compound 6: 1H NMR (400 MHz, CDCl3) d 5.37 (br s, 1H), 4.71 (br s, 2H), 4.12–
4.03 (m, 2H), 3.91 (dd, J = 6.8, 2.4, 1H), 3.76 (dd, J = 7.6, 6.0, 1H) 3.66 (d, J = 6.8,
2H), 3.42–3.33 (m, 1H), 3.18–3.10 (m, 1H), 2.06–1.96 (m, 1H), 1.39 (s, 3H), 1.32
(s, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 9H). 13C NMR
(100 MHz, CDCl3) d 159.3, 109.3, 77.1, 72.7, 67.9, 62.4, 44.7, 39.5, 26.8, 26.1,
D2O) d 68.3, 67.8, 62.0, 44.1, 41.9, 41.2. ½a D22
ꢀ2.7 (c 0.93, EtOH). Anal. Calcd for
ꢁ
C6H13NO3: C, 48.97; H, 8.90; N, 9.52. Found: C, 49.02; H, 8.96; N, 9.48.
23. Compound 3 can be preferentially synthesized by using the procedure reported
in Ref. 12 (LDA, SnCl4, Et2O, ꢀ78 °C).
25.5, 18.4, ꢀ4.0, ꢀ4.3, ꢀ5.2.
½ ꢁ +8.7 (c 1.6, CHCl3). Anal. Calcd for
a 2D2
C22H48N2O5Si2: C, 55.42; H, 10.15; N, 5.88. Found: C, 55.38; H, 10.23; N, 5.79.