Orthogonally protected carbohydrate-based scaffolds

Article abstract of DOI:10.1016/j.tetlet.2005.07.081

A series of orthogonally protected polyaminated carbohydrate scaffolds have been prepared on a multi-gram scale.

Full text of DOI:10.1016/j.tetlet.2005.07.081

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6191–6194
Orthogonally protected carbohydrate-based scaffolds
Nicolas Moitessier,* Christophe Henry, Nicolas Aubert and Yves Chapleur
Groupe SUCRES, Unite´ Mixte 7565 CNRS, Universite´ Henri Poincare´-Nancy 1, B.P. 239, F-54506 Nancy-Vandoeuvre, France
Received 27 April 2005; revised 8 July 2005; accepted 19 July 2005
Abstract—A series of orthogonally protected polyaminated carbohydrate scaffolds have been prepared on a multi-gram scale.
Ó 2005 Elsevier Ltd. All rights reserved.
NHPr
1. Introduction
O
O
HOOC
Although biologically relevant peptidomimetics are reg-
ularly reported with activities on a wide range of recep-
tors and enzymes, most of them are constructed around
an achiral template and the use of chiral scaffolds has
little precedence. Good activity of any drug is related
to the precise positioning of crucial pharmacophoric
groups within the biological target binding site leading
to optimal shape and interacting group orientation.
One of the main tasks is therefore to identify a correct
scaffold. Towards this end, monosaccharide units are
attractive synthons, since a judicious choice of the car-
bohydrate core would properly position the various
appendages that are anchored on the hydroxyl groups
into the binding site.1 In fact, carbohydrate-based scaf-
folds for peptidomimetics were first introduced by
Hirschmann et al. a decade ago and led to potent
somatostatin mimics.2
O
OBn
OBn
1
Figure 1. Carbohydrate-based peptidomimetics, integrin antagonists.
type of scaffold was dictated by the desire to disclose
versatile chiral templates for peptidomimetics. Two
main issues have to be addressed: (1) the orthogonal
protection of each anchor; and (2) the projected large
scale preparation of such compounds which requires
practical and high yielding steps.
Polyamino sugars have also recently shown to be build-
ing blocks in the preparation of oligosaccharide mim-
ics.4 This report prompted us to disclose our efforts in
the preparation of orthogonally protected polyamino
sugar scaffolds.
The stereodiversity potential of carbohydrate-based
templates (made possible by the availability of a wide
range of monosaccharides) was the impetus for initiat-
ing the preparation of carbohydrate-based scaffolds for
peptidomimetics. Based on this concept, we developed
xylose-based RGDF mimics exhibiting encouraging
activity towards integrins (Fig. 1, 1).3
2. First-generation orthogonally protected glucosediamine
A first scaffold 8 based on the glucose core was designed.
Its synthesis, outlined in Scheme 1, began with the pro-
tection of the free hydroxyl of the readily available
methyl 2-(acetylamino)-2-deoxy-4,6-O-benzylidene a-D-
glucopyranoside 25 by a bulky pivaloyl group to furnish
3. Execution of the synthetic plan with the correspond-
ing acetyl analogue led to an undesired migration at a
later stage in the synthesis. Regioselective opening of
the benzylidene acetal ring was next achieved by treat-
ment with an equimolar mixture of triethylsilane and tri-
fluoroacetic acid to provide compound 4.6 This method
At this point, we decided to expand the scope of this
approach and designed orthogonally protected scaffolds
based on carbohydrate templates. The design of this
Keywords: Carbohydrate; Peptidomimetics; Scaffolds.
*
Corresponding author at present address: Department of Chemistry,
´
´
McGill University, 801 Sherbrooke St. W., Montreal, Quebec,
Canada H3A 2K6. Tel.: 514 398 8543; fax: 514 398 3797;
e-mail: nicolas.moitessier@mcgill.ca
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.081

6192
N. Moitessier et al. / Tetrahedron Letters 46 (2005) 6191–6194
O
O
tured by this amino acid. The free hydroxyl group was
well tolerated under these conditions, although a negligi-
ble amount of side products was observed.
BnO
HO
Ph
O
O
b
c
OMe
OMe
RO
NHAc
PivO
NHAc
The depicted route to 8 allowed for the preparation of
multi-gram quantities from commercially available
derivative 2. The chemoselective removal of the protect-
ing groups led us to revise the selection of orthogonal
protecting groups.
2, R = H
4
a
3, R = Piv
BnO
BnO
N3
O
O
R1
R2
OMe
OMe
g
e
PivO
5, R1 = H, R2 = OH
6, R1 = H, R2 = OMs
NHAc
PivO HN R
7, R = Ac
8, R = Boc
Cbz
3. Second-generation orthogonally protected
polyaminated carbohydrates
d
f
3.1. Gluco diamine
OH
HO
O
H2N
MeOOC
NH
A new set of protecting groups was envisaged. A silyl
ether was introduced at position 6 and a benzyl ether
at position 3. Polyfunctionalized carbohydrates such as
8 or 24 would be bulky and removal of a hydroxyl group
would simplify the structure. Thus, aiming at mimicking
peptides, we also prepared the corresponding deoxy
derivative 25.
O
OMe
h
OMe
N
O
H
PivO
NHBoc
PivO
10
NHBoc
9
Scheme 1. Preparation and use of the orthogonally protected scaffold
8. Reagents and conditions: (a) PivCl, Et3N, 0 °C then rt, CH2Cl2,
87%; (b) Et3SiH, TFA, CH2Cl2, 0 °C then rt, 90%; (c) (i) Tf2O,
pyridine, 0 °C then rt, CH2Cl2; (ii) NaNO2, DMF, 76% (over 2 steps);
(d) MsCl, Et3N, 0 °C then rt, CH2Cl2; (e) NaN3, DMF, 110 °C, 88%
(over 2 steps); (f) (i) Boc2O, DMAP, THF, reflux; (ii) NH2NH2ÆxH2O,
MeOH/THF, 85% (over 2 steps); (g) H2, 10% Pd–C, dioxane, 79%; (h)
Cbz-Asp(OMe)-OH, HBTU, HOBt, DIPEA, 85%.
The synthesis shown in Scheme 2 started with the benzyl-
ation or stepwise Barton and McCombie10 deoxygen-
ation of readily available glucosamide 2 leading to 11
R2O
HO
O
Ph
O
O
d
f
was more conveniently scaled up than the usual combi-
nation of NaBH3CN and ethereal HCl.7
OMe
O
OMe
R1
NHAc
R
NHAc
14: R1=OBn, R2 =H
2: R = OH
The crucial double inversion was next investigated and
began by triflation of the remaining free hydroxyl of
4.8 The resulting triflate proved to be fairly unstable
on silica gel, and was therefore used without further
purification. Thus, hydrolysis of the crude triflate pro-
ceeded smoothly, affording the galactosamine intermedi-
ate 5 in good yield and in diastereomerically pure form.
Subsequent mesylation produced 6, which was reactive
towards sodium azide used as a masked amine group.
Again, the reaction took place with complete inversion
yielding 7. Alternative preparation of the chloro coun-
terpart using PPh3–CCl4 and displacement with sodium
azide gave 7 in a modest yield owing to the observed
competitive elimination.
a
15: R1=R2=H
b
11: R = OBn
12: R = OC(=S)Im
13: R = H
e
16: R1=OBn, R2 =TBS
17: R1=H, R2=TBS
c
TBSO
TBSO
N3
O
O
i
R1
R2
j
OMe
OMe
R
NHAc
R
NHBoc
18/19: R1, R2=O
20/21: R1=OH, R2=H
22/23: R1=H, R2=N3
24: R = OBn
25: R = H
g
h
OTBS
O
TBSO
H2N
MeOOC
Cbz
O
O
k
OMe
OMe
N
H
Access to the Boc protected amine 8 was made possible
by a formal exchange between acetyl and Boc group that
proceeded smoothly using previously reported mild con-
ditions.9 Thus, upon treatment with Boc2O and DMAP,
7 was converted into the diprotected amine, which was
isolated and then reacted with hydrazine hydrate to
afford the fully protected advanced intermediate 8. To
evaluate the use of 9 as an orthogonally protected scaf-
fold, reduction of the azide and simultaneous deprotec-
tion of the benzyl ether group was accomplished under
catalytic hydrogenolysis conditions to give 9. The corre-
sponding amine was next coupled with an amino acid
leading to pseudopeptide 10. The choice of aspartic acid
was dictated by the additional functional groups fea-
N
Bn
R
NHBoc
R
NHBoc
28
26: R = OBn
27: R = H
Scheme 2. Preparation and use of the orthogonally protected scaffolds
24 and 25. Reagents and conditions: (a) NaH, BnBr, DMF, 91%; (b)
(Im)2CS, DMAP, THF, reflux, 92%; (c) Bu3SnH, toluene, reflux, 91%;
(d) AcOH/THF/H2O, 40 °C, 92% (14), 88% (15); (e) TBSCl, pyridine,
˚
67% (16), TBSCl, DMF, Im, 96% (17); (f) TPAP, NMO, CH2Cl2, 4 A
MS, 98% (18), 97% (19); (g) L-selectride, THF, À78 °C, 80% (20), 83%
(21); (h) DPPA, DEAD, PPh3, CH2Cl2, 62% (22), 89% (23); (i) Boc2O,
DMAP, THF, reflux; then NH2NH2ÆxH2O, MeOH, 92% (24), 92%
(25); (j) H2, 10% Pd–C, dioxane, 83% (26), 83% (27); (k) Cbz(Bn)-
Asp(OMe)-OH, HBTU, HOBt, DIPEA, DMF, 54%.

N. Moitessier et al. / Tetrahedron Letters 46 (2005) 6191–6194
6193
and 13, respectively. The benzylidene acetals were next
hydrolyzed upon acidic treatment, giving the diols 14
and 15 which were regioselectively protected as the
corresponding silyl ethers 16 and 17. Investigation of
the inversion and azide introduction steps led to the
optimized oxidation/stereoselective reduction sequence
shown in Scheme 2 followed by a Bose–Mitsunobu reac-
tion11 which completed the sequence. The use of such
scaffolds was evaluated by hydrogenation followed by
coupling with an amino acid to afford structures 28 in
acceptable yields.
high yielding. The chemoselective reduction of the azide
in presence of the benzyl ether was achieved using the
Staudinger reduction.13
3.3. Ido triamine
We next explored the design and synthesis of triamine
derivatives. For this purpose, derivative 36 was depro-
tected and reacted under Mitsunobu conditions14 to af-
ford the orthogonally protected triamine 41. Attempts
were made to orthogonally functionalize positions 4 or
6. For instance, position 6 was quantitatively unmasked
by treatment with hydrazine leading to the primary
amine 42 which was quantitatively acetylated. The sec-
ond amine was next deprotected under Staudinger con-
ditions13 then coupled with an acid leading to the highly
functionalized scaffold 45. The overall sequence shown
in Scheme 4 was achieved in reasonable yields.
3.2. Ido diamine
With these first scaffolds and optimized syntheses in
hand, we explored the preparation of another stereoiso-
mer. The idose scaffold was selected and prepared as
shown in Scheme 3. Although the presented scaffolds
are polydeoxy, polyamino allosides, the stereoche-
mistry of the scaffolds is that of idosides. We therefore,
will use ꢀidoseꢁ throughout this manuscript. Readily
available compound 2912 was used as starting material.
The sequence used to prepare compound 24 was
adapted for the preparation of its ido counterpart 36.
Opening of the cyclic acetal was followed by silylation
and introduction of a masked amine on position 4 with
complete inversion. This sequence led to the orthogo-
nally protected scaffold 36 in good yields. As for the pre-
vious scaffolds, reduction and coupling were found to be
In parallel, we have shown that position 4 can be reacted
first through reduction of the azide followed by regio-
selective reprotection of position 6 (Scheme 5).
The thus obtained 4-amino derivative can be subse-
quently coupled leading to the orthogonally protected
scaffold 47. This last scaffold features a Teoc group sen-
sitive to TBAF treatment, an ester that can be saponi-
fied, a double bond that can be further functionalized
or reduced, a benzyl ether that can be cleaved by
hydrogenolysis, and a Boc carbamate that can be re-
moved under acidic conditions. These various functional
groups can be treated in this order in the preparation of
OR
O
O
Ph
O
O
d
OMe
b
HO
OMe
OTBS
OH
RO
N3
BnO
31: R=H
N3
O
29: R=H
O
a
a
b
N3
BnO
OMe
c
N3
BnO
OMe
30: R=Bn
32: R=TBS
NHBoc
NHBoc
OTBS
OTBS
O
36
40
O
g
h
N3
BnO
OMe
MsO
OMe
O
NH2
NHBoc
BnO
R
N
O
O
O
33: R=N3
c
d
36
e
N3
BnO
OMe
N3
BnO
OMe
34: R=NH2
f
35: R=NHBoc
NHBoc
NHBoc
42
OR
OTBS
41
MeOOC
Cbz
O
O
O
O
O
i
OMe
H2N
BnO
OMe
NHBoc
NH
N
H
BnO
NH
NH
O
e,f
NHBoc
R
O
HN
OMe
N3
OMe
38: R=TBS
39: R=H
37
j
BnO
44, R = H
45, R = C(O)CH2=CH2COOEt
NHBoc
BnO
NHBoc
43
Scheme 3. Preparation and use of the orthogonally protected scaffold
36. Reagents and conditions: (a) NaH, BnBr, DMF, 89%; (b) AcOH/
H2O, 100 °C, quant.; (c) TBSCl, Im, DMF, 85%; (d) MsCl, Et3N,
CH2Cl2, 84%; (e) PPh3, THF then H2O, 60 °C, 79% or H2, 5% Pd–C,
EtOH, 81%; (f) Boc2O, Et3N, CH2Cl2, 93%; (g) NaN3, DMF, 100 °C,
80%; (h) H2, 5% Pd–C, EtOH, 88%; (i) Cbz-Asp(OMe)-OH, HBTU,
DIPEA, DMF, 82%; (j) AcOH/H2O/THF, 95%.
Scheme 4. Preparation and use of the orthogonally protected scaffold
41. Reagents and conditions: (a) 1 M TBAF/THF, 89%; (b) phthal-
imide, PPh3, DEAD, THF, 79%; (c) NH2NH2ÆH2O, EtOH, quant.; (d)
Ac2O, K2CO3, CH2Cl2, quant.; (e) PPh3, THF then H2O, 60 °C, 73%;
(f) RCOOH, HOBt, EDC, DIPEA, DMF, 67%.

6194
N. Moitessier et al. / Tetrahedron Letters 46 (2005) 6191–6194
ences, see: (e) Papageorgiou, C.; Haltiner, R.; Bruns, C.;
Teoc
NH2
NH
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O
a,b
O
R
N3
BnO
OMe
HN
OMe
NHBoc
BnO
NHBoc
42
46: R = H
47: R=C(O)CH2=CH2COOEt
Scheme 5. Reagents and conditions: (a) (i) PPh3, THF/H2O, DMF,
68%; (ii) TMSCH2CH2OH, phosgene, toluene, Et3N, 32% (along with
di-Teoc, 16%); (b) EtOOCCH@CHCOOH, HOBT, EDC, DIPEA,
DMF, 75%.
highly functionalized peptidomimetics. Similarly, the
scaffold 41 can be selectively deprotected with hydrazine
(position 6), triphenylphosphine (position 4), hydrogen
(position 3) and trifluoroacetic acid (position 2).
In summary, we have designed and prepared original
carbohydrate-based scaffolds featuring differentially/
orthogonally protected groups as potential anchors.
Their synthesis called for key inversion steps. The
syntheses were carried out on a multi-gram scale. The
scaffolds 8, 24, 25, 30, 41 and 47 are the first members
of a larger series well suited for preparation of
stereodiverse libraries. Further applications to the
preparation of biologically relevant compounds are
underway.
2. (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) Hirschmann, R.;
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Arison, B.; 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.
Acknowledgements
´
We thank La Region Lorraine, LꢁInstitut Nanceien de
´
3. (a) Moitessier, N.; Minoux, H.; Maigret, B.; Chretien, F.;
´
Chimie Moleculaire and lꢁAssociation pour la Recherche
Chapleur, Y. Lett. Pept. Sci. 1998, 5, 75; (b) Moitessier,
contre le Cancer for financial support and a fellowship
´
N.; Dufour, S.; Chretien, F.; Thiery, J.-P.; Maigret, B.;
to C.H.
Chapleur, Y. Bioorg. Med. Chem. 2001, 9, 511.
4. Sicherl, F.; Wittmann, V. Angew. Chem., Int. Ed. 2005, 44,
2096.
5. Emmerson, D. P. G.; Hems, W. P.; Davis, B. G.
Tetrahedron: Asymmetry 2005, 16, 213.
Supplementary data
6. DeNinno, M. P.; Etienne, J. B.; Duplantier, K. C.
Tetrahedron Lett. 1995, 36, 669.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.07.081.
´
7. Chapleur, Y.; Boquel, P.; Chretien, F. J. Chem. Soc.,
Perkin Trans. 1 1989, 703.
8. Moule, C. J.; Clements, P. R.; Hopwood, J. J.; Crisp,
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9. Henry, C.; Joly, J.-P.; Chapleur, Y. J. Carbohydr. Chem.
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