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. 2023 Oct 24;8(44):41855-41864.
doi: 10.1021/acsomega.3c06640. eCollection 2023 Nov 7.

One-Step Synthesis of 3-(Fmoc-amino acid)-3,4-diaminobenzoic Acids

Min-Cheng Chien  1 , Yi Kai Lin  1 , Yong Liao  2 , Szu-Hsuan Chen  1 , Yen-Wei Chen  1 , Chien-Yu Liang  1 , Vijayasimha Molakaseema  1 , Sodio C N Hsu  1 , Chun-Cheng Lin  1   3 , Hui-Ting Chen  2 , Chai-Lin Kao  1   4   5   6   7
Affiliations

One-Step Synthesis of 3-(Fmoc-amino acid)-3,4-diaminobenzoic Acids

Min-Cheng Chien et al. ACS Omega. .

Abstract

A one-step method for synthesizing 3-(Fmoc-amino acid)-3,4-diaminobenzoic acids was used to prepare preloaded diaminobenzoate resin. The coupling of free diaminobenzoic acid and Fmoc-amino acids gave pure products in 40-94% yield without any purification step in addition to precipitation except for histidine. For the proline residue, crude products were collected and used for solid-phase peptide synthesis to give a moderate yield of a pentapeptide. In addition, this method was used to prepare unusual amino acid derivatives, namely, (2-naphthyl) alanine and 6-aminohexanoic acid derivatives, in 50 and 65% yield, respectively.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Schematic showing the three methods for preparing Dbz resin.
Figure 2
Figure 2
Structure of compounds 1a and 1b.
Scheme 1
Scheme 1. Formation of Compound 3 (Route a) and Compound 4 (Route b)
Figure 3
Figure 3
HPLC profile of (a) crude 1c after the treatment of HCl and (b) 4 through the reaction condition shown in Scheme 1, route b. HPLC conditions were the same as those shown in Figure s51.
Figure 4
Figure 4
Results of the preparation of Fmoc-amino acid-Dbz derivatives 1d–1n. The purification procedure was as follows. After the completed reaction, the crude product was poured into ice water and precipitated. The resulting mixture was filtrated, and the residue was stirred in dichloromethane for 1 h. The final product was collected by filtration. a Methanol (2%) in dichloromethane was used. b The collected product was dissolved in acetone and reprecipitated by adding H2O.
Figure 5
Figure 5
Results of the preparation of Fmoc-amino acid-Dbz derivatives 1o–1w. The purification procedure was as follows. After the completed reaction, the crude product was poured into ice water and precipitated. The resulting mixture was filtered, and the residue was washed with dichloromethane and hexane (1:1) to collect the product. aAdditional purification: the crude product was dissolved in acetone and reprecipitated by adding dichloromethane/hexane (1:1). bChromatography was applied as an extra purification step.
Scheme 2
Scheme 2. Synthesis of Pentapeptide 8 from Crude 3-(Fmoc-proline)-3,4-diaminobenzoic Acids 1x
The yield of 8 was calculated based on the amount of crude 1x.
See this image and copyright information in PMC

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