Synthesis of two D-glucosamine derived 3,4-epoxides as potential scaffolds for combinatorial chemistry

Full text of DOI:10.1081/CAR-120021699

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Synthesis of Two d‐Glucosamine Derived 3,4‐Epoxides
as Potential Scaffolds for Combinatorial Chemistry
Lars Svejgaard a e , Henrik Fuglsang a f , Peter B. Jensen a , Nicholas M. Kelly a g , Henrik
Pedersen b , Kim Andersen c , Thomas Ruhland c & Knud J. Jensen d h
a Department of Chemistry , Technical University of Denmark , Building 201, Kemitorvet,
DK‐2800, Lyngby, Denmark
b Department of Spectroscopy , Lundbeck A/S , Ottiliavej 9, DK‐2500, Valby, Denmark
c Department of Combinatorial Chemistry , Lundbeck A/S , Ottiliavej 9, DK‐2500, Valby,
Denmark
d Department of Chemistry , Royal Veterinary and Agricultural University , Thorvaldsensvej
40, DK‐1871, Frederiksberg, Denmark
e Analytical Chemistry , Novo Nordisk , Bagsværd, Denmark
f Combio , Valby, Denmark
g ACADIA A/S , Glostrup, Denmark
h Department of Chemistry , KVL , Thorvaldsensvej 40, DK‐1871, Frederiksberg, Denmark
Published online: 28 Oct 2011.
To cite this article: Lars Svejgaard , Henrik Fuglsang , Peter B. Jensen , Nicholas M. Kelly , Henrik Pedersen , Kim Andersen ,
Thomas Ruhland & Knud J. Jensen (2003) Synthesis of Two d‐Glucosamine Derived 3,4‐Epoxides as Potential Scaffolds for
Combinatorial Chemistry, Journal of Carbohydrate Chemistry, 22:3-4, 179-184, DOI: 10.1081/CAR-120021699
To link to this article: http://dx.doi.org/10.1081/CAR-120021699
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 22, Nos. 3 & 4, pp. 179–184, 2003
Synthesis of Two D-Glucosamine Derived 3,4-Epoxides as
Potential Scaffolds for Combinatorial Chemistry
1,
1
Lars Svejgaard,1, Henrik Fuglsang, Peter B. Jensen,
#
z
Nicholas M. Kelly,1, Henrik Pedersen, Kim Andersen,
2
3
x
Thomas Ruhland,3 and Knud J. Jensen4,
*
1Department of Chemistry, Kemitorvet, Technical University of Denmark,
Lyngby, Denmark
2Department of Spectroscopy, Lundbeck A/S, Valby, Denmark
3Department of Combinatorial Chemistry, Lundbeck A/S, Valby, Denmark
4Department of Chemistry, Royal Veterinary and Agricultural University,
Frederiksberg, Denmark
Key Words: D-Glucosamine; 3,4-epoxide; Amino; Regioselective O-tosylation;
Opening.
Combinatorial chemistry allows the synthesis of libraries of compounds by com-
bination of building blocks or by combinatorial elaboration of a central scaffold.[1,2]
Carbohydrates hold great promise as scaffolds due to their high degree of func-
tionalization, relative conformational rigidity, commercial availability of many stereo-
isomeric forms, and their well-described chemistry. Hirschmann, Nicolaou, Smith, and
their coworkers pioneered the use of carbohydrates as scaffolds in their design and
synthesis of b-D-glucose derived non-peptide peptidomimetics of the peptide hormone
#
Current address: Lars Svejgaard, Analytical Chemistry, Novo Nordisk, Bagsværd, Denmark.
Current address: Henrik Fuglsang, Combio, Valby, Denmark.
z
x
Current address: Nicholas M. Kelly, ACADIA A/S, Glostrup, Denmark.
*
Correspondence: Knud J. Jensen, Department of Chemistry, KVL, Thorvaldsensvej 40, DK-1871
Frederiksberg, Denmark; Fax: + 45 3528 2398; E-mail: kjj@kvl.dk.
179
DOI: 10.1081/CAR-120021699
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2003 by Marcel Dekker, Inc.

180
Svejgaard et al.
somatostatin (SRIF).[3,4] However, only relatively few examples on the application of
carbohydrates as scaffolds in combinatorial chemistry have been described.[5–11] For
example, Brill et al. anchored a 1,6-anhydro-b-D-glucopyranoside (levoglucosan) de-
rived epoxide to a solid support and introduced diversity by opening of the support-
bound 2,3-epoxide.[9] Hirschmann et al. employed the opening of a D-glucose derived
1,2-epoxide with a thiol in one of the initial steps towards the synthesis of a library of
D-glucose derived compounds.[10]
We reasoned that introduction of all substituents by O-acylation or carbamoyla-
tion would give final products with too high a degree of conformational freedom. To
introduce substituents directly on the carbohydrate ring and to keep protecting group
manipulations on the resin-bound carbohydrate scaffold to a minimum, we decided to
prepare a scaffold in which diversity would be introduced by opening of an epoxide.
Also, it was a requirement that the scaffold should contain nitrogen, as amines are
found in many pharmacologically relevant molecules, e.g., CNS active compounds. We
chose inexpensive D-glucosamine as starting material, to prepare a 3,4-epoxide, and to
block the C-1 as the methyl glycoside (Scheme 1). Both solution and solid-phase
strategies were envisioned; for the solid-phase strategy, the amine could serve as a
convenient point for anchoring to a solid support through a Backbone Amide Linker
(BAL).[12,13] Here we present the synthesis of two new D-glucosamine derived amino
epoxides and preliminary studies on opening of one of the epoxides in solution.
First, methyl 2-acetamido-2-deoxy-a-D-glucopyranoside, 1, easily accessible by
Fischer glycosylation, was N-deacetylated by treatment with hydrazine to give known
methyl 2-amino-2-deoxy-a-D-glucopyranoside 2 (Scheme 1). The N-acetyl group served
well here as it was stable to Fischer glycosylation conditions; however, it had to
be exchanged with a more labile N-trifluoroacetyl group to allow final deprotection
Scheme 1. Synthesis of amino epoxide 7.

Synthesis of D-Glucosamine
181
Scheme 2. Synthesis of amino protected epoxide 11 and opening with thiols.
under milder conditions. Initial experiments had shown that Fischer glycosylation of
2-trifluoroacetamido-D-glucopyranose resulted in only low yields of the desired methyl
glucoside, probably due to cleavage of the N-trifluoroacetyl moiety. Treatment of triol
amine 2 with tert-butyldiphenylsilyl chloride (TBDPS-Cl) in N,N-dimethylformamide
(DMF) in the presence of imidazole selectively protected O-6 to give diol amine 3,
which was chemoselectively N-trifluoroacetylated by reaction with ethyl trifluoroace-
tate in MeOH to give 4 in 45% for the two steps. Treatment of diol 4 with tosyl
chloride in CH2Cl2 in the presence of N,N-dimethylaminopyridine (DMAP) and Et3N
provided monotosylate 5 in a high yield with a remarkable O3/O4 ratio of 9:1. This
was essential, as tosylation at O-3 or O-4 give different epoxides in the next step. In the
key step, the epoxide was smoothly established by treatment of tosylate 5 with sodium
hydride in DMF[14] to give 6. Hovewer, control of the reaction time was essential, as
the maximal yield was obtained after a 45 min reaction. Substituting sodium hydride
in DMF for 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in CH2Cl2 at reflux or with
potassium tert-butoxide in DMF both resulted in reduced yields. In the final step, the
N-trifluoroacetyl group was removed to give target amino epoxide 7.a However,
treatment with 1M aq sodium hydroxide also partly removed the TBDPS protecting
group, without affecting the epoxide. The three steps (4!7) proceeded in an overall
yield of 34% yield (Scheme 1).
For solution studies, we required an epoxide derivative with the amine protected.
Reductive amination of starting amine 2 with benzaldehyde in DMF-HOAc (99:1) in
the presence of NaBH3CN provided the N,N-dibenzylated derivative 8 (Scheme 2)
(N,N-Dibenzyl protected glucosamine donors have been prepared by N-alkylation with
benzyl bromide: see Ref. [15]). Previous studies on reductive alkylation of amino acids
had shown that whereas DMF as solvent promoted dialkylation, MeOH preferably
gave the monoalkylated product.[16] The following transformations to 9, 10, and 11
were achieved with procedures similar to those for synthesis of epoxide 7. Interestingly,
1
1
aSelected H chemical shifts, d, in ppm (coupling constants in Hz to the following H) for 7: H-1,
4.58 (4.9); H-2, 3.14 (2.2); H-3, 3.31 (4.7); H-4, 3.45 (0.6); H-5, 3.92 (4.7); H-6 3.88 (m).

182
Svejgaard et al.
O-tosylation of 9 occurred regioselectively at O-4 in contrast to the 3-O-tosylation
found in 4. Treatment of 4-O-tosylate 10 with sodium hydride in DMF, as above for 6,
formed the expected stereoisomeric epoxide 11 (Scheme 2).b Attempted hydrogenolytic
debenzylation also gave rise to several byproducts, probably due to destruction of
the epoxide.
The control of regioselectivity in O-tosylation by the 2-amino protecting group is
noteworthy. Glycosylation of O-3 in N-Phth protected acceptors has been reported to be
difficult.[17,18] N,N-dibenzyl, but not N-trifluoroacetyl, now appears to have an
analogous steric influence. This proved fortunate for the present application as it gave
access to the two different stereoisomeric forms of the epoxide.
In preliminary studies on the opening of the epoxides, N,N-dibenzylated epoxide
11 was reacted in solution with thiophenol in THF-dioxane in the presence of
LiHMDS (Scheme 2).[9] The 4-deoxy-4-thiophenyl D-gluco configured derivative 12a
was obtained in 68% isolated yield. Benzyl mercaptan opened epoxide 11 in a
similar manner to give 12b in 31%. The reduced yield was probably due to loss
during work-up. The gluco configuration was easily established by analysis of 1H
3
3
3
NMR J coupling constants (for both 12a and b: J2,3 10.2 Hz; J3,4 10.7 Hz);cthe
position of the thioether was evident from the chemical shift of H-4 (12a 3.00 ppm;
12b 2.57 ppm).d
In conclusion, two stereoisomeric D-glucosamine derived 3,4-epoxides with
TBDPS protection at O-6 were synthesized in 5 and 6 steps, respectively, from
methyl 2-acetamido-a-D-glucopyranoside. The stereochemical orientation of the
epoxide was controlled through amino protecting group directed regioselective
O-tosylation prior to epoxide formation. Solution experiments showed that the
N,N-protected epoxide was opened to give the D-gluco configured product with a
4-thiophenyl moiety. These epoxides are potential scaffolds for combinatorial chem-
istry applications.
ACKNOWLEDGMENTS
We thank Mrs. Lene Kastrup for preparation of some intermediates and Dr. Klaus
Gundertofte for valuable discussions. A Bøje Benzon Fellowship from the Alfred
Benzon Foundation to KJJ is gratefully acknowledged.
bSelected 1H chemical shifts, d, in ppm (coupling constants in Hz to the following 1H) (d, J) for 11:
H-1 4.47 (4.3 Hz); H-2 2.97 (4.5); H-3 and H-4 3.29-3.34; H-5 3.94 (t, 7.1 Hz); H-6a 3.74 (dd, 6.3
Hz, 10.5 Hz); H-6b 3.65 (3.9 Hz, 9.9 Hz).
1
1
cSelected H chemical shifts, d, in ppm (coupling constants in Hz to the following H) (d, J) for
12a: H-1 4.76 (3.0 Hz); H-2 2.84 (10.2 Hz); H-3 4.13 (10.7); H-4 3.00 (11.1 Hz); H-5 3.70; H-6a
3.97 (11.1 Hz, 1.7 Hz); J-6b 3.86 (5.1Hz).
1
1
dSelected H chemical shifts, d, in ppm (coupling constants in Hz to the following H) (d, J) for
12b: H-1 4.73 (3.0 Hz); H-2 2.75 (10.2 Hz); H-3 4.10 (10.7); H-4 2.57 (10.7 Hz); H-5 3.64; H-6a
3.96 (11.3 Hz, 1.7 Hz); J-6b 3.81 (5.5 Hz).

Synthesis of D-Glucosamine
183
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Received July 31, 2002
Accepted February 28, 2003