Dmab-P-alanine

Many reports confirm notable reductions in reaction times when carrying out reactions under micro flow conditions. Concerning p-dipeptide synthesis, for example, a comparison between batch and micro-reactor processing was made for the reaction of Dmab-P-alanine and Fmoc-i-P-homophenylalanine [158]. While the micro reactor gave a 100% yield in 20 min, only about 5% was reached with the batch method. Even after 400 h, only 70% conversion was achieved. 

A reduction in reaction time by virtue of the improved transport properties in eledroosmotic-driven microreadors was demonstrated for the P-dipeptide synthesis using pentafluorophenyl O-activation. Fmoc-P-alanine was preactivated by introducing the pentafluorophenyl fundion as ester group [9]. Dmab-P-alanine and the pentafluorophenyl ester of Fmoc-P-alanine readed, and the synthesis of the corres-... 

In the next step, the preparation oflonger chain peptides was done in electroosmotic microreactors. For this purpose, deprotection and peptide bond forming reactions had to be developed resulting in a yield of 30% [6,9]. In this way, the formation of tripeptides was achieved. Dmab-P-alanine and Fmoc-P-alanine were reacted in the first step to a dipeptide [6]. After cleavage of the Fmoc function, Fmoc-[3-alanine was added to such a dipeptide that resulted in tripeptide formation in 30% yield. 

P 12] The micro channels were primed with anhydrous N,N-dimethylformamide (DMF) to remove air and moisture before carrying out the reaction [88]. A 50 pi volume of a solution of Fmoc-y9-alanine (0.1 M) in anhydrous DMF was placed in one reservoir of a micro chip, driven by electroosmotic flow. A 50 pi volume of a solution of EDCl (0.1 M) in anhydrous DMF and 50 pi of a solution of Dmab-y9-alanine (0.1 M) in anhydrous DMF were inserted in the other two reservoirs. Anhydrous DMF was placed in the fourth reservoir, for collection of the product. Room temperature was applied for reaction for a 20 min period. The voltage was set in the range 500-700 V. 

P 14] For the reaction of the pentafluorophenyl ester of Fmoc-y9-alanine with Dmab-y0-alanine, a similar protocol to that for [P 13] was used [5, 88]. 

OS 17] ]R 5] ]P 14] Using continuous flow in an electroosmotic-driven micro reactor gave a quantitative yield of the dipeptide in only 20 min (700 V for both Dmab-y0-alanine and the Boc ester) [88]. Batch synthesis under the same conditions gave only a 40-50% yield [5] (57% in [5]), needing 24 h. 

Microreaction technology has also been applied to peptide synthesis. Haswell and coworkers demonstrated that, using a borosihcate glass microreactor, the desired dipeptide was obtained by the reaction of N-Fmoc-(3-alanine with P-alanine Dmab ester in the presence of DCC (1,3-dicydohexykarbodiimide) (Scheme 5.30) [41,42]. It also was demonstrated that the Fmoc group could be removed by DBU... 

OS 24] [R 5] [P 16/Dmab-y0-alanineand Emoc-yS-alanine were reacted to give a dipeptide [5], After cleavage of the Emoc function, Emoc-yS-alanine was added to such a dipeptide resulting in tripeptide formation with 30% yield [5]. 

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