Mild and efficient synthesis of Fmoc-protected amino azides from Fmoc-protected amino alcohols

Article abstract of DOI:10.1055/s-2005-923589

Fmoc-protected amino azides - key intermediates for monomers of oligomeric urea and guanidine - can be efficiently prepared from the corresponding amino alcohol through iodination followed by substitution with sodium azide. This synthetic route avoids the

Full text of DOI:10.1055/s-2005-923589

306
LETTER
Mild and Efficient Synthesis of Fmoc-Protected Amino Azides from
Fmoc-Protected Amino Alcohols
F
moc-Protecte
o
d
A
mino
A
z
m
ide
s
nath Mondal, Erkang Fan*
Biomolecular Structure Center, Department of Biochemistry, Box-357742, University of Washington, Seattle, WA 98195, USA
Fax +1(206)6857002; E-mail: erkang@u.washington.edu
Received 28 September 2005
stable in the presence of sodium azide during heating.
Abstract: Fmoc-protected amino azides – key intermediates for
Keeping in mind the displacement reaction with NaN3, we
sought to introduce a better leaving group instead of the
mesyl and tosyl groups so that the final substitution with
monomers of oligomeric urea and guanidine – can be efficiently
prepared from the corresponding amino alcohol through iodination
followed by substitution with sodium azide. This synthetic route
avoids the preparation, storage, and handling of the highly toxic azide can be carried out under mild conditions to avoid the
azidic acid that is used in an alternative method.
loss of the Fmoc group.
Key words: amino azides, amino alcohols, iodine
An iodine group can be an excellent candidate for this re-
gard, not only because it can act as a good leaving group,
but also because it can be easily synthesized from Fmoc-
Unnatural biooligomers – peptido- or nucleotidomimetics
that are built on alternative backbones – have attracted in-
creasing attention in recent years as platforms for design-
ing novel foldamers or biological effectors.1–6 Among
these unnatural oligomers are oligomeric ureas7–11 and
guanidines12–20 that use monomers containing a diamine
function. For peptidomimetics, these monomers should
ideally be derived from a-amino acids so that mimicking
of the common peptide side chains is achievable. There-
fore, in solid-phase synthetic routes that utilize azide as
the mask of amine,8,10,19,20 Fmoc-protected amino azides
derived from Fmoc-protected amino acids are key inter-
mediates for the monomer synthesis.
protected amino alcohols. For the formation of iodide
from alcohol, we followed a very mild and efficient pro-
cedure that uses PPh3, imidazole and iodine, which was
originally developed for the iodination of carbohydrates24
and shown to work both in solution and on solid sup-
port.25,26 In particular, the solid-phase procedure reported
by Benito and co-workers showed that the iodination
reaction was compatible to amino acid side chains.25
Although the solid-phase protocol by Benito et al. uses
10–15 equivalents of reagents to drive the reaction to
completion, our solution-phase procedure suggests that
the use of 3–5 equivalents of reagents can lead to excellent
results. The overall conversion of amino alcohols to ami-
no azides is shown in Scheme 1 and the yields are listed in
Table 1.
Currently, synthesis of Fmoc-protected amino azides is
commonly carried out with Fmoc-protected amino alco-
hols and azidic acid under Mitsunobu conditions.10,21,22
Although this transformation is a one-step procedure, in
practice, a separate step for the preparation of azidic acid23
is required. Thus, one disadvantage of the current protocol
involves the preparation, storage and handling of the high-
ly toxic azidic acid in benzene. In addition, the reaction re-
quires extremely dry conditions to proceed well. Here, we
report an alternative synthetic strategy for the conversion
of Fmoc-protected amino alcohols to the corresponding
azides through an easy-to-perform, mild, and efficient
two-step protocol.
R
R
a, b
Fmoc
OH
Fmoc
N3
N
N
H
65–98%
H
1
2
R = amino acid side chains
Scheme 1 Synthesis of Fmoc-protected amino azides 2a–k.
Reagents and conditions: (a) PPh3 (3 equiv), iodine (3 equiv), imid-
azole (5 equiv), CH2Cl2, r.t., 1.5–2 h; (b) NaN3 (5 equiv), DMF, r.t.,
3–5 h. Overall yields: 65–98% for the two steps from 1.
The starting Fmoc-protected amino alcohols 1a–k are
commercially available or can be prepared by a one-step
reduction according to Rodriguez and co-workers.27
These alcohols were then transformed into the corre-
sponding iodides using PPh3 (3 equiv), iodine (3 equiv),
and imidazole (5 equiv) in dry CH2Cl2. The reactions were
allowed to proceed at room temperature for 1.5–2 hours.
TLC showed that all the starting alcohols were converted
to the desirable iodides during this period, except for the
reaction with the proline-based system 1k which did go
to completion after overnight reaction. The reaction
mixtures were then concentrated under reduced pressure
and the iodides were purified by silica gel column
General methods for the synthesis of an azide from an al-
cohol are mesylation or tosylation of alcohol using meth-
anesulfonyl chloride or tosyl chloride, respectively (MsCl
or TsCl, Et3N, dry CH2Cl2 or THF), followed by displace-
ment with azide (NaN3, DMF). These systems work well
with Teoc- [2-(trimethylsilyl)ethoxycarbonyl],8 Boc-,8 or
Cbz-protected21 amino alcohols, but not with Fmoc-pro-
tected amino alcohols because the Fmoc group is not
SYNLETT 2006, No. 2, pp 0306–0308
0
1.
0
2.
2
0
0
6
Advanced online publication: 23.12.2005
DOI: 10.1055/s-2005-923589; Art ID: S09805ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Fmoc-Protected Amino Azides
307
chromatography using 10–20% ethyl acetate in hexane derivative with 72% yield using the one-step Mitsunobu
(70% ethyl acetate in hexane for the arginine-based sys- reaction,22 while our two-step procedure gave a 65% yield
tem). In most of the cases, the transformations from for the Arg(Pbf) derivative 2i.
alcohols to iodides were quantitative, except a yield of
74% for the proline-based system.
In summary, we have demonstrated a mild and efficient
two-step method for the synthesis of Fmoc-protected
The iodides were then converted into the corresponding amino azides from the corresponding alcohols. These
azides 2a–k by displacement reaction with azide (5 equiv Fmoc-protected amino azides are versatile intermediates
NaN3 in DMF) and stirred at room temperature for 3–5 for the synthesis of monomers of oligomeric peptido-
hours (monitored by TLC). The product azides were then mimetics. Our protocol avoids the preparation and use of
purified by silica gel column chromatography using 10– azidic acid, and is a good complement to the existing
20% ethyl acetate (70% for the arginine-based system 2i) synthetic strategies.
in hexane in 65–98% overall yields for the two steps from
alcohol 1.28
Acknowledgment
Compared to the direct conversion of amino alcohols to
amino azides under Mitsunobu conditions, our two-step
protocol gave very similar or better overall isolated yields.
Microbial Pathogens at the University of Washington.
For example, Fmoc-protected amino azides were reported
This work is supported in part by the National Institutes of Health
(grant GM94655) and by the W. M. Keck Foundation Center for
with Val (80%), Leu (88%), Phe (80%), Tyr(Ot-Bu)
References and Notes
(87%), Ser(Ot-Bu) (73%), Lys(Boc) (87%), and Pro
(92%) side chains by Boeijen et al.10 Except for the pro-
line-based system, our protocol gave higher yields for
those derivatives despite the two-step procedure
(Table 1). The lower overall yield for the proline-based
system 2k is primarily due to a low conversion from the
alcohol to the iodide at 74%, as the conversion from the
iodide to the azide was achieved at 90%. For arginine-
based system, the Meldal group reported a Arg(Pmc)
(1) Soth, M. J.; Nowick, J. S. Curr. Opin. Chem. Biol. 1997, 1,
120.
(2) Schneider, S. E.; Anslyn, E. V. Molecular Recognition and
Solid Phase Organic Synthesis: Synthesis of Unnatural
Oligomers, Techniques for Monitoring Reactions, and the
Analysis of Combinatorial Libraries, In Advances in
Supramolecular Chemistry, Vol. 5; Gokel, G. W., Ed.; JAI
Press: Stamford CT, 1999, 55–120.
(3) Kirshenbaum, K.; Zuckermann, R. N.; Dill, K. A. Curr.
Opin. Struct. Biol. 1999, 9, 530.
(4) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev.
2001, 101, 3219.
Table 1 Overall Yields for Azides 2a–k from Alcohols 1a–k
(5) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore,
J. S. Chem. Rev. 2001, 101, 3893.
(6) Oh, K.; Jeong, K. S.; Moore, J. S. Nature (London) 2001,
414, 889.
Product number
Side chain R
Overall yields (%)
93
2a Val
(7) Burgess, K.; Linthicum, D. S.; Shin, H. W. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 907.
(8) Kim, J. M.; Bi, Y. Z.; Paikoff, S. J.; Schultz, P. G.
Tetrahedron Lett. 1996, 37, 5305.
(9) Burgess, K.; Ibarzo, J.; Linthicum, D. S.; Russell, D. H.;
Shin, H.; Shitangkoon, A.; Totani, R.; Zhang, A. J. J. Am.
Chem. Soc. 1997, 119, 1556.
(10) Boeijen, A.; van Ameijde, J.; Liskamp, R. M. J. J. Org.
Chem. 2001, 66, 8454.
2b Leu
2c Phe
98
90
2d Tyr(Ot-Bu)
90
ButO
(11) Guichard, G.; Semetey, V.; Rodriguez, M.; Briand, J.-P.
Tetrahedron Lett. 2000, 41, 1553.
(12) Dempcy, R. O.; Luo, J.; Bruice, T. C. Proc. Natl. Acad. Sci.
U.S.A. 1996, 93, 4326.
(13) Tanatani, A.; Kagechika, H.; Azumaya, I.; Fukutomi, R.; Ito,
Y.; Yamaguchi, K.; Shudo, K. Tetrahedron Lett. 1997, 38,
4425.
2e Ser(Ot-Bu)
2f Lys(Boc)
92
90
ButO
BocHN
2g Gln(Trt)
77
O
Trt
N
H
(14) Schneider, S. E.; Bishop, P. A.; Salazar, M. A.; Bishop, O.
A.; Anslyn, E. V. Tetrahedron 1998, 54, 15063.
(15) Tanatani, A.; Yamaguchi, K.; Azumaya, I.; Fukutomi, R.;
Shudo, K.; Kagechika, H. J. Am. Chem. Soc. 1998, 120,
6433.
(16) Linkletter, B. A.; Bruice, T. C. Bioorg. Med. Chem. Lett.
1998, 8, 1285.
(17) Linkletter, B. A.; Szabo, I. E.; Bruice, T. C. J. Am. Chem.
Soc. 1999, 121, 3888.
2h Glu(Ot-Bu)
2i Arg(Pbf)
94
65
O
ButO
NPbf
H2N
N
H
2j Trp(Boc)
2k Pro
80
67
BocN
(18) Linkletter, B. A.; Bruice, T. C. Bioorg. Med. Chem. 2000, 8,
1893.
N
Synlett 2006, No. 2, 306–308 © Thieme Stuttgart · New York

308
S. Mondal, E. Fan
LETTER
by silica gel column chromatography (10% EtOAc in
(19) Zhang, Z.; Carter, T.; Fan, E. Tetrahedron Lett. 2003, 44,
3063.
(20) Zhang, Z.; Fan, E. J. Org. Chem. 2005, 70, 8801.
(21) Horwell, D. C.; Hughes, J.; Hunter, J. C.; Pritchard, M. C.;
Richardson, R. S.; Roberts, E.; Woodruff, G. N. J. Med.
Chem. 1991, 34, 404.
(22) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057.
(23) Wolff, H. Schmidt Reaction, In Organic Reactions, Vol. 3;
Adams, R.; Bacjmann, W. E.; Fieser, L. F.; Johnson, J. R.;
Snyder, H. R., Eds.; John Wiley and Sons: New York, 1947,
307–336.
(24) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem.
Commun. 1979, 978.
(25) Benito, J. M.; Christensen, C. A.; Meldal, M. Org. Lett.
2005, 7, 581.
(26) Olsen, C. A.; Witt, M.; Jaroszewski, J. W.; Franzyk, H. Org.
Lett. 2004, 6, 1935.
(27) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez,
J. Tetrahedron Lett. 1991, 32, 923.
(28) All compounds gave satisfactory analytical data. Described
below are a representative procedure and spectral data for
Fmoc-protected glutamate azide 2h. Fmoc-protected
glutamate alcohol 1h (50 mg, 0.12 mmol) in dry CH2Cl2 was
added to a pre-mixed (5 min) solution of PPh3 (94 mg, 0.36
mmol, 3 equiv), iodine (91 mg, 0.36 mmol, 3 equiv) and
imidazole (41 mg, 0.6 mmol, 5 equiv) in 1.2 mL dry CH2Cl2.
The reaction mixture was stirred at r.t. for 1.5 h. After
completion of the reaction the solvent was evaporated at
reduced pressure and the corresponding iodide was purified
hexane). The iodide was then dissolved in 0.5 mL DMF,
mixed with NaN3 (39 mg, 0.6 mmol, 5 equiv with respect to
alcohol 1h) and stirred at r.t. for 3.5 h. After solvent removal
and silica gel column chromatography (10% EtOAc in
hexane), azide 2h was obtained as a white solid in high yield.
Yield 50 mg (94% overall from alcohol 1h); mp 65–66 °C.
1H NMR (CDCl3): d = 1.47 (s, 9 H), 1.82–1.86 (m, 2 H),
2.29–2.36 (m, 2 H), 3.42–3.48 (m, 2 H), 3.75–3.87 (br m, 1
H), 4.23 (t, 1 H, J = 6.9 Hz), 4.38–4.50 (m, 2 H), 5.03 (d, 1
H, J = 7.7 Hz), 7.31–7.45 (m, 4 H), 7.61 (d, 2 H, J = 7.2 Hz),
7.79 (d, 2 H, J = 7.2 Hz). ESI-MS: m/z = 437.0 [M + H]+.
Additional list of 1H NMR of new compounds:
Compound 2g: 1H NMR (CDCl3): d = 1.76–1.83 (m, 2 H),
2.29–2.31 (m, 2 H), 3.31–3.37 (m, 2 H), 3.72 (br m, 1 H),
4.20 (t, 1 H, J = 6.5 Hz), 4.37–4.50 (m, 2 H), 5.01 (d, 1 H,
J = 7.9 Hz), 6.75 (s, 1 H), 7.18–7.29 (m, 17 H), 7.35–7.41
(m, 2 H), 7.57 (d, 2 H, J = 7.4 Hz), 7.74 (d, 2 H, J = 7.4 Hz).
Compound 2i: 1H NMR (CDCl3): d = 1.42 (s, 6 H), 1.41–
1.58 (m, 4 H), 2.06 (s, 3 H), 2.49 (s, 3 H), 2.56 (s, 3 H), 2.90
(s, 2 H), 3.16–3.31 (m, 4 H), 3.72 (br m, 1 H), 4.14 (t, 1 H,
J = 6.5 Hz), 4.32–4.41 (m, 2 H), 5.30 (d, 1 H, J = 8.4 Hz),
6.34 (br s, 2 H), 7.24–7.27 (m, 2 H), 7.34–7.38 (m, 2 H),
7.54–7.55 (m, 2 H), 7.73 (d, 2 H, J = 7.4 Hz).
Compound 2j: 1H NMR (CDCl3): d = 1.65 (s, 9 H), 2.93–
2.99 (m, 2 H), 3.45–3.49 (m, 2 H), 4.17–4.22 (m, 2 H), 4.41–
4.43 (m, 2 H) 4.98 (d, 1 H, J = 7.8 Hz), 7.27–7.41 (m, 6 H),
7.46–7.63 (m, 4 Hz), 7.76 (d, 2 H, J = 7.4 Hz), 8.14 (br s,
1 H).
Synlett 2006, No. 2, 306–308 © Thieme Stuttgart · New York