LETTER
Fmoc-, Boc-, and Alloc-Protected Amino Acids
2015
Table 3 The Purity of N-Protected Glycine
Acknowledgment
We thank the University of Florida, The Kenan Foundation and
King Abdulaziz University, Jeddah, Saudi Arabia for financial sup-
port. Authors thank Dr. C. D. Hall for helpful discussions. Mr. T. S.
Ibrahim is grateful to the ministry of higher education in Egypt for
a scholarship.
N-Pg-Gly-OH 5a,m
Purity (%) N-Pg-Gly-Gly-OH 7 (%)
of 5a,m
Fmoc-Gly-OH 5a
Alloc-Gly-OH 5m
>99
7a, no detectable formation
7b, no detectable formation
>99
References and Notes
(
1) Present address: Department of Medicinal Chemistry,
College of Pharmacy, University of Minnesota,
Minneapolis, MN 55455, USA.
Preparation of 1-[(9-Fluorenylmethyloxycarbonyl)-]benzotri-
azole [Fmoc-Bt] (3a)
(
9H-Fluoren-9-yl)methyl chloroformate (1a, 1 g, 3.87 mmol), ben-
(
(
2) Somoza, Chem. Soc. Rev. 2008, 37, 2668.
zotriazole 2 (0.92 g, 7.74 mmol), and Et N (0.7 mL, 7 mmol) were
3
3) Codée, J. D. C.; Ali, A.; Overkleeft, H. S.; Van der Marel, G.
A. C. R. Chim. 2011, 14, 178.
stirred in CH Cl (20 mL) for 2 h at 10 °C. The precipitate formed
2
2
was filtered off, and the filtrate was evaporated under reduced pres-
(
4) (a) Greene’s Protective Groups in Organic Synthesis, 4th
ed.; Wuts, G. M.; Greene, T. W., Eds.; John Wiley and Sons:
Hoboken, 2007. (b) Isidro-Llobet, A.; Àlvarez, M.;
Albericio, F. Chem. Rev. 2009, 109, 2455.
sure to give the crude product, which was washed with Et O and re-
2
crystallized from CH Cl –hexanes to afford Fmoc-Bt 3a as white
2
2
1
microcrystals; mp 90.0–91.0 °C, yield 88%. H NMR (300 MHz,
DMSO-d ): d = 4.58 (s, 1 H), 5.10 (d, J = 5.1 Hz, 2 H), 7.23 (br s, 1
6
(
5) (a) Timmer, M. S. M.; Stocker, B. L.; Northcote, P. T.;
Burkett, B. A. Tetrahedron Lett. 2009, 50, 7199. (b) Jana,
A.; Atta, S.; Sarkar, S. K.; Singh, N. D. P. Tetrahedron 2010,
H), 7.29–7.38 (m, 2 H), 7.39–7.51 (m, 4 H), 7.81 (d, J = 7.2 Hz, 2
1
3
H), 7.91 (d, J = 7.2 Hz, 2 H), 8.09–8.18 (m, 1 H). C NMR (75
MHz, DMSO-d ): d = 46.2, 69.5, 113.0, 119.9, 120.2, 125.0, 125.8,
6
66, 9798.
1
27.3, 127.9, 130.1, 130.8, 140.9, 143.1, 145.0, 148.0. Anal. Calcd
(
(
6) (a) Barany, G.; Merrifield, R. B. J. Am. Chem. Soc. 1977, 99,
for C H N O : C, 73.89; H, 4.43; N, 12.31. Found: C, 73.84; H,
21
15
3
2
7363. (b) Barany, G.; Albericio, F. J. Am. Chem. Soc. 1985,
4
.06; N, 12.29.
107, 4936.
7) (a) Carpino, L. A.; Han, G. Y. J. Am. Chem. Soc. 1970, 92,
Allyl 1H-Benzo[d][1,2,3]triazole-1-carboxylate [Alloc-Bt] (3b)
5748. (b) Carpino, L. A.; Han, G. Y. J. Org. Chem. 1972, 37,
To a solution of benzotriazole 2 (2 g, 7 mmol) and Et N (0.7 mL, 7
3
3404.
mmol) in THF (350 mL) was added with vigorous stirring allyl
chloroformate 1b (1.7 mL, 7 mmol) at 10 °C. After 2 h, the resulting
precipitates were removed by filtration and washed with EtOAc
(8) Anderson, G. W.; McGregor, A. C. J. Am. Chem. Soc. 1957,
9, 6180.
7
(
9) Busnel, O.; Bi, L.; Dali, H.; Cheguillaume, A.; Chevance, S.;
Bondon, A.; Muller, S.; Baudy-Floc’h, M. J. Org. Chem.
2005, 70, 10701.
(
3 × 30 mL). The filtrate and washings were collected and the sol-
vent evaporated to give a solid that was recrystallized from CH Cl –
hexanes as white microcrystals; mp 105.0–107.0 °C (lit. oil),
yield 92%. H NMR (300 MHz, CDCl ): d = 5.11 (d, J = 6.0 Hz, 2
H), 5.45 (d, J = 10.5 Hz, 1 H), 5.58 (d, J = 17.1 Hz, 1 H), 6.04–6.30
2
2
3
0c
1
(10) (a) Stevens, C. M.; Watanabe, R. J. Am. Chem. Soc. 1950,
3
725. (b) Kunz, H.; Unverzagt, C. Angew. Chem., Int. Ed.
Engl. 1984, 23, 436.
(
m, 1 H), 7.48 (t, J = 7.5 Hz, 1 H), 7.64 (t, J = 7.5 Hz, 1 H), 8.10 (t,
1
3
(11) (a) Grieco, P.; Gitu, P. M.; Hruby, V. J. J. Pept. Res. 2001,
J = 9.3 Hz, 2 H). C NMR (75 MHz, CDCl ): d = 69.2, 113.4,
1
3
5
7, 250. (b) Hurevich, M.; Tal-Gan, Y.; Klein, S.; Barda, Y.;
Levitzki, A.; Gilon, C. J. Pept. Sci. 2010, 16, 178.
c) Körner, C.; Raiber, E.-A.; Keegan, S. E. M.; Nicolau,
D. C.; Sheppard, T. D.; Tabor, A. B. Tetrahedron Lett. 2010,
1, 6381.
12) (a) Biron, E.; Chatterjee, J.; Kessler, H. Org. Lett. 2006, 8,
417. (b) Albericio, F. Biopolymers 2000, 55, 123.
c) Bogdan, F. M.; Chow, C. S. Tetrahedron Lett. 1998, 39,
897. (d) Hayakawa, Y.; Wakabayashi, S.; Kato, H.; Noyori,
20.4, 120.9, 125.8, 130.2, 130.4, 131.7, 145.8, 148.7. Anal. Calcd
for C H N O : C, 59.11; H, 4.46; N, 20.68. Found: C, 59.15; H,
10
9
3
2
(
4
.38; N, 20.91.
5
General Procedure for Fmoc-, Boc-, and Alloc-Protected Amino
Acids 5a–q and Fmoc- and Alloc-Protected Glycylglycines 7a,b
(
2
(
1
To a solution of amino acid 4 or glycylglycine 6 (1 mmol) and Et N
3
(
2 mmol) in MeCN–H O (3:1, 8 mL) was added the corresponding
2
N-Pg-benzotriazole 3a–c (1 mmol). The mixture was stirred at r.t.
for 2 h. Solvent was removed under reduced pressure and EtOAc
R. J. Am. Chem. Soc. 1990, 112, 1691.
(
13) Kates, S. A.; Solé, N. A.; Johnson, C. R.; Hudson, D.;
Barany, G.; Albericio, F. Tetrahedron Lett. 1993, 34, 1549.
14) Gracia, C.; Isidro-Llobet, A.; Cruz, L. J.; Acosta, G. A.;
Álvarez, M.; Cuevas, C.; Giralt, E.; Albericio, F. J. Org.
Chem. 2006, 71, 7196.
(
10 mL) was added. The organic layer was washed with 2 M HCl
and brine. Evaporation of the solvent followed by recrystalization
EtOAc–hexanes, 3:1) gave N-protected amino acids 5a–q or N-
protected dipeptides 7a,b.
(
(
(
15) (a) Fernandez-Forner, D.; Casals, G.; Navarro, E.; Ryder,
H.; Albericio, F. Tetrahedron Lett. 2001, 42, 4471.
(b) Dessolin, M.; Guillerez, M.-G.; Thieriet, N.; Guibé, F.;
Loffet, A. Tetrahedron Lett. 1995, 36, 5741. (c) Gómez-
Martínez, P.; Dessolin, M.; Guibé, F.; Albericio, F. J. Chem.
Soc., Perkin Trans. 1 1999, 2871.
2
[
-{([(9H-Fluoren-9-yl)methoxy]carbonyl)amino}-acetic Acid
Fmoc-L-Gly-OH] (5a)
White microcrystals, mp 166.0–167.0 °C (lit. mp 163.0–165.0
2
0b
1
°
C), yield 94%. H NMR (300 MHz, DMSO-d ): d = 3.72 (d, J = 6.0
6
Hz, 2 H), 4.25 (t, J = 7.2 Hz, 1 H), 4.34 (d, J = 6.9 Hz, 2 H), 7.34 (t,
J = 7.5 Hz, 2 H), 7.43 (t, J = 7.5 Hz, 2 H), 7.68 (t, J = 6.0 Hz, 1 H),
(16) Chang, C.-D.; Waki, M.; Ahmad, M.; Meienhofer, J.;
Lundell, E. O.; Haug, J. D. Int. J. Pept. Protein Res. 1980,
7
.74 (d, J = 7.2 Hz, 2 H), 7.90 (d, J = 7.5 Hz, 2 H), 12.68 (s, 1 H).
1
3
C NMR (75 MHz, DMSO-d ): d = 42.2, 46.7, 65.8, 120.1, 125.2,
6
15, 59.
1
27.1, 127.7, 140.8, 143.9, 156.5, 171.6.
(
17) (a) Keller, O.; Keller, W. E.; Look, G.-V.; Wersin, G. Org.
Synth. 1990, Coll. Vol. VII, 70; Org. Synth. 1985, 63, 160.
(b) Sennyey, G.; Barcelo, G.; Senet, J.-P. Tetrahedron Lett.
1987, 28, 5809.
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