Synthesis of an iminosugar based peptidomimetic analogue

Article abstract of DOI:10.1016/j.tetlet.2004.01.064

The synthesis of an 1-deoxymannojirimycin based analogue of a known HIV-protease inhibitor is described. The strategies employed for introduction of the pharmacophore groups onto the azasugar scaffold were based on regioselective reactions of the hydroxyl

Full text of DOI:10.1016/j.tetlet.2004.01.064

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2067–2069
Synthesis of an iminosugar based peptidomimetic analogue
Florence Chery and Paul V. Murphy*
Centre for Synthesis and Chemical Biology, Chemistry Department, Conway Institute of Biomolecular and Biomedical Research,
University College Dublin, Belfield, Dublin 4, Ireland
Received 16 December 2003; accepted 16 January 2004
Abstract—The synthesis of 1-deoxymannojirimycin based analogue of a known HIV-protease inhibitor is described. The strategies
employed for introduction of the pharmacophore groups onto the azasugar scaffold were based on regioselective reactions of the
hydroxyl groups of the natural product and of
Ó 2004 Elsevier Ltd. All rights reserved.
D-fructopyranoside derivatives.
Peptidomimetic research has a goal of developing bio-
active compounds with improved pharmacokinetic
properties.1 The general principle is that pharmaco-
phoric groups are grafted onto a nonpeptide scaffold,
which can orient them in the direction of their respective
binding subsites. Farmer first proposed the use of
cyclohexane as such a scaffold.2 Later Belanger and
Dufresne designed target 1 as an enkephalin mimic.3
Subsequently researchers at the University of Pennsyl-
P1
P1
Binds to
Binds to
aspartic acids
aspartic acids
Charged
H-bond
and H-bond donor
O
acceptor
H
N
OH
O
OH
O
O
O
O
P3
P3
OH
O
OH
O
O
O
3
4
P1'
P1'
vania introduced b-
enantiomers and a diastereomer (b-
D
-glucopyranose (e.g., 2), its
-mannopyranose)
Figure 1. Design of putative azasugar peptidomimetic.
D
as scaffolds that provided bioactive compounds.4 Con-
currently Olson et al. reported a similar approach
employing a cyclohexane scaffold.5 Validation of the
concept has led other groups to utilize sugar scaffolds in
peptidomimetic and other research.6;7
scaffolds has been recently reported.8 One of the com-
pounds, which showed activity in this study was b-
D
-
glucopyranose derivative 3. We hypothesize that
the activity of 3 is due to it binding competitively in
the active site of the enzyme; the t-butyl groups and the
phenyl group are oriented into enzyme subsites and
the 2-OH group interacts with the catalytic aspartates in
the active site (Fig. 1). Although 3 has the glucose
(CH )
NH
NH
2 5
2
BnO
BnO
O
N
HO
O
O
configuration there were b-D-mannopyranosides that
2
1
were also active.8 On this basis we have designed the
putative inhibitor 4, which is based on the naturally
occurring glycosidase inhibitor 1-deoxymannojirimycin
(DMJ). Possible advantages of using DMJ or other aza-
sugars as scaffolds in peptidomimetic design over the
The design, synthesis, and evaluation of the first gener-
ation peptidomimetic inhibitors of HIV-1 protease that
incorporate b-
D
-manno- and b-D-glucopyranoside
b-D-glucopyranose variants are that the azasugar could
be charged atphysiological pH and also be a hydrogen
bond donor; this contrasts with 3 where the pyranose
oxygen atom has hydrogen bond acceptor potential.
Molecular modeling indicates that the protonated
nitrogen of 4 could hydrogen bond with a carbonyl
group of the HIV-protease amide backbone, assuming
Keywords: Peptidomimetic; Scaffold; Deoxynojirimycin; Azasugar;
1-Deoxymannojirimycin; Protease inhibitor.
* Corresponding author. Tel.: +353-1-7162504; fax: +353-1-7162127;
e-mail: paul.v.murphy@ucd.ie
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.064

2068
F. Chery, P. V. Murphy / Tetrahedron Letters 45 (2004) 2067–2069
OMe
OH
OMe
O
O
O
O
O
b
c
a
OH
OH
OH
O
a
O
O
b
D-Fructose
O
O
O
HO
PivO
OLev
O
O
OH
OPiv
14
OH
5
13
O
O
O
f, g
d, e
O
O
N
LevO
HO
HO
O
OH
OH
OH
OPiv
OH
O
HN
BnO
N
BnO
PivO
a
PivO
OLev
16
OLev
HO
HO
OH
15
OH
OH
OH
7
8
6
O
PivO
O
OH
i
h
LevO
PivO
c
OPiv
OPiv
OPiv
Br
Ph
OPiv
OH
LevO
OLev
OLev
18
OPiv
OH
d
HN
N
17
PivO
PivO
OH
OPiv
OH
OH
9
OH
10
O
HN
l
j
k
Br
4
11
PivO
PivO
OH
OH
Scheme 1. Reagents and conditions: (a) PivCl (2 equiv), Py 2 h; (b)
BnCOCl, NaHCO3, dioxane, H2O, 74%; (c) 10% Pd–C, H2, MeOH,
61%; (d) K2CO3, BnBr, DMF, 71%.
19
20
Scheme 3. Reagents and conditions: (a) acetone, H2SO4, 54%; (b)
levulinic acid, DCC (2 equiv), DMAP (cat.), THF, 91%; (c) 80%
AcOH, 45 °C, 4 h; (d) PivCl (1.1 equiv), Py )78 °C to rt overnight, 98%;
(e) levulinic acid (1.8 equiv), DCC (2 equiv), DMAP (cat.), THF, 77%;
(f) TFA/H2O (4:1), 2 h, 85%; (g) PivCl (1.2 equiv), Py 15 h, 90%; (h)
PPh3Br2, Py CH2Cl2, 3 h, heatatreflux, 93%; (i) NH 2NH2ÆH2O,
AcOH, H2O, 0 °C, 66%; (j) NaN3, DMF, rt, 48 h, 53%; (k) 10% Pd–C,
H2, MeOH, 22%; (l) K2CO3 (0.6 equiv), BnBr (1.15 equiv), DMF, 60%.
OH
O
O
N3
O
OH
PO
O
4
OPiv
O
OH
OP
12
P =Orthogonal protecting group
PivO
O
11
Scheme 2. Retrosynthetic analysis.
The levulinate ester 14 was firstprepared by DCC–
DMAP promoted coupling of levulinic acid13 with 13.14
Selective deprotection of the 4,5-di-O-isopropylidene
using 80% aqueous acetic acid at 45 °C gave 15. Regio-
selective pivaloylation of the 4-OH of 15 was followed
by introduction of a second levulinate group at O-5 and
gave 16. The 1,2-di-O-isopropylidene was nextremoved
using aqueous TFA and subsequentpivaloylaiton gave
17. Reaction of 17 with triphenylphosphine-bromine as
the compound would bind as predicted (Fig. 1). We thus
developed a synthetic route to 4.
There have been a number of syntheses of DMJ 6
including a route developed by our group.9 Attempts to
use DMJ as a starting compound for preparation of 4
were notsuccessful. In general we found ht atreacitons
of DMJ were low yielding and the products obtained
were prone to decomposition. Also the chemical
behavior of DMJ and that of its derivatives cannot be
€
described by Stutz gave the 6-deoxy-6-bromo-fructose
derivative 18 (93%). The levulinate groups were then
removed using hydrazine hydrate to give furanose 19
and its subsequent reaction with sodium azide in DMF
gave 11. The catalytic hydrogenation of 11 gave the 3,6-
di-O-pivaloylated DMJ 20 (22%), which was then con-
verted to the desired N-benzyl derivative 415 using
potassium carbonate and benzyl bromide in DMF (60%)
(Scheme 3).
compared directly to
ple, whereas the di-O-pivaloylation of methyl a-
D-mannopyranosides. For exam-
D
-
mannopyranoside gave 510 the corresponding reaction
of 7 was found to proceed to give 8 as a resultof
pivaloylation at the 2- and 6-OH groups (Scheme 1).
The reason for this is that introduction of the Cbz group
to give 7 results in a conformational switch of the DMJ
ring from 4C1 to 1C4; the 2-OH group is thus equatorial
and more nucleophilic than the 3- or 4-OH groups.
Attempts to alter the regioselectivity of the pivaloylation
by using (Bu3Sn)2O/PivCl led only to intractable prod-
uct mixtures or the recovery of 7. However, itwas
possible to convert 8 into 2,6-di-O-pivaloylated DMJ
derivative 9 and N-benzylated DMJ derivative 1011 as
shown in Scheme 1.
The use of the levulinate as opposed to other protecting
groups was necessary in order to complete the synthesis
of 4. Other potential intermediates such as 21 were
prepared but the selective removal of the acetates could
notbe achieved in our hands. Also hte reaciton of
21
with sodium azide led to decomposition and resulted in
an intractable product mixture.
One of the shortest syntheses of DMJ has been achieved
D
-fructose.12 We thus
PivO
O
€
by Stutz and co-workers from
OPiv
Br
investigated alternative routes to 4 via intermediates
derived from this ketohexose. It was proposed (Scheme
2) that the 1,4-di-O-pivaloylated-6-azido-fructofurano-
side 11 would be a viable intermediate and that it could
be prepared from 12.
AcO
OAc
21
We have demonstrated a strategy for selective manipu-
lation of hydroxyl groups of 1-deoxymannojirimycin so

F. Chery, P. V. Murphy / Tetrahedron Letters 45 (2004) 2067–2069
2069
Chem., Int. Ed. Engl. 1998, 37, 2503; (c) Boer, J.;
Gottschling, D.; Schuster, A.; Holzmann, B.; Kessler, H.
Angew. Chem., Int. Ed. Engl. 2001, 40, 3870; (d) Wessel, H.
P.; Banner, D.; Gubernator, K.; Hilpert, K.; Myller, K.;
Tschopp, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 751; (e)
that pharmacophoric groups could be grafted onto this
scaffold. Herein we have focused on synthesis of a
compound that might prove useful as a peptidomimetic
based HIV protease inhibitor. The biological evaluation
of 4 and related compounds are underway. To the best
of our knowledge azasugar derived peptidomimetics
have notbeen synhtesized previously. They may have
potential applications more widely as scaffolds for pre-
sentation of pharmacophore groups and have applica-
tion in other areas of bioorganic and medicinal
chemistry.
ꢀ
Moitessier, N.; Dufour, S.; Chretien, F.; Thiery, J. P.;
Maigret, B.; Chapleur, Y. Bioorg. Med. Chem. 2001, 9,
511; (f) Papageorgiou, C.; Haltiner, R.; Bruns, C.; Petcher,
T. J. Bioorg. Med. Chem. Lett. 1992, 2, 135; (g)
LeDiguarher, T.; Boudon, A.; Elwell, C.; Paterson, D.
E.; Billington, D. C. Bioorg. Med. Chem. Lett. 1996, 6,
1983; (h) Sofia, M. J.; Hunter, R.; Chan, T. Y.; Vaughan,
A.; Dulina, R.; Wang, H. M.; Gange, D. J. Org. Chem.
1998, 63, 2802; (i) Hanessian, S.; Huynh, H. K. Synlett
1999, 1, 102; (j) Nakayama, K.; Kawato, H. C.; Inagaki,
H.; Ohta, T. Org. Lett. 2001, 3, 3447.
Acknowledgements
7. (a) Peri, F.; Cipolla, L.; Forni, E.; Nicotra, F. Monatsh.
Chem. 2002, 133, 369–382; (b) Krueger, E. B.; Hopkins, T.
P.; Keaney, M. T.; Walters, M. A.; Boldi, A. M. J. Comb.
Chem. 2002, 4, 229–238.
8. (a) Murphy, P. V.; OꢀBrien, J. L.; Gorey-Feret, L. J.;
Smith, A. B., III. Bioorg. Med. Chem. Lett. 2002, 12,
1763–1766; (b) Murphy, P. V.; OꢀBrien, J. L.; Gorey-Feret,
L. J.; Smith, A. B. Tetrahedron 2003, 59, 2259–2271.
9. OꢀBrien, J. L.; Tosin, M.; Murphy, P. V. Org. Lett. 2001,
3, 3353.
The authors are grateful to IRCSET for a postdoctoral
fellowship to F.C. and to Enterprise Ireland (Sc/2002/
0225) for funding.
References and notes
10. Jiang, L.; Chan, T.-H. J. Org. Chem. 1998, 63, 6035.
1. (a) Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30,
1278; (b) Ripka, A. S.; Rich, D. H. Curr. Opin. Chem. Biol.
1998, 2, 441; (c) Hruby, V. J. Acc. Chem. Res. 2001, 34,
389.
2. Farmer, P. S. In Drug Design; Ariens, E. J., Ed.;
Academic: New York, 1980; 10, p 119.
11. Analytical data for 10: ½aŠ ¼ )93 (c 0.33, CHCl3), 1H
D
NMR (300 MHz, CDCl3): d ¼ 1:26, 1.30 (2s, 9H each,
Piv), 2.26 (dd, 1H, J1b–2 ¼ 2:8, J1a–1b ¼ À13:2, H-1b), 2.44
(dd, 1H, J4–5 ¼ 8:4, H-5), 2.99 (dd, 1H, J1a–2 ¼ 3:6,
J1a–1b ¼ À13:2, H-1a), 3.09 (d, 1H, J ¼ À17:4, CH2),
3.67–3.79 (m, 2H, H-3, H-4), 4.30 (d, 1H, J ¼ À17:4,
CH2), 4.56 (d, 1H, J5–6b < 0:5, J6a–6b ¼ À12:6, H-6b), 4.73
(dd, 1H, J5–6a < 0:5, J6a–6b ¼ À12:6, H-6a), 5.12 (br s, 1H,
H-2), 7.27–7.38 (m, 5H, Bn); 13C NMR (75 MHz, CDCl3)
d ¼ 27:2, 27.3 (CH3, Piv), 39.0 (C, Piv), 52.9, 56.6, 60.5
(CH2, C-1, C-6), 65.8, 69.2, 69.4, 74.0 (C-2, C-3, C-4, C-5),
127.2, 127.4, 128.3, 128.4 (CH-arom), 138.7 (C-arom),
178.5, 179.5 (CO, Piv); MS: [M+H]þ ¼ 422.3,
[M+Na]þ ¼ 444.3.
ꢀ
3. Belanger, P. C.; DuFresne, C. Can. J. Chem. 1986, 64,
1514.
4. (a) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.;
Salvino, J.; Leahy, E. M.; Sprengeler, P. A.; Furst, G.;
Smith, A. B., III; Strader, C. D.; Cascieri, M. A.;
Candelore, M. R.; Donaldson, C.; Vale, W.; Maechler,
L. J. Am. Chem. Soc. 1992, 114, 9217; (b) Nicolaou, K. C.;
Salvino, J. M.; Raynor, K.; Pietranico, S.; Reisine, T.;
Freidinger, R. M.; Hirschmann, R. In Peptides––Chemis-
try, Structure, and Biology: Proceedings of the 11th
American Peptide Symposium; Rivier, J. E., Marshall, G.
R., Eds.; ESCOM: Leiden, 1990; pp 881–884; (c) Hirsch-
mann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy, E. M.;
Salvino, J.; Arison, B. H.; Cichy, M. A.; Spoors, P. G.;
Shakespeare, W. C.; Sprengeler, P. A.; Hamley, P.; Smith,
A. B., III; Reisine, T.; Raynor, K.; Maechler, L.;
Donaldson, C.; Vale, W.; Freidinger, R. M.; Cascieri,
M. A.; Strader, C. D. J. Am. Chem. Soc. 1993, 115, 12550;
(d) Hirschmann, R.; Hynes, J., Jr.; Cichy-Knight, M. A.;
van Rijn, R. D.; Sprengeler, P. A.; Spoors, P. G.;
Shakespeare, W. C.; Pietranico-Cole, S.; Barbosa, J.;
Liu, J.; Yao, W.; Rohrer, S.; Smith, A. B., III. J. Med.
Chem. 1998, 41, 1382–1391.
€
12. Spreitz, J.; Stutz, A. E.; Wrodnigg, T. Carbohydr. Res.
2002, 337, 183.
13. Glushka, J. N.; Perlin, A. S. Carbohydr. Res. 1990, 205,
305.
14. This was prepared by thermodynamically controlled
acetonation of fructose in acetone with sulfuric acid. See
Brady, R. F., Jr. Carbohydr. Res. 1970, 15, 35.
15. Analytical data for 4: 1H NMR (300 MHz, CDCl3):
d ¼ 1:25 (s, 18H, Piv), 2.33 (br d, 1H, J1b–2 < 0:5,
J1a–1b ¼ À12:0, H-1b), 2.55 (dt, 1H, H-5), 2.87 (dd, 1H,
J1a–2 ¼ 4:5, J1a–1b ¼ À12:0, H-1a), 3.35 (d, 1H, J ¼ À13:2,
CH2), 3.86–3.91 (m, 2H, H-2, H-4), 4.15 (d, 1H,
J ¼ À13:2,
CH2),
4.54
(dd,
1H,
J5–6b ¼ 2:7,
J6a–6b ¼ À12:6, H-6b), 4.61 (dd, 1H, J5–6a ¼ 3:3,
J6a–6b ¼ À12:6, H-6a), 4.68 (dd, 1H, J2–3 ¼ 3:0, J3–4 ¼ 9:0,
H-3), 7.26–7.38 (m, 5H, Bn); 13C NMR (75 MHz, CDCl3)
d ¼ 26:1, 26.2 (CH3, Piv), 37.9, 38.1 (C, Piv), 52.9, 55.8,
59.3 (CH2, C-1, C-6), 65.8, 65.9, 67.4, 77.2 (C-2, C-3, C-4,
C-5), 126.5, 127.6, 127.7, 127.9 (CH-arom), 136.8 (C-
arom), 177.8, 178.0 (CO Piv); ESMS: [M+H]þ ¼ 422.3,
[M+H2O]þ ¼ 439.5, [M+Na]þ ¼ 444.3.
5. Olson, G. L.; Cheung, H.-C.; Foss, M. E.; Kahn, M.;
Madison, V. S.; Cook, C. M.; Sepinwall, J.; Vincent, G. In
Proc. Biotechnol. (USA); Conference ManagementCor-
poration, Norwalk, 1989; pS. 348.
6. (a) Ghosh, M.; Dulina, R. G.; Kakarla, R.; Sofia, M. J. J.
Org. Chem. 2000, 65, 8387; (b) Wunberg, T.; Kallus, C.;
Opatz, T.; Henke, S.; Schmidt, W.; Kunz, H. Angew.