Name: (2S,3R)-(Fmoc-amino)-3-azidobutyric acid
Brand: BOC Sciences
Rating: 5 (1 reviews)

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Synonyms

Fmoc-L-Abu(3R-N3)-OH; (2S,3R)-3-Azido-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid

IUPAC Name

(2S,3R)-3-azido-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid

Canonical SMILES

CC(C(C(=O)O)NC(=O)OCC1C2=CC=CC=C2C3=CC=CC=C13)N=[N+]=[N-]

InChI

InChI=1S/C19H18N4O4/c1-11(22-23-20)17(18(24)25)21-19(26)27-10-16-14-8-4-2-6-12(14)13-7-3-5-9-15(13)16/h2-9,11,16-17H,10H2,1H3,(H,21,26)(H,24,25)/t11-,17+/m1/s1

InChIKey

LLJMYBCJYQGZOS-DIFFPNOSSA-N

Melting Point

150-156°C

Appearance

White crystalline powder

Storage

Store at 2-8 °C

(2S,3R)-(Fmoc-amino)-3-azidobutyric acid, a specialized amino acid derivative, plays a crucial role in peptide synthesis and bioconjugation applications. Here are four key applications presented with a high degree of perplexity and burstiness:

Solid-Phase Peptide Synthesis: In the realm of solid-phase peptide synthesis (SPPS), this compound stands out for its capacity to introduce azido-functional groups into peptides. The Fmoc protection group, with its ability for selective reactions, enables the incremental assembly of intricate peptides. This functionality facilitates the fabrication of peptides with distinct chemical properties, which are pivotal for both research endeavors and therapeutic applications.

Click Chemistry: Harnessing the azido group within (2S,3R)-3-azidobutyric acid, click chemistry emerges as a powerful tool for linking the peptide to various alkyne-containing molecules. This technique allows for the conjugation of peptides to drugs, fluorescent markers, or other proteins, expanding the versatility of synthesized peptides. Particularly advantageous in target-specific drug delivery and imaging applications, click chemistry opens up new avenues for innovation in biomedicine.

Bioorthogonal Labeling: A cornerstone in bioorthogonal labeling methodologies, this compound facilitates the incorporation of non-native chemical functionalities into biological molecules without disrupting natural biochemical processes. By leveraging (2S,3R)-(Fmoc-amino)-3-azidobutyric acid, researchers can label and track biomolecules within living cells with minimal interference. This approach is indispensable for investigating dynamic biological processes and complex interactions within cellular environments.

Orthogonal Protection Strategies: (2S,3R)-(Fmoc-amino)-3-azidobutyric acid plays a pivotal role in orthogonal protection strategies within intricate peptide synthesis. Its Fmoc protection group can be selectively removed from other protective units, enabling multi-step synthesis with exceptional precision. This strategic approach is essential for crafting highly functionalized peptides and proteins, essential for biochemical research endeavors and therapeutic advancements.

1. A Versatile Boc Solid Phase Synthesis of Daptomycin and Analogues Using Site Specific, On-Resin Ozonolysis to Install the Kynurenine Residue

Buzhe Xu, Yann Hermant, Sung-Hyun Yang, Paul W R Harris, Margaret A Brimble Chemistry. 2019 Nov 7;25(62):14101-14107. doi: 10.1002/chem.201903725. Epub 2019 Sep 30.

A de novo solid-phase synthesis of the cyclic lipodepsipeptide daptomycin via Boc chemistry was achieved. The challenging ester bond formation between the nonproteinogenic amino acid kynurenine was achieved by esterification of a threonine residue with a protected tryptophan. Subsequent late-stage on-resin ozonolysis, inspired by the biomimetic pathway, afforded the kynurenine residue directly. Synthetic daptomycin possessed potent antimicrobial activity (MIC100 =1.0 μg mL-1 ) against S. aureus, while five other daptomycin analogues containing (2R,3R)-3-methylglutamic acid, (2S,4S)-4-methylglutamic acid or canonical glutamic acid at position twelve prepared using this new methodology were all inactive, clearly establishing that the (2S,3R)-3-methylglutamic acid plays a key role in the antimicrobial activity of daptomycin.

2. α-Azido Acids in Solid-Phase Peptide Synthesis: Compatibility with Fmoc Chemistry and an Alternative Approach to the Solid Phase Synthesis of Daptomycin Analogs

Chuda Raj Lohani, Benjamin Rasera, Bradley Scott, Michael Palmer, Scott D Taylor J Org Chem. 2016 Mar 18;81(6):2624-8. doi: 10.1021/acs.joc.5b02882. Epub 2016 Mar 3.

α-Azido acids have been used in solid phase peptide synthesis (SPPS) for almost 20 years. Here we report that peptides bearing an N-terminal α-azidoaspartate residue undergo elimination of an azide ion when treated with reagents that are commonly used for removing the Fmoc group during SPPS. We also report an alternative solid-phase route to the synthesis of an analog of daptomycin that uses a reduced number of α-azido amino acids and without elimination of an azide ion.

3. A high-yielding solid-phase total synthesis of daptomycin using a Fmoc SPPS stable kynurenine synthon

Ryan Moreira, Jacob Wolfe, Scott D Taylor Org Biomol Chem. 2021 Apr 14;19(14):3144-3153. doi: 10.1039/d0ob02504f. Epub 2021 Jan 28.

A high-yielding total synthesis of daptomycin, an important clinical antibiotic, is described. Key to the development of this synthesis was the elucidation of a Camps cyclization reaction that occurs in the solid-phase when conventionally used kynurenine (Kyn) synthons, such as Fmoc-l-Kyn(Boc,CHO)-OH and Fmoc-l-Kyn(CHO,CHO)-OH, are exposed to 20% 2-methylpiperidine (2MP)/DMF. During the synthesis of daptomycin, this side reaction was accompanied by intractable peptide decomposition, which resulted in a low yield of Dap and a 4-quinolone containing peptide. The Camps cyclization was found to occur in solution when Boc-l-Kyn(Boc,CHO)-Ot-Bu and Boc-l-Kyn(CHO,CHO)-OMe were exposed to 20% 2MP/DMF giving the corresponding 4-quinolone amino acid. In contrast, Boc-l-Kyn(CHO)-OMe was stable under these conditions, demonstrating that removing one of the electron withdrawing groups from the aforementioned building blocks prevents enolization in 2MP/DMF. Hence, a new synthesis of daptomycin was developed using Fmoc-l-Kyn(Boc)-OH, which is prepared in two steps from Fmoc-l-Trp(Boc)-OH, that proceeded with an unprecedented 22% overall yield. The simplicity and efficiency of this synthesis will facilitate the preparation of analogs of daptomycin. In addition, the elucidation of this side reaction will simplify preparation of other Kyn-containing natural products via Fmoc SPPS.