Synthesis of azide-alkyne fragments for 'click' chemical applications; formation of oligomers from orthogonally protected trialkylsilyl-propargyl azides and propargyl alcohols

Article abstract of DOI:10.1016/j.tetlet.2006.07.131

A series of orthogonally protected 1,4-disubstituted-1,2,3-triazoles were prepared from the corresponding alkynols and trialkylsilyl-propargyl azides via 1,3-dipolar cycloaddition. These cycloadducts were selectively deprotected and extended in a stepwise fashion via further 'click' reactions to form oligomeric peptidomimetic compounds. This methodology gives access to triazole-based peptidomimetics in a controlled fashion and lays the foundation for a fragment-based approach to drug discovery.

Full text of DOI:10.1016/j.tetlet.2006.07.131

Tetrahedron Letters 47 (2006) 6971–6974
Synthesis of azide-alkyne fragments for ‘click’ chemical
applications; formation of oligomers from orthogonally protected
trialkylsilyl-propargyl azides and propargyl alcohols
Oliver D. Montagnat,a Guillaume Lesseneb and Andrew B. Hughesa,*
aDepartment of Chemistry, La Trobe University, Melbourne, Victoria 3086, Australia
bThe Walter and Eliza Hall Institute of Medical Research, Structural Biology Division, Medicinal Chemistry Group,
4 Research Avenue, La Trobe University Research and Development Park, Victoria 3086, Australia
Received 20 June 2006; revised 18 July 2006; accepted 25 July 2006
Abstract—A series of orthogonally protected 1,4-disubstituted-1,2,3-triazoles were prepared from the corresponding alkynols and
trialkylsilyl-propargyl azides via 1,3-dipolar cycloaddition. These cycloadducts were selectively deprotected and extended in a step-
wise fashion via further ‘click’ reactions to form oligomeric peptidomimetic compounds. This methodology gives access to triazole-
based peptidomimetics in a controlled fashion and lays the foundation for a fragment-based approach to drug discovery.
Ó 2006 Elsevier Ltd. All rights reserved.
Protein–protein interactions are increasingly recognised
as important therapeutic targets due to their involve-
ment in essential biological pathways.1 Progress in this
area of drug discovery has been slow as these interac-
tions are hard to target with small molecules because
the domain in which the inhibitor binds, usually via
hydrophobic interactions, is often large, shallow and less
defined. These challenges have led to the development of
novel methods for making small molecule inhibitors of
protein–protein interactions. Amongst the concepts
developed, fragment-based drug discovery is particu-
larly attractive.2 Drug identification can be improved
via the use of ‘fragments’ that, when used indepen-
dently, have lower activity and affinity for binding sites,
but when appropriately linked give significantly
enhanced activity.3 Several strategies can be imple-
mented to screen for useful fragments: NMR,4 X-ray
crystallography5 and tethering.6
proceed in excellent yields under biologically compatible
conditions. The 1,3-dipolar cycloaddition (1,3-DC) of
azides and alkynes, as described by Sharpless and
coworkers, is an example of such a reaction.7 It has been
applied to biological targets such as an acetylcholines-
terase (AchE) inhibitor8,9 and a carbonic anhydrase II
inhibitor.10
Recently, Angelo and Arora11 described the synthesis of
novel triazole oligomers derived from a-amino acids
using an iterative reaction sequence. They prepared
chiral azides and alkynes from a-amino acid esters and
combined them via cycloaddition and azide formation
reactions to prepare triazole oligomers with four R
groups or side-chains. Independently, we devised an
alternative fragment-based approach to these non-pep-
tidic oligomers that provided for an increased range of
R groups and the ability to extend the oligomer in either
direction through orthogonal protection of the two ter-
mini. We now wish to report the results of these studies.
Another potentially powerful fragment-based method
used in the search for drug hits relies on fragments react-
ing in situ to form privileged high affinity binders. This
technique depends on a specific linking reaction that can
In planning the synthesis of triazole oligomers we
wanted to prepare fragments with the attributes of ami-
no acids in regard to side-chain structural diversity and
the possibility of peptidomimetic assemblage but with-
out the labile amide bond (Scheme 1). Azido-alkynes
met these criteria but before undertaking any biologi-
cally relevant experiments, several questions had to be
addressed: Can the fragment be prepared? Can the
Keywords: ‘Click’ chemistry; Triazole oligomers; 1,3-Dipolar cyclo-
addition; Peptidomimetics.
*
Corresponding author. Tel.: +613 9479 1353; fax: +613 9479 1399;
e-mail: a.hughes@latrobe.edu.au
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.131

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O. D. Montagnat et al. / Tetrahedron Letters 47 (2006) 6971–6974
R2
( )m
Si(R3)3
R2
O
R1
( )m
H
+
N3
R1
HO
+
( )n
(m, n) = (0 or 1)
H
( )n
Li
nBuLi, THF, -78 oC
ref. 12,13
receptor
[1,3-DC]
OH
OH
K2CO3,
R2
Si(R3)3
MeOH, rt
R1
R1
N
R1
( )m
N
N
R2
H
( )m
( )n
HO
( )n
2a: R1 = nPr
2b: R1 = sBu
2c: R1 = Bn
1a: R1 = nPr, R2 = TMS
1b: R1 = sBu, R2 = TMS
1c: R1 = Bn, R2 = TMS
1d: R1 = sBu, R2 = TIPS
(m, n) = (0 or 1)
Scheme 1.
Et3N, MsCl,
fragment be orthogonally protected in a fashion similar
to amino acids? Can a sequential approach be followed
to form an oligomeric (peptidomimetic) chain?
CH2Cl2, 0 oC
NaN3,
DMF, rt
OMs
N3
R1
R1
This report is focussed on answering the questions posed
above using fragments where n = 0, m = 0 (Scheme 1).
The preparation of fragments and their use in forming
triazole oligomers is presented.
R2
R2
4a: R1 = nPr, R2 = TMS
4b: R1 = sBu, R2 = TMS
4c: R1 = Bn, R2 = TMS
4d: R1 = sBu, R2 = TIPS
3a: R1 = nPr, R2 = TMS
3b: R1 = sBu, R2 = TMS
3c: R1 = Bn, R2 = TMS
3d: R1 = sBu, R2 = TIPS
The initial plan involved use of aldehydes to form
trimethylsilyl propargylic alcohols, based on several
factors: a large number of aldehydes are commercially
available with side-chains constituting the ‘residue’ of
the azido-alkyne fragment. Further, there is also a
significant body of literature on alkyne additions to
aldehydes,12 including enantioselective reactions.13 It
was thought that hydroxyl groups could represent a
latent azide since the latter can be obtained in one step
from the OH group or the hydroxyl group can be
activated for subsequent azide substitution.
Scheme 2.
Table 1. Synthesis of alkynols and azido-alkynes
Entry R1
R2
Product (%)
1
2
3
4
nPr
SiMe3 1a (97)
2a (À)a 3a (92) 4a (70)
sBu SiMe3 1b (86)
Bn SiMe3 1c (86)
sBu SiiPr3 1d (100)
2b (67)
2c (75)
—
3b (89) 4b (85)
3c (76) 4c (87)
3d (90) 4d (80)
a Yield was not recorded as the product is highly volatile.
The trialkylsilyl-protected propargyl alcohols 1a–d
(Scheme 2) (Table 1) were generated in 86–100% yields
by addition of lithiotrimethylsilylacetylide to aldehydes.
The alkynols were then deprotected by exposure to
K2CO3 in methanol, generating the free alkynes 2a–c
in 67–75% yields. It was found that fragments with a
molecular weight of ꢀ100–150 were volatile and thus
gave lower isolated yields. The alkynols 2a–c, as the tri-
ple bond partners of the 1,3-DC, were subsequently used
for the generation of the triazole oligomeric chains.
A range of fragments were then subjected to the condi-
tions described in entry 8 (Table 2) to provide a series of
1,4-disubstituted-1,2,3-triazoles 5a–j (Table 3).
It can be seen that as the molecular weight of the
fragment increases, so does the yield of the cyclo-
adduct, most likely due to the volatility of the unprotected
alkynols 2a and 2b.
It was also found (via mass spectrometry) that a small
amount of the dimeric cycloadduct 5 was being desilyl-
ated and was then participating in a further 1,3-DC
reaction to generate a range of trimeric cycloadducts.
Attempts to prevent trialkylsilyl deprotection and subse-
quent trimer formation led to the use of Cu(0) powder in
a 1:2 mixture of tBuOH:H2O. These conditions not only
arrested the deprotection and trimer formation, but they
also improved the yield of the cycloaddition (76%)
(Table 2, entry 11). These final improvements confirmed
that the problem of orthogonal protection had been
solved.
Alternatively, exposure of the protected propargyl alco-
hols to methanesulfonyl chloride in the presence of tri-
ethylamine gave the mesylates 3a–d in 76–92% yields.
These mesylates were then treated with sodium azide
in DMF to give the azides 4a–d in 70–87% yields. This
azide displacement was found to proceed readily, and
was complete within 1–2 h at ambient temperature.
The azides 4a–d have the latent reactive alkyne that
was required for iterative extension of the triazolic
chain.
With the two partners for the 1,3-DC in hand, we sought
to optimise the reaction conditions for reactants 2b and
4b (Table 2). In general, it was found that the reaction
gave the best yields when conducted in the presence of
H2O as co-solvent (entries 6–11).
Attempts were then made to generate higher order
cycloadducts via a sequential process (Scheme 3). We
decided to extend in the alkyne direction, as trialkylsilyl
deprotection requires simple conditions, is a clean

O. D. Montagnat et al. / Tetrahedron Letters 47 (2006) 6971–6974
6973
Table 2. Optimisation studies for the 1,3-DC between azide 4b and
alkyne 2b
Table 3. 1,3-Dipolar cycloaddition of acetylenes 2a–c and azides 4a–d
to form triazoles 5a–j
2b
0.1 eq. CuSO4.5H2O,
0.2 eq. Na ascorbate,
R3
2a-c
[1,3-DC]
+
+
4a-d
R1
HO
N
N N
tBuOH:H2O, 1:1
4b
R2
SiMe3
HO
N
N N
5e
5a-j
Entry Ratio Reagents
Solvent
T
Yield
Entry
R1
R2
R3
Time (h)
Product (%)
2b/4b (equiv)
(h) (%)
1
2
1
1
—
Et2O
THF
15
21
—
—
1
2
3
4
5
6
7
8
9
nPr
nPr
nPr
sBu
sBu
sBu
Bn
Bn
Bn
sBu
nPr
sBu
Bn
nPr
sBu
Bn
nPr
sBu
Bn
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TIPS
6
4
19
7
6
7
8
5
5
15
5a (6)
CuI (2)
DIPEA (5)
CuI (2)
DIPEA (2)
CuI (1)
5b (17)
5c (18)
5d (41)
5e (62)
5f (53)
5g (33)
5h (45)
5i (52)
5j (71)
3
1
MeOH
CH2Cl2
MeCN
31
—
4
1
18 41
78 <10
DIPEA (1.1)
5
1
CuSO4Æ5H2O (0.1)
Na asc.a (0.2)
CuSO4Æ5H2O (0.5)
Na asc.a (1)
6
1
tBuOH:H2O 22 37
1:1
10
sBu
7
1
CuSO4Æ5H2O (0.1)
Na asc.a (0.2)
CuSO4Æ5H2O (0.1)
Na asc.a (0.2)
Cu(0) (2)
tBuOH:H2O 17 50
1:1
tBuOH:H2O 19 62
1:1
tBuOH:H2O 25 57
in 82% yield (Scheme 4). Compound 10 constitutes the
precursor for chain extension from the azide terminus.
8
1
9
1
Reaction of the propargyl amine carbamate with the
azide 4b gave cycloadduct 11 in 71% yield (Scheme 5).
This first ‘azide’ direction extension is a variation in the
reactions of the azides 4 with the alcohols 2 shown in
Table 3. In addition, the azide cycloadduct 10 reacts with
similar efficiency to give the ‘trimeric’ cycloadduct 12.
0.5 mM CuSO4 (0.01) 1:1
10
11
0.5
1
Cu triflate (0.1)
Na asc.a (0.2)
Cu(0) (xs)
tBuOH:H2O 21 46
1:1
tBuOH:H2O 18 76
1:2
a Sodium ascorbate.
Thus in summary the conditions described afford the
possibility to grow the cycloadduct on either side
(alkyne or azide/alcohol).
reaction and applies to a range of structures. The
cycloadduct 5e was deprotected with potassium carbon-
ate in methanol (92% yield) and then subjected to the
latter optimum conditions (Table 2, entry 11). 1,3-DC
conditions with compound 4b gave a trimeric compound
7 (76% yield). Repeating this sequence afforded the acet-
ylene 8 (100%) and then tetrameric compound 9 (73%).
It should be stressed that the adducts 5a–j, 7, 9 and 12 in
this study were all prepared from compounds 1a–d
DIAD, Ph3P,
5e
N3
N
N N
10 82%
DPPA, THF
Extending the chain in the other direction was difficult
and required more careful conditions. Attempts to mes-
ylate the dimeric cycloadduct failed, so we instead pre-
pared the azido dimer 10 under Mitsunobu conditions
TMS
-78—0 ºC
Scheme 4. Mitsunobu reaction of 5e to form azide 10.
Cu(0), 4b,
K2CO3,
MeOH
tBuOH:H2O 2:1
HO
N
N N
HO
N
N N
HO
N
TMS
H
N N
TMS
2
5e
6 92%
7 76%
Cu(0), 4b,
tBuOH:H2O 2:1
K2CO3,
MeOH
HO
HO
N
N
N N
N N
H
TMS
2
3
8 100%
Scheme 3. Generation of triazole oligomers in the ‘alkyne’ direction.
9 73% (overall yield 51%)

6974
O. D. Montagnat et al. / Tetrahedron Letters 47 (2006) 6971–6974
Boc
N
N
N
N
N3
H
Cuº,
Boc
+
N
H
tBuOH:H2O 2:1
TMS
TMS
4b
11 71%
Cuº,
Boc
+
Boc
N
H
N3
N
N N
N
H
N
N N
N
N N
tBuOH:H2O 2:1
TMS
TMS
10
12 72%
Scheme 5. Generation of triazole oligomers in the ‘azide/alcohol’ direction.
(Scheme 1), which are racemic. Thus the adducts are
mixtures of diastereomers. There was no evidence of dia-
stereoselection in the formation of the compounds 5a–j,
7, 9 and 12. Thus a study of the conformations of these
materials was deemed inappropriate and will be
addressed in subsequent investigations.
References and notes
1. Yin, H.; Hamilton, A. D. Angew. Chem., Int. Ed. 2005, 44,
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Rev. Drug Disc. 2004, 3, 660–672.
In this account, we have shown that the 1,3-DC-based
strategy of selective and efficient construction of higher
order cycloadducts is valid. We have also demonstrated
that it is possible to do so in a sequential and controlled
fashion in either direction (azide or alkyne terminus)
where the alcohol and TMS moieties act as precursors/
protecting groups for the azide and alkyne reactive
groups, respectively. We are confident that the results
presented will transpose to chiral substrates. We are cur-
rently working on chiral fragments with n = 0, m = 0
(Scheme 1) and also n = 1, m = 0 via enantioselective
epoxide openings. This will enable access to a broad
range of fragments. A full account of this work will be
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One of us (O.M.) thanks the Australian Government for
the grant of an Australian Post-Graduate Award.