ALPHA AZIDO Analogues of Amino Acids
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circle-arrow-right Triple N The transformation of the amino
group of amino acids to an azide moiety provides versatile building blocks. Discover their beauty! page 1
α-Azido acting as masked
α-Azido acids performing
α,β-Diamines with
amino function.
Click chemistry.
azido function.
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pages 1, 2 Version: IF2_1
Alpha Azido
Alpha Azido Analogues of Amino Acids Applications α-Azido acids have been used in solid phase peptide synthesis (SPPS) for almost 20 years. The first example of using α-azido acids in SPPS was reported by Meldal in 1997. They are readily prepared in a single step without racemization from α-NH2-, α-COOH-unprotected amino acids using diazotransfer
reagents and often do not require chromatographic purification. Azido acids are particularly useful for the synthesis of complex peptides, in achieving hindered couplings, and for reducing the formation of diketopiperazines during SPPS. As protecting group, the atom-efficient azide moiety is easy to install and acts as masked amino group. It is of particular use if additional orthogonalities are needed. The azido group is stable towards treatment with piperidine (Fmoc deprotection), Pd(0) (Alloc removal) and acidic treatment (cleavage of Mtt, Trt or other acid sensitive groups). α-Azido acids can be reduced in the presence of many other protecting groups and are less bulky compared to their urethane-protected counterparts, making them ideal for the synthesis of branched and/or cyclic peptides. Reduction of the α-azido group to an α-amino group is readily achieved under mild conditions with phosphines or DTT/DIPEA. However, as it is a pseudohalogenide, care has to be taken during coupling steps, as HATU will cause high racemization. This can be avoided using collidine or other non-nucleophilic bases instead of DIPEA. Certainly, α-azido acids can be used for any type of click conjugation with any available alkynyl residue forming Diels-Alder conjugates of peptides or any other organic molecule.
O
O H2N
(S)
OH
N3
R
(S)
OH
R
Transformation of alpha-amino to alpha-azido.
α,β-Diamines and Diamino Acids Chiral α,β-diamines and diamino acids have become an increasingly targeted functional motif in organic synthesis owing to their ubiquity in natural products and medicinal agents. For example, it is found in biotin, penicillins, and the antiinfluenza neuraminidase inhibitor Tamiflu. Chiral vicinal diamines and their metal complexes have been employed in stereoselective organic synthesis, in particular, as chiral auxiliaries and ligands in catalytic asymmetric synthesis. Also for such derivatives, the azido function is of high value acting either as masked amino group or as reaction partner for Click chemistry.
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Fmoc
O
H N
OH
(S) (S)
N3 R Masked Amino Function
R N H
O
R N H
O
O
N
O
N3
R
N
Unmasking
R
O
R N H
O
OH (S)
+ Me3P toluene, water, dioxane 2 h, 25 °C
N H
H2N
H N
NH2
N
Click Conjugate
H N O
α,β-Diamino acids with azido functionalization and applications.
Product details
HAA3360
N3 -L-Phe-OH*DCHA
(S)-2-Azido-3-phenylpropanoic acid dicyclohexylamine CAS-No. Formula Mol. weight
79410-36-9 C9H9N3 O 2*C13H23N 191,19*181,32 g/mol
HAA2170
N3 -L-Lys(Boc)-OH
O N3
(S)-2-Azido-6-[(t-butyloxycarbonyl)amino]hexanoic acid CAS-No. Formula Mol. weight
333366-32-8 C11H20 N4O4 272,3 g/mol
(S)
OH
O N3
HN
(S)
OH
O O
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Alpha Azido Product details
HAA2130
N3 -L-Dap(Boc)-OH
(S)-2-Azido-3-((t-butyloxycarbonyl)amino)propanoic acid CAS-No. Formula Mol. weight
1932432-15-9 C 8H14N4O4 230,22 g/mol
HAA2135
N3 -D-Dap(Boc)-OH
(R)-2-Azido-3-((t-butyloxycarbonyl)amino)propanoic acid Formula Mol. weight
O N3
(S)
OH NH
O
O
O N3
(R)
OH
C 8H14N4O4 230,22 g/mol
NH O
HAA2140
O
N3 -L-Dap(Fmoc)-OH O
(S)-2-Azido-3-[(9-fluorenylmethyloxycarbonyl)amino] propanoic acid CAS-No. Formula Mol. weight
880637-82-1 C18H16N4O4 352,34 g/mol
HAA2145
N3 -D-Dap(Fmoc)-OH
O O
(R)-2-Azido-3-[(9-fluorenylmethyloxycarbonyl)amino] propanoic acid CAS-No. Formula Mol. weight
1807631-13-5 C18H16N4O4 352,34 g/mol
HAA2150
N3 -L-Dab(Boc)-OH
(S)-2-Azido-4-((t-butyloxycarbonyl)amino)butanoic acid CAS-No. Formula Mol. weight
1932403-71-8 C9H16N4O4 244,25 g/mol
(S)
N3
OH
N H
O O
N3
O
(R)
OH
N H
O N3
(S)
O
OH
NH O
HAA2155
N3 -D-Dab(Boc)-OH
(R)-2-Azido-4-((t-butyloxycarbonyl)amino)butanoic acid CAS-No. Formula Mol. weight
1922891-74-4 C9H16N4O4 244,25 g/mol
O N3
(R)
O
OH
NH O
3
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Product details
HAA2160
N3 -L-Lys(Fmoc)-OH
(S)-2-Azido-6-[(9-fluorenylmethyloxycarbonyl)amino] hexanoic acid CAS-No. Formula Mol. weight
473430-12-5 C 21H22N4O4 394,42 g/mol
O N3
HN
OH
(S)
O O
HAA2225
N3 -L-Orn(Fmoc)-OH
(S)-2-Azido-5-[(9-fluorenylmethyloxycarbonyl)amino] pentanoic acid CAS-No. Formula Mol. weight
1994267-98-9 C 20 H20 N4O4 380,4 g/mol
HAA2820
N3 -L-Leu-OH*CHA
O N3
NH O
(S)-2-Azido-4-methylpentanoic acid cyclohexylamine CAS-No. Formula Mol. weight
1286670-79-8 C 6H11N3 O 2*C 6H13N 157,17*99,18 g/mol
HAA2810
N3 -L-Cys(Trt)-OH*CHA 1286670-90-3 C 22H19N3 O 2 S*C 6H13N 389,47*99,17 g/mol
HAA2880
N3 -L-Lys(Mtt)-OH
(S)-2-Azido-6-[(4-methyltrityl)amino]hexanoic acid CAS-No. Formula Mol. weight
1333231-26-7 C 26H28N4O 2 428,53 g/mol
HAA3170
N3 -L-Dab(Fmoc)-OH
(S)-2-Azido-4-[(9-fluorenylmethyloxycarbonyl)amino] butanoic acid CAS-No. Formula Mol. weight
2250436-44-1 C9H16N4O4 366,37 g/mol
O
O N3
(R)-2-azido-3-(tritylthio)propanoic acid cyclohexylamine CAS-No. Formula Mol. weight
OH
(S)
(S)
OH
O N3
OH
(R)
S
O
Me N3
OH
(S)
H N
O N3
(S)
O
OH
NH O
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Alpha Azido Product details
HAA4980
N3 -L-Cit-OH*DCHA
(S)-2-Azido-citrulline dicyclohexylamine CAS-No. Formula Mol. weight
O N3
1799421-66-1 net C 6H11N 5O 3*C12H23N 201,18*181,32 g/mol
(S)
OH O N H
HAA9285
NH2
N3 -L-Val-OH*CHA
Azido-L-valine cyclohexylammonium salt CAS-No. Formula Mol. weight
1217462-63-9 C 5H9N3 O 2*C 6H13N 143,15*99,17 g/mol
OH
(S)
N3
O
HAA2175
N3 -D-Lys(Boc)-OH
(R)-2-Azido-6-[(t-butyloxycarbonyl)amino]hexanoic acid CAS-No. Formula Mol. weight
O N3
1178899-92-7 C11H20 N4O4 272,3 g/mol
(R)
HN
OH
O O
HAA2165
N3 -D-Lys(Fmoc)-OH
(R)-2-Azido-3-[(9-fluorenylmethyloxycarbonyl)amino] propanoic acid CAS-No. Formula Mol. weight
O N3
1994300-35-4 C 21H22N4O4 394,42 g/mol
HN
OH
(R)
O O
HAA2210
N3 -D-Orn(Boc)-OH*CHA
(R)-2-Azido-5-[(t-butyloxycarbonyl)amino]pentanoic acid cyclohexylamine CAS-No. Formula Mol. weight
2165877-62-1 net C10 H18N4O4*C 6H13N 258,27*99,18 g/mol
HAA3350
N3 -L-Leu-OH*BHA
(S)-2-azido-4-methylpentanoic acid benzhydrylamine salt CAS-No. Formula Mol. weight
5
79410-33-6 C 6H11N3 O 2*C13H13N 157,17*183,25 g/mol
O N3
(R)
OH O N H
O
O N3
(S)
OH
Iris Biotech GmbH • Email: info@iris-biotech.de • www.iris-biotech.de • Empowering Peptide Innovation
References: → α,β-Diamino Acids: Biological Significance and Synthetic Approaches; A. Viso, R. Fernández de la Pradilla, A. García, A. Flores; Chem Rev 2005; 105(8): 3167-3196. https://doi.org/10.1021/cr0406561 → Update 1 of: α,β -Diamino Acids: Biological Significance and Synthetic Approaches; A. Viso, R. Fernández de la Pradilla, M. Tortosa, A. García, A. Flores; Chem. Rev. 2011; 111: PR1–PR42. https://doi.org/10.1021/cr100127y → Synthesis of Azido Acids and Their Application in the Preparation of Complex Peptides; R. Moreira, M. Noden, S. D. Taylor; Synthesis 2021; 53(03): 391-417. https://doi.org/10.1055/s-0040-1707314 → α-Azido Acids in Solid-Phase Peptide Synthesis: Compatibility with Fmoc Chemistry and an Alternative Approach to the Solid Phase Synthesis of Daptomycin Analogs; C. R. Lohani, B. Rasera, B. Scott, M. Palmer, S. D. Taylor; J. Org. Chem. 2016; 81(6): 2624-2628. https://doi.org/10.1021/acs.joc.5b02882 → Improved Solid-Phase Peptide Synthesis Method Utilizing a-Azide-Protected Amino Acids; Lundquist, J. C. Pelletier; Org. Lett. 2001; 3(5): 781-783. https://doi.org/10.1021/ol0155485
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