Stereo- and regio-selective one-pot synthesis of triazole-based unnatural amino acids and β-amino triazoles

Article abstract of DOI:10.1039/c2cc32392c

Synthesis of triazole based unnatural amino acids and β-amino triazoles has been described via a stereo and regioselective one-pot multi-component reaction of sulfamidates, sodium azide, and alkynes under MW conditions. The developed method is applicable to a broad substrate scope and has significant potential for the synthesis of unnatural amino acids with a triazole side chain.

Full text of DOI:10.1039/c2cc32392c

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Stereo- and regio-selective one-pot synthesis of triazole-based unnatural
amino acids and b-amino triazolesw
R. B. Nasir Baig and Rajender S. Varma*
Received 2nd April 2012, Accepted 19th April 2012
DOI: 10.1039/c2cc32392c
Synthesis of triazole based unnatural amino acids and b-amino
triazoles has been described via a stereo and regioselective one-pot
multi-component reaction of sulfamidates, sodium azide, and alkynes
under MW conditions. The developed method is applicable to a
broad substrate scope and has significant potential for the synthesis
of unnatural amino acids with a triazole side chain.
The Huisgen 1,3-dipolar cycloaddition of azides and alkynes
resulting in 1,2,3-triazoles is one of the most powerful click
reactions.1 After the pivotal discovery by Sharpless et al.2 that
Cu(I) catalyzes the formation of triazoles in a 1,4-substituted
fashion, the chemistry of triazoles was brought from oblivion to
renaissance. Triazole chemistry has seen exponential growth over
the years and enormous gain in popularity in diverse areas of
chemistry such as organic, material3 and medicinal chemistry.4
The 1,2,3-triazole moiety is present in many compounds exhibiting
different biological properties such as antibacterial5 (cefatrizine,
Fig. 1), anti-HIV,6 antiallergic,7 and inhibitory8 (tazobactam,
Fig. 1) properties. Triazolobenzodiazepines9 have shown a high
affinity toward benzodiazepine receptors. The triazole chemistry
has evolved to a great extent in recent years.3–9 A comprehensive
synthesis of triazole-modified unnatural amino acids was
demonstrated by Mariusz et al. (Scheme 1).10
Scheme 1 Reported method for the synthesis of triazole-modified
unnatural amino acid.
3-alkyl derivatives of serine (e.g. threonine) afford dehydroamino
acids instead of the corresponding azide (ESIw, Scheme 1) which
limits its scope thereby restricting its use to only serine-derived
triazole-based unnatural amino acids.
To promote the development of green methods for the
synthesis of biologically active molecules, a general method
for the synthesis of triazole modified unnatural amino acids was
developed. These amino acids could be very useful to modify
biologically active peptide molecules as they are stable to
metabolic degradation. 1,2,3-Triazoles are capable of hydrogen
bonding which can be favorable in the binding of biomolecular
targets and improving the solubility.12 To eliminate the use of
toxic hydrogen azide, we envisage aziridines or sulfamidates as
important intermediates.
Almost all the papers reported in the literature followed the
same synthetic strategy for the synthesis of triazole-based
unnatural amino acid derivatives.11 This method involves the
Mitsunobu reaction, which requires the highly toxic and explosive
dry hydrogen azide for the synthesis of azide intermediate along
with other expensive and toxic reagents. Under these conditions,
Sulfamidates are emerging as important chiral intermediates in
organic synthesis.13–15 Although they are the synthetic equivalents
of aziridines, sulfamidates have added advantages over aziridines
in terms of reactivity and selectivity,13a i.e. because the regio-
selectivity problem could occur when aziridine intermediates are
used (Fig. 2). The tedious separation of regio isomers and loss of
up to 50% of the starting material (aziridine intermediate) would
be another issue. Consequently, sulfamidates appear to be a better
choice as intermediate for the development of an eco-friendly
one-pot multi-step method for the synthesis of triazole-based
unnatural amino acids and b-amino triazoles. In continuation
of previous work on expeditious microwave (MW)-assisted
chemistry,16 a reaction scheme that involves the in situ generation
of an azide intermediate followed by the cycloaddition to yield
the corresponding triazole-unnatural amino acid and b-amino
triazole has been designed.
Fig. 1 Triazole-based antibiotics.
Sustainable Technology Division, National Risk Management
Research Laboratory, U. S. Environmental Protection Agency, MS 443,
Cincinnati, Ohio 45268, USA. E-mail: varma.rajender@.epa.gov;
Fax: +1 513-569-7677; Tel: +1 513-487-2701
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc32392c
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5853–5855 5853

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Table 1 Synthesis of side chain modified unnatural amino acids
Time/
min Product
Yielda
(%)
Entry Sulfamidate Alkyne
1
20
20
20
25
20
30
84
85
81
76
79
86
2
3
4
5
6
Fig. 2 Competitive nucleophilic attack on aziridine and sulfamidate.
Scheme 2 Synthesis of sulfamidates.
At the outset, sulfamidate carboxylate 1 from threonine was
synthesized using a reported method (Scheme 2)13 and treated
with sodium azide [1.2 mmol, t-BuOH : H2O (1 : 1)] under
MW irradiation conditions (120 1C, 100 watts, 10 min). After
isolation and confirmation of the azide intermediate using IR
spectroscopy, the intermediate was subjected to the azide–alkyne
cycloaddition (120 1C, 100 watts, 10 min) in a t-BuOH : H2O
mixture which led to the diastereoselective formation of the
corresponding triazole amino acid 1a (Scheme 3).
7
8
20
20
85
83
Subsequently, a one-pot strategy was envisioned which
entails treating sulfamidate 1 with NaN3 and alkyne in a
t-BuOH–water mixture using CuSO4/sodium ascorbate or
CuSO4/Cu(metal).17 However, the best results were obtained
when the reaction was performed using CuSO4/sodium ascorbate
and Cu-metal (Scheme 2). After successful optimization of
the reaction conditions, the efficacy and scope of the reaction
were examined using various substrates. The reaction of
sulfamidate carboxylate (Table 1, entries 1–8) and sulfamidate
(Table 1, entries 9–16) with a variety of alkynes afforded the
corresponding triazole amino acids and b-amino triazoles,
1a–16a, using a general method successful in all the cases
(Table 1). The reactions proceeded smoothly to completion
within 20–30 min and the products were isolated in good
yields. In almost all the cases the reaction attained completion
within 20 min except where the alkyne counterpart was
p-nitrophenyl acetylene and homopropargyl alcohol which required
25 and 30 min respectively (Table 1, entries 4, 6, 11, 16).
9
20
20
25
20
25
84
85
71
85
79b
10
11
12
13
14
15
20
85
20
25
86
72
16
a
Reaction conditions: (i) 1.0 mmol of sulfamidate, 1.2 mmol of NaN3,
1.2 mmol of alkyne, 5 mol% of CuSO4, 10 mol% of sodium ascorbate,
10 mg of Cu metal, MW, 120 1C, power 100 watts; (ii) saturated citric
b
acid solution, 5 min at rt. Reaction conditions: (i) 1.0 mmol of
sulfamidate, 1.2 mmol of NaN3, 120 1C, power 100 watts, 10 min;
(ii) 1.2 mmol of alkyne, 5 mol% of CuSO4, 10 mol% of sodium
ascorbate, 10 mg of Cu metal, MW, 70 1C, power 100 watts, 15 min;
(iii) saturated citric acid solution, 5 min at rt.
Scheme 3 Synthesis of triazole modified unnatural amino acid.
5854 Chem. Commun., 2012, 48, 5853–5855
c
This journal is The Royal Society of Chemistry 2012

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The presence of various functional groups (–CHO, –Cl, –NO2,
–OH, –OMe etc.), heterocyclic ring system and different
protecting groups present in sulfamidate did not have any
significant effect on the product formation in the one-pot
treatment of sulfamidate, alkyne, sodium azide and the catalyst
with the exception of ethyl propionate (Table 1, entry 13), which
formed a mixture of products. To minimize the formation of
undesirable byproducts, we further modified the procedure. First,
sulfamidate (1.0 equiv.) was treated with NaN3 (1.2 equiv.) in
t-BuOH : H2O (1 : 1) and irradiated with microwaves (120 1C,
100 watts, 10 min). Subsequently, ethyl propionate (1.2 equiv.)
and the catalyst were added and subjected to further MW
irradiation (70 1C, 100 watts) for 15 min. The reaction proceeded
cleanly and furnished the corresponding b-amino triazole 13a in
79% yield (Table 1).
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A very efficient and safe procedure for the synthesis of
triazole-based unnatural amino acids and b-amino triazoles has
been developed using a one-pot multi-component reaction of
sulfamidates under MW irradiation conditions. To the best of our
knowledge, this is an unprecedented example for the synthesis of
triazole-modified unnatural amino acids. This newer protocol
eliminates the use of highly toxic and explosive HN3 and DEAD
(diethylazodicarboxylate) reagents required for the synthesis of
azide intermediates10 under dry conditions. An additional green
attribute is that the reaction can be performed in aqueous media.
Nasir Baig R. B. was supported by the Postgraduate
Research Program at the National Risk Management Research
Laboratory administered by the Oak Ridge Institute for Science
and Education through an interagency agreement between the
U.S. Department of Energy and the U.S. Environmental
Protection Agency.
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This journal is The Royal Society of Chemistry 2012
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