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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!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.
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.
Masked Amino Function
Unmasking
+ Me3P toluene, water, dioxane 2 h, 25 °C
α,β-Diamino acids with azido functionalization and applications.
HAA3360 N3 -L-Phe-OH*DCHA
(S)-2-Azido-3-phenylpropanoic acid dicyclohexylamine
CAS-No. 79410-36-9
Formula C9 H9 N3 O 2*C13 H23 N
Mol. weight 191,19*181,32 g/mol
HAA2170 N3 -L-Lys(Boc)-OH
(S)-2-Azido-6-[(t-butyloxycarbonyl)amino]hexanoic acid
CAS-No. 333366-32-8
Formula C11H20 N4O4
Mol. weight 272,3 g/mol
(S)-2-Azido-3-((t-butyloxycarbonyl)amino)propanoic acid N3 (S) OH
CAS-No. 1932432-15-9
Formula C 8 H14N4O4
Mol. weight 230,22 g/mol
(R)-2-Azido-3-((t-butyloxycarbonyl)amino)propanoic acid N3 (R)
CAS-No. 1630044-08-4
Formula C 8 H14N4O4
Mol. weight 230,22 g/mol
(S)-2-Azido-3-[(9-fluorenylmethyloxycarbonyl)amino]
CAS-No. 880637-82-1
Formula C18 H16 N4O4 Mol. weight 352,34 g/mol
(R)-2-Azido-3-[(9-fluorenylmethyloxycarbonyl)amino] propanoic acid
CAS-No. 1807631-13-5
Formula C18 H16 N4O4 Mol. weight 352,34 g/mol
(S)-2-Azido-4-((t-butyloxycarbonyl)amino)butanoic acid
CAS-No. 1932403-71-8
Formula C9 H16 N4O4
Mol. weight 244,25 g/mol
(R)-2-Azido-4-((t-butyloxycarbonyl)amino)butanoic acid
CAS-No. 1922891-74-4
Formula C9 H16 N4O4
Mol. weight 244,25 g/mol
HAA2160 N3 -L-Lys(Fmoc)-OH
(S)-2-Azido-6-[(9-fluorenylmethyloxycarbonyl)amino] hexanoic acid
CAS-No. 473430-12-5
Formula C 21H22N4O4
Mol. weight 394,42 g/mol
HAA2225 N3
(S)-2-Azido-5-[(9-fluorenylmethyloxycarbonyl)amino] pentanoic acid
CAS-No. 1994267-98-9
Formula C 20 H20 N4O4
Mol. weight 380,4 g/mol
HAA2820 N3 -L-Leu-OH*CHA
(S)-2-Azido-4-methylpentanoic acid cyclohexylamine
CAS-No. 1286670-79-8
Formula C 6 H11N3 O 2*C 6 H13 N
Mol. weight 157,17*99,18 g/mol
HAA2810 N3 -L-Cys(Trt)-OH*CHA
(R)-2-azido-3-(tritylthio)propanoic acid cyclohexylamine
CAS-No. 1286670-90-3
Formula C 22H19 N3 O 2 S*C 6 H13 N
Mol. weight 389,47*99,17 g/mol
HAA2880 N3
(S)-2-Azido-6-[(4-methyltrityl)amino]hexanoic acid
CAS-No. 1333231-26-7
Formula C 26 H28 N4O 2
Mol. weight 428,53 g/mol
HAA3170 N3 -L-Dab(Fmoc)-OH
(S)-2-Azido-4-[(9-fluorenylmethyloxycarbonyl)amino] butanoic acid
CAS-No. 2250436-44-1
Formula C9 H16 N4O4
Mol. weight 366,37 g/mol
(S)-2-Azido-citrulline dicyclohexylamine
CAS-No. 1799421-66-1 net
Formula C 6 H11N 5 O 3*C12H23 N
Mol. weight 201,18*181,32 g/mol
Azido-L-valine cyclohexylammonium salt
CAS-No. 1217462-63-9
Formula C 5H9 N3 O 2*C 6 H13 N
Mol. weight 143,15*99,17 g/mol
(R)-2-Azido-6-[(t-butyloxycarbonyl)amino]hexanoic acid
CAS-No. 1178899-92-7
Formula C11H20 N4O4
Mol. weight 272,3 g/mol
(R)-2-Azido-3-[(9-fluorenylmethyloxycarbonyl)amino] propanoic acid
CAS-No. 1994300-35-4
Formula C 21H22N4O4
Mol. weight 394,42 g/mol
(R)-2-Azido-5-[(t-butyloxycarbonyl)amino]pentanoic acid cyclohexylamine
CAS-No. 2165877-62-1 net
Formula C10 H18 N4O4*C 6 H13 N
Mol. weight 258,27*99,18 g/mol
O
(S)-2-azido-4-methylpentanoic acid benzhydrylamine salt N3 (S) OH
CAS-No. 79410-33-6
Formula C 6 H11N3 O 2*C13 H13 N
Mol. weight 157,17*183,25 g/mol
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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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