1894
A. E. Cohrt et al.
LETTER
zhydryl removal. The NH-1,2,3-triazolyl peptides 15 and References and Notes
6 were cleaved from the solid support in excellent purity
>95%) by alkaline treatment (Scheme 3b). Attempts to
1
(
(
1) (a) Fray, M. J.; Bull, D. J.; Carr, C. L.; Gautier, E. C. L.;
Mowbray, C. E.; Stobie, A. J. Med. Chem. 2001, 44, 1951.
b) Komeda, S.; Lutz, M.; Spek, A. L.; Chikuma, M.;
Reedijk, J. Inorg. Chem. 2000, 39, 4230.
(2) Dabak, J.; Sezer, Ö.; Akar, A.; Anaç, O. Eur. J. Med. Chem.
003, 38, 215.
functionalize the corresponding ortho-substituted iodo-
aryls for both subsets proved to be futile as no conversion
was observed in the corresponding Sonogashira cross-
coupling reactions. In the third subset, the aim was to syn-
thesize a structurally more flexible set of peptides (5 and
(
2
(
3) Bennet, I. S.; Brooks, G.; Broom, N. J. P.; Calvert, S.;
Coleman, K.; Francois, I. J. Antibiotics 1991, 44, 969.
4) Kallander, L. S.; Qing, L.; Chen, W.; Tomaszek, T.; Yang,
G.; Tew, D.; Meek, T. D.; Hofmann, G. A.; Schulz-
Pritchard, C. K.; Smith, W. W.; Janson, C. A.; Ryan, M. D.;
Zhang, G.-F.; Johanson, K. O.; Kirkpatrick, R. B.; Ho, T. F.;
Fisher, P. W.; Mattern, M. R.; Johnson, R. K.; Hansbury, M.
J.; Winkler, J. D.; Ward, K. W.; Veber, D. F.; Thompson, S.
K. J. Med. Chem. 2005, 48, 5644.
17–19) by triazole formation on four alkyne-functional-
(
ized aliphatic handles. The NH-1,2,3-triazole-containing
peptides 5 and 17–19 were successfully synthesized ac-
cording to the procedures above and released in excellent
purity (>95%) (Scheme 3c).
Triazolylalanine has previously been investigated as a his-
tidine analogue and synthesized as a racemic compound in
(
5) (a) Dimroth, O.; Fester, G. Ber. Dtsch. Chem. Ges. 1910, 43,
2219. (b) Hartzel, L. W.; Benson, F. R. J. Am. Chem. Soc.
1954, 76, 667.
1
3
seven steps from N-α-Boc-L-asparagine. With the meth-
odology outlined above, 1,2,3-triazol-4-yl-alanine-con-
taining peptides should be readily available from the
corresponding propargyl glycine precursors. Rewarding-
ly, enantiopure NH-1,2,3-triazole-containing tripeptide 20
was synthesized and released from the solid support in
(
6) (a) Tanaka, Y.; Velen, S. R.; Miller, S. I. Tetrahedron 1973,
29, 3271. (b) Tanaka, Y.; Miller, S. I. J. Org. Chem. 1973,
38, 2708. (c) Woerner, F. P.; Reimlinger, H. Chem. Ber.
1970, 103, 1908.
(
(
7) Jin, T.; Kamijo, S.; Yamamoto, Y. Eur. J. Org. Chem. 2004,
8, 3789.
>
95% purity (Scheme 4).
1
8) Maeda, C.; Yamaguchi, S.; Ikeda, C.; Shinokubo, H.; Osuka,
A. Org. Lett. 2008, 10, 549.
(9) Loren, J. C.; Krasiński, A.; Fokin, V. V.; Sharpless, K. B.
Synlett 2005, 2847.
(10) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057. (b) Rostovtsev, V. V.; Green, L. G.;
Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002,
Ph
Ph
O
O
O
H
N
H
H
a–g
N
N
H2N
O
N
H
OH
O
O
O
3
NH
N
N
4
1, 2596.
11) Cohrt, A. E.; Jensen, J. F.; Nielsen, T. E. Org. Lett. 2010, 12,
414.
2
0 (purity: >95%)
(
(
5
Scheme 4 Reagents and conditions: (a) Fmoc-Pra-OH, TBTU,
12) (a) Negishi, E.-I.; Kotora, M.; Xu, C. J. Org. Chem. 1997,
62, 8957. (b) Sonogashira, K.; Tohda, Y.; Hagihara, N.
Tetrahedron Lett. 1975, 4467. (c) King, A. O.; Okukado, N.;
Negishi, E.-I. J. Chem. Soc., Chem. Commun. 1977, 683.
NEM; (b) 20% piperidine (DMF); (c) 20% Ac O (DMF); (d) 1, 2,6-
2
lutidine, sodium ascorbate, CuI, NMP/H O (4:1); (e) 50% TFA
CH Cl ); (f) 0.1 M aq NaOH; (g) 0.1 M aq HCl.
2
(
2 2
(
2
d) Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975, 93,
59.
In summary, we have demonstrated the use of 4,4′-bisme-
thoxybenzhydryl azide as a building block for the synthe-
(13) (a) Sheehan, J. C.; Robinson, C. A. J. Am. Chem. Soc. 1949,
71, 1436. (b) Ikeda, Y.; Kawahara, S.-I.; Taki, M.; Kuno, A.;
Hasegawa, T.; Taira, K. Protein Eng. 2003, 16, 699.
14) General Experimental Procedure for the Synthesis of
Terminal Alkynes on Solid Support; Sonogashira Cross-
Coupling/TMS Deprotection (8–10, 13 and 14): Iodoaryl-
functionalized resins (1 equiv) were swollen in DMF and
degassed with a stream of Ar for 20 min. CuI (0.5 equiv),
DIEA (50 equiv), TMS-acetylene (10 equiv), and [1,1′-
bis(diphenylphosphino)ferrocene]dichloropalladium (II)
1
4,15
sis of biologically interesting NH-1,2,3-triazoles.
The
building block was synthesized in high yield in three steps
from readily available starting materials. Being complete-
ly stable towards base, the 4,4′-bismethoxybenzhydryl
protecting group is ideal for use in Fmoc-based peptide
synthesis and represents a viable alternative to previously
reported azide-containing building blocks. Furthermore,
we have developed robust protocols for the formation of
terminal alkynes on solid support to expand the utility and
scope of the methodology for the parallel synthesis of NH-
(
(0.1 equiv) were added, and the reaction vessel was sealed
before shaking for 24 h at r.t. The resin was then transferred
to a flat-bottomed PE-syringe fitted with a PPE filter and
washed with MeOH (6 ×), pyridine (6 ×), DMF (6 ×), MeOH
1,2,3-triazole-containing peptides.
(
6 ×) and CH Cl (6 ×).
2 2
Deprotection of the TMS group was achieved by addition of
TBAF (4 equiv, 1 M in THF) and AcOH (4.5 equiv) to the
resin preswollen in THF. The mixture was allowed to react
for 1 h, upon which the resin was washed with DMF (6 ×)
and CH Cl (6 ×). The resin was lyophilized to remove all
Acknowledgment
The DSF Center for Antimicrobial Research, Lundbeck Foundati-
on, and the Danish Council for Independent Research are gratefully
acknowledged for financial support.
2
2
traces of solvent. The product was cleaved off the resin by
treatment with 0.1 M NaOH (aq) for 2 h, followed by
neutralization with 0.1 M HCl (aq) and washings with
MeCN (4 ×) and CH Cl (2 ×). Evaporation of all volatiles
Supporting Information for this article is available online
at
2
2
1
0.1055/s-00000083.SunpfgIpi
o
nr
i
o
in vacuo provided the crude products.
Synlett 2014, 25, 1891–1895
© Georg Thieme Verlag Stuttgart · New York